Handbook of Medical Device Regulatory Affairs in Asia PDF

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Contents
Preface xxxi
Asia Regulatory Professional Association xxxiii
1. How to Train University Students in Regulatory Affairs 1

Raymond K. Y. Tong
1.1 Introduction 1
1.2 A Sample of Regulatory Affairs Exercises for Students 2
1.2.1 Background 2
Part 1 Introduction
2. The Evolution of the Regulatory Professional: Perspectives on
the Skill Sets and Capabilities That Will Define the Next
Generation of Regulatory Professionals 7
David Martin and Neil Lesser
2.1 Introduction 7
2.2 Drivers of Change 8
2.3 Historical Role and Skill Set of a Regulatory
Professional 10
2.4 Changing Role and Skill Set of the Regulatory
Professional 12
2.5 Develop as a Center of Intelligence 12
2.6 Advance Toward Strategic Relationship
Management 13
2.7 Develop as a Strategic Business Partner 13
2.8 Conclusion: What Will It Take to Get There? 14
vi Contents
3. Ensuring Smooth Product Launch: Regulatory Interfaces

with Marketing and Supply Chain 17
Alok Mishra
3.1 Introduction 17
3.2 New Product Pipeline 18
3.3 Planned Launch Dates 18
3.4 New Product Forecasts 19
3.5 New Product Approval Dates 19
4. What Is the Right Thing to Do? 21
Jack Wong
4.1 Right Job 21
4.2 Two Key Challenges in Our Job 22
4.2.1 Quality 22
4.2.2 Speed 22
4.3 Regulatory Affairs Job Is a Combination of Science,
Legal Affairs, and Moral 22
4.4 Persons versus Things 22
5. Affordable Access to Medical Devices in Developing
Countries 25
Rosanna W. Peeling and Tikki Pang
5.1 Introduction 25
5.2 Why Is Affordable Access to Medical Devices
Important for Developing Countries? 26
5.2.1 Emergency Preparedness 27
5.2.2 Efficiency and Effectiveness of Health Systems 27
5.2.3 Health Equity 28
5.3 Case Studies 29
5.3.1 Delay in Eligibility to Treatment for HIV 29
5.3.2 Delay in Access to Early Diagnosis of
Tuberculosis 29
5.3.3 Misleading Claims of Test Performance for
Dengue Rapid Tests 30
5.3.4 Case Study — Access versus Performance: Basis
for FDA Approval of the First Over-the-Counter
Rapid HIV Test in the United States 31
Contents vii
5.3.4.1 Background 31
5.3.4.2 Performance expectations 31
5.3.4.3 Risk beneit analysis 32
5.4 The Way Forward 33
6. A Story of Attention to Detail 35
Richard Liu
P 2 M D
S R ISO S
7. Biomedical Devices: Overview 39
Piu Wong
7.1 Historic Aspect of Medical Devices 39
7.2 Biomedical Market Environment 41
7.3 Orthopedics 42
7.3.1 Market 42
7.3.2 Materials 43
7.3.3 Biocompatibility 43
7.3.4 Fabrication 44
7.3.5 Polyethylene Fabrication 44
7.4 Vision Care 46
7.4.1 Market 46
7.4.2 Diagnostic Devices 46
7.4.3 Treatment 47
7.5 Diabetics 48
7.6 Obesity 48
7.7 Vascular Disease 48
7.8 Concluding Remarks 49
8. Labeling, Label, and Language: A Truly Global Matter 53
Evangeline D. Loh and Jaap L. Laufer
8.1 Introduction 53
8.2 Deinition of Labeling 55
8.3 Elements of Labeling 56
8.4 Risk Management, Clinical Evaluation and Labeling:
The Core Triangle for Safe and Effective Use of
the Device 59
8.5 Labeling and Promotion 60
viii Contents
8.6 e-Labelling, Web Sites, Internet, and Social Media:

A Brave New World for Labeling 61
8.7 Language, Language Level and Intended User 63
8.8 Conclusion 64
9. Clinical Trials: Legal and Ethical Considerations of
Increasing Globalization 67
Paula Celine Trepman
9.1 Introduction 67
9.2 The Increasing Trend of Offshore Clinical Trials 68
9.3 International Standards to Protect Patients 69
9.4 Breaches of Clinical Trial Legality 70
9.5 Issues of Informed Consent 71
9.6 Cultural and Social Factors 71
9.7 Vulnerable Patient Populations 72
9.8 Economic Considerations 72
9.9 Comparison of Trial Population to Target
Population 73
9.10 Conclusion 75
10. Regulatory Affairs for Medical Device Clinical Trials in
Asia Pacific 79
Seow Li-Ping Geraldine
10.1 Introduction 79
10.2 Medical Device Clinical Trials versus
Pharmaceutical Clinical Trials 80
10.3 Regulation of Clinical Trials 83
10.4 Country Regulations 87
10.4.1 Australia 89
10.4.2 China 91
10.4.3 Hong Kong 91
10.4.4 India 91
10.4.5 Malaysia 92
10.4.6 New Zealand 92
10.4.7 Singapore 93
10.4.8 South Korea 94
Contents ix
10.4.9 Taiwan 95
10.4.10 Thailand 96
10.5 Moving Ahead as Regulatory Affairs Professionals 96
11. Medical Device Classification Guide 101
Patricia Teysseyre
11.1 How to Carry Out Medical Device Classification 101
11.1.1 Scope 101
11.1.2 Definitions 102
11.2 Main Classifications 103
11.2.1 Medical Devices 103
11.2.2 Active Devices 103
11.2.3 IVD Devices 104
11.2.4 IVD Case Study 106
11.2.4.1 US FDA 107
11.2.4.2 Canada 107
11.2.4.3 EU 108
11.2.4.4 Singapore 109
11.3 Medical Device Classification: Practical
Examples 109
12. ISO 13485:2003 Medical Devices — Quality Management
Systems — Requirements or Regulatory Purposes 125
Ann Goodall and Gert Bos
12.2 Background and Origins of ISO 13485:2003 126
12.3 Management Systems Standard 128
12.4 Quality Management Systems 129
12.5 ISO 9000 and ISO 13485 Quality Management
System Family of Standards 130
12.6 ISO 13485:2003 and Regulatory Requirements
Around the World 131
12.7 Good Reasons to Implement an ISO 13485:2003
Quality Management System 132
12.8 Process Approach 132
12.9 Planning the Implementation 133
Contents
12.10 Scope, Exclusions and Non-Applicability 134

12.11 Document Control 134
12.12 Record Completion and Control 135
12.13 Management Responsibility 135
12.14 Resource Management 136
12.15 Product Realisation 136
12.16 Risk Management 136
12.17 Design and Development 137
12.18 Purchasing and Supplier Control 138
12.19 Production and Service Provision 138
12.20 Monitoring and Measuring, Including
Internal Audits and Management Review 139
12.21 Control of Non-Conforming Product 140
12.22 Analysis of Data 140
12.23 Improvement: Corrective Action and
Preventive Action 140
12.24 Purpose and Goal of ISO 13485:2003
Certification 141
12.25 Achieving Certification and Continuing to
Maintain Certification 141
13. ISO 14971: Application of Risk Management to
Medical Devices 145
Tony Chan and Raymond K. Y. Tong
13.2 The Foundation of a Risk Management (RM)
Framework: Policy, Plan, Team, Process, and
Documentation 149
13.2.1 Policy 149
13.2.2 Plan 149
13.2.3 Team 149
13.2.4 Process 150
13.2.5 Documentation 150
13.3 The RM Process 150
13.3.1 Analyze Risk 150
13.3.2 Evaluate Risk 151
Contents xi
13.3.3 Control Risk 151

13.3.4 Feedback from Production and
Post-Production Information 153
13.4 Conclusion 154
13.5 Case Study — An Example to Illustrate Risk
Management on a Medical Device: Functional
Electrical Stimulation System for Walking 154
13.5.1 Risk Management Process 156
Part 3 Harmonization of Medical Devices in Asia
14. Medical Devices in the World Health Organization 165
Adriana Velazquez Berumen and Jack Wong
15. Asian Harmonization Working Party 169

Saleh Al Tayyar
15.2 Future Directions 170
16. Asia-Pacific Economic Cooperation 173
Lindsay Tao
16.1.1 Trade and Investment Liberalization 174
16.1.2 Business Facilitation 175
16.1.3 Economic and Technical Cooperation 175
16.2 APEC LSIF: Life Sciences Innovation Forum
(Reports to Committee on Trade and Investment) 176
16.3 APEC LSIF/RHSC: Regulatory Harmonization
Steering Committee 178
17. Harmonization of Medical Device in ASEAN 183
Petahn McKenna
17.1.1 Medical Device Market in ASEAN 183
17.1.2 Medical Device Regulatory Environment
in ASEAN 184
17.2 ASEAN Medical Device Directive and
Harmonization 184
xii Contents
17.2.1 Provisions of the AMDD 185

17.2.2 Definition of a Medical Device 186
17.2.3 Medical Device Classification 187
17.2.4 Common Submission Dossier Template 187
17.2.5 Post-Market Alert System 188
17.2.6 AMDD Status 188
17.2.7 Future of ASEAN Harmonization 189
18. Regulatory Affairs Professionals Society 191
Sherry Keramidas and Zachary Brousseau
18.2 Importance in Today’s Global Environment 192
18.3 The Global Regulatory Community 193
18.4 Building Knowledge and Competencies 194
18.5 The RAC Credential 195
18.6 Professional Knowledge and Standards 196
18.7 News and Information 197
19. Expediting Innovation in Singapore with Regulatory
Knowledge 199
Patricia Ho and Jui Lim
19.1 The Biodesign Innovation Process 201
19.1.1 Identify 202
19.1.2 Invent 202
19.1.3 Implement 204
19.2 The Innovator’s Resource 204
19.3 Current Direction 207
Part 4 Medical Device Regulatory System in the United
States and the European Union
20. United States Medical Device Regulatory Framework 211
Carole C. Carey
20.2 The FDA Center for Devices and Radiological
Health 213
20.3 Total Product Life Cycle Approach 213
Contents xiii
20.4 Legislation and Device Laws 214

20.4.1 FDA Law vs. FDA Regulations vs. FDA
Guidance 215
20.5 The Regulatory Environment for Bringing a
Medical Device to Market 215
20.6 Regulatory Considerations to Market and Keep
Devices in Distribution 216
20.6.1 Definition of Medical Devices 216
20.6.2 Classification of Medical Devices 217
20.6.3 Adulteration and Misbranding 218
20.6.4 Establishment Registration and Medical
Device Listing 219
20.6.5 Premarket Notification (510(k)) 220
20.6.5.1 Kits 221
20.6.5.2 Predicate device and
substantial equivalence 221
20.6.5.3 Planning and assembling the
510(k) submission process 223
20.6.6 Premarket Approval (PMA) 225
20.6.7 Investigational Device Exemption (IDE) 226
20.6.8 Labeling 226
20.6.9 Quality System (QS) Regulation/Good
Manufacturing Practices (GMP) 227
20.6.10 Medical Device Reporting (MDR) 227
20.6.11 User Fees 228
20.7 Summary 229
21. European Union: Medical Device Regulatory System 233
Patricia Teysseyre
21.1 Glossary of Terms 233
21.2 European Union: History and Structure 234
21.3 New Approach — Global Approach Concepts 235
21.4 Harmonized Standards and Presumption of
Conformity 239
21.5 European Associations 243
21.6 Overview of Medical Devices Directives 243
xiv Contents
21.7 Guidelines 244

21.8 Definitions 245
21.8.1 Medical Device 245
21.8.2 CE Mark 245
21.8.3 Competent Authority 246
21.8.4 Notified Body: Conformity Assessment
Body 247
21.8.5 Legal Manufacturer 248
21.8.6 Authorized Representative 249
21.9 Classification 249
21.9.1 Medical Devices 249
21.9.2 Active Implantable Medical Devices 250
21.9.3 In vitro and Diagnostics Medical Devices 251
21.10 Conformity Assessment Procedures 252
21.11 Essential Requirements 255
21.12 Labelling 257
21.13 Technical Documentation 258
21.14 Quality Management System 258
21.15 Risk Management 264
21.16 Clinical Evaluation 264
21.17 CE Mark Certificate and Declaration of
Conformity 266
21.18 Post-Market Surveillance 267
21.19 Recent Changes of MDD 93/42/EEC and
Impacts 268
21.20 Trends 270
21.21 Overview of All Interactions and Key
Terminology 271
22. Regulation of Combination Products in the United States 275
John Barlow Weiner and Thinh X. Nguyen
22.2 What Products Are Considered Combination
Products 276
22.3 The Standards for Determining If a Product Is a
Combination Product 276
Contents xv
22.4 The Standards for Determining Which FDA

Component has Primary Responsibility for
Regulating a Combination Product 277
22.5 Requests for Designation 280
22.6 Premarket Review Considerations 280
22.7 Post-Market Regulatory Considerations 281
22.8 Role of Office of Combination Products 282
22.9 Near-Term Developments That May Arise in
the US 284
22.10 International Harmonization and Coordination
Activities with Foreign Counterparts 284
22.11 FDA Resources for Obtaining Additional
Information 285
23. Regulation of Combination Products in the European
Union 287
Janine Jamieson and Elizabeth Baker
23.1 Introduction: Legal Basis 287
23.1.1 Definitions 288
23.1.1.1 Medical device 288
23.1.1.2 Medicinal product 289
23.1.1.3 Combination products:
Principal mode of action 290
23.1.1.4 Borderline products:
MEDDEV 2.1/3 291
23.1.1.5 Borderline products: Manual
of decisions 291
23.2 Combination Products Regulated as Medicinal
Products 291
23.2.1 Examples of Combination Products
Regulated as Medicinal Products 292
23.3 Combination Products Regulated as Medical
Devices 292
23.3.1 Examples of Combination Products
Regulated as Drug-Delivery Devices 292
23.4 Combination Products Regulated as Devices
Incorporating, as an Integral Part, an Ancillary
Medicinal Substance 293
xvi Contents
23.4.1 Examples of Devices Incorporating an

Ancillary Medicinal Substance 293
23.4.2 Examples of Drug Substances Incorporated
into Devices 294
23.4.3 Assessment of the Medicinal Substance
Aspects of a Device Incorporating an
Ancillary Medicinal Substance 294
23.5 The Consultation Process 294
23.6 Information to Be Provided on the Ancillary
Medicinal Substance 295
23.6.1 General 295
23.6.2 Quality, Safety, Usefulness (Clinical
Benefit/Risk) 295
23.6.2.1 Quality 295
23.6.2.2 Safety and usefulness
(clinical benefit/risk) 296
23.6.2.3 Guidance 296
23.7 Other Combination Products 297
Part 5 Medical Device Regulatory System

in Asia-Pacific Region
24. Australian Medical Device Regulations: An Overview 301
Petahn McKenna
24.1.1 Medical Device Market in Australia 301
24.2 Medical Device Regulations 302
24.2.1 Overview 302
24.2.2 Regulating Authority 303
24.2.3 Legislation and Guidance 303
24.3 Definition of Medical Device 303
24.4 Classification of Medical Devices 304
24.4.1 Classification of IVD Medical Devices 304
24.5 Inclusion of Medical Devices on the ARTG 306
24.5.1 Process for Supplying a Medical Device in
Australia 306
Contents xvii
24.5.2 Process for Including Class 1 IVD Medical

Devices (Other Than Export Only) in the
ARTG 307
24.5.3 Process for Including IVD Medical Devices
(Other Than Class 1) in the ARTG 310
24.6 Same Kind of Medical Device (SKMD) 312
24.7 Unique Product Identifier 312
24.8 In vitro Diagnostic UPIs 313
24.9 Renewal 314
24.10 Documentation Requirements 314
24.10.1 Conformity Assessment Applications 314
24.11 Application Audits 315
24.12 Access to Unapproved Medical Devices 316
25. China: Medical Device Regulatory System 317

Jack Wong
25.2 Market Overview 318
25.3 Overview of Regulatory Environment and What
Laws/Regulations Govern the Medical Devices 318
25.3.1 Measuring Function 319
25.3.2 Standards 319
25.4 Regulatory Body 320
25.5 Regulatory Overview 321
25.5.1 Definition of Medical Device 321
25.5.2 Classification of Medical Device 321
25.5.3 Registration Process 322
25.5.3.1 Medical devices registration
certificate 322
25.4.5.2 Product testing 323
25.5.3.3 Clinical trials 324
25.5.3.4 Exemption of clinical trial data
for Class II devices 325
25.5.3.5 Enforcing GMPs 325
25.5.3.6 Timeframes 326
xviii Contents
25.5.3.7 The CCC mark 327

25.6 Monitoring Adverse Events 328
25.7 Managing Recalls 329
26. Hong Kong: Medical Device Regulatory System 331
Jack Wong
26.1.1 Market Environment 331
Laws/Regulations Govern Medical Devices 332
26.3 Regulatory Body 333
26.4.1 Definition of Medical Device (It Follows
GHTF) 334
26.4.2 The Classification of Medical Devices 335
26.4.3 Role of Distributors or Local Subsidiaries 336
26.4.4 Product Registration or Conformity
Assessment Route and Time Required 337
26.4.4.1 Suggested registration
routes/steps 338
26.4.4.2 Technical material
requirement 338
26.4.4.3 The labelling requirement of
medical device 338
26.4.4.4 Post-marketing surveillance
requirement 338
26.4.4.5 Manufacturing-related regulation:
Do manufacturers need
registration/authorization? 339
26.4.4.6 Clinical trial-related regulation:
Are medical device clinical trials
regulated? 339
26.4.4.7 Is there a procedure for mutual
recognition of foreign marketing
approval or international
standards? 339
Contents xix
26.5 Commercial Aspect 339

26.6 Next Steps 340
27. India: Medical Device Regulatory System 341
Kulwant S. Saini
27.1.2 Overview of Regulatory Environment and
What Laws/Regulations Govern Medical
Devices 342
27.1.3 Functions Undertaken by DCGI and Central
Government 346
27.1.3.1 Statutory functions 346
27.1.3.2 Other functions 346
27.1.4 Functions Undertaken by the FDA and
State Governments 347
27.1.4.1 Statutory functions 347
27.1.5 Guidance Documents 348
27.1.6 Indian Pharmacopoeial Commission 349
27.1.7 Detail of Key Regulator(s) 349
27.2.3 Role of Distributors or Local Subsidiaries
(LRP) 353
27.2.4 Product Registration or Conformity
Assessment Route and Time Required 354
27.2.5 Quality System Regulation 356
27.2.6 Product Registration and Quality System
Regulation for Combined Device–Drug
Product 356
27.2.7 Registration Fee 356
27.2.8 Technical Material Requirement 357
27.2.9 The Labelling Requirement of Medical
Device 358
27.2.10 Post-Marketing Surveillance Requirement 359
xx Contents
27.2.11 Manufacturing-Related
Regulation 359
27.2.12 Clinical Trial-Related
Regulation 360
27.2.13 Is There a Procedure for Mutual Recognition
of Foreign Marketing Approval or
International Standards? 361
27.3.1 Any Price Control of Medical Device 361
27.3.2 Are Parallel Imports Allowed? 362
27.3.3 Any Advertisement Regulation of
Medical Device? 362
27.4 Upcoming Regulation Changes 362
27.5 Related Agencies/Departments and Ministries 363
28. Indonesia: Medical Device Regulatory System 365

Mita Rosalina
28.2 Regulating Authority 367
28.5 Registration of Medical Devices 369
28.5.1 Process 368
28.5.2 Documents Required 370
28.5.3 Official Registration Fee 370
28.5.4 Time Line 370
28.5.5 Validity of Product License 371
28.5.6 Indonesian Labeling Requirement 371
28.5.7 Regulatory Action for Changes and
Device Modifications 371
28.6 Post Market Surveillance System 372
29. Japan: Medical Device Regulatory System 387
Atsushi Tamura
29.2 Regulatory Agency in Japan 388
Contents xxi
29.2.1 The Ministry of Health, Labour and

Welfare 388
29.2.2 Pharmaceuticals and Medical Devices
Agency 388
29.2.3 Shared Responsibility of MHLW and PMDA
on Medical Device Regulation 388
29.3 Legislation of Medical Devices 391
29.3.1 Classiication of Medical Devices 392
29.3.2 Type of Product’s Registration 393
29.3.2.1 Notiication 393
29.3.2.2 Pre-market certiication
(third-party certiication) 393
29.3.2.3 Pre-market approval 394
29.3.3 Marketing Authorization Holder 394
29.3.4 Manufacturer License (Art. 13)/
Accreditation of Foreign Manufacturer
(Art. 13-3) 394
29.4 Related Requirements 396
29.4.1 Quality Management System 396
29.4.1.1 QMS conformity as an
essential requirement 396
29.4.1.2 QMS inspections 397
29.4.2 Good Quality Practices 397
29.5 MAH’S Obligations during Post-Market Phase 397
29.5.1 Collection, Analysis and Reporting of
Safety Information 399
29.5.2 Recall 399
29.5.3 Post-Marketing Safety Management 400
29.6 PMDA’s Obligations during Post-Market Phase 400
29.6.1 New Challenge 401
29.6.2 Information Services 401
30. Jordan: Medical Device Regulatory System 403
Anan Abu Hassan
30.1 Jordan Food and Drug Administration:
Introduction 403
xxii Contents
30.1.1 Vision 403

30.1.2 Mission 404
30.1.3 Overview of Structure of Jordan Food and
Drug Administration 404
30.2 Medical Device Market in Jordan 404
Laws/Regulations Govern the Medical Devices 404
30.4 Data about Jordan 409
30.5 Price Control of Medical Device 409
30.6 Priorities 409
31. Republic of Korea (South Korea): Medical Device
Regulatory System 421
Peter Lee
31.1.1 Facts about South Korea 421
31.1.2 Medical Device Market Scale in South
Korea 422
31.1.4 Detail of Key Regulator 423
31.2 Introduction to Korea Medical Device Regulatory
System 424
31.2.1 History 424
31.2.2 Procedures 425
31.2.3 KGMP: Quality Management System 426
31.2.4 Product Notification: Class I Devices 429
31.2.5 Product License: Class II, III, and
IV Devices 430
31.2.6 Technical File 430
31.2.7 Clinical Trials 431
31.2.8 Device Notification/License 432
31.2.9 Technical File Review 433
31.2.10 Type Testing (Mandatory for Class II, III,
and IV Devices) 434
31.2.11 KFDA-Registered 13 Laboratories 436
Contents xxiii
31.2.12 Applying for a Product License 437

31.2.13 Business License 437
31.2.14 Audit of Quality Management System
(KGMP Certification) 438
31.2.15 Post-Market Surveillance System 438
31.3 Importer’s Note 439
31.3.1 Import Labelling 439
31.3.2 Import Packaging 439
31.3.3 Import Documentation 439
31.3.4 Other Agencies 440
31.3.5 Medical Device Advertisements 441
31.3.6 Contacts 439
32. Malaysia: Medical Device Regulatory System 445
Yean Ting Ong
32.2 Regulating Authority 446
32.5 Registration of Medical Devices 449
32.5.2 Conformity Assessment Process 451
32.5.3 Combination Products 453
32.6 Post-Market Surveillance and Vigilance 453
32.6.1 Mandatory Reporting 453
32.6.2 Field Corrective Action 454
32.6.3 Recall 454
32.6.4 Labeling 455
32.7 Regulatory Action for Changes and Device
Modifications 455
33. Philippines: Medical Device Regulatory and Licensing 457
Mary Claire Cacanindin and Jennifer Cheah
xxiv Contents
33.3 History of Medical Device Regulation 460

33.4 Regional Medical Device Harmonization under
Development through ASEAN 461
33.5 Definition of Medical Device in Philippines 462
33.6 Registration with BFAD 463
33.6.1 License to Operate 463
33.6.2 License to Operate: Requirements 464
33.6.3 Certificate of Product Registration 465
33.6.4 Certificate of Product Registration:
Technical Requirements 465
33.6.5 Certificate of Product Registration: Legal
Requirements 466
33.7 Import Labeling 466
33.8 Import Documentation 467
33.9 Summary of Regulatory System 467
33.10 Contacts 468
34. Saudi Arabia: Medical Device Regulation System 469
Ali M. Al Dalaan

34.2 Legislative Responsibilities 470
34.3 Executive Responsibilities 470
34.4 Surveillance Responsibilities 471
34.5 Regulation Overview 472
34.6 Registration Requirements 473
34.7 Information to Be Provided to SFDA 473
34.8 Medical Device Marketing Authorization
(MDMA) 476
34.9 Medical Device Listing 478
34.10 Registration Fees 478
34.11 General Information and Documentary
Evidence to Be Provided to SFDA 480
34.12 Labeling Requirement for Medical Device 481
34.13 Post-Market Surveillance Requirement 481
Contents xxv
35. Singapore: Medical Device Regulatory System 487

Lee Ching Hwee
35.1 Market Overview Introduction: An Explanation of
the Process and Approach 487
Devices 488
35.1.2.1 Phase I implementation 489
35.1.2.2 Phase II implementation 489
35.1.2.3 Phase III implementation 489
35.2 Detail of Key Regulator(s) 491
35.3.1 The Definition of Medical Device 492
35.3.2 Classification of Medical Devices
(Classes A, B, C, and D) 493
35.3.2.1 Principle 493
35.3.2.2 Classification 493
35.3.2.3 Determination 494
35.4 Product Grouping 494
35.4.1 Single 494
35.4.2 Family 495
35.4.3 System 495
35.4.4 Group 496
35.4.5 IVD Cluster 496
35.5 Product Registration and Time Required 496
35.5.1 Application Process: Product Registration
for Higher Risk Medical Devices (Class B, C,
and D) 496
35.5.2 Product Registration for Lower Risk Medical
Devices (Class A) 497
35.5.3 Evaluation Routes 498
35.6 Product Registration for Combined Device–Drug
Product 499
35.7 Application Fee 499
xxvi Contents
35.8 Technical Material Requirement 499

35.9 Labeling Requirement of Medical Devices 501
35.10 Post-Marketing Surveillance Requirement 502
35.11 Manufacturing-, Importing-, and Wholesaling-
Related Regulation 503
35.12 Good Distribution Practice for Medical Devices 504
35.13 Clinical Trial-Related Regulation 504
35.14 Special Access 505
35.15.1 Any Price Control of Medical Device 506
35.15.3 Any Advertisement Regulation of Medical
Device? 507
35.16 Upcoming Regulatory Implementation 507
35.16.1 Regulatory Framework for Cell- and
Tissue-Based Therapeutic Products 507
36. Taiwan: Medical Device Regulatory System 513
Li-Ling Liu

36.1.1 Overview of Structure and Funding of
Local Healthcare System 513
Laws/Regulations Governing Medical
Devices 515
36.2.3 Role of Distributors or Local Subsidiaries 518
36.2.4 Products Registration, Technical Material
Requirement, and Time Required 518
36.3 Quality System Regulation 519
36.4 Combined Device–Drug Product 520
36.5 Registration Fee 520
Contents xxvii
36.6 Labeling Requirements of Medical Devices 520

36.7 Any Post-Marketing Surveillance Requirement 521
36.8 Manufacturing-Related Regulation 521
36.9 Clinical Trial-Related Regulation 521
36.10 International Cooperation 522
36.11 Commercial Aspects 522
36.11.1 Price Control of Medical Device 522
36.11.2 Parallel Imports 523
Devices? 523
37. Thailand: Regulatory and Medical Device Control 525
Patanawong Yuwadee

37.2 Medical Device Regulations and Regulators 526
37.3 Definition of a Medical Device 527
37.5 Product Registration 529
37.5.1 Licensed Medical Devices and Notified
Medical Devices 529
37.5.2 General Medical Devices 530
37.5.3 Review Period (as Promulgated in 2012) 531
37.5.4 Fees and Validity of Granting or Issued
Document 532
37.6 Labeling 532
37.7 Advertisement Control 533
38. UAE: Overview of Medical Device/IVD Regulatory System 535
Amin Al Amiri
38.1 Ministry of Health 535

38.1.1 Registration and Drug Control Department 535
38.1.2 Mission Statement 536
38.1.3 Medical Device Registration 536
38.2 Introduction to Md/ivd Regulatory System in Uae 537
xxviii Contents
38.3 Medical Devices Marketing Approval Flow Chart 538

38.4 Approval on Importation Level 539
38.5 Definition of a Medical Device 540
38.6 Classification of Medical Device/IVD 540
38.7 Authorized Representative Concept 541
38.8 Company Registration 542
38.8.1 Medical Devices Classified as
Nonpharmaceutical Dosage Form 542
38.8.2 Medical Devices Classified as Containing
Pharmaceutical Ingredients 543
38.9 Product Registration 543
38.9.1 Medical Devices Subject for Listing 543
38.9.2 Product Registration: Main Documents 544
38.9.3 Required Attachments per Device Class 545
38.10 Pricing 546
38.11 Parallel Importation 546
39. Vietnam: Medical Device Regulatory System 547
Thuy Nguyen Thi Thu

39.2 Overview of Regulatory Environment and Laws/
Regulations Governing Medical Devices 548
39.4 Classification of Medical Devices (Class A, B, C, D) 550
39.5 Role of Distributors or Local Subsidiaries 550
39.6 Product Registration or Conformity Assessment
Route and Time Required 550
39.6.1 Quality System Regulation 551
Regulation for Combined Device–Drug
Product 551
39.6.3 Registration Fee 551
Contents xxix
39.6.4 Technical Material Requirement 552

39.6.5 Labeling Requirements for Medical Devices 552
39.6.6 Post-Marketing Surveillance Requirement 552
39.6.7 Manufacturing-Related Regulation 552
39.6.8 Clinical Trial-Related Regulation 552
39.6.9 Is There a Procedure for Mutual
Recognition of Foreign Marketing
Approval or International Standards? 552
39.7 Commercial Aspects 553
39.7.1 Any Control over Prices of Medical
Devices? 553
39.7.3 Any Regulation Regarding Advertisement
of Medical Devices? 553
39.8 Upcoming Events 553
Appendix 555
Index 575
Preface
Medical device regulation in Asian markets has become important.

Governments and regulatory bodies of countries across the region
have placed new regulatory systems or refined the existing ones.
Regulatory affairs (RA) is a science of how to get a medical product
registered with different countries’ health authorities. A registered
product would demand a lot of technical documentation to prove
its efficacy, safety, and quality. To successfully and smoothly register
a product, many soft skills are required for dealing with various
key stakeholders in governments, testing centers, hospitals, and
medical doctors.
The handbook is the first to cover medical device regulatory
affairs in Asia. It is enriched by contributions by authors working
with several regulatory bodies, including the US Food and Drug
Administration (FDA), UK Medicines and Healthcare Products
Regulatory Agency (MHRA), Japan Pharmaceuticals and Medical
Devices Agency (PMDA), Saudi Food and Drug Authority (SFDA),
Korea Testing Laboratory (KTL), Taiwan FDA, World Health
Organization (WHO), Asian Harmonization Working Party (AHWP),
Regulatory Affairs Professionals Society (RAPS), and British
Standards Institution (BSI). Each chapter provides substantial
background materials relevant to a particular area to provide the
reader a better understanding of regulatory affairs. The text also
presents in-depth discussion on requirements for medical device
registration in China and India.
Government bodies will find this book useful to understand the
global regulatory environment to help enhance their regulatory
systems. The medical device industry can use it to better understand
and access the Asian market. Academics and students will find this
book very important for their careers in biomedical engineering and
medical device–related fields. In research and development, with
the help of this book, companies can plan their projects and ensure
that the developed medical devices adhere to the global regulatory
environment.
xxxii Preface
The chapters have been grouped into five main parts as follows:
• Part 1 explains what RA is, how to be a good RA professional,
how a RA professional works with other team members,
and some associated soft skills.
• Part 2 focuses on medical device fundamentals, such as
history, labeling requirement, clinical trial requirement,
how to do classification, and two important standards for
medical device regulatory (ISO 13485 and ISO 14971).
• Part 3 introduces key global (WHO, APEC, RAPS) and
regional (AHWP, ASEAN) organizations.
• Part 4 discusses the US and EU regulatory systems in detail.
We also invite two experts from the US FDA and the UK
MHRA to share their experience on combinational product
regulatory. Their experience will be very helpful for Asia.
• Part 5 is the core of this book. It describes the regulatory
system in the Asia-Pacific market, with contributions from
regulatory authorities, testing laboratories, and industries.
This book would not have been possible without contributions
from outstanding experts in various topics discussed in it. We wish
to express our gratitude to all of them for their precious efforts
and strong support.
Fifty percent of the revenue from this book will be donated to the
Asia Regulatory Professional Association and the remaining 50% to
the Interdisciplinary Division of Biomedical Engineering in Hong
Kong Polytechnic University for future regulatory professionals’
development.
Finally, many thanks to our families (Jack Wong’s mother, Cheung
Shim Kuen, wife, Sherry Kwan Suet Sum, and son, Jay Wong Yat;
Raymond Tong’s wife, Wai-nga Lam, and daughter and sons, Lok-
ching, Lok-tin, and Lok-ting), for their support, encouragement, and
patience. They have been our driving forces.
Jack Wong
Asia Regulatory Professional Association
Raymond Kai-yu Tong
Professor, The Hong Kong Polytechnic University
Hong Kong Academy Chair, Asia Regulatory Professional Association
Asia Regulatory Professional Association xxxiii
The Asia Regulatory Professional Association (ARPA) is an

organization of Healthcare Regulatory Affairs professionals in Asia.
ARPA aims to raise the standard and social recognition of Regulatory
Professionals as part of healthcare team.
We are working with different regulatory expertise globally to
achieve the above objectives. ARPA created this first Regulatory
textbook in Asia and arranged a number of Regulatory Certificate
courses in order to raise the standard of Regulatory Professionals.
You will also get awareness from key regulatory bodies, including
the US Food and Drug Administration, the Japan Pharmaceuticals
and Medical Devices Agency, Korea Testing Laboratory, and Taiwan
FDA, and regulatory organizations, including the World Health
Organization, Regulatory Affairs Professionals Society, and British
Standards Institution, which support this book and endorse the
importance of Regulatory Professional development.
The ARPA membership is free. Anyone who is interested in
the Asia regulatory affairs can join ARPA. For more details, visit
http://www.healthcare.org.hk/Health2.aspx?id=1&Cid=0.
Jack Wong
General Manager
speedxquality@yahoo.com
Chapter 1
How to Train University Students in

Regulatory Affairs
Raymond K. Y. Tong
Hong Kong Polytechnic University, Hung Hom, Hong Kong
Asia Regulatory Professional Association (ARPA)
k.y.tong@polyu.edu.hk
This chapter focuses on how to design a regulatory course to train

university students in regulatory affairs.
1.1 Introduction
Medical device regulations are coming up in many Asian markets.
The course should be suitable for students who are studying
biomedical engineering, healthcare, or medical device engineering.
These students should have some experience in a health- or
engineering-related field and should wish to start working in
the growing field of regulatory affairs. The course in regulatory
affairs aims to give both factual and practical knowledge of what is
regulatory requirement and how to handle future regulatory tasks.
Handbook of Medical Device Regulatory Affairs in Asia

Edited by Jack Wong and Raymond K. Y. Tong
Copyright © 2013 Pan Stanford Publishing Pte. Ltd.
ISBN 978-981-4411-21-9 (Hardcover), 978-981-4411-22-6 (eBook)
www.panstanford.com
How to Train University Students in Regulatory Affairs
On completion of the course, students will be able to demonstrate

their understanding of how to meet the standards and regulatory
requirements, and they will be able to handle regulatory tasks,
including classification, risk management, ISO standard, product
registration, and commercial materials review.
Students will be trained to understand the global, regional, and
local medical device regulatory requirements and trends. Besides
conducting lectures, students will be arranged into a small group to
work on a medical device and practice preparing a medical device
registration submission to a competent authority. The competent
authority is a body that has authority to act on behalf of the
government to ensure that the requirements of the medical device
directives are transposed into the national law and are applied.
Guest lecturers with regulatory experience and network will be
invited to share their experience. Students who finish the course
will be eligible for attending related medical device regulatory
examination conducted by external bodies, such as notified bodies
and the Asia Regulatory Professional Association.
1.2 A Sample of Regulatory Affairs Exercises

for Students
1.2.1 Background
Consider this case. You have just been recruited by a manufacturing
company, Poly Technologies Corporation (PTC), as project manager
under its newly found business section for medical and healthcare
products. The company has little, if any, experience in designing and
manufacturing medical devices. Your primary duty is to provide
internal consultancy to the top management of the company on new
business development analysis and management of medical device
design and manufacturing projects.
Last month your company’s top management signed a business
agreement to collaborate with an overseas client, which is a global
distributor of medical products. Under this collaboration agreement,
your client and PTC will co-develop a series of medical devices for
global markets. Your client has proposed to start a project with the
sterile disposable hypodermic syringes with needles — for single-
dose hypodermic injection (Fig. 1.1).
A Sample of Regulatory Affairs Exercises for Students
Figure 1.1 Various sizes of hypodermic syringes.
To begin with, your client has suggested designing and

manufacturing the products for the US and EU markets and,
if possible, extend the market to China in future.
Task 1: Classification

Your first task is to brief your management about the product
classifications of the device. For more details, see Chapter 11,
“Medical Device Classification Guide.”
Classification
rules applied
What are to the product
the US FDA under EU Notified body
Target Device regulation medical device involvement for
market classification numbers directive CE marking?
EU
US
China
Task 2: Risk Analysis

(For more details, see Chapter 13 on ISO14971.)
During the design phase of the device, suggest hazards for the
product that the product design team has to include in the design
input considerations.
Suggest the severity and occurrence for the suggested hazards.
Ensure that you have provided your own table and definition of
different levels of severity and occurrence.
Task 3: Risk Evaluation and Risk Control

(For more details, see Chapter 13 on ISO14971.)
How to Train University Students in Regulatory Affairs
You have to develop a risk graph (group for risk regions and decide
the risk acceptability) and risk matrix (put all the above risks in your
device)
Implement risk control measures for all of your hazards. After
all risk control measures have been implemented and verified, the
manufacturer shall decide whether the overall residual risk posed
by the medical device is acceptable using the criteria defined in the
risk management plan.
Task 4: Medical Device Registration Submission

Prepare a medical device registration submission to your competent
authority.
References
1. ISO 13485 (Medical devices — Quality management systems —

Requirements for regulatory purposes).
2. ISO 14971 (Medical devices — Application of risk management to
medical devices).
3. EU Directive 93/42/EEC regarding medical devices.
4. MDCO, http://www.mdco.gov.hk/eindex.html.
5. AHWP, http://www.ahwp.info/.
6. GHTF, http://www.ghtf.org/.
7. Asia Regulatory Professional Association (ARPA) http://www.
healthcare.org.hk/E_Doctors/Health2.aspx?id=1&Cid=0.
8. International Organization for Standardization, http://www.iso.ch/
iso/.
Part 1
Introduction
Chapter 2
The Evolution of the Regulatory

Professional: Perspectives on the Skill
Sets and Capabilities That Will Define
the Next Generation of Regulatory
Professionals
David Martin and Neil Lesser

Deloitte Consulting LLP
davidmartin@deloitte.com, nlesser@deloitte.com
2.1 Introduction
Historically, the role of the regulatory affairs function within
companies that develop and sell medical devices has been more
tactical than strategic. While this tactical focus has served the
industry well in the past, regulatory authorities around the world
are raising the bar for market access. Regulatory reforms as well
as the increased availability of real-world safety and efficacy data
continue to alter the path to approval and the underlying investment
case for medical devices. Globalization will also play a key role in
shifting regulatory requirements — New regulatory frameworks
are evolving and regional partnerships will be the main driver
of harmonization going forward, especially in the Asia-Pacific
market area.

www.panstanford.com
The Evolution of the Regulatory Professional
In response, manufacturers are seeking a new type of regulatory

professional that can continuously adapt to this more complex
regulatory environment. The new regulatory professional will
continue to execute tactical requirements and will also own strategic
relationships with regulators and thought leaders that can help
shape future policies. Guiding the regulatory professional will be
a fluent understanding of the organization’s strategy and active
participation in product development and commercialization,
making them a more robust business partner to the clinical and
commercial functions.
2.2 Drivers of Change

The regulatory environment in the global medical device industry
is and will continue to undergo major shifts. In December 2011, the
Asia-Pacific Economic Cooperation group announced a new plan to
harmonize regulations for medical devices by 2020. The proposal is
based on the Global Harmonization Task Force (GHTF) — recently
re-formed into the International Medical Devices Regulators’
Forum (IMDRF) — and intends to create a predicable regulatory
framework for device manufacturers. This large-scale initiative will
require an unprecedented level of cooperation across national health
authorities. If successful, the harmonization will eliminate some
of the unknowns in the regulatory environment, but getting there
will challenge manufacturers that must reconcile the harmonized
promise of tomorrow against the fragmented regulatory landscape
of the near term. In addition, regulations have a history of lagging
behind the rate of product innovation, meaning there will be a
continued need for sophistication in the regulatory affairs function
to navigate the evolution of the national, regional, and global
regulatory environment. Regulatory professionals in the medical
device and diagnostics industry must become aware of the three main
influencers to the environment: rapid change, harmonization on a
global scale, and increased safety and effectiveness requirements.
First, the regulatory environment is changing rapidly and
professionals must be able to gauge how new developments will
affect the future environment. New regulations with far-reaching
ramifications have emerged in only the last few months; in January
of 2012, Chinese officials issued a set of rules to deal with the conflict
of interest of healthcare government officials in connection with
Historical Role and Skill Set of a Regulatory Professional
pharmaceutical and device manufacturers, and released a new Five

Year Plan for the pharmaceutical and medical device industries.
Second, as firms increasingly develop a global footprint, the
comparative global regulatory frameworks must be taken into
account. These regulatory frameworks are embarking on a period
of standardization, led predominantly by the Global Harmonization
Task Force, founded in 1992 with the stated goal of achieving
greater uniformity between national medical device regulatory
systems. This agency is playing a key role in driving standardization
and continues to leverage existing international organizations
(such as the Association of Southeast Asian Nations (ASEAN)) to
achieve greater coordination. For example, the Malaysian Medical
Device Control Division has drafted guidelines for the in vitro
diagnostics sector which are based on recommendations from GHTF
and ASEAN guidelines. In addition, these regulatory frameworks
are also currently going through a period of change. The GHTF itself
has recently announced a successor organization, the International
Medical Devices Regulatory Forum (IMDRF) which will continue the
goal of acceleration of harmonization, but will also assemble ad hoc
working groups comprised of various stakeholders to discuss key
issues.
Third, there has been an increased emphasis placed on safety
and effectiveness in the data required for clinical trials. Several
developing nations are incorporating adverse event reporting
capabilities and requirements into their regulatory frameworks,
including India and China. Singapore is also planning to introduce
regulations for medical device clinical trials in 2012. This trend is of
increased importance, as clinical data will become more crucial for
pre-market decisions due to the greater overall emphasis placed on
patient safety recently. However, this trend will need to be monitored
closely across the region as China has actually begun to relax clinical
trial regulations for specific medical device classes.
2.3 Historical Role and Skill Set of a

Regulatory Professional
Historically, the regulatory professional has served an important
operational role within a life sciences organization. The role could be
described as process oriented in nature: managing the submission
10 The Evolution of the Regulatory Professional
process, communicating to stakeholders and ensuring compliance

with rules and policies to secure the smooth delivery of a product
submission (see Fig. 2.1 below for an example of a job description
for a traditional regulatory position).
• Compile and format departmental documentation for inclusion in

regulatory submissions (IDE, 510(k), International Registrations).
• Participate in the complaint management process and ensure timely
completion of adverse event reporting as required by the FDA and
international regulatory agencies.
• Work closely with the Sr. Director of Regulatory and related
departments in order to support Regulatory submission activities.
• Coordinate and consult with other departments, including
Engineering, Manufacturing, Marketing and Quality, in order to
support the collection of documentation, review and assembly of
regulatory submissions.
• Ensure the quality, content and format of regulatory submissions to
state, federal and international agencies.
• Ensure consistency, completeness and adherence of standards for
all submissions. Submissions will include IDEs, 510(k)s, federal and
state establishment licensing applications, international regulatory
device licensing applications, etc.
Figure 2.1 Sample job description for a traditional regulatory professional

role.
The primary skill sets necessary for the completion of the above
tasks are excellent organizational and managerial skills as well
as a thorough understanding of standards and regulations. The
requirements for this position are more focused on adherence to
regulations and curating the appropriate compliance documentation,
with less emphasis on analyzing the larger regulatory-industry
environment to understand its far reaching implications.
While these process and organizational skills will remain
essential, tectonic shifts in the environment have manufacturers
seeking to unlock the strategic value of the regulatory function.
They are looking for their regulatory leaders to contribute outside
of their functional vertical and leverage their expertise across the
organization. This enhanced position requires a broader skill set
and leading manufacturers have already begun hiring for this
evolved regulatory role as evidenced in the job description below
(Fig. 2.2).
Changing Role and Skill Set of the Regulatory Professional 11
• Independently lead global regulatory strategy development,

planning, and implementation for multiple complex programs and
platforms. Participate in identification of risk areas and develop
alternative courses of action including anticipation of regulators
responses through scenario planning and development of
contingency plans.
• Guide and influence technical groups in areas of product develop-
ment and lifecycle enhancement. Participate in potential and estab-
lished third part efforts (i.e. due diligence activities, joint ventures,
etc.).
• Initiate and maintain appropriate communication within the RA
function and represent Regulatory Affairs with business units and
other functions. Implement policies to ensure ongoing compliance
of regulatory requirements.
• Develop and implement regulatory strategy aligned with business
strategy. Assess impact of new regulations and implement
appropriate changes as well as lead development of company policy
and positions on draft regulation and guidance.
• Responsible for negotiating and decision making with regulators
and stakeholders with complex and high-risk projects.
• Provide direct supervision of individuals including mentoring,
performance management and staffing decisions.
• Represent company externally at appropriate industry associations.
May act as primary contact with regulatory authorities including
the planning and leadership of meetings. May participate in
management of budgets.
Figure 2.2 Example job description for the changing regulatory pro-
fessional role.
2.4 Changing Role and Skill Set of the

Regulatory Professional
In light of the aforementioned shifts in the regulatory environment,
it is clear that an expansion of capabilities will be required in the
future within regulatory departments. These capabilities will go
beyond the traditional realm of regulatory affairs and move the
function closer to “heart of the business” issues that shape the
strategic direction of the organization. Regulatory professionals
that are able to make this leap will become trusted partners and
contributors as they will have found ways to unlock value in the
regulatory process. Described below are a few of the next-generation

capabilities that will empower the regulatory professional.
2.5 Develop as a Center of Intelligence

To adjust to the dynamic regulatory environment found in both
the Asia-Pacific region and the broader global environment,
the regulatory function should strive to operate as a center of
intelligence for the organization — proactively sensing signals of
change in the external environment and disseminating the insights
to the organization. Such a role requires that the professional be
capable of synthesizing data and trends from a variety of sources
and developing a recommendation that considers complex points of
view. To do this successfully requires that regulatory professionals
are able to capture intelligence from a variety of sources and detect
signals from extraneous noise.
Regulatory intelligence is available from myriad sources:
interactions with health authorities, conversations with key
opinion leaders (KOLs), in the presentations of academics, through
networking at conferences and summits, and from the outcome of
product submissions. The efficiency and certainty of signal detection
will improve with the collective experience of the regulatory
professional and the level of rigor used to assess and document
regulatory trends. In summary, the regulatory professional will
need to develop a process to collect data, perform trend analysis,
develop summary insights, and possess the ability to communicate
the findings to various stakeholders within the organization.
2.6 Advance Toward Strategic

Relationship Management
As the fundamental gatekeeper to market access, health authorities/
regulatory agencies play a “make or break” role in the success of
a product. For this reason, it is paramount that manufacturers
consider means to maximize the value of interactions with key
figures from a regulatory body. One such way to maximize value is
to implement a more thoughtful approach to interacting with key
figures in the approval process and those external stakeholders (e.g.,
Conclusion: What Will It Take to Get There? 13
KOLs) that might influence it. By formulating a clear understanding

of its goals and needs, a manufacturer can align its outreach
efforts to effect more purposeful and productive conversations
with external figures. By cultivating advanced communication and
negotiation skills the organization can help shape the dialogue
around reforms and regulatory findings rather than being blocked
from the conversation. While not necessarily a cure-all or a quick
fix, an organization with a deep understanding of the landscape of
influencers and a network to match is more prepared to respond in
times of crisis or more able to pick up the phone and get an answer
to a burning question.
2.7 Develop as a Strategic Business Partner

Foundational to the aforementioned capabilities will be the expan-
sion of the regulatory professional as a strategic minded individual.
With primary access to regulators and a keen understanding of the
levers that guide their review and lines of inquiry, the regulatory
professional is in a unique position to add value to the organization.
By understanding where the key interests and points of debate
are for a health authority (e.g., efficacy, safety, cost) the regulatory
professional can help guide the direction of a clinical program or
a commercial campaign toward those areas most likely to satisfy a
regulators priorities while still serving the organization’s needs. Part
of this role will include actively participating in the strategic business
planning process to lend a perspective on feasibility and any prior
precedent. It will be critical for the internal expert to communicate
across the organization into both commercial and clinical functions
and serve as a strategic business partner that can help decipher
the “noise” to guide informed decision making for commercial and
clinical investment. Delivering in this expanded role will require
flexible strategic thinking, complex stakeholder management and a
firm understanding of the organization’s goals and plans.
2.8 Conclusion: What Will It Take to Get There?

Having laid out a few of the capabilities and skills that the regulatory
professional of the future will need, what follows is a discussion
of how one can attain the skills and experiences to best position
themselves for future success.
Primarily, one must gain the foundational strategic, analytical
and communication skills that will be required. This is best
accomplished through coursework in Strategy, Operations and
Communications. Further coursework in the fields of Negotiation
and Marketing would provide the necessary “big picture” view
required of the new regulatory role, a skill set in synthesizing
information and an understanding of how to manage multiple
shareholders and their diverse incentives.
To complement this coursework, one should pursue opportu-
nities to network with a wide array of students and professionals
from across life sciences, health care, and the government in order to
enrich one’s understanding of the needs and motivations of various
stakeholders in the system. Memberships in professional societies
and industry groups and attending summits and conferences should
be at the forefront of any career development strategy, but in this
case these associations are particularly important in order to gain a
viewpoint on the changing environment of regulation and develop a
network of colleagues throughout the industry.
Further, a rotational role within a life sciences organization
would be especially valuable. Such a role would provide exposure
to a broad spectrum of functions and stakeholders and their
diverse incentives and viewpoints. This position represents an ideal
experience for a professional in this industry seeking to become
fluent in the internal workings of an organization and competent in
a strategic partner role.
Ultimately, success in this field requires that professionals
recognize that the regulatory role is evolving and that this evolution
must be matched by a new, broader focus in their education and
career development. Fortunately, the resources exist to prepare
for this evolved position and to build a career in this challenging,
growing field — One might even say there has never been a more
exciting time to be on the regulatory side of the medical device and
diagnostics industry.
Acknowledgment
Contributions to this chapter have been made by Chris Nuesch, Bill
Chiodetti, and Riddhi Roy, all from Deloitte Consulting LLP.
References 15
References
1. http://www.sidley.com/newsresources/newsandpress/Detail.aspx?
news=5061.
2. http://www.pacificbridgemedical.com/newsletter/article.php?
id=567.
3. http://www.rajpharma.com/productsector/medicaldevices/
Malaysia-consults-on-four-draft-guidelines-for-IVD-sector-324052?
autnID=/contentstore/rajpharma/codex/4072005d-15cc-11e1-
bbe6-4d8e6a53eb99.xml.
4. http://www.emergogroup.com/blog/2011/11/ghtf-unveils-succe-
ssor-organization.
5. “China Drug and Device Regulatory Update 2009”, Pacific Bridge
Medical Group, May 2009.
6. http://www.rajpharma.com/productsector/medicaldevices/Singa-
pore-plans-to-introduce-new-framework-for-medtech-trials-in-2012-
323092?autnID=/contentstore/rajpharma/codex/b5848548-046e-
11e1-bbe6-4d8e6a53eb99.xml.
7. http://www.sidley.com/sidleyupdates/Detail.aspx?news=5019.
8. http://regulatorycareers.raps.org/jobs/4660783/regulatory-affairs-
specialist.
9. http://regulatorycareers.raps.org/jobs/4699968/sr-manager-
regulatory-affairs-cmc-biologics.
Chapter 3
Ensuring Smooth Product Launch:

Regulatory Interfaces with Marketing
and Supply Chain
Alok Mishra
Asia Pacific, Strategic Business Systems,
Johnson & Johnson Medical Singapore
amishra@its.jnj.com
3.1 Introduction
The Regulatory step is perhaps the most critical step in the New
Product Introduction process as it involves externalities — both
within and outside the organization. In a large multinational device
manufacturer, the product is often launched in geographies far
from the originating company and involves a variety of regulatory
and reimbursement authorities who can be quite different in their
priorities, processes, requirements, and approach. This is key
interfacial step in the launch and one that can create — or destroy
— the significant value for the corporation.
A rough calculation can highlight the impact of achieving speed
to market. Assume a product will achieve a forecast of $30 million

Copyright © 2013 Johnson & Johnson Medical Asia Pacific
www.panstanford.com
18 Ensuring Smooth Product Launch
per year of peak sales. This translates to sales of over $82,000 per
day. The company would lose a million dollars for each 12 days
of delay! Alternatively, faster launch makes the company almost
$2.5 million extra per month.
What does this have to do with Marketing and Supply Chain? To
understand this, we need to look at interfaces and delays.
There are thus several areas where better communication
processes can improve efficiency, reduce time to market, and thus
have a positive impact on the bottom-line.
3.2 New Product Pipeline

In most cases, Marketing is exposed to new products in the
pipeline much before anyone else. However, quite often they fail to
convey this information to other parts of the organization — most
importantly, Regulatory Affairs and Supply Chain — which creates
suboptimal conditions later. Early information to regulatory affairs
is critical for their being able to establish key connections for the
documentation, providing heads up and getting feedback from
regulators regarding possible requirements and overall being able
to create appropriate Regulatory Strategy for the quickest path.
Information to Supply Chain is important as many new
products, especially biologics and drug–device combinations,
have unique storage requirements and its takes time to optimize
vendors and locations to handle such products. In one case, the
transportation cost of a biologic product was over 50% of the
product’s landed costs, and it took months of vendor negotiation to
bring it down to a reasonable level.
3.3 Planned Launch Dates

It is important for Marketing to develop launch dates in early
consultation with Regulatory Affairs as the latter are in the best
position to assess Regulatory difficulty and provide guidelines for
feasible dates. In addition, some products may have additional
requirements, e.g., mandatory clinical trials, which need detailed
budgeting and resource planning to be able to complete registration
requirements.
New Product Approval Dates 19
3.4 New Product Forecasts

It is often said forecasting is difficult, especially of the future! The
new product forecast of a medical device is a challenging task
as it has several barriers that determine the growth rate. These
are summarized as 4A’s (Access, Adoption, Awareness, and
Affordability) (Fig. 3.1 ).
Figure 3.1 The four A’s.
It is thus essential that the Marketing manager works with

folks in Regulatory and Reimbursement to assess times and rates
of approval and build good assumptions around rate of adoption
and awareness to arrive at robust forecasts. The importance of this
cannot be overemphasized as there is no bigger embarrassment
than to have forecasted a wrong approval date and be sitting on
valuable inventory when other parts of the world have shortages.
3.5 New Product Approval Dates

Finally, Regulatory Affairs also has an important responsibility to
provide timely feedback to Marketing and Supply Chain so that they
can plan the launch effectively and not waste resources by planning
to early or miss revenue opportunity by not being prepared when
the product approval comes through.
Working together of Regulatory Affairs, Marketing, and
Supply Chain in a seamless fashion that identifies delays early and
responds to problems proactively, thus minimizing the time to
market, can be a key source of competitive advantage for a medical
device company (Fig. 3.2). It is not easy but is worth all the time and
money spent in making it happen.
20 Ensuring Smooth Product Launch
Marketing
M
Ͳ NewProductfo orecasts Ͳ NewProductpipeline
Ͳ Plannedlaunch hdates Ͳ Planned
dlaunchdates
Ͳ Pricinginformaation
Regulatorry
Suppllychain
Affairs

Figure 3.2 Team work for
success.

Chapter 4
What Is the Right Thing to Do?
Jack Wong
4.1 Right Job

I am a health care professional who graduated as a pharmacist and
worked as a Regulatory Affairs officer in healthcare companies. I am
very proud of working in the health care sector as my products or
services are very important for people. My job as Regulatory Affairs
officer is to make available new medical products to patients by
utilizing scientific data from R&D, to ensure a good-quality system
in manufacturers, to liaise with the health authority, and finally
to obtain relevant certificates prior to supplying the products to
patients who need it. To provide high-quality medical products to
patients fast is my core job.

www.panstanford.com
22 What Is the Right Thing to Do?
4.2 Two Key Challenges in Our Job

4.2.1 Quality
To ensure good quality, many international standard bodies (e.g.,
ISO and BSI) and local standard bodies in many countries such
as the United States, Japan, and China actively develop better
product standards for manufacturers so that products with
better specifications are manufactured. After a product with good
specifications has been developed, its production needs to be
done within a good system, too (e.g., GMP and ISO 13485), and the
process needs to be regularly audited by certification bodies and
governments. As regulatory professionals, we need to understand
this and explain this to relevant government bodies and finally
obtain relevant approvals before supplying the product to patients.
4.2.2 Speed
Taking medical devices as an example, it usually takes 90 working
days to get approval in the United States and Europe. Surprisingly,
it can take up to 1–2 years to get approval in Asia. Health care
sectors and governments in Asia are working hard to streamline the
process.
4.3 Regulatory Affairs Job is a Combination of

Science, Legal Affairs, and Moral
The following formula can explain our job aptly:
RA = (Science × Law)Moral
The Science and Legal parts may be obvious to readers. I would
like to explain the Moral part. To begin, I would like to start a story
of moral situation.
4.4 Persons versus Things

To explain the moral part of the Regulatory Affairs job, I would like
to start with a moral question/situation:
Persons versus Things 23
Suppose you were a trolley car driver driving at 60 miles an

hour. Suddenly, you see five persons standing in your way. You
try to stop, but the brakes do not work. You feel bad as the
persons may die.
Then you notice a side track on your right hand side, but there
is a person standing there. You can turn right hitting that one
person but sparing the five.
What will you do? Sacrificing one life in order to save five seems
the right thing to do.
Now consider another version of the trolley car situation:
You are not the driver but an onlooker standing on a bridge
overlooking the track, and there is no side track this time. Along
the track, there are five persons. The trolley car cannot stop as
the brakes do not work, and it is about to crash into the five
persons. You feel desperate to help them. Suddenly, you notice a
heavy man standing next to you. You can push him off the bridge
into the path of the trolley car. He could die, but the five persons
would be saved. (Assume that this approach will work and the
option of you jumping onto the track will not help as you are too
small to stop the trolley).
Will you push the heavy man?
I studied some literature on human rights and philosophy to

look for an answer to this question and came up with the following
statement:
It is wrong to use people for the sake of the general welfare.
Pushing the heavy man onto the track to block the trolley uses him
as a means and, hence, fails to respect him and his dignity.
We value things not just “more” or “less,” but in qualitatively
higher and lower ways.
The Right Thing to Do

A human being is not an object but a person with dignity. As health
care professionals, our sole aim is to help them receive good medical
services/products fast. By respecting human dignity, we should
put human dignity first and minimize all administrative,
bureaucratic, and political issues. This drives our work in
Regulatory Affairs.
Chapter 5
Affordable Access to Medical Devices in

Developing Countries
Rosanna W. Peelinga and Tikki Pangb

aLondon School of Hygiene and Tropical Medicine, London, UK
bWorld Health Organization, Geneva, Switzerland
rosanna.peeling@lshtm.ac.uk, pangtikki@gmail.com
5.1 Introduction
National regulatory approval for drugs provides safeguards for the
safety and effectiveness of drugs used in a country. Most countries
have established a process for reviewing the evidence from drug
trials to support the introduction of new drugs. Over time, this
has improved the quality of drugs used in developing countries.
Unfortunately, in the developing world, apart from tests used for
blood banking, more than 50% of countries do not regulate in
vitro diagnostics (IVD) for infectious diseases [1, 2]. More broadly,
medical devices are often sold and used in most of the developing
world without any formal evaluation of their performance and
effectiveness. Access to good-quality medical devices is problematic
in these countries as companies with good-quality products are
often unable or reluctant to compete in a market that is flooded with
cheap, poor-quality products.

www.panstanford.com
26 Affordable Access to Medical Devices in Developing Countries
In countries that do regulate medical devices, the regulatory

landscape is highly variable and continuously changing, resulting in
greater challenges associated with transparency, language barriers,
and costs. Regulatory reviews consist of technical and administrative
components which can vary significantly between countries, even
in the same region. Time frames for approval and the complexity of
the approval process vary widely. Because of the onerous process
and costs, companies tend to target countries with markets that
allow for a substantial return for investment. Smaller countries
in the developing world are currently paying significantly higher
prices for medical devices than countries with sizeable markets,
largely because of the many distribution channels that health
program and providers need to go through to access the products
that they need. Another important outcome of this scenario is that
these complex, lengthy and variable regulatory approval processes
have driven up the cost of goods making products unaffordable
and become a major disincentive to innovation.
Recent investments in the development of tools to improve
global health will soon lead to the commercialization of novel
classes of medical devices. However, regulatory directives have
not kept pace with technological development [3].
In recent years, the global economic crisis has led to drastic
cutback in health programs. Companies have less resources for
the research and development of medical devices. International
aid programs for HIV have declined from US$ 8.7 billion in 2009 to
US$ 7.6 billion in 2010. The Global Fund, one of the major sources
of support for global health, recently announced that no new
projects will be funded until 2014. But now more than ever,
affordable medical devices, in particular IVDs, are urgently needed
in the developing world and these products need to be accessible
and affordable to patients in the developing world.
5.2 Why Is Affordable Access to Medical

Devices Important for Developing Countries?
In times of the global financial crisis, limited resources and
competing priorities, affordable and sustainable access to medical
devices in developing countries represents a critical first step in
ensuring the optimal delivery of health care. In particular, access
Affordable Access in Developing Countries 27
to rapid, point-of-care (POC) diagnostic tests is fundamental in

emergency preparedness, in ensuring health system efficiency
and, ultimately, for achieving health equity.
5.2.1 Emergency Preparedness

A rapid and accurate identification of a new or a re-emerging
pathogen is the critical first step in the investigation of a potential
epidemic or pandemic emergency. Together with standard public
health measures to contain an outbreak, surveillance activities
are dependent on the availability of rapid, accurate, sensitive, and
specific diagnostics which can provide critical information relating
to the most appropriate treatment (which drugs?), preventive
strategies (are there any vaccines available?), and appropriate
public health measures (border controls?). Coupled with standard
microbiological procedures and molecular biology techniques in
reference laboratories, rapid tests can quickly help to pin down the
identity of a new (or re-emerging, or mutant) infectious agent. For
example, a suspected dengue fever outbreak in Nicaragua several
years ago proved, after rapid diagnosis, to be leptospirosis instead
with important repercussions and implications for the needed public
health measures, i.e. there are differences in strategies for dealing
with a mosquito-borne virus as compared to a water-borne bacterial
infection. Early identification of outbreaks leading to appropriate
control interventions will also reduce the socioeconomic burden
often associated with epidemics.
5.2.2 Efficiency and Effectiveness of Health Systems

Beyond emergency response and preparedness, diagnostics can
have very significant impact on the efficiency and effectiveness of the
health system as a whole. In the context of both infectious and non-
infectious diseases, an accurate diagnostic test can clearly lead to
more rational therapy decisions, e.g., deciding the use of an antibiotic
or an anti-viral drug. Because of limited access to rapid point of care
(POC) diagnostic tests, many treatment decisions in the developing
world are made based on clinical/syndromic manifestations,
which, arguably, is the cause of wrong, under-, or over-treatment
thus resulting in wastage, inefficiency, and the potential selection
for resistant strains of microbes. At the population level, a rapid and
accurate diagnostic can also guide public health measures needed

to contain a potential outbreak as mentioned previously. Finally,
the recent trend towards generic, common platforms for multiple
rapid diagnostic tests, potentially also including tests for chronic
diseases, also promises standardization, increased efficiency and
cost savings to the health system. As an example, a generic open
platform (see below) will obviate the need to specially train
laboratory staff to perform a variety of different diagnostic tests.
5.2.3 Health Equity

Ultimately, however, access to medical devices which improve
efficiency of health care delivery in the developing world can
help achieve the higher objective and mission of the World
Health Organization of “the attainment by all peoples of the highest
possible level of health” and the more recent goal of achieving
universal health care. Gross inequities in health standards continue
to exist between the developed and developing countries, and
ensuring access to affordable diagnostics can bridge the equity
gap. However, and despite enormous progress in the prevention,
diagnosis, and treatment of diseases, developing countries often
remain excluded from the benefits of innovations. High-quality
diagnostic tests are often not affordable or accessible to patients in
the developing world because of health infrastructure constraints.
In other words, the inequity extends to the practical aspect of access
to diagnostics.
In order to address this inequity, the Bill & Melinda Gates
Foundation and Grand Challenges Canada, for example, have
created a joint initiative, Grand Challenges in Global Health — Point
of Care (POC) Diagnostics. The goal of this initiative is to create a
sustainable market for high-performance, low-cost, POC tests for
the developing world. Currently, POC diagnostic components are
not inter-operable, leading to higher costs of goods and customised
training for each test. The vision of this initiative is to develop open
platforms that can support an extended menu of tests from different
manufacturers, including those based in developing countries.
Ideally, a future user will be able to purchase one of these open
technology platforms on which a menu of tests can be run according
to local needs and capacities. An analogous example would be USB
memory sticks which are made by many companies but can work
Case Studies 29
with any computer for data storage and transfer. To make progress
towards this vision of a more equitable and “level playing field”, it
is critical that a diagnostic technology framework be developed
with four related sets of standards: Product Standards, Interface
Standards, Regulatory Standards and Business Standards.
Finally, it should be emphasized that all three aspects of
emergency preparedness, efficiency and equity must be considered
in the context of health systems as a holistic, integrated entity. A
fundamental commitment to correct inequities is the foundation
for the development of stronger, more robust and more efficient
health systems which are well-prepared to deal with emergency
situations.
5.3 Case Studies

5.3.1 Delay in Eligibility to Treatment for HIV
• Not only access to HIV treatment has been shown to be
beneficial for HIV-infected patients, but also it plays a major
role in the prevention of onward transmission.
• Eligibility to HIV treatment depends on a white blood cell
count (CD4 assay), which is an indicator of the immune status
of the patient.
• These assays require sophisticated equipment and are
neither affordable nor accessible, especially to patients living
outside of urban centres in the developing world.
• The first POC test for CD4 count has been developed, but the
company has had to conduct 29 trials in Africa and 49 trials
worldwide to obtain regulatory approval.
• The WHO estimates that currently 11 million HIV patients are
waiting for CD4 testing to determine eligibility to treatment.
The cost of these trials will inevitably be passed onto the cost
of goods making the product unaffordable.
• The lengthy approval processes will lead to delays in getting
patients on treatment and, in some cases, death.
5.3.2 Delay in Access to Early Diagnosis of Tuberculosis

• The WHO estimates that 1.8 million people die of tuberculosis
(TB) every year.
• TB diagnostic trials are lengthy and expensive.

• A new POC TB test has been developed and is commercially
available.
• The introduction of this novel life-saving technology will is
likely to take 2–5 years for regulatory approval.
• Without expedited approval and harmonization, 4–9 million
TB patients will die before this new technology can be widely
used to save lives.
5.3.3 Misleading Claims of Test Performance for Dengue

Rapid Tests
• One-third of the world is at risk of dengue.
• Countries need accurate diagnostics to rapidly identify
the cause of outbreaks so that appropriate public health
interventions can be put in place to control the outbreak
without delay.
• However, many dengue tests are sold and used with mis-
leading claims of test performance (see Table 5.1).
• New and improved dengue tests are being developed, but
approvals may delay their deployment to identify and control
outbreaks.
Table 5.1 Misleading claims of test performance for dengue IgM tests
Manufacturers’ claims WHO evaluation

accuracy (%) accuracy (%)
Test Sens Spec Sens Spec
Test A 100 100 23 99
Test B NS NS 18 98
Test C 80 >99 63 69
Test D NS NS 9 100
Test E 70 100 65 98
Test F 93 100 22 99
Test G 100 100 6 99
Note: NS, not stated.
Adapted from Blacksell et al., Clin Infect Dis 2006; 42:1127.
Case Studies 31
5.3.4 Case Study — Access versus Performance: Basis

for FDA Approval of the First Over-the-Counter
Rapid HIV Test in the United States
5.3.4.1 Background
An HIV-infected person does not show any remarkable symptoms
in the early stages of infection but is capable of transmitting the
virus to others. A key component of the prevention and control
of HIV is the early detection of infection through a blood test and
counseling or treatment to interrupt the chain of transmission
within the population. Laboratory methods to detect HIV infection
have been used for more than two decades, but individuals need
to take the initiative to present at a clinic for testing. Simple rapid
HIV tests, available since the 1990s, have made testing accessible
beyond clinic settings, but at-risk individuals, who are typically
drivers of the HIV epidemic, frequently remain stigmatized and
marginalized from care. In the United States, it is estimated that 1.2
million people are infected with HIV, of whom 18% do not know
their HIV status and are continuing to transmit their infection
to their sexual partners (http://www.cdc.gov/hiv/resources/
factsheets/us.htm). In recent years, a simple rapid HIV test that
can be used with oral fluids instead of blood has become available
for purchase by consumers over-the-counter. This first-of-a-kind
test offers the opportunity for testing in the privacy of one’s home.
The US FDA examined the personal and public health risks and
benefits of approving the OraQuick® In-Home HIV Test to support
its decision-making. http://www.fda.gov/AdvisoryCommittees/
CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/
BloodProductsAdvisoryCommittee/ucm298652.htm
5.3.4.2 Performance expectations

A US FDA Advisory Committee recommended that the OraQuick
test should have sensitivity and specificity that are >95%, as the
lower bound of the 95% confidence interval (CI) around the point
estimates for the over-the-counter test (vs. 98% for professional
use rapid HIV tests). Performance studies showed that, for
professional use, the sensitivity and specificity the HIV test exceeded
the recommended threshold of >98% as the lower bound of the 95%
confidence interval. Likewise, the specificity of the over-the-counter
OraQuick test exceeded the minimum recommended performance.

However, the OraQuick test sensitivity failed to reach the threshold
of the minimum recommended lower 95% CI bound of 95% as
shown follows:
Professional Over-the-
Use counter
OraQuick OraQuick
Test Test
performance Minimum performance Minimum
Performance (2-sided recommended (2-sided 95% recommended
measure 95% CI*) performance CI*) performance
Sensitivity 99.3% 98% (lower 92.98% 95% (lower
(98.4–99.7%) bound of the 2- (86.64– bound of the 2-
sided 95% CI) 96.92%) sided 95% CI)
Specificity 99. 8% 98% (lower 99.98% 95% (lower
(99.6–99.9%) bound of the 2- (99.90–100%) bound of the 2-
sided 95% CI) sided 95% CI)
*95% CI = 95% Confidence Interval.
5.3.4.3 Risk benefit analysis

The FDA performed a risk analysis to understand the public and
individual health implications of approving a test with these per-
formance characteristics. Potential outcomes evaluated included
the following:
• Estimated test results for numbers of individuals projected
to be tested annually who would not otherwise be tested,
including number of true positives and negatives and false
positives and negatives
• Estimated the net transmissions averted through the use of
this test (assuming a change in behavior following a positive
test result)
• The impact of switching from professional testing to self-
testing
• The impact of who will use the test
• Do the benefits outweigh the risks?
A risk assessment model was developed, and the projected
outcome in the first year of use was that there would be a projected
net public health benefit from use of the OraQuick® In-Home HIV
Test resulting from the net increase in the number of HIV infections
newly identified among HIV-infected individuals who were unaware
Case Studies 33
of their HIV status (approximately 4,500 individuals) and 2,700,000

who would test negative. The FDA concluded that the public
health benefit of averting 4,000 transmissions would outweigh
the individual risk of increased numbers of false negative results
(approximately 1,100).
The fact that individual risk remained prompted FDA to
address this risk through messages in the test kit labeling:
• A positive result with this test does not mean that you are
definitely infected with HIV, but rather that additional testing
should be done in a medical setting.
• A negative result with this test does not mean that you are
definitely not infected with HIV, particularly when exposure
may have been within the previous three months.
• Testing is recommended if you test negative and continue to
engage in behavior that puts you at risk for HIV infection.
• A negative result does not imply it is safe to engage in risk
behavior for HIV infection.
5.4 The Way Forward

The regulation of medical devices is critical in assuring their safety
and effectiveness. However, regulatory oversight in much of the
developing world is limited, leading to products being sold and
used without evidence of effectiveness. In countries with regulatory
authorities, the approval process often lacks transparency and
can be costly and lengthy. This is a major barrier to innovation
and access. What is needed is the development of a clearly defined
set of standards and a critical pathway for preclinical and clinical
testing of medical devices within a transparent framework that
takes into account benefit for patients while ensuring safety and
effectiveness [4]. While there are strong political and financial
incentives for national regulatory authorities to insist on their own
approval processes, there is a compelling need for harmonization
or convergence of regulatory approval standards so that companies
would not be required to conduct clinical trials in every country,
thus reducing the cost of goods and decreasing lengthy delays. As
the Global Harmonization Task Force (GHTF) transitioned to the
International Medical Devices Regulatory Federation (IMDRF),
there is hope that progress will continue to be made in harmonization
of regulatory standards for medical devices and in particular, for
IVDs. The Asian Harmonization Working Party has made good

progress with the result that countries from other regions have
joined this initiative. Regional initiatives such as the formation of the
Latin America IVD Association and the Pan-African Harmonization
Working Party illustrate the need to ensure affordable access of
medical devices in these regions. Similar harmonization efforts
are being considered to expedite the approval of badly needed
vaccines [5]. Regulatory authorities and the regional harmonization
working parties need to work with the medical devices industry,
departments of health, and standards setters to develop models for
rapid assessment and efficient approval of novel classes of medical
devices, and for the harmonization of regulatory processes in
the developing world to ensure that patient needs are met in all
resource settings.
References
1. Peeling RW, Smith PJ, Bossuyt PMM (2006) A guide for diagnostic
evaluations. Nat Rev Microbiol Suppl: S2–S6. January 10, 2012. From
http://www.nature.com/nrmicro/supplements.
2. World Health Organization. Regulation of in vitro diagnostics: a
global perspective. Annex in: Diagnostics for Tuberculosis: Global
Demand and Market Potential. Geneva: WHO 2006; pp. 194–203.
3. Gibbs JN (2011). Regulating molecular diagnostic assays: developing
a new regulatory structure for a new technology. Expert Rev Mol Diag;
11:367–381. United Kingdom.
4. Woosley RL (2007). The FDA’s Critical Path Initiative. Pharmaco
Vigilance Rev; 1:16–18. Euromed Communications Ltd, United
Kingdom.
5. Mahoney R, Chocarro L, Southern J, Francis DP, Vose J, Margolis
H (2011). Dengue vaccines regulatory pathways: A report on two
meetings with regulators of developing countries. PLoS Med; 8(2):
e1000418. doi:10.1371/journal.pmed.1000418. United Kingdom and
USA.
6. Mabey D, Sollis K, Kelly H, Benzaken A, Bitarakwate E, Changalucha
J, Chen XS, Yin YP, Garcia P, Strasser S, Chintu N, Pang T, Peeling RW.
Point-of-care tests to strengthen health systems and save newborn
lives: The case of syphilis. PLoS Med. 2012 Jun; 9(6):e1001233. Epub
2012 Jun 12. PMID: 22719229.
Chapter 6
A Story of Attention to Detail
Richard Liu
MCI Shanghai
richard.liu@mci-group.com
MCI is a globally integrated company that helps companies,

governments, and associations bring people together to create
meaningful connections and provide professional event service to
various conferences, seminars or board meetings. Beginning my
job as a team lead for Johnson & Johnson two years ago, I mainly
focused on providing professional conference/meeting services to
our customer.
Today I would like to tell you a story about a drop of water. It
might be something that you are indifferent to, or something you
may ignore even if you are aware of it. From my point of view, it is
something crucial that might determine the final success. Once I
served for Johnson & Johnson regulatory meeting in China in March
2012. When a waitress served water for the Johnson & Johnson
staff, a drop of water fell on the table. My first response would be to

www.panstanford.com
36 A Story of Attention to Detail
quickly and gently wipe it away. In my opinion, it is not something

related to hygiene only, but it is something that may cause problem;
for instance, it may spoil the customer’s important documents or it
may lead to the breakdown of the customer’s e-products. To provide
professional and best service, it is required that people always pay
attention to detail.
Do you think it is a very minor issue? You may remember an
interesting instance in the movie Mission Impossible. When Tom
Cruise hangs down to take his mission target, a disc with top secret
data, a drop of sweat trickles down. In that essential moment, Tom
stops what he was doing and makes an attempt to trap the drop of
sweat. If the drop of sweat touches the desk, it will raise an alarm
and the mission would become impossible to achieve. To me, a drop
of water is, to some extent, what a drop of sweat is to Tom in the
movie.
As explained by Johnson & Johnson, in regulatory work, we need
to pay attention to detail. The above story may explain what the right
attitude to provide service to the customer should be. Sometimes, a
tidier dossier will make product registration quicker !
Part 2
Medical Device
Safety and Related ISO Standards
Chapter 7
Biomedical Devices: Overview
Piu Wong
The Whitehead Institute for Biomedical Research, Cambridge, USA
pwong0610@gmail.com
7.1 Historic Aspect of Medical Devices

Medical devices are part of our daily life. They could range from
simple equipment such as a thermometer to a highly sophisticated
machine such as a pacemaker for a person with heart problem. They
all serve to meet the medical needs. In contrast to pharmaceutical
products, their modes of action are not pharmacological, metabolic,
or immunological. Some of the landmarks in medical device
development are illustrated in Table 7.1 [1–2].

www.panstanford.com
40 Biomedical Devices
Table 7.1 Landmarks in medical devices
Year Device Inventor

1943 Dialyzer Dutch physician, Willem Kolff
1950 Artificial hip Performed by English surgeon Sir
replacement John Charnley
1951 Artificial heart US team led by electrical engineer
valve Miles Edwards
1952 External cardiac US cardiologist Paul Zoll
pacemaker
1960 Internal US electrical engineer Wilson
pacemaker Greatbatch
1970 Computerized Nobel Prize winners Godfrey
axial tomography Hounsfield and Allen Cormack
(CT) scanner
1977 Magnetic US team led by physician Raymond
resonance Damadian
imaging
1982 Artificial heart Willem Kolff
1985 Implantable Polish cardiologist Michel Mirowski
cardioverter
defibrillator
2000–2010 Robotic medical Various inventors
devices, such as
(http://www.mritechnicianschools.
NeuroArm and
org/twelve-amazing-robots-that-are-
CyberKnife
revolutionizing-medicine/)
Between 1980 and 2000, high-resolution imaging devices,

in particular, radiographic and fluoroscopic units, became more
commonly used in hospitals and clinics. Devices designed for the
real-time monitoring of cardiovascular parameters such as heart
rate and blood pressure were part of the standard equipment.
Moreover, there was no effective treatment for some of the diseases
such as chronic kidney failure until dialysis machines were used to
greatly improve their quality of life. Computerized axial scanners
(CT) and magnetic resonance imaging (MRI) have become crucial
tools in medical imaging to supplement X-rays and ultrasound for
screening disease such as patients with a high risk of colon cancer.
It is estimated that approximately 50,000 people died because of
the human error [3]. From 2000 onward, robotics became a reality
Biomedical Market Environment 41
and began to be used in clinical procedures where extreme precision

is critical. For example, a minor error in neurosurgery will lead to
paralysis. NeuroArm combines MRI and a surgical robot to perform
microsurgery and biopsy-stereotaxy with high precision [4].
Another advantage is that remote-controlled surgery is
possible if the doctor is not next to the patient. Da Vinci Surgical
System has developed over 100 devices so that surgeons can
remotely access the machine and perform surgery such as double
vessel bypass surgery in the human heart [5].
7.2 Biomedical Market Environment

Aging population, enhanced awareness of the patients, and
improved quality of the medical system are the driving forces for
the continued demand and growth of the medical device industry
in Asia. HSBC’s “The Future of Retirement” report estimates
that the number of people aged 65 or older will reach 1.4 billion
by 2050. The United Nations also predicts that the number of
people aged 60 or older will reach 2 billion by 2050, representing
32% of the world’s population. For example, in China, 25% of
the population will be over 65 by 2050. In Japan, 35.6% of the
population will be over 65 by 2050. Standard & Poor’s (S&P)
reported that 80% of the older individuals suffer from at least one
of the chronic health conditions, such as arthritis and cataracts
[6, 7]. Therefore, there is a strong need and market to develop
technologies to better diagnose disease and improve the treatment
for the aging population.
The global medical devices industry has generated
revenues in excess of $300 billion in 2011 worldwide [8]. Despite
the fact that Asia has more than 60% of the world’s population,
the healthcare expenses constitute about 15% of the global
healthcare expenditure. This suggests that there is an enormous
upside potential in the Asian market to improve the healthcare
system possibly by better diagnosis and treatment using advanced
medical devices. For example, China’s import of US medical devices
has increased steadily, and it is the second largest market for
US medical devices after Japan, with 1.5 billion US medical devices
imported in 2008 [9].
The United States is the largest producer of medical devices

worldwide. S&P reports that US medical device manufacturers
receive 40–50% of their revenues from the foreign markets.
The largest US-based medical device companies based on S&P
Healthcare products and supplies survey, 2010, are Johnson &
Johnson, GE Healthcare, Medtronic, Boston Scientific, Abbott
Labs, Becton Dickinson, Stryker, Zimmer, and St. Jude Medical.
Companies based outside the United States, such as Siemens
(Germany), Hitachi Medical Corporation, and Toshiba (Japan),
are major players in the biomedical device industry [10]. US
firms are building manufacturing and marketing centers in
Asia to streamline manufacturing and distribution efficiencies.
High-technology medical products that address the prevalent
health issues, especially for the aging population, have a very
positive outlook in the future. Here I will illustrate the importance
of medical devices by focusing on only diagnosis and treatment of
age-related diseases such as arthritis and vision degeneration.
7.3 Orthopedics
7.3.1 Market
Approximately 1 million patients worldwide are treated annually
for total replacement of arthritic hips and knees joints. One in
forty persons requires orthopedic surgery because of the common
joint disorder, osteoarthritis. The number is increasing because
of the aging population and enhanced awareness among patients.
Stryker Corporation reported that the 2009 worldwide market for
reconstructive devices was in the order of $12 billion in size [11].
Knee reconstruction is the most common surgery, constituting 50%
of the total joint replacement market. For example, DePuy Rotating
Platform Knee mimics the human knee’s natural range of motion
(Fig. 7.1). Spinal surgery such as thoracolumbar (relating to thoracic
and lumbar region of the vertebral cord) implant generates about
$5.5 billion worldwide revenue. The United States contributes about
60% of the global orthopedic device market. Major players include
Johnson & Johnson (DePuy), Stryker, Zimmer Inc, Medtronics, and
Biomet [12].
Orthopedics 43
Figure 7.1 The DePuy Rotating Platform Knee mimics human knee’s
natural range of motion.
7.3.2 Materials
Lightweight, strength, and biocompatibility are the key
requirements for the material to be chosen for medical implants.
The most commonly used orthopedic implant materials are
stainless steels, cobalt–chromium alloys, and titanium alloys
(13). Stainless steel is often preferred for making bone plates,
screws, pins, and rods because of its resistance to chemicals
and environmental conditions found inside the human body.
Cobalt–chromium alloys are used in joint replacement and
fracture repair implants. Titanium alloys have a significantly
higher strength-to-weight ratio than stainless steels. The higher
flexibility offered by titanium alloys allows the design of shape-
memory-based implants to aid in bone in-growth for better grip.
Trabecular metal, which is made from tantalum over carbon, is also
strong, flexible, and biocompatible and is porous enough to allow
tissue in-growth. Ceramic materials are also used to make implant
surfaces that rub each other but do not require flexibility, such as
the surface of the hip joint [14].
7.3.3 Biocompatibility
The evaluation of medical device compatibility determines if the
contacts of the device with the body produce any harmful local
or systemic effect, e.g., degraded products are carcinogenic. The
ISO 10993 guidelines have been developed to cover the testing of
materials and devices that come into direct or indirect contact with
the patient’s body [15]. The very first consideration of the selection
of materials shall be fitness for purpose with regard to characteristics
of the materials such as chemical, toxicological, physical, electrical,
morphological, and mechanical properties. The extent of the test
depends on the existing pre-clinical and clinical safety data. More
stringent tests will be carried out for a novel material. Some of the
critical issues include characterizing the material for genotoxicity,
carcinogenicity, and reproductive toxicity, irritation and
skin sensitization in vitro cytotoxicity, and identification and
quantification of degradation products from polymeric medical
devices ceramics and metals. Importantly, testing should be done on
the sterile final product, or representative samples processed in the
same manner as the final products [16].
7.3.4 Fabrication
The characteristics of the metal or the biomaterial that I described
earlier can be changed depending on the methods to shape the
material into the implant, a process called fabrication. In other
words, some fabrication methods can strengthen the material,
while others can weaken them [17]. The most common fabrication
methods used for metal implants are machining, investment casting,
and hot and cold forging.
Machining of implant materials is usually performed with
computer to allow high precision and reproducibility. For example,
cobalt–chrome stem caps for hip transplant are often made using
automated machining process. Investment casting is often employed
for more complex shapes such as knee implants. Metal is melted
and poured into a ceramic mold to create the desired shape of the
implant. Forging process presses materials into shape between two
molds. This often involves heat treating for molding (hot forging),
or the metals are shaped at room temperature (cold forging) [18].
Implants made by forging are often stronger than similar parts made
by casing.
7.3.5 Polyethylene Fabrication

Turning powdery polyethylene into a solid piece of polyethylene is
called consolidation. Different ways of consolidation can influence
Orthopedics 45
the characteristics of the final implants. One of the consolidation

processes is called ram extrusion. The polyethylene powder is
heated and forced out through a tube. The combination of heat and
pressure deposits the powder into the solid bar for further
machining. Another way to fabricate polyethylene implants is
called compression molding, where the raw powder is heated
and then pressed into sheets that can be cut and shaped to create
the implant. A slight variation of this process is called net-shape
compression molding. The powder is directly deposited into the
final implant shape, instead of some intermediate product. This
method improves wear reduction of the finished material. After
fabrication, heat-treating the metal implant and then slow cooling
it reduces brittleness [19, 20]. Because of its durability and
performance, metal-on-polyethylene has been the leading artificial
hip component material chosen by surgeons since the approval
by the US Food and Drug Administration (FDA) 30 years ago. The
metal ball is cobalt chrome molybdenum alloy and the liner is
polyethylene. This ability to adapt and customize during the surgical
procedure is an important attribute of polyethylene (Fig. 7.2).
Figure 7.2 This artificial hip is composed of cobalt chromemolybdenum

alloy made metal ball and polyethylene liner. Polyethylene
liner provide flexibility during surgical procedure. (http://
bonesmart.org/hip/hip-replacement-implant-materials/).
7.4 Vision Care

7.4.1 Market
Age-related vision disorders such as cataract, muscular
degeneration, and glaucoma have boosted the growth of eye-care
industry in the area of cosmetic surgery such as the implantation
of refractive lens. BCC Research reported that the global market for
ophthalmic devices, diagnostics, and surgical equipment was valued
at $15.2 billion in 2009, excluding consumer eye-care products
[21]. The market is estimated to reach $19 billion by 2014. Major
manufacturers include Advanced Medical Optics, Bausch & Lomb,
Canon, Nidek, Topcon, and Zeiss Meditec.
7.4.2 Diagnostic Devices

Diagnostic instruments are the key tools to identify diseases by
high-resolution inspection of the cornea and the macula. One of
the most commonly used equipment among ophthalmologist is slit
lamp (Fig. 7.3). The most important field of application is the
examination of the anterior segment of the eye, including the crystalline
lens and the anterior vitreous body. The illumination system produces
a slit image that is as bright as possible, at a pre-defined distance from
Figure 7.3 Digital slit imaging used for the detection of cataracts,
corneal injury, and other eye diseases (http://www.in.all.biz/
g182258/).
Vision Care 47
the instrument. The slit imaging system is used for detecting

cataracts, corneal injury, muscular degeneration, and retinal
detachment. Another commonly used procedure is tonometry,
which is used to determine the intraocular pressure, the fluid
pressure inside the eye. It is a critical test to evaluate the risk of
glaucoma [22].
7.4.3 Treatment
Cataracts lead to blurred and cloudy vision. Cataracts grow very
slowly and become denser over time. More than 90% people have
a cataract and half of them will lose part of the vision by age 75
[23]. Cataract surgery is the most effective treatment. Further
advancement of technology in intraocular lens implants such as
multifocal refractive lens has significantly improved the vision of
the cataracts patients [24], e.g., the implant of artificial lens such as
ReZoom IOL, marketed by Abbott restore vision (Fig. 7.4), after the
removal of patients’ clouded native lens.
Figure 7.4 ReZoom is a multifocal refractive intraocular lens that scatters

light over five optical zones, as indicated, to provide near,
intermediate, and far vision.
7.5 Diabetics
Glucose monitoring is essential for diabetes management.
LifeScan, J&J company One Touch Ultralink blood glucose monitoring
system allows accurate estimation of blood glucose [25]. In
combination of an insulin pump, proper dosing can be administered
in response to blood glucose level before or after meals. To
streamline these processes, an artificial pancreas system helps
reduce the severity of a drop in glucose levels by automatically
adjusting insulin flow. The system combines a continuous glucose
monitor, an insulin infusion pump, and a glucose meter [26].
7.6 Obesity
Obesity is a major global problem affecting billions of people.
Unfortunately, there is no single FDA-approved pill that can
effectively stop this pandemic. In addition to the traditional
obesity surgery to reduce the size of the stomach, there are a few
less invasive devices that slow down digestion, making people feel
fuller longer. EndoBarrier, is a flexible tube inserted into the small
intestine, forming a barrier between food and intestinal walls. It
has been approved in Europe and Australia and clinical trials are
being run in the United States [27]. SatisSphere is a device that can
be placed in the small intestine, mimicking the shape of duodenum.
Therefore, the food journey is delayed and possibly gives the body
wrong perception that plenty of food has been taken [28].
7.7 Vascular Disease

One of the major vascular diseases, abdominal aortic aneurysms
(AAA) is a localized swelling (ballooning) of the abdominal aorta,
caused by the weakness of the aortic wall. Untreated condition is
likely to cause rupture and associated death in one-third of patients.
Although there are about 27 million people worldwide suffering
from AAA, only 20% are detected [29]. Ultrasound screening for
AAA can be adopted to improve the accuracy of the detection.
Endovascular aneurysm repair (EVAR) is a minimally invasive
procedure that is also used in the treatment of AAA. In an EVAR, a
manufactured device known as a stent-graft is deployed under x-ray
Concluding Remarks 49
guidance inside the aneurysm to exclude it from the circulation (30).

The principle is illustrated in Fig. 7.5.
Figure 7.5 Reconstruction of a stent graft in AAA. (A) A catheter is inserted

into the weakened artery. The stent graft is then released.
(B) The stent supports the artery walls and divert the blood
to pass through the aneurysm, therefore preventing it from
rupture (http://www.hearthealthywomen.org/treatment-and
-recovery/pvd-treatment-and-recovery/aortic-aneurysm-
repair/page-3.html).
7.8 Concluding Remarks

Biomedical devices are diverse and rapidly evolving. This brief
introduction aims to highlight representative examples, and we
hope the readers will gain an appreciation of medical devices in
everyday life. Recent trends have indicated that various health care-
related disciplines such as biological sciences, nanotechnology,
cognitive sciences, information technology, and material sciences
converge into the development of medical devices. This will
ultimately improve the quality of medical devices.
References
1. Health Technologies Timeline. Retrieved October 10, 2011, from

http://www.greatachievements.org/?id=3824.
2. Reiser SJ. (1978). Medicine and the Reign of Technology, Cambridge
University Press, New York.
3. Kohn LT, Corrigan JM, Donaldson MS (1999). To Err Is Human: Building
a Safer Health System, National Academy Press, Washington, D.C.
4. Neuroarm. Retrieved October 11, 2011, from: http://www.neuroarm.
org/.
5. The da Vinci® Surgical System. Retrieved October 11, 2011, from
http://www.davincisurgery.com/davinci-surgery/davinci-surgical-
system/.
6. World Health Statistics 2009. (2009). Geneva, World Health
Organization. Retrieved October 20, 2011, from www.who.int/enti-
ty/.../world_health_statistics/EN_WHS09_Full.pdf.
7. Department of Economic and Social Affairs, Population Division
(2002). World Population Ageing, 1950–2050. United Nations, New
York.
8. Medical Device Revenue to Top $300 Billion This Year: Kalorama.
Retrieved February 25, 2012, from http://www.kaloramainformation.
com/about/release.asp?id=1826.
9. U.S. Department of Commerce and the U.S. International Trade
Commission (2009). Medical Devices Industry Assessment. US Trade
Department, USA.
10. Industry Surveys Healthcare Product and Supplies. Retrieved
October 19, 2011, from http://issuu.com/alanahealthcare/docs/s-p-
healthcare-product-and-supplie_20110819_142411.
11. Handout on Health: Osteoarthritis. Retrieved October 30, 2011, from
http://www.niams.nih.gov/health_info/osteoarthritis/default.asp.
12. Tanna S (2004). Osteoarthritis — Opportunities to Address
Pharmaceutical Gaps. Geneva, World Health Organization, Switerland.
13. Breme HJ, Helsen JA (1998). Metals as Biomaterials, Chichester, John
Wiley & Sons, United Kingdom.
14. Alireza N, Peter DH, Cui’e W (2007). Biomimetic Porous Titanium
Scaffolds for Orthopedic and Dental Applications, Institute for
Technology Research and Innovation, Deakin University, Australia.
References 51
15. Practical Guide to ISO 10993. Retrieved October 30, 2011, from www.
distrupol.com/images/ISO_10993.pdf.
16. Use of International Standard ISO-10993, “Biological Evaluation of
Medical Devices Part 1: Evaluation and Testing” Retrieved October 28,
2011, from http://www.fda.gov/MedicalDevices/DeviceRegulation
andGuidance/GuidanceDocuments/ucm080735.htm.
17. Nakajima H (2007). Fabrication, properties and application of porous
metals with directional pores. Progress in Materials Science, 52,
1091–1173.
18. Ryan G, Pandit A, Apatsidis DP (2006). Fabrication methods of
porous metals for use in orthopaedic applications. Biomaterials, 27,
2651–2670.
19. Avitzur B (1987). Metal forming, Encyclopedia of Physical Science &
Technology, 8, 80–109.
20. Drozda T; Wick C, Bakerjian, Ramon V, Raymond F, Petro L (1984). Tool
and Manufacturing Engineers Handbook: Forming, SME.
21. Global Markets for Ophthalmic Devices, Diagnostics and Surgical
Equipment. Retrieved October 30, 2011, from http://www.bccresearch.
com/report/ophthalmic-devices-markets-hlc083a.html.
22. Amm M, Hedderich J (2005). Transpalpebral tonometry with a
digital tonometer in healthy eyes and after penetrating keratoplasty.
Ophthalmologe, 102(1), 70–76.
23. Cataract. Retrieved October 27, 2011, from: http://www.who.int/
topics/cataract/en/.
24. ReZoom multifocal lens. Retrieved 25 October 2011 from http://www.
rezoomiol.com/rezoom_multifocal_lens.html.
25. One touch. Retrieved October 25, 2011, from http://www.onetouch.
com/our_products.
26. Artificial pancreas system. Retrieved October 25, 2011, from http://
www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/
HomeHealthandConsumer/ConsumerProducts/ArtificialPancreas/
default.htm.
27. Endobarrier. Retrieved October 24, 2011, from: http://www.
endobarrier.com/.
28. Columbus may be the home to the next big craze in weight loss.
Retrieved October 22, 2011, from http://www.examiner.com/extreme-
weight-loss-in-columbus/columbus-may-be-the-home-to-the-next-
big-craze-weight-loss.
29. First patients enrolled in Cordis Trial of New Stent Graft System to
Treat Abdominal Aortic Aneurysm. Retrieved October 23, 2011, from
http://www.investor.jnj.com/textonly/releasedetail.cfm?ReleaseID
=457755.
30. Greenhalgh RM, Powell JT (2008). Endovascular repair of abdominal
aortic aneurysm. N. Engl. J. Med., 358(5): 494–501.
Chapter 8
Labeling, Label, and Language: A Truly

Global Matter
Evangeline D. Loh and Jaap L. Laufer

Emergo Group
evangeline@emergogroup.com, Jaap.Laufer@dekra.com
8.1 Introduction
For most medical devices, the label on the product is the primary
interface between the user and the product. As an integral part of the
product proper, it provides a visual way to verify that the product in
the packaging is what the user intends to use and ensures the
packaging is used as intended (e.g., for a sterile, double packed
product). But labeling is a lot more — it encompasses the whole
interface between the user and the manufacturer. Labeling tells
the reader what the product may be used for and when not, what
benefits and risks it is expected to have, and which precautions the
user should take or consider when used as intended. Some legal
labeling definitions include any and all promotional utterances, while
others restrict its remit to the printed materials that accompany the

www.panstanford.com
54 Labeling, Label, and Language
product. Labeling also establishes the use intended by the

manufacturer and depending on the classification of the product,
may have been reviewed in the regulatory submission.
But all labeling must be based on the risk management
performed by the manufacturer during design and development, no
exceptions. This pivotal document dictates not only in essence the
labeling content but also the fundamentals upon which the clinical
evaluation of the product should be based. So, as the product is on
the market, the experience gained in the “post-market” phase will
dictate through its feedback on the risk management an evolution of
the labeling content commensurate with the stage in the life cycle of
the device.
Labeling and languages are often mentioned in one breath.
However, languages required by the respective countries or
economies are just a subsection of the need to adapt the language
of the instruction for use to the intended user or users. Complicated
use of even absence of the native language of a user may defy the
purpose of communicating the essential elements of the information
required to use the device safely and for its intended use. So,
labeling language should be interpreted in those two distinct ways.
It constitutes a critical aspect of Human Factors in Design and other
core considerations when creating a new product or adapting an
existing one.
An aspect not always appreciated is that “world” languages such
as English, French, Spanish, and increasingly, Mandarin Chinese,
have an (often unintended) impact beyond the national borders
of the jurisdiction for which they were intended. This may lead
to conflicting versions of label content in different countries and,
thus, cause confusion among the readers. This calls for a global
harmonization of labeling content — a lofty but often elusive goal.
Note that label content is distinguished from the indications for
use, which is also conveyed by the labeling. There can often be
different indications for use based on what the manufacturer was
able to substantiate in their regulatory submission in a particular
market. (Or stated another way, what the regulatory authorities in a
particular market were comfortable to accept as indications for use
based on the clinical data.)
Finally, the revolution in information has impacted the
requirements put forward by notably hospitals and other
electronically advanced users. While we included the information
Definition of Labeling 55
available at this time, this is most certainly the aspect that will need
to be updated in the next five years.
8.2 Definition of Labeling

Labeling means different things in different countries. The
European Medical Devices Directive 93/42/EEC as amended by
Directive 2007/47/EC (the MDD) does not define labeling per se
or its constituent components. Apart from the ubiquitously present
stipulations in the MDD when and where the CE-marking must be
affixed, par. 13 of Annex I (Essential Requirements) spells out in great
detail which information must be supplied by the manufacturer. The
elements of labeling mentioned there are limited to the information
accompanying the device (i.e., package insert or instruction for
use, which includes a manual for large or complex devices) and the
label(s) proper for individual units either on the product itself or on
the unit packaging, on the “sales packaging.” Terms such as “shipping
carton,” labeling for double packaging, and other commonly used
designations have not been codified in the law.
One of the key elements of labeling in the near future will be
the use of a UDI, a unique device identifier. While the idea itself
makes eminent sense, it must be feared that in absence of a well-
defined electronic structure allowing for the proper handling and
management of the huge quantity of data influx, the objective of the
electronic tracing of individual products from the manufacturer to
the user will stay an illusion for many years to come. To this end,
the Global Harmonization Task Force (GHTF) has issued guidance on
UDI [1] (UDI System, September 16, 2011) which implores countries
to consider the GHTF guidance in promulgating regulations on UDI.
It would appear the USA FDA will be the first in line to publish a
draft rule (expected in the fall of 2011) [2]. The FDA has published
this draft UDI as a proposed rule (Federal Register, Vol. 77, No. 132,
10 July 2012). http://www.gpo.gov/fdsys/pkg/FR-2012-07-10/
html/2012-16621.htm; however, the EU, with their revision of the
medical devices directives, will similarly seem to require UDI [3].
The draft Medical Device Regulation introduces the use of UDI.
http://www.gpo.gov/fdsys/pkg/FR-2012-07-10/html/2012-
16621.htm.
As the concept of “labeling” in Europe means different things in
the respective EU Member States, vastly different regulatory regimens
exist. France, Germany, the United Kingdom, and even Italy and Spain
show an increasingly strong enforcement of their respective laws
concerning promotion, including the Internet. The enforcement
of a harmonized label content (especially concerning intended
uses, indications, and claims as well as contra-indications) is just
beginning, enhanced by the COEN (Committee of Enforcement), and
lately by the CMC (Central Management Committee), two Member
State-only committees that promotes a coordinated approach
toward interpretation and implementation of laws and regulations
for devices.
Based on Title 21, Section 820.1 of the Code of Federal Regulations
(CFR), the United States has had a long and historically driven
tradition of strong and sometimes even heavy-handed enforcement
of labeling compliance. Labeling in the United States means any
written or verbal expression of information accompanying or
concerning the device and controlled in any way by the manu-
facturer, including but not limited to labels in the strict sense,
promotional materials, any verbal statement by company
representatives, the Internet, and even information about products
not yet approved but shown to the public at trade fairs. The FDA
is strictly monitoring the compliance of labeling content with the
claims approved. Any proof that a manufacturer is intentionally or
commercially exploiting the often gray area of “off-label” use can
lead to draconian fines and/or criminal prosecution.
In Korea, a medical device label is one attached onto the outer
most packaging though there does not appear to be an official
reference to the definition of labeling. In China, SFDA Order No.
10 regulates the labeling (Instructions, Labels, and Packaging of
Medical Devices). There are 23 Articles in the Order. Countries such
as Singapore and Hong Kong, which use more GHTF (or AHWP)-like
regulatory systems, have similarly defined labeling as in the EU.
8.3 Elements of Labeling

Labeling may consist of
• The label proper (see above) increasingly including the UDI
code.
• A manual, instruction for use, package insert, etc., intended
for the intended user(s).
Elements of Labeling 57
• Where applicable or demanded by laws or regulations,

promotional materials where they relate to the “approved”
claims or intended uses. For instance, where an insulin pump
must not be used when the user is swimming, the manu-
facturer or distributor cannot show a lady on the beach wearing
that pump. (Historic example! The case was whistle-blown
by a competitor and the manufacturer cancelled the ad.)
• Materials placed by a manufacturer or a distributor of
the product on the Internet or spread by e-mail, social
media, involuntary pop-ups, etc. This is such a growing and
complicated subject that we will treat it separately further in
this chapter. Suffice it to say here that electronic utterances
that are in perfect compliance with the laws in one country
may be offensive in another, even when the national language
of the latter country is not used. A historic example springs to
mind: When a representative of a UK-based company showed
a training video to illustrate the use of a new invasive surgical
device (hardly glamorous) to physicians, he was arrested in
Libya for “pornography.” The video had used a female patient.
A good source for labeling content guidance is the GHTF
document “SG1-N70:2011 Label and Instructions for Use for Medical
Devices,” issued on September 22, 2011. It is a bit general but gives
a solid basis for which aspects of labeling should absolutely be
considered before placing a device on the market. Also, while there
are country differences and deviations, there is generally a core
set of elements in labeling, which is captured in the GHTF guidance.
In many countries in Asia, South America, and even North
America (Mexico specifically), there is a requirement that the
medical device registration number be included on the labeling.
In Korea, labeling is generally a sticker that is attached onto
every product intended for the Korean market, which must
include the information about the following: KFDA registered
model number, manufacturer information, Korean license holder
information, KFDA registration number, manufacturing date/lot
number, etc. In China in particular, the SFDA Order No. 10, Article
8, stipulates the number of the Import Medical Device Registration
Certificate (IMDRC) number as well as the reference to the relevant
technical standards.
The Australian system leverages the EU system, and generally

labeling developed for the EU can be used in Australia with the
addition of the Australian Sponsor. In New Zealand, the Medicines
Regulations 1984, Regulation 12(4) [4], establishes the requirements
for the labeling of medical devices. The regulation states, “No person
shall sell any medical device that does not bear the name of the
manufacturer of the medical device or the name of the manufacturer’s
distributor in New Zealand.”
In Hong Kong, the Medical Device Administrative Control System
(MDACS) is modeled on the recommendations of the GHTF, and, thus,
compliance should not be particularly burdensome for products that
have already met the criteria in the EU. The labeling requirements
are delineated in Appendix 3, Additional Medical Device Labelling
Requirements of the guidance, GN-01. Again, the device’s Listing
Number (“HKMD No. ####”) needs to be on the label. There is
guidance on labeling in the form of the Singapore Health Sciences
Authority (HSA) GN-23 Guidance on Labelling for Medical Devices,
August 2009; and, again, the medical device regulatory system in
Singapore is largely based on the GHTF guidance documents.
The applicable Brazilian labeling requirements are described
in Resolution RDC No. 185, Annex III.B, information on the
labeling and IFU for medical devices. The name and address of
the Brazilian importer should be included if appropriate (2.1), but
more specifically, the Brazilian Registration Holder, technical expert
certified by ANVISA, technical expert’s name must be delineated on
the label (2.11). Also, once ANVISA has accepted the application, the
ANVISA registration number must be included on the product label
preceded by “ANVISA” (2.12). For the most part, Resolution RDC
No. 185, Annex III.B, resembles the MDD, Annex I, ER, Section 13.
Information supplied by the manufacturer.
In Chile, at the writing of this section, only a limited number of
products are subject to mandatory control by the ISP: examination
gloves, surgical gloves, condoms, and sterile hypodermic needles
and syringes for single use. The regulatory framework for medical
devices is based on Law 19,497 and Products Control Regulations
and Medical Use Elements (DS No. 825/98), and Article 26 discusses
the labels. Again, as observed in many countries, the Chilean device
Risk Management, Clinical Evaluation and Labeling 59
registration number issued by the ISP must be included as well as all

the standard elements.
8.4 Risk Management, Clinical Evaluation and

Labeling: The Core Triangle for Safe and
Effective Use of the Device
Few risk analyses are concluded without specific inclusion of risk
mitigating statements in the labeling, mostly in the instructions for
use. These statements are commonly divided into contra-indications,
warnings when used as intended, precautions to be taken before or
after device use, and which side effects may be expected, as well as
other considerations. Most countries do not define under which
header a particular statement must be placed; however, this aspect
is usually emphasized by a regulatory authority whenever a risk
mitigating statement is insufficiently complied with by the user,
sometimes replete with the instruction to print bold or similar.
Clinical evaluation and investigation are the tool to validate
critical labeling content, e.g., under what conditions the device
should be used, what performance specifications may be expected,
what precautions need to be taken, etc. Very important, the specific
nature, relevance and incidence of adverse events or incidents must
be critically evaluated, as it directly relates to the expectations
expressed in the initial risk assessment. The final conclusion about
the risk/benefit ratio is frequently determined by the capability to
address the residual risks adequately by explicitly stated warnings
in the instruction for use or the manual. Any risk that turns out to
have been underestimated in any way will have to be reassessed,
especially whether it can be mitigated by improved design and/or
labeling content, or poses an insurmountable block to further use.
So, even though the labeling content is drafted in the course of
the design development, the adequacy of the instruction for use
can only be verified when it is applied in practice, i.e., in a clinical
investigation or in the post-market phase. (Note also, the regulatory
authority review of the regulatory submission can lead to changes
in the labeling content as well.) Consequently, the post-market
surveillance (PMS) is the single most important feedback phase in the

life cycle of a label. This is where refinements of the actual handling,
expanded indications (if they do not require further corroboration),
more detailed warnings, precautions, etc., as well as government-
dictated insertions occur. For instance, in a case not too long ago, the
United Kingdom demanded that for a relatively low-risk device, a
cautionary statement be included about the lack of data for pediatric
use, and consequently, the restricted use in patients under 16. In
another case, the French agency determined that the package insert
of mammary implants must display a warning that such products
may interfere with the effectiveness of classic mammography.
This leads to one more consideration: In this global age, any
intervention at the government level of one country will lead to
inquiries by other regulatory authorities, especially if the initial
intervention originated in one of the GHTF founding countries, but
increasingly also in emerging economies. This puts a big stake in the
proper formulation of label content.
In conclusion, any significant deviations between the risk
assessment, the results of clinical evaluation, and the labeling will
likely lead to problems for the manufacturer. Both competitors and
regulatory authorities are watching this matter closely!
8.5 Labeling and Promotion

A general rule is that promotion must be consistent with labeling.
A medical device cannot be promoted beyond the comments
delineated in the labeling for which the manufacturer obtained the
regulatory approval, clearance, or registration. It is not common for
manufacturers of medical devices to be marketing professional-use
medical devices to consumers.
Widely different regulatory regimens exist for promotional
materials for devices. For example, in the EU, promotion and
advertising are not explicitly discussed in the MDD, nor in the
proposed Draft Revision of the Directives.
Promotion directed to patients or lay users may also be regulated
differently [5]. This is specifically the case in Australia, where a
code exists: the Therapeutic Goods Advertising Code 2007 [6].
Advertisements related to medical devices directed to consumers
must comply with this code.
e-Labelling, Web Sites, Internet, and Social Media 61
Many lesser developed economies do not have specific

regulations for promotional materials, or they may be regulated by
pharmaceutical laws.
8.6 e-Labelling, Web Sites, Internet, and Social

Media: A Brave New World for Labeling
While the term e-labeling has been widely accepted to mean electr-
onic labeling, the official reference to the source was not readily
apparent, of course, an adoption from the moniker electronic mail,
“email.” For the purposes of this discussion, electronic should mean
non-paper though this is a moniker that each regulatory environment
will need to define.
At the time of this writing, Europe appeared to have made the
greatest accomplishment with e-labeling. A European guidance,
MEDDEV, was published in 2007 on e-labeling of IVDs [7]. The
guidance established the use of the other-than-paper format IFUs
(different media) by different means of supply for certain categories
of in vitro diagnostic devices. There were, of course, very stringent
provisions that needed to have been addressed in order to supply
IFUs by different media and through different means of supply, not
withstanding a toll-free telephone number. A toll-free number within
the 27 EU member states as well as Norway, Iceland, Lichtenstein,
and Switzerland is quite a feat! In the summer of 2011, the European
Commission issued draft regulations on electronic labeling (e-
labeling) and shared these publically as part of their WTO Technical
Barriers Trade activities [8]. At that time, the publication date was
December 14, 2011. While this date has passed, this legislation is
expected in Q1 2012. There is now published an EU Commission
Regulation (Regulation (EU) No 207/2012) on electronic instructions
for use of medical devices. http://eur-lex.europa.eu/LexUriServ/
LexUriServ.do?uri=OJ:L:2012:072:0028:0031:EN:PDF.
While recitals are in essence background comment without legal
merit, Recital (3), of the draft indicates: “In order to reduce potential
risks as far as possible, the appropriateness of the provision of
instructions for use in electronic form should be subject to a specific
risk assessment by the manufacturer.” Ultimately, provided the
medical device meets the provisions of the legislation, this still needs
to be considered. This, of course, is similar to the recommendation

for labeling, provided the device in the EU is a category that qualifies
for e-labeling; ultimately, the decision is risk management related.
“The draft Regulation sets out conditions according to which
instructions for use in paper form may be replaced by electronic
instructions for use. It limits the possibility of providing instructions
for use in electronic form to defined medical devices and accessories
intended to be used in specific conditions. Furthermore, it contains a
range of procedural safeguards. Thus instructions for use have to be
provided in paper form on request, and a specific risk assessment by
the manufacturer and information on how to access to the instructions
for use is needed.”
The draft Regulation also sets up a few basic safety requirements
for the following:
• instructions for use in electronic form which are provided in
addition to complete instructions for use in paper form
• Web sites containing such instructions for use
Article 1 of the draft legislation states the premise that
information supplied by the manufacturer may be in “electronic
form instead of in paper form.” Article 2(2) describes electronic
IFUs: electronic form by the device, electronic storage medical
with the device, and on a Web site. Only manufacturers of explicit
categories of medical devices can consider e-labeling (Article 3(1)):
fixed installation, implanted medical devices, devices built-in system
visually displaying the IFUs, software, and professional use.
As it stands, many of the AHWP members do not accept
e-labeling. In Korea, the package insert including intended use,
instructions for use, etc., can be provided in an electronic format
such as a CD ROM [9]. In China, e-labeling is not permitted, per se,
but can certainly be provided in addition to the paper version.
At this time, one can comfortably assert that there is nothing to
preclude provision of hard copy labeling with e-labeling. Whether
e-labeling alone is accepted is an entirely different matter and will
likely be increasingly permitted over time.
Early 2012, social media have yet to make a visible impact on
the sale or promotion of medical devices. It is to be expected that
we will see an increased use of sale channels especially for “OTC”
devices. This is addressed cursorily in the proposed European Draft
Regulation to become enforceable later in this decade.
Language, Language Level and Intended User 63
8.7 Language, Language Level and

Intended User
One of the more critical aspects of the labeling content is the
language. The famous non-verbal IKEA® “manuals” and labels do
not use any language predicated on the assumption that every
individual will recognize certain pictures and symbols. The same is
true for the universally recognized symbol for “exit.” So, the problem
posed by the limited space (as well the high cost) on most devices
relative to the need for translation in national languages has been
partially resolved by the use of symbols. Insofar these have been
included in the “Harmonized Standard” European standard EN
980, there is a “presumption of compliance” with the respective
subsections of the ER 13 of Annex I of the MDD. Any other symbols,
including but not limited to those in ISO 15223, must be explained
in the instruction for use in all applicable languages. That said,
EN 980:2008 at the time of publication of this text will have been
withdrawn, and the EN harmonized standard EN ISO 15223-
1:2012.
In the United States, the use of symbols is much less appreciated.
There, as well as in many other mainly Anglosaxon jurisdictions,
culture dictates a graphic description of details in the instruction for
use, which in the United States is also driven by the fear of liability
for anything not explicitly expressed in the labeling. Health Canada
does not explicitly state that symbols are accepted and Health Canada
does not recognize EN 980 or ISO 15223 though Health Canada
appears to accept symbols. While this attitude is most outspoken
in the Anglosaxon cultures, it tends to become also increasingly
prominent in other ones. The ultimate result is an instruction for
use or manual that is for most intended readers, at best difficult to
access or comprehend.
Brazilian RDC No. 185, Annex III.B, Section 1.4, permits the
use of symbols; however, symbols must comply with regulations
and technical standards. If there are no regulations or technical
standards applicable, symbols used must be described in the IFU.
The standards that are published by Associação Brasileira de Normas
Técnicas (ABNT) include ABNT NBR ISO 15223-1:2010 titled
Productos para a saúde — Símbolos a serem utilizados em rótulos,
rotulagem e informações a serem fornecidas de produtos para saúde.
This dilemma between readability and completeness has been

partially resolved by demanding that manufacturers develop and
enclose instruction for use that represents a language comprehension
of a 12-year-old individual, taking into account that the language used
is native. The use of a language other than the native language(s)
is in most countries of the world restricted to higher professional
users or specialists. For instance, an insulin pump might be used
by an array of users from a highly educated physician diabetologist
to a semi-literate elderly person. An implantable left ventricular
assist device (LVAD) may have up to four different manuals for the
respective users of the device and its accessories.
The EU requires that the knowledge and experience of the user
be considered (MDD Annex I, Section 1). In the United States, there
has been greater emphasis on human use factors [10]. One should
not dismiss the standard of IEC 62366:2007, Medical Devices —
Application of Usability Engineering to Medical Devices. Human
use factors have implications on the labeling, which should also be
considered.
Then there is the language proper. Especially in multi-country
or -language areas (most of the world, actually….), it is very difficult
for a manufacturer to develop an instruction for use with sufficient
coverage of languages to satisfy the users’ needs. Oddly enough,
it is here that e-labeling (see elsewhere in this article) accessible by
smartphones could provide a very legitimate solution. This appears
to be a very cost-effective, environmentally friendly, and practical
solution for many sparsely populated or developing regions of the
world, with the only limitation being expressed by the saying “you
can lead the horse to the well, but you cannot make it drink”: The
user — even an educated one — should at least a few times, read
the instructions for use and not discard them unread when opening
the package.
8.8 Conclusion
Labels and labeling are among the most important parts of a medical
device. While cultures, educational levels, reading proficiency,
and familiarity with a product do vary, manufacturers must pay
utmost attention to the formulation of content for the respective
References 65
components of labeling to ensure the safe use of the device when

used as intended. The use of language commensurate with the
various intended users is critical, as is the effort by the manufacturer
to keep the labeling contents current to the knowledge gained by
the use of the product in practice.
References
1. GHTF Guidance on UDI. Retrieved December 2011 from http://www.

ghtf.org/documents/ahwg/AHWG-UDI-N2R3.pdf.
2. US FDA Draft Rule on UDI. Retrieved December 2011 from http://
www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/
UniqueDeviceIdentification/default.htm. http://www.gpo.gov/fdsys/
pkg/FR-2012-07-10/html/2012-16621.htm.
3. EU UDI. Retrieved December 2011 from http://ec.europa.eu/health/
medical-devices/specific-areas-development/udi/index_en.htm.
4. New Zealand Regulations. Retrieved December 2011 from http://
www.legislation.govt.nz/regulation/public/1984/0143/latest/DLM
96155.html.
5. TGA Online. Retrieved December 2011 from http://www.tga.gov.au/
industry/legislation-tgac.htm.
6. Australia Regulation. Retrieved December 2011 from http://www.
comlaw.gov.au/Details/F2007L00576.
7. E-labelling of IVD. Retrieved December 2011 from http://ec.europa.
eu/health/medical-devices/files/meddev/2_14_3_rev1_ifu_final_
en.pdf.
8. EU Draft regulation on e-labelling. Retrieved December 2011 from
http://ec.europa.eu/enterprise/tbt/index.cfm?fuseaction=Search.
viewDetail&Country_ID=EEC&num=381&dspLang=en&nextpage=1&
basdatedeb=&basdatefin=&baspays=&baspays2=&basnotifnum=&b
asnotifnum2=&bastypepays=ANY&baskeywords=electronic%20inst
ructions&fromform=viewKeyword”.
9. Korean Ministry of Health and Welfare (2011) Korea Medical Device
Act No. 0564, Amended as of April 7, 2011 effective from October 08,
2011.
10. US FDA. Retrieved December 2011 from http://www.fda.gov/
downloads/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/UCM095300.pdf.
11. Council of the European Parliament (July 12, 1993), Council Directive
of 14 June 1993 concerning Medical Devices (MDD 93/42/EEC), as
amended by Directive 2007/47/EC of the European Parliament and
of the Council of 5 September 2007, Official Journal of the European
Communities (OJ) L169, p1.
12. CEN/CENELEC EUROPEAN STANDARD (May 2008), Symbols for use in
the labelling of medical devices, EN 980, ICS 01.080.20; 11.120.01.
13. CEN/CENELEC EUROPEAN STANDARD (October 2008), Information
supplied by the manufacturer of medical devices, EN 1041.
14. Code of Federal Regulations, Title 21, Volume 8 (Revised as of
April 1, 2011), Title 21-Food and Drugs, Chapter I-Food And Drug
Administration, Department of Health and Human Services, Subchapter
H — Medical Devices, Part 820 — Quality System Regulation, CITE:
21CFR820.1.
Chapter 9
Clinical Trials: Legal and Ethical

Considerations of Increasing
Globalization
Paula Celine Trepman

Massachusetts Institute of Technology,
4316 Forest Avenue SE, Mercer Island, WA 98040, USA
ptrepman@mit.edu
9.1 Introduction
Clinical trials constitute a critical aspect of regulatory affairs in the
biomedical device industry. Class III devices, which are defined as
highly regulated, high-risk instruments that may pose significant
risk or injury, must go through pre-marketing approval.1 These
include central life-saving devices such as pacemakers, joint
implants, and cardiac catheters. Before a device becomes approved
by health authorities and merchandisable for use in humans, it
must be proven to be harmless to patients and be able to deliver its
expected benefits.2 Clinical trials are the primary means of obtaining
this assurance. Within the growing biomedical device industry in

www.panstanford.com
68 Clinical Trials
Asia, running proper clinical trials will guarantee the safety and
efficacy of newly developed medical devices.
9.2 The Increasing Trend of Offshore Clinical

Trials
Offshore clinical trials are becoming increasingly more common
in testing biomedical devices. Outsourcing can reduce costs by
10–30%, due to less expensive recruitment and labor costs, site
fees, and compensatory payments; they can also be completed up to
seven months sooner in low-cost countries compared with the
United States and Western Europe.3 In 2011, total clinical trials
registered on Clinicaltrials.gov,4 a service of the National Institutes
of Health in the United States, were distributed as shown in
Fig. 9.1.
Table 9.1 Total clinical trials in 2011 arranged by region and quantity
performed
Region Number of trials

North America 63,591
Europe 30,509
East Asia 9183
Middle East 4637
South America 3834
Pacifica 3320
Africa 2549
Southeast Asia 2222
North Asia 2084
South Asia 2034
Central America 1641
Note: As of 2008, 40% of trials conducted by US-owned companies were performed
outside of the United States. By the end of 2011, this figure is expected to rise to
65% among these FDA-approved studies.5 The general trend is toward an increase
in offshore trials as a means of bringing devices to the market more quickly and
inexpensively.
International Standards to Protect Patients 69
Figure 9.1 Geographic distribution of clinical trials registered by the

United States National Institutes of Health.
9.3 International Standards to Protect Patients

The Guidelines for Good Clinical Practice determined by the
International Conference on Harmonization of Technical
Requirements for Patient Use (ICH-GCP) contain specific
recommendations to protect the rights, safety, and well-being of
trial subjects in clinical trials globally.6 The ICH-GCP also serves
to minimize human exposure to untested devices, increase the
quality of scientific data, speed up marketing of new devices,
and aid in lowering costs to both producers and consumers.
Following inspection, devices are approved for sale on the market.
To ensure safety of devices and study design, all clinical trial
protocols should be approved prior to the start of the study.7
In addition, regulatory institutions play a key role in the
integrity of clinical trials.8 Health authorities are responsible for
verifying compliance to ICH-GCP and approved protocols, accuracy
of record-keeping, and proper informed consent of patients.
Infrastructure at the testing site is also closely examined. Prior to
inspection, health authorities may require documentation, such as
curriculum vitae of trial investigators and monitoring reports. With
a month of inspection, a Corrective and Preventative Action Plan
(CAPA) is issued, with classification of No Action Indicated (NAI),
70 Clinical Trials
Voluntary Action Indicated (VAI), and Official Action Indicated

(OAI). In the case of OAI classification, remedial measures may be
required within the following month. Currently, the number of
warning letters issued has increased, from 3 in 2005 to 23 in 2009;
rejection of CAPA plans by the FDA has also increased.8 These
realities emphasize the importance of following ICH-GCP guidelines
in trial design.
9.4 Breaches of Clinical Trial Legality

Failure to follow standard ICH-GCP protocols can result in
infringement of patient rights and sometimes illness or death. Legal
action may be raised against the device companies. For example, in
the United States court case Friter v. Iolab Corp., the hospital had
contracted with the FDA to test intra-ocular lenses.7 The FDA had
required the hospital to receive signed patient consent forms since
the devices had not yet been tested, but the hospital failed to do
so. Friter, who had just undergone cataract surgery, had not been
notified that an experimental lens was being tested in his eye, but as
a result of the experimental lens, he endured hemorrhage, corneal
damage, and other complications. The trial ruling was found to be
in favor of Friter, and the hospital was liable for $1.75 million in
damages. The Council of Europe’s Convention on Human Rights
and Biomedicine also entitles injured parties to fair compensation.
Following ICH-GCP and receiving pre-approval of experimental
devices by health authorities can minimize legal actions and reduce
amount of damages paid.
In transnational biomedical trials, the case falls under national
protocols of private international law. This can raise issues for
consumers in court systems that lack proper infrastructure or are
corrupt. For instance, in 1996, an experimental antibiotic called
Trovan was tested that caused paralysis, deafness, and blindness in
a number of child subjects.9 In the Trovan Trial Litigation of 2001,
the ethics of the trial protocol were examined. However, the case
was dismissed 14 times in the country in which the trial occurred;
similarly, the case against the US-based pharmaceutical company
was dismissed on grounds that the case should be raised in the
country of the clinical trial. Current debate exists on the role
of courts in transnational lawsuits and the hurdle of forum non
Cultural and Social Factors 71
conviens, when courts refuse to take jurisdiction over trials run by

companies in their districts but executed in another region.
9.5 Issues of Informed Consent

Receiving patient consent is a complicated but important aspect of
conducting ethical clinical trials; this is especially true in the case
of offshore trials. Several factors may influence an individual’s
decision to take part in clinical trials, including the patient’s culture
and education level, subject vulnerability within the healthcare
system, and economic background.
9.6 Cultural and Social Factors

Cultural and language barriers, as well as differences in education
level, can make proper patient consent difficult to obtain. First,
patients may be unclear about the risks associated with the trial;
they may think that they are receiving approved, established
treatment rather than a device that is still being developed and
evaluated. Additionally, there may not be a clear understanding
of placebo groups in the study among poorly educated
individuals or those unfamiliar with standard scientific methods.10
There may also be deviation from approved protocols due to
miscommunications in the amount or frequency of dosage; greater
confusion may exist in regions where units of time may differ from
standard days or weeks or where the concept of time differs from
the United States and Europe.
Individuals frequently are recruited to participate in trials via
advertisements. To ensure ethical recruiting practices, the health
authorities should review advertisements to ensure that they do not
promise specific results or coerce the patients into participating.
Additionally, these advertisements should not state the product’s
safety, efficacy, or superiority over existing devices. It is also
important that subjects are aware that research is not the only option
available for them. Whenever possible, viable alternatives should be
discussed with patients. Potential subjects should be provided with
specific data including the risks, benefits, and alternative courses
of treatment before deciding to participate in the trial and signing
consent forms.7 In the case of a cultural or language barrier, it is
72 Clinical Trials
ideal if an interpreter with a similar cultural background can be

made available. This is important for overcoming cultural barriers
in explaining scientific theories and methods. To aid in translation
and the crossing cultural barriers, it is suggested that the language
of the consent document be as clear and short as possible. Through
conservative advertising and comprehensive patient education,
patient consent can be obtained in an ethical manner.
9.7 Vulnerable Patient Populations

Vulnerability of the population may also affect enrollment
in trials. Extra precautions must also be taken in the consent of
individuals who may not be in the position to give consent
themselves, such as children, the elderly, and the mentally ill.11
These populations may not have the capacity to make value
judgments, so a court-appointed official often aids these subjects
in decision-making. An unequal patient–doctor relationship
may also persuade patients to take part in trials. Doctors are often
viewed as prominent and trustworthy individuals in society;
due to hierarchical class structures, patients are more likely to
listen to doctors’ encouragements to participate without fully
understanding the associated risks. Therefore, it is critical that
the entire consent document is reviewed with each patient. In
vulnerable or underprivileged populations, the presence of proper
court-appointed officials or supportive family members may aid in
assessing trial participation.
9.8 Economic Considerations

When financial disparities are a major constraint, patients
may not have other treatment options available or may be drawn by
money. In individuals lacking medical coverage, patients may not be
able to afford treatments that are already on the market. They may
also be compensated heavily for participation, strengthening the
incentive to participate in low-income or unemployed populations.
In fact, in offshore settings, companies often take advantage of the
ready-to-recruit strategy because patient pool consists primarily of
individuals with intractable health conditions, no health insurance,
and economic need. From a financial standpoint, it is suggested
Comparison of Trial Population to Target Population 73
that the device being tested not be commercialized by charging

investigators or subjects a higher price than is required to cover
device and study costs. Conversely, participants should not be
overcompensated to participate in clinical trials as this may
lead to patient oversight of potential risks of involvement. Over
compensation can affect the integrity of the results as well as
overall enrollment in the trials. Through fair reimbursement,
financial factors will be eliminated from the decision-making
process, ensuring careful consideration of the risks of the trial.
9.9 Comparison of Trial Population to

Target Population
Another problem arises when studies are conducted in areas not
representative of the final target population. Clinical research
should be responsive to the needs of the communities where it is
conducted; yet in the case of offshore trials, the most prevalent
illnesses in high-income countries may be vastly different from
those in the developing world. This discrepancy can result from
genetic mutations or environmental factors that may affect
treatment efficacy.12 For example, although cardiovascular disease
and cancer are prevalent problems in the developed world,
infectious diseases such as malaria and tuberculosis are much
more rampant in low-income areas. Even when similar diseases
are present in both settings, populations with geographically
distinct populations can have genetic profiles that markedly affect
the efficacy and safety of biomedical devices.
The treatment setting can also cause differences in device
efficacy. Organization of hospitals and clinics, preferred treatments,
and available quality of care may differ markedly between state-of-
the-art facilities with expert physicians and clinics with minimal
resources and doctors with less experience. Therefore, even if
the same biomedical devices existed in both resource-poor and
wealthier settings, if doctors in underprivileged areas are not as well
trained, devices may be less effective. In large-scale clinical trials,
however, information on physician training and existing medical
infrastructure is generally not provided.
Also, treatment naïve patients are more difficult to find in
the developed world; in fact, some patients may be enduring
74 Clinical Trials
several existing therapies. This differs from low-income and rural

settings, where patients are less likely to have previous exposure
to medications due to cost and geographical barriers. So for this
target population of developed-world individuals, it would remain
unclear if combining novel treatments with established regimens
would improve, reduce, or have no effect on patient outcomes.
Even among different nations in the developing world,
biomedical theories and priorities may diverge, in part due to the
role of the government in providing health care. For instance, in the
United States, with its privatized system of medicine, individuals
are more likely to have undergone invasive heart procedures
than Canadians, who are an otherwise fairly comparable patient
population.13
There are several means of addressing disparities between
clinical trial and target populations. One method is to include
standard treatments as controls in place of a placebo. In 1994,
a clinical trial for the antiretroviral AIDS drug azidothymidine
(AZT) was run using a placebo control. This led to a controversy
regarding placebo use, since a proven AIDS treatment existed
at the time and the control group was knowingly not given this
treatment.14 Following this incident, the Helsinki Declaration, which
provides guidelines for human biomedical research, was modified
to state that when known treatments exist, they should be utilized
in place of a placebo. This eliminated the ethical concerns of with-
holding treatment when effective treatments are available. From
a scientific perspective, comparison against standard treatments
may be more useful as well, allowing results to be more accurately
assessed for populations of the first world and of the upper-class
of the developing world. The environmental variables for which
offshore trials are often criticized can be accounted for by comparing
efficacy data of standard treatments in offshore populations (to be
used as the clinical control) to existing data in developed regions.
Statistical analyses should also be used to draw comparisons
between testing and targeted populations such that environmental
and genetic differences are accounted for.
Another way to minimize such discrepancies is to collect data on
physician training in addition to patient data during the trial. It may
then be determined if the caliber of the facility or past experience
of the doctors influence outcome. This, in turn, would increase the
scientific quality of the trial by allowing for adjustment in efficacy
References 75
based on available healthcare facilities. Using standard treatment

controls in place of placebo controls while accounting for variation
in facilities and training will aid in determining treatment efficacy in
the target population.
9.10 Conclusion
Clinical trials serve to ensure effectiveness and safety of biomedical
advices prior to sale on the market. Offshoring of clinical trials is
a growing trend to reduce costs and shorten time to completion.
To prevent ethical and legal misconduct, the ICH-GCP should be
followed and proper approval should be received from the health
authorities prior to the implementation of the trial. One key aspect of
the ICH-GCP is obtaining informed consent from trial subjects. This
is oftentimes complicated by cultural, social, and financial factors.
Difficulties also exist in relating the results from trial population to
the targeted population for the device. To eliminate ethical concerns
and improve scientific legitimacy of clinical trials, potential trial
subjects should be informed accurately and completely prior to the
start of the trial. Other involved parties should be included in the
decision-making process if appropriate, and patients should not
be over- or undercompensated for trial participation. Last, standard
treatment controls may be used in place of placebo controls and
statistical analyses should be performed to account for differences
among clinical trial and target populations. These measures will
ensure trials are performed ethically and that results accurately
represent the efficacy of the device in the targeted population.
References
1. Bailey W, Cruickshank C, and Sharma N. Make Your Move: Taking Clinical

Trials to the Best Location, Vertical View, A.T. Kearney, 2:56–62 (online),
available (2012): http://graphics.eiu.com/upload/gtf/1571871942.
PDF.
2. Barnes K. China “Most Attractive” Offshore Clinical Trial Location,
Outsourcing-Pharma.com (online), available (January 4, 2007) http://
www.outsourcing-pharma.com/Clinical-Development/China-most-
attractive-offshore-clinical-trial-location.
76 Clinical Trials
3. ClinicalTrials.gov. Map of All Studies in Clinical Trial.gov (online),

available (2011): http://clinicaltrials.gov/ct2/search/map.
4. Dunne G (2011). Medical Device Clinical Trials: The Changing Scene,
Regulatory Affairs Medtech January/February, 18–19 (Clinica/United
Kingdom).
5. Ford J, and Tomossy G (2004). Clinical Trials in Developing
Countries: The Plaintiff’s Challenge, (1) Law, Social Justice & Global
Development Journal (LGD). http://elj.warwick.ac.uk/global/issue/
2004-1/fordtomossy.html (Australia).
5. Glickman SW, et al. (2009). Ethical and Scientific Implications of the
Globalization of Scientific Research, New England Journal of Medicine,
360: 816–823 (United States).
6. Goldenberg M (2004). Recent Controversies in Consumer Lawsuits:
When Biomedical Devices Fail, Pharmacy and Therapeutics, 29(9):
581–583 (United States).
7. International Conference on Harmonisation of Technical Require-
ments for Registration of Pharmaceuticals for Human Use (2002). ICH
Harmonised Tripartite Guideline, Guidelines for Good Clinical Practice,
6th edition, revision 1.
8. London AJ (2011). Offshoring Science: The Promise and Perils of the
Globalization of Clinical Trials, IRB: Ethics and Human Research (The
Hastings Center/United States).
9. Solovay K. Medical Device Firms Do Many Trials Offshore. Here’s Why,
Healing Innovation, Medcity News (online), available (April 4, 2011):
http://www.medcitynews.com/2011/04/medical-device-firms-do-
many-clinical-studies-offshore-heres-why.
10. Manthei J, Thoelke KR, and Haas JB (2008). Global Clinical
Trials: Potential Pitfalls of Offshore Trials, BAYBIO2008 (online),
available (2008): http://www.baybio.org/files/AC08_T4S3_Global_
Clinical_Trials.pdf.
11. Marwah R, Van de Voorde K, and Parchman J (2010). Good Clinical
Practice Regulatory Inspections: Lessons for Indian Investigator
Sites, Perspectives in Clinical Research, 1(4): 151–155 (Bristol-Myers
Squibb/United States).
12. Schipper I and Weyzig F (2008). Ethics for Drug Testing in Low and
Middle Income Countries: Considerations for European Market Approval,
Center for Research on Multinational Corporations (Stichting
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13. Singer N (February 18, 2009). Outsourcing of Drug Trials Is Faulted,

The New York Times (United States).
14. Stiffler H (2003). Guidelines for Obtaining Informed Consent for
Clinical Research, Applied Clinical Trials.
15. Sunita, Service Outsourcing Opportunities in Medical Device Market
Worth US$26.77 Billion by 2014, PR Newswire (online), available
(November 12, 2009) http://www.prnewswire.com/news-releases/
service-outsourcing-opportunities-in-medical-device-market-worth-
us2677-billion-by-2014-69837522.html.
16. Pozgar G. (2012). Legal Aspects of Health Care Administration (Jones
and Bartlett Publishers/ United States).
17. Yuling F, et al. (2000). Canadian-American Differences in the
Management of Acute Coronary Syndromes in the GUSTO IIb Trial,
Circulation, 102(12): 1375–1381 (Canada).
18. Wenland CL (2008). Research, Therapy, and Bioethical Hegemony:
The Controversy Over Perinatal AZT Trials in Africa, African Studies
Review, 51(3): 1–23 (African Studies Association/ United States).
Chapter 10
Regulatory Affairs for Medical Device

Clinical Trials in Asia Pacific
Seow Li-Ping Geraldine

Johnson & Johnson Medical Asia Pacific,
No. 2 International Business Park,
#07-01, Tower One, The Strategy, 609930 Singapore
lseow@its.jnj.com
10.1 Introduction
Over the past decade, the Asia-Pacific region has grown to become
an important player in global clinical research development and
has contributed to the provision of quality clinical data to gain
market access for new products. Even though the most remarkable
growth has been observed mainly in pharmaceutical clinical trials,
industry stakeholders have recognised the high potential of medical
device clinical trials which have hitherto been unregulated in most
Asia-Pacific countries. In recent years, more regional regulators
have too been turning their focus on the regulation controls
required for medical device clinical trials. As both regulators and
industry stakeholders seek for direction in this changing landscape,
there is a generated demand for regulatory affairs professionals

www.panstanford.com
80 Regulatory Affairs for Medical Device Clinical Trials in Asia Pacific
to participate actively in this quest, and work synergistically with

their clinical research colleagues, to ensure that any additional
regulatory controls would be better managed without impeding
the path to market access for new medical devices. It is therefore
pertinent for regulatory affairs professionals to gain a good
understanding of medical device clinical trials and develop expertise
in related regulatory requirements.
10.2 Medical Device Clinical Trials versus

Pharmaceutical Clinical Trials
For those who are new to the world of medical device clinical trials,
it would be fair to assume that there are differences between
medical device clinical trials and pharmaceutical clinical trials,
whereas they share a similar overall clinical trial process (Fig.
10.1).
HealthAuthority
Submission
&Approval
EthicsCommittee
Submission
START Essential &Approval
Protocol
Documents SiteSelection SiteInitiation
p
Development
Preparation
ClinicalTrial
Agreement
Investigational
ProductsImport&
Products Import &
Supply
FirstPatient LastPatient
Subject DataCollection
FirstVisit SiteMonitoring LastVisit
Enrolment &Cleaning
(FPFV) (LPLV)
TrialReport& Submissionfor
SiteClosure DatabaseLock DataAnalysis Publication Marketing
Preparation Authorisation END
Figure 10.1 The clinical trial process (simplified).
The most obvious difference would be the product types

involved in the trial. Medical devices vary in complexity and would
include a wide range of health or medical instruments used in the
treatment, mitigation, diagnosis or prevention of disease or abnormal
Medical Device Clinical Trials versus Pharmaceutical Clinical Trials 81
physical condition. Medical devices with pharmaceutical components

may be categorised as a combination product or a medical device or
a pharmaceutical product. Interestingly, some medical devices are
classified and regulated as drugs in a few countries. The classification
of the investigational medical device should be clarified upfront
by the sponsor with the relevant regulatory bodies as this would
influence the requirements for conducting the clinical trial.
Trials are designed to answer medical questions. The purpose
of a trial is to test out a hypothesis about the effect of a particular
intervention upon a disease or condition. This effect could be tested
using a single-arm (uncontrolled) design or a comparative (controlled)
design (Fig. 10.2). The comparator could be (1) no intervention, (2) a
sham device/procedure (placebo in pharmaceutical studies), or (3)
existing therapies. The use of placebo or a blinded product may not
always be ethical or possible in medical device trials. A comparator
could be an existing product which has either been first in the
market or has proven efficacy and safety, or an existing procedure
which uses different products and instrumentation but has
similarities to the investigational procedure, or existing standard of
care which may not be linked to a product or a procedure. The added
clinical value compared to an existing medical device is of interest
to healthcare providers, patients and payers. Due to the innovative
nature of medical devices, this “gold standard” may not always exist.
For first in class medical devices, it is also a challenge to identify the
comparator to be used for the study. Alternatively some trials are
conducted with a single arm design, only to compare the results with
those from a historical trial involving a predecessor.
Figure 10.2 Uncontrolled versus controlled trial design.

The focus in a pharmaceutical clinical trial is solely on the inves-

tigational drug. In the medical device context, the investigational
device is but part of a complex system comprising the device, the
instrumentation or accessory devices and the procedure for using
the device. Sometimes all components are unregistered products
and the indicated procedure has an investigational status. The
clinical trial protocol needs to address how the device is the
only investigational component without being influenced by the
variability from the other components of this system, for example,
through standardised certified surgical technique training before
using the device in the trial. Another relevant consequence would
be the scope of safety and complaints reporting which should cover
all components and the expectedness of events, unless otherwise
specified in the protocol.
The pharmaceutical phasing of trials from phase 1 to 4 does not
apply to medical device clinical trials. Instead the 4Ps are commonly
used: Preclinical trials including in vitro/bench-top testing and
animal studies, Pilot trials, Pivotal trials and Post-marketing studies
(Table 10.1). Generally, the clinical development of a medical
device tends to move at a faster pace in order to attain the innovative
leader position for the technology involved and to ensure that the
customers can access to the latest device. Some devices, depending
on their classification and the selected regulatory path, do not even
require clinical data for registration which is based on literature
evaluation of data from predicate or previously approved devices,
thus some regulatory bodies warrant the need for post-marketing
studies to monitor long-term effects and to gain additional safety and
effectiveness clinical data for the new device.
Many similarities exist between medical device clinical trials
and pharmaceutical clinical trials. Those with experience in
pharmaceutical clinical trials could leverage on this experience
and apply their knowledge with an open mindset and adaptability
to the different scenarios in medical device clinical trials. The
principles of the Good Clinical Practice Guideline by the International
Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) Guideline,
or commonly referred to as ICH GCP [1], that form the ethical
foundation for pharmaceutical clinical trials, do apply to medical
device clinical trials.
Regulation of Clinical Trials 83
Table 10.1 Phases of clinical trials involving medical devices
Phase Description
In vitro In vitro research takes place in the laboratory. Laboratory
Preclinical trials
(benchtop) researchers attempt to simulate conditions of the human

testing body, conducting multiple tests to establish whether the
device is effective, safe, and functioning properly.
Animal studies Initial tests to establish safety of the product or materials
in question will be conducted on animals.
Feasibility A feasibility, or pilot, study will be conducted to test safety
(pilot) studies and performance of the product in question, usually a
multi-centre study, involving 30 to about 200 subjects and
lasts for 30 days to 6 months.
Clinical trials
Pivotal trials Pivotal trials are conducted to gain evidence of safety and
effectiveness, also usually multi-centre studies, with 100 to
over 1,000 subjects and lasts for 30 days to several years.
Used to obtain regulatory approval from the relevant
approval body.
Post-marketing After the launch of a product, post-marketing studies will
studies be conducted to monitor long-term effects and to gain
additional safety and effectiveness data.
10.3 Regulation of Clinical Trials

Basically, regulation of clinical trials is necessary to ensure
(i) The safety, well-being and rights of the clinical trial subjects
(ii) The scientific conduct of the clinical trial
(iii) The credibility of the clinical trial data
This is in coherence with a Regulatory Authority’s role in
the governance of public health and safety. When a clinical trial
application is submitted to the regulatory authorities for approval,
the reviewers would typically evaluate the protocol, the informed
consent form as well as product-related essential documents like the
Investigator’s Brochure to establish an expert opinion on whether the
trial should be conducted from a scientific perspective and whether
there are measures in place to ensure the safety, well-being and
rights of the subjects. Credibility of clinical trial data, which would be
analysed and collated into a clinical trial report, is reviewed as part
of the evaluation of a product registration dossier. In some countries,
these aspects are further verified through inspections performed
by the health authority either during or after the trial. Other basic
aspects of regulation would also cover standards for the conduct of
the clinical trial, reporting of safety-related events, product defects
and regular trial status updates, and labelling, import, accountability
and traceability of investigational medical devices which should be
manufactured according to relevant standards. A risk-based approach
to the scope of control is adopted by most regulatory authorities.
Observations of latest regional trends also reveal that Regulatory
Authorities are going beyond merely enforcing regulation by playing
a more contributing role, to enhance the local clinical research
infrastructure and competency of clinical trial personnel, through
organising training programmes in medical device clinical trials for
clinical trial personnel, provisioning for the registration of trials in
a public clinical trial registry, and even revising their local version
of GCP to keep up with the changing clinical trial environment
(Table 10.2).
Table 10.2 Possible areas of regulation
New clinical trial application Local GCP

Protocol & amendment review Reporting of trial status & deviations
Informed consent form review Reporting of safety-related events
Investigator’s brochure review Reporting of product defects
Surgical technique review Clinical trial report review
Label & packaging review Inspection-sponsor, site, CRO, warehouse
Instructions for use review Clinical personnel qualification & training
Product import into country Public clinical trial registry
Product accountability Certification of competent sites
Apart from the Regulatory Authority, the responsibility of

upholding the above-mentioned three ethical pillars of a clinical trial
is also shared by the other major stakeholders in a clinical trial albeit
from different perspectives: the Investigator, the Sponsor and the
Institutional Review Board (IRB), which is sometimes also referred
to as the Ethics Committee (EC) (Fig. 10.3). In fact, although ICH
GCP, being a guideline to be followed when generating clinical trial
data that are intended to be submitted to regulatory authorities, is
commonly used as a basis to regulate clinical trials, it does not have
a section specifically for “Regulatory Authority”. The Declaration of
Helsinki, which describes the ethical principles for medical research
Regulation of Clinical Trials 85
involving human subjects, is addressed primarily to physicians, i.e.

the Investigator [2]. The other common reference for medical device
clinical trials, ISO14155:2011 (E) [3], does not describe the role and
responsibilities of the regulatory authority. Hence, while regulatory
affairs professionals from the Sponsor organisations have guidance
on the scope of their responsibility, those from the regulatory
authorities need to establish their specific role and responsibilities
within their own clinical research environment.
Regulatory
Authority
Institutional
Review
Board
Sponsor Investigator
Figure 10.3 Major stakeholders in a clinical trial.
The harmonisation of regulation within the region and the

opportunity to learn about the implementation of regulation in
other countries including outside the Asia-Pacific region will
definitely help local regulators and regulatory affairs professionals
to formulate regulation that would effectively meet the needs of
their country as well as to increase acceptance of local clinical trial
data in overseas submissions. The US Food and Drug Administration
(US FDA) would be a forerunner in medical device clinical trial
regulations since implementing medical device amendments to the
Federal Food, Drug & Cosmetic Act on 28 May 1976. The European
Medical Directives, which were implemented in the last decade,
adopt a different regulatory approach through a combination of
regional and local laws, ISO standards and notified bodies. Within
the region, within the last decade, the regulatory authorities in
Japan, South Korea and Taiwan have implemented changes to their

organisations and clinical trial regulations to address the needs
of the growing number of local medical device clinical trials.
From an operational perspective, using the same clinical trial
reviewer team who has been evaluating pharmaceutical clinical
trials may seem like an easily adaptable and convenient approach
to undertake the task of evaluating medical device clinical trials.
However, a copy and paste success should not be expected without
investing in equipping and/or building up the team with knowledge
and experience in medical device clinical development process,
investigational methodology and the greater emphasis on technology
expertise, diagnostic approach and surgical techniques. A similar
consideration should be made for the team who traditionally reviews
safety reports and product complaints for pharmaceutical products.
This scaling up of clinical trial and safety vigilance resources should
be part of the medical device regulation development strategy. Due
to the rapidness and specificity of the technology and innovation
involved in medical device clinical development, the engagement
of independent experts to perform the evaluation could help to
augment the required resources to support this effort.
Industry stakeholders who often take on the role of the Sponsor
or clinical research organisations are watching these developments
closely. Changes to clinical trial regulations have an impact on
clinical trial operations and more crucially affect the clinical
development pathway in terms of speed and complexity. Proper
change management coupled with effective organisational strategy
for regulatory affairs and clinical research will help to cushion the
impact of these changes and prepare the industry to take on the
challenges of a changing regulatory landscape.
Interestingly, there is a heavy reliance on the IRB to be the
only ethical and scientific “third party” gatekeeper to evaluate and
approve medical device clinical trials when the regulatory authority’s
approval is not required. Inadvertently, most of these regulatory
authorities would have guidelines regarding IRB’s organisation and
procedures. In 2001, the Association for the Accreditation of Human
Research Protection Programs, Inc. (AAHRPP), an independent
human research protection accreditation program, was established
in the United States and has defined domains of responsibility:
Organization, Institutional Review Board (IRB) or Ethics Committee
(EC), and Researchers and Research Staff. AAHRPP has even
Country Regulations 87
accredited eight organisations outside the United States among

which there are three each from India and South Korea and one
each from China and Singapore.
In the United States, clinical evaluation of devices that have
not been cleared for marketing requires an Investigational Device
Exemption (IDE); if the clinical trial involves a significant risk
device, the IDE must also be approved by the US FDA. The scope and
strategy for regulation of medical device clinical trials varies within
the Asia-Pacific region. This could be influenced by the maturity of
medical device regulation, the adoption of medical device clinical
trial regulation from other countries, the available infrastructure,
regulation and resources for pharmaceutical clinical trials, the role
and responsibilities of the IRBs, and the local demand for regulation
of medical device clinical trials, among others. Most countries
require compliance to ICH GCP or a localised version of GCP in their
regulations, noting that localised GCP or local regulation will generally
prevail over ICH GCP requirements where there is a conflict between
the local and international references. Some implement more
stringent controls on clinical trials involving unapproved products
than those involving approved registered products. Countries
with well established regulatory organisations for evaluation of
pharmaceutical clinical trials, for example Australia, Japan, South
Korea and Taiwan, have leveraged on their experience and allocated
dedicated teams for evaluation and consultation for medical device
clinical trials. In Southeast Asia, Singapore is taking the lead in the
implementation of medical device clinical trial regulation from
2013. In a few countries where the specific regulations are not
implemented, certain regulations for pharmaceutical clinical trials
could sometimes apply to medical device clinical trials on a case-by-
case basis; for these countries, prior consultation with the relevant
authorities would be advised. As of the end of 2011, Hong Kong and
Malaysia currently do not have any regulation on medical device
clinical trials and import of investigational medical device for clinical
trial use.
10.4 Country Regulations

Figure 10.4 describes the typical regulatory activities that are
relevant to the clinical trial process.
88
Table 10.3
Country Regulatory authority Submission Notification Approval Import licence Safety reporting Inspection
Overview of the current regulation of medical device clinical trials in some Asia-Pacific countries
Australia Therapeutic Goods Sequential Within 10 Within 50 days (CTX Part of CTN/ Local SUADEs/ NA
Administration (TGA) business days scheme for review of CTX SUSARs within
(CTN scheme) safety of device) 7–15 days
China Center of Medical Device Sequential (Before Yes (protocol NA NA SAE within 24 Site-
Evaluation, State Food and Drug IRB submission) only) hours specific
Administration (CMDE, SFDA)
Hong Kong Medical Device Control Office, NA NA NA NA Voluntary NA
Department of Health
India Medical Device Division, Parallel NA About 12–16 weeks. Yes Local SUADEs/ NA
Central Drugs Standard Control Prior IRB approval SUSARs within 14
Organization, Drugs Controller required days
General (India) (DCGI)
Malaysia Medical Device Control Division, NA NA NA NA Yes NA
Ministry of Health (MOH)
New Zealand New Zealand Medicines and Sequential Within 45 NA NA Local SUADEs/ NA
Medical Devices Safety Authority business days. SUSARs within
(Medsafe) 7–30 days
Singapore Clinical Trials Branch & Medical NA NA NA Yes Local SUADEs/ NA
Regulatory Affairs for Medical Device Clinical Trials in Asia Pacific
Device Branch, Health Sciences SUSARs within 48

Authority (HSA) hours or 10–30
days
South Korea Medical Device Safety Parallel NA Officially 30 days Per import Local SUADEs/ NA
Bureau, Korean Food & Drug SUSARs within
Administration (KFDA) 7–15 days
Taiwan Division of Medical Device and Parallel NA 1–3 months Yes Local SUADEs/ GCP
Cosmetics, Taiwan Food and Drug SUSARs within inspection
Administration (TFDA) 7–14 days by TFDA
Thailand Thailand Food and Drug NA NA NA Yes NA NA
Administration
Figure 10.4 Typical regulatory activities in the clinical trial process.
Table 10.3 shows an overview of the current regulation of

medical device clinical trials in some of the Asia-Pacific countries.
10.4.1 Australia
Medical devices that are not in the Australian Register of Therapeutic
Goods (ARTG) can be legally supplied in a clinical trial through the
Clinical Trial exemptions mechanism (Clinical Trial Notification
(CTN) Scheme or the Clinical Trial Exemption (CTX) Scheme), which
is managed by the Therapeutic Goods Administration or TGA. In
addition, prior quarantine clearance must be obtained to import
any material of biological origin (human, animal, plant or bacterial)
and questions about requirements for an import permit should be
directed to the Australian Quarantine & Inspection Service (AQIS).
The responsibility for monitoring a clinical trial rests with the
Sponsor, Institution in which the trial is being conducted, the Ethics
Committee and the Investigator. Clinical trials must be approved by a
Human Research Ethics Committee (HREC) which must be constituted
and operating in accordance with the NHRMC’s National Statement
on Ethical Conduct in Human Research. The HREC is responsible
for considering the scientific and ethical issues of the proposed
clinical trial protocol. Approval of a trial is required from a HREC
with jurisdiction over the specific site where the trial is conducted.
The Sponsor decides whether to use the CTN CTX Scheme when the
trial involves any device which is not included in the ARTG or used
beyond the conditions of its marketing approval. The Sponsor in this

scenario must be an Australian clinical trial Sponsor. Clinical trials
in which the medical devices are used within the conditions of their
marketing approval are not subject to CTN or CTX requirements but
still require approval by a HREC before the start of the trial.
The CTN process involves a notification only to the TGA with a
nominal notification fee, thus no approval or decision is made by the
TGA. CTN trials cannot commence until the appropriately completed
CTN scheme form and the notification fee is submitted to the TGA
who will send the clinical trial sponsor an acknowledgement letter.
The notification of the CTN form and the associated fee automatically
creates the exemption necessary to allow lawful supply of the
unapproved medical devices for the clinical trial.
In the CTX approval process, TGA reviews the safety of the device
by assessing the summary data and usage guidelines for a proposed
clinical development programme within 50 working days, and if
approval if granted, subsequent trials must be carried out under the
terms of the approval and be notified to the TGA. The CTX application
does not require the submission of the clinical trial protocol which
should be reviewed by the HREC. A CTX trial cannot commence
until TGA has provided written advice that the application has been
approved, and a HREC and the institution at which the trial will be
conducted have provided approval for the conduct of the trial.
The clinical trial Sponsor needs to notify TGA of the data of trial
completion and the reason for completion. TGA does not require
notification of protocol amendments which clarify the use of, and/or
monitoring of treatment but may require if there is a major change
to the protocol and the HREC requires a change to the conditions of
their approval.
In terms of adverse event reporting, the clinical trial Sponsor is
required to report to TGA about serious and unexpected adverse
device events. Fatal or life-threatening adverse device events must
be reported initially within 7 calendar days of knowledge, followed
by a full report within 8 additional calendar days. Other serious
unanticipated device events must be reported within 15 calendar
days of knowledge. The Investigator is responsible for adverse event
reporting to the HREC as required by the HREC and to the Sponsor
as required by the protocol [4–7].
10.4.2 China
Submission of a clinical trial application in China is currently
limited to Class III medical devices implanted into human body that
are not yet available in the market, or those medical devices that
are based on the theory of traditional Chinese medicines only [8].
The clinical trial protocol should be filed with the Center of Medical
Device Evaluation (CMDE) of the State Food and Drug Administration
(SFDA). Medical devices to be used in a clinical trial must fulfill certain
conditions including measuring up to the registered product or
industrial standard, possession of a testing report from the Sponsor
and a qualified type testing report from a SFDA-recognised testing
centre, as well as data from animal studies. Approval requirements
are set on a case by case basis after consultation with SFDA since
the need for a SFDA approval before commencing a clinical trial is
not clearly stated in the regulations. Once the protocol has been
filed with the CMDE, the Sponsor can proceed with the submission
to the IRB for review and approval. All serious adverse effects must
be reported to SFDA within 24 hours; however, there is no clear
definition for “serious adverse effects” in the regulations. SFDA
may conduct site inspections during or after the end of the trial. It
is not mandatory to obtain local clinical data if global clinical data
is available for imported medical devices. In addition, there is new
regulation with regards to clinical data exemption for some class II
medical devices [9]. As of the fourth quarter of 2012, China is in the
process of revising its Medical Device GCP.
10.4.3 Hong Kong

Hong Kong has not implemented regulations for medical device
clinical trials. Although reporting of serious adverse events in a
medical device clinical trial is still done on a voluntary basis, the
Medical Device Control Office would prefer to be notified of local
reportable adverse events which have occurred at sites in Hong
Kong.
10.4.4 India
Generally an approval from the Drugs Controller General (India)
(DCGI) is required for first-in-man and pivotal clinical trials; this is
also dependent on whether the investigational device is included in a

list of notified devices which are classified by the DCGI as drugs. The
medical device advisory committee (MDAC) reviews the submitted
clinical trial application for completeness and, in the case of early
phase of first-in-man trials, may refer the application to the Indian
Council for Medical Research for scientific review. The application
dossier is rather comprehensive and consists of many sections
requesting for most essential documents including the insurance
certificate and indemnity agreement but excluding the clinical trial
agreement with each site. Both DCGI approval and IRB approval for
the institution(s) where the trial will be conducted are required
before the trial can commence. An import licence is required for
importing investigational medical devices into India.
The application for an import licence for the investigational
medical devices is submitted together with the clinical trial
application. Any unexpected serious adverse event (SAE), as defined
in the Indian GCP Guidelines, occurring during a clinical trial should
be communicated promptly (within 14 calendar days) by the
Sponsor to the Licensing Authority and to the other Investigator(s)
participating in the study [10–12].
10.4.5 Malaysia
As of end of 2011, regulation of medical device clinical trials has not
officially implemented in Malaysia. Future guidelines based on the
recently passed Medical Device Bill will provide more information
on the regulation of medical device clinical trials in Malaysia.
10.4.6 New Zealand

Clinical trials of medical devices do not require approval under New
Zealand legislation, but the New Zealand Medicines and Medical
Devices Safety Authority or Medsafe would like to be informed
by email of such trials. However, Health and Disability Ethics
Committee approval should be obtained for medical device clinical
trials. If the medical device used in a clinical trial contains a
hazardous substance or a new organism, an approval under the
requirements of the Hazardous Substances and New Organisms Act
1986 (HSNO Act) is required. Any medical device imported for use
in a clinical trial is exempted from mandatory notification to the
Web Assisted Notification of Devices (WAND) database [13].
All clinical trials conducted in New Zealand are expected to

be conducted in accordance with the CPMP Note for Guidance on
Good Clinical Practice, regardless whether an approval under the
Medicines Act is required for the trial. The Sponsor, who must be
a person in New Zealand, assumes responsibility, including legal
liability, for the trial in New Zealand in terms of preservation of
records, reporting adverse events, submit 6 monthly progress
reports, notifying protocol changes and ensuring that the trial is
conducted in accordance with both New Zealand law and Good
Research Practice standards. Expedited reports of all fatal or
life-threatening suspected unexpected serious adverse reactions
(SUSARs) occurring in New Zealand trial participants must be
sent to Medsafe by the Sponsor within 7 days of knowledge. The
Sponsor is required to hold reports of all worldwide SUSARs which
may be requested by Medsafe. Adverse events that cause injury and
that are associated with medical devices should also be reported
to Medsafe, initial reports within 7 calendar days for actual or
potential death or serious injury and within 30 calendar days for
those with or without actual or potential injury [14].
Medsafe also administers a self-certification scheme for clinical
trial sites that have patients in residence, and maintains a list of
sites for which it has received evidence of compliance with GCP
requirements.
10.4.7 Singapore
Import of unregistered medical devices into Singapore for use in
clinical trials requires the approval of the Health Sciences Authority
(HSA). An application form for Clinical Trial Test Materials (CTM
for Medical Devices) must be submitted by the the Sponsor [15,
16]. Upon importation of the investigational medical devices into
Singapore, the Sponsor is responsible for complying with safety and
defects reporting, notification of device recalls, and device labelling,
accountability and traceability requirements. Although currently
medical device trials do not require regulatory approval, all adverse
events or defects in medical device trials must be reported. Adverse
events that represent a serious threat to public health must be
reported within 48 hours while those that have led to the death,
or a serious deterioration in the state of health, of a patient, a user
of the medical device or any other person must be reported within
10 days. Events where a recurrence of which might lead to the death

of the medical device or any other person must be reported within
30 days. Initial reports should be followed by a final report within
30 days of the initial report, detailing the investigation into the
adverse event.
During the final phase of implementation of the medical
device regulatory framework in Singapore in the fourth quarter of
2012, the new Health Products (Clinical Trials) Regulations will
introduce regulations for medical device clinical trials in Singapore
using a risk-based approach. Proposed changes, which affects
clinical trials to determine safety and performance of all Class C
and D registered and unregistered medical devices, will include
a new Clinical Trial Notification route for listed investigational
devices versus a Clinical Trial Approval route for unregistered
investigational devices. Clinical trials involving Class A and B
medical devices, non-invasive and non-confirmatory in vitro
diagnostic products as well as observational trials are excluded
from this scope of regulation. Changes to current safety reporting
requirements are also expected. Another proposed change of
interest is the allowance of a trial to have more than one Sponsor in
order to address various industry business and outsourcing models
where the Sponsors may have joint or allocated responsibilities.
All unregistered medical devices which are imported for non-
investigational purpose in the conduct of a clinical trial, regardless
of product risk class, will be regulated under the Health Products
(Medical Device) Regulations instead.
10.4.8 South Korea

From 2007 to 2011, the Korean Food and Drug Administration
(KFDA) has approved 120 medical device clinical trials. Applications
for clinical trial protocol and amendment approval and reporting
for adverse events, product defects, trial status updates and import
quantities are submitted online via the KiFDA Electronic Filing
System. For trials where the essential documents are prepared in
English, a Korean translation of the protocol and participant-facing
written material must be prepared and submitted in addition to the
English versions. Otherwise all remaining essential documentation
can be submitted in English. Submission to KFDA can be done in
parallel with the submission to the IRB, however KFDA requires

an IRB approval for the site where the trial is conducted before KFDA
issues the approval. Although the official review time for a clinical
trial application is 30 days, this timeline could be delayed by, for
example, IRB-required changes to the informed consent form.
Device-related death or life threatening adverse events must
be reported within 7 days for the initial report and a follow-up
detailed report within the next 8 days; all other types of SAEs must
be reported within 15 days of knowledge of the event [17–19].
KFDA has even taken one step further by creating a new system
requiring hospitals and medical doctors to be qualified specifically
as medical device clinical centres. To be qualified, hospitals must
have standard operating procedures according to GCP and medical
doctors must have training in medical device clinical development
and GCP. By the end of September 2011, a total of 94 university
hospitals were registered by KFDA as medical clinical device centres
nationwide.
10.4.9 Taiwan
The regulatory system for investigational medical devices in
clinical trials consists of regulation for GMP (Good Manufacturing
Practice) or QSD (Quality System Design), determination of device
classification and regulation for import of these devices. The
documents required for the import of investigational medical
devices used in a clinical trial and the clinical trial approval include
the Certificate of Free Sale in marketed countries, the protocol
and the informed consent form as well as most other clinical
trial essential documents including the clinical trial agreement,
insurance certificate and indemnity agreement. If the Certificate
of Free Sale in marketed countries is not available, technical data
including preclinical safety and functional tests plus the IRB
approval letter must be provided. The clinical trial application can
be submitted in parallel both to the IRB and the Division of Medical
Device and Cosmetics, Taiwan Food and Drug Administration (TFDA)
for review. After the clinical trial results are submitted as reference
for product registration, a TFDA review team will perform a GCP
inspection at the site before approving the use of these results as
reference for product registration. To shorten the review time for
medical device clinical trials, the review process has recently been
simplified for clinical trials which have obtained US FDA approval
and for those with minor changes to the protocol (excluding safety
and design changes).
In addition, TFDA has implemented a local version of GCP as
well as established a list of good clinical research centres, mandated
attendance of compulsory GCP training programme for clinical
trial personnel and organised training on clinical trials involving
medical devices and technology for regulators, industry and site
personnel.
Reporting of adverse medical device reactions (ADR) and product
defects can be done online, using the National Reporting System of
Adverse Medical Device Reactions and the Medical Product Defect
Reporting System respectively, by consumers, medical personnel and
manufacturers. For SAEs, manufacturers are expected to provide an
oral or initial report is expected within 7 days of knowledge of the
event, followed by a full report within 14 days [20].
10.4.10 Thailand
To date, the Thailand Food and Drug Administration (Thai FDA)
does not have any regulation on the conduct of medical device
clinical trials in Thailand. Only the import of unapproved medical
devices used in clinical trial must be pre-approved by Thai FDA who
will issue an import licence that specifies the approved quantity
before the products can be shipped into Thailand.
10.5 Moving Ahead as Regulatory Affairs

Professionals
Existing regulations will change as the learning curve progresses.
The clinical research environment and the regulations for medical
device clinical trials will evolve to meet the demands and challenges
in the conduct of medical device clinical trials in the Asia-Pacific
region. A careful effort to streamline regulations governing clinical
trials could reduce redundancy in the system while ensuring ethical
conduct [21]. In order for Asia Pacific to contribute even more
significantly to the globalisation of evidence based medicine, the
crucial role of regulatory affairs professionals in this evolution could
References 97
be enhanced by exploring various possibilities of continuous personal

development of regulatory affairs and clinical research knowledge
and trends, and through collaborations with their clinical research
colleagues in the same quest using a synergistic goal approach.
Implementation of new or revised regulations should be coupled
with motivated considerations for appropriate change management
measures within the organisations. Resources could be dedicated
to extend the organisation’s knowledge database, outside their area
of jurisdiction or countries, about sites, investigators, participants,
other key stakeholders, clinical research practices and the quality
of trial data. The continuation of using a risk-based approach may
not be disadvantageous, though more long-term benefits could be
derived from a proactive strategy than a reactive one. Meanwhile,
where regulations are not yet available, the principles of globally
recognised good clinical practice guidelines, like ICH GCP, should be
used as foundation beacons to guide the management and conduct
of medical device clinical trials.
References
1. International Conference On Harmonisation Of Technical Requirements

For Registration Of Pharmaceuticals For Human Use (10 June
1996). International Conference on Harmonisation (ICH) Tripartite
Guideline, Guideline for Good Clinical Practice E6 (R1). Retrieved 10
January 2011, from http://www.ich.org/fileadmin/Public_Web_Site/
ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.
pdf.
2. World Medical Association (2008). Declaration of Helsinki: Ethical
Principles for Medical Research Involving Human Subjects. Retrieved
10 January 2011, from http://www.wma.net/en/30publications/
10policies/b3/17c.pdf.
3. International Organisation for Standardisation (2011). ISO
14155:2011: Clinical Investigation of Medical Devices for Human
Subjects- Good Clinical Practice.
4. Therapeutic Goods Administration, Australia Government (March
2006). The Australian Clinical Trial Handbook. Retrieved 10 January
2011, from http://www.tga.gov.au/industry/clinical-trials.htm.
5. Therapeutic Goods Administration, Australia Government (May 2011).
Australian Regulatory Guidelines for Medical Devices version 1.1.
Retrieved 10 January 2011, from http://www.tga.gov.au/industry/

devices-argmd.htm.
6. Therapeutic Goods Administration, Australia Government (October
2004). Access to Unapproved Therapeutic Goods: Clinical Trials in
Australia. Retrieved 10 January 2011, from http://www.tga.gov.au/
industry/clinical-trials.htm.
7. National Health and Medical Research Council. Australian Government
(October 2007). National Statement on Ethical Conduct in Human
Research. Retrieved 10 January 2011, from http://www.nhmrc.gov.
au/health-ethics/human-research-ethics-committees-hrecs/human-
research-ethics-committees-hrecs/national.
8. State Food and Drug Administration, P.R. China (17 January 2004).
Provisions of Clinical Trials for Medical Devices, SFDA Order No.5.
Retrieved 10 January 2011, from http://eng.sfda.gov.cn/WS03/
CL0768/61644.html.
9. State Food and Drug Administration, P.R. China (24 November 2011).
Notification about Clinical Data Exemption for Certain Class II Medical
Devices (In Chinese). Retrieved 10 January 2011, from http://www.
sda.gov.cn/WS01/CL0845/67233.html.
10. Central Drugs Standard Control Organisation, Ministry of Health, India
(December 2008). Guidance for Industry on Submission of Clinical
Trial Application for Evaluating Safety and Efficacy, CT/71108, Version
1.1. Retrieved 10 January 2011, from http://cdsco.nic.in/CDSCO-
GuidanceForIndustry.pdf.
11. Central Drugs Standard Control Organisation, Ministry of Health,
India (04 August 2010). Requirements for Conducting Clinical Trial(s)
of Medical Devices in India - Draft. Retrieved 10 January 2011, from
http://cdsco.nic.in/Requirements%20for%20Conducting%20Clinica
l%20Trial(s)%20of%20Medical%20Devices%20in%20India.PDF.
12. Ministry of Health and Family Welfare, Government of India (20 April
2010). List of Notified Medical Devices. Retrieved 10 January 2011,
from http://cdsco.nic.in/Medical_div/medical_device_division.htm.
13. New Zealand Medicines and Medical Devices Safety Authority (May
2011). Guideline on the Regulation of Therapeutic Products in New
Zealand Part 11: Clinical Trials- Regulatory Approval and Good Clinical
Practice Requirements, Edition 1.1. Retrieved 10 January 2011, from
http://www.medsafe.govt.nz/regulatory/clinicaltrials.asp.
14. New Zealand Medicines and Medical Devices Safety Authority (10
May 2011). Information for Medical Device Suppliers: Medical
Device Adverse Event Reporting. In MedSafe Regulatory Information.
References 99
Retrieved 10 January 2011, from http://www.medsafe.govt.nz/

regulatory/devicesnew/9adverse-event.asp.
15. Health Sciences Authority, Singapore (01 September 2010). Health
Products Act (Chapter 122D): Health Products (Medical Devices)
Regulations 2010. Retrieved 10 January 2011, from http://www.
hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_
regulation/legislation/health_products_act.Par.69129.File.dat/HEALT
H%20PRODUCTS%20(MEDICAL%20DEVICES)%20REGULATIONS%
202010.pdf
16. Health Sciences Authority, Singapore (01 September 2010). Health
Products Act (Chapter 122D): Health Products (Medical Devices)
(Exemption) Order 2010. Retrieved 10 January 2011, from http://
www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_
regulation/legislation/health_products_act.Par.94239.File.dat/HEALT
H%20PRODUCTS%20(MEDICAL%20DEVICES)(EXEMPTION)%20OR
DER%202010.pdf.
17. Korean Food and Drug Administration, South Korea (25 November
2011). Guideline for Medical Device Korean Good Clinical Practice (In
Korean). Retrieved 10 January 2011, from http://www.kfda.go.kr/
index.kfda?mid=90.
18. Korean Food and Drug Administration, South Korea (28 November
2010). Enforcement Regulations of the Medical Device Act. Retrieved
10 January 2011, from http://www.kfda.go.kr/eng/eng/index.do;jses
sionid=VAnDsf9zaa5M8jZvOtuhIQi8TiICe6RPiZA5PK1o3UtxBONueQ
7AEtlQxPaNsgTE?nMenuCode=46&searchKeyCode=125&page=1&m
ode=view&boardSeq=66026.
19. Korean Food and Drug Administration, South Korea (01 September
2010). Enforcement Decree of the Medical Device Act. Retrieved 10
January 2011, from http://www.kfda.go.kr/eng/eng/index.do;jsessio
nid=VAnDsf9zaa5M8jZvOtuhIQi8TiICe6RPiZA5PK1o3UtxBONueQ7A
EtlQxPaNsgTE?nMenuCode=46&searchKeyCode=125&page=1&mode
=view&boardSeq=66026.
20. Taiwan Food and Drug Administration, Taiwan (12 April 2006).
Guidelines for the Registration of Medical Devices. Retrieved 10
January 2011, from http://www.fda.gov.tw/eng/people_laws_list.
aspx.
21. Seth W. Glickman, et al (2009). Ethical and Scientific Implications of the
Globalization of Clinical Research. N Engl J Med 360:816–823.
Chapter 11
Medical Device Classification Guide
Patricia Teysseyre
No. 2, International Business Park,
pteyssey@its.jnj.com
11.1 How to Carry Out Medical Device

Classification
11.1.1 Scope
It is the responsibility of the manufacturer to determine the
classification of its medical device as early as possible in the device
development. Its determination should be based on rules derived
from the potential of a medical device to cause harm to a patient or
user and thereby on its intended use and the technology it utilizes.
The manufacturer should first clearly define the intended
use of the device [1]. The next step is to consider the applicable
classification regulations in force in the country where the product
is going to be registered before being marketed. Most countries have
their own classification scheme, such as Japan, People’s Republic
of China [5], and India. The classification schemes of Canada and

www.panstanford.com
102 Medical Device Classification Guide
Australia/New Zealand resemble the European one, whereas the

one in the United States is different. Efforts are under way to effect
a global harmonization of classification. For instance, Study Group 1
of the Global Harmonization Task Force (GHTF/SG1/N15:2006) [8]
has made progress and has been taken as a reference in some Asian
countries such as Singapore, but it can still be noticed that systems
differ and it is the up to the manufacturer to check and adapt its
medical device class to the appropriate local classification scheme.
Although different in many jurisdictions, they carry remarkable
resemblance in most cases, having 4 categories of risks identified and
treating in vitro diagnostics in their own right [3]. A large percentage
of the products would be in the same class across the globe, but
care should be taken to examine individual product classifications
carefully. GHTF consolidates the classes as A to D, with A being the
lowest risk, and D the highest.
In accordance with the classification rules, the manufacturer
should document and justify the class of the device.
The class determination can be influenced by several factors,
including the duration of device contact with the body, the degree
of invasiveness, whether the device delivers medicinal products or
energy to the patient.
In general, when two or more classification rules may apply to
the device, the device is allocated to the highest level of classification.
In case of doubts, the appropriate Notified Body or Regulator should
be consulted.
11.1.2 Definitions
Central circulatory system: the major internal blood vessels
including the following: arteriae pulmonales, aorta ascendens,
arcus aorta, aorta descendens to the bifurcatio aortae, arteriae
coronariae, arteria carotis communis, arteria carotis externa,
arteria carotis interna, arteriae cerebrales, truncus brachio-
cephalicus, venae cordis, venae pulmonales, vena cava superior,
vena cava inferior.
Central nervous system: means brain, meninges, and spinal cord.
Duration
Transient: Normally intended for continuous use for less than
60 minutes.
Short term: Normally intended for continuous use for not more
than 30 days.
Long term: Normally intended for continuous use for more than
30 days.
Main Classifications 103
Intended use/intended purpose: means the use for which the

device is intended according to the data supplied by the manu-
facturer on the labelling, in the instructions and/or in promotional
materials.
Invasiveness
Invasive devices: A device which, in whole or in part, penetrates
the body, either through a body orifice or through the surface of
the body.
Body orifice: Any natural opening in the body, as well as the
external surface of the eyeball, or any permanent artificial opening,
such as a stoma.
Surgically invasive device: An invasive device which penetrates
inside the body through the surface of the body, with the aid of or
in the context of a surgical operation.
Implantable device
Any device which is intended
(i) to be totally introduced into the human body or
(ii) to replace an epithelial surface or the surface of the eye by
surgical intervention which is intended to remain in place
after the procedure.
Any device intended to be partially introduced into the human
body through surgical intervention and intended to remain in
place after the procedure for at least 30 days is also considered an
implantable device.
11.2 Main Classifications

11.2.1 Medical Devices
The flow chart in Fig. 11.1 shows the main steps to be taken and
questions to be addressed when carrying out a medical device
classification. This decision tree is based on the GHTF (GHTF/SG1/
N15:2006) [8] and MEDDEV 2.4/1 Rev. 9 Guidance [6].
11.2.2 Active Devices

The classification of rules for active medical devices in some
jurisdictions differ from the medical devices ones and are shown
in Fig. 11.2, as they are defined in the European Medical Devices
Directive 93/42/EEC [2]. Figure 11.2 is an extract from the MEDDEV
2.4/1 Rev. 9 Guidance [6]. It should be noted that these are additional
classification rules for active devices. The general rules 1–8, and the
higher-numbered special rules may be applicable as well.
11.2.3 IVD Devices

Regarding in vitro diagnostic devices, their classification is well
defined in each local regulation, which usually provides the class cor-
responding to the assay or reagent (and the associated equipment).
For instance, GHTF has a separate risk based classification.
Europe uses risk assessment from 10 years ago. Health Canada has
a separate classification for IVD but bringing them individually into
the generic 4 risk classes.
In vitro Diagnostic (IVD) product means any reagent product,
calibrator, control material kit, instrument, apparatus, equipment or

Whatistheproductintendeduse?

Deviceincorporatinga
medicinalsubstancewhich
has an ancillary action ClassD
Productnotclassifiedas Istheintended
NO Devicemanufacturedfrom
MD useachieved
ÎToberegulatedunder orincorporatinganimal ClassD
bymechanical
Drugsorotherregulation mean? tissues,cellsorderivatives
asapplicable
ClassD
Ifthedeviceincorporates
humanbloodderivative
YES ClassC
Forcontraception
ClassA Nocontactwith
Implantable/Longterm ClassD
patient/intactskin NO
Isthe
ClassA Channelling/storing device Tosterilize/disinfectMD ClassB
foradministration/ invasive?
infusion
Bloodbags ClassC

YES
ClassA Modify
biological/chemical
compositionof TransientUse(<60minutes) ClassA
blood/bodyliquid Invasive YES
inbody ShortTerm(<30days) ClassB
ClassA Incontactwith orifice?
injuredskin LongTerm(>30days) ClassC
NO

TransientUse(<60minutes) ClassB
Surgically
YES
Invasive? ShortTerm(<30days) ClassB

LongTerm(>30days) ClassC
OrImplant
Ifindirectcontactwith
ClassD
Heart,orCentral
Circulatory/NervousSystem
Figure 11.1 Steps to be considered while carrying out medical device

classification.

Main Classifications
Figure 11.2
105
Classification of rules for active medical devices.

system, whether used alone or in combination, that is intended by its

product owner to be used in vitro for the examination of specimens,
including blood and tissue donations, derived from the human body,
solely or principally for
(i) providing information concerning a physiological or
pathological state,
(ii) providing information concerning a congenital abnormality,
(iii) determining the safety and compatibility of donations, including
blood and tissue donations, with potential recipients, or
(iv) monitoring therapeutic measures
and includes a specimen receptacle but not a product for general
laboratory use, unless that product, in view of its characteristics,
is specifically intended by its product owner to be used for in vitro
diagnostic examination.
According to GHTF standards [7], IVD medical devices are
classified into four classes, based on the individual risk and public
health risk level (Table 11.1).
Table 11.1 Classification system for IVD Medical Devices
Class Risk level Device examples

A Low individual risk and low Clinical chemistry analyser, prepared
public health risk selective culture media
B Moderate individual risk Vitamin B12, pregnancy self-testing,
and/or low public health risk anti-nuclear antibody. urine test strip
C High individual risk and/or Blood glucose self testing, HLA typing,
moderate public health risk PSA screening. Rubella
D High individual and high HIV blood donor screening, HIV blood
public health risk diagnostic
11.2.4 IVD Case Study

IVDs are medical devices intended to perform diagnoses from
assays in hematology, immunology, microbiology, etc. Table 11.2
Table 11.2 Classification overview of Chlamydia serological reagents in
different legislations
Country/
region
US Canada EU Singapore
Class Class I Class III List B Class C
Rule 21CFR866.3120 Rule 2(b) (ii) of Directive GN-14 Guidance on
SOR/ 98/79/EC the Risk Classification
98-282) — Annex. II of in vitro Diagnostic
SCHEDULE 1 Medical Devices
(Section 6)
Main Classifications 107
illustrates the Chlamydia serological reagents. The exercise

conducted around it aimed to determine its classification within
different regulations; the rules which served as a reference to
determine the class are highlighted.
11.2.4.1 US FDA
• Rule: 21CFR866.3120 [10]:
Title 21 — Food And Drugs: Chapter I — Food And Drug Administra-
tion Department Of Health and Human Services Subchapter
H — Medical Devices Part 866 — Immunology and Microbiology
Devices
Subpart D — Serological Reagents
Sec. 866.3120 Chlamydia serological reagents.
(a) Identification. Chlamydia serological reagents are devices that
consist of antigens and antisera used in serological tests to
identify antibodies to chlamydia in serum. Additionally, some
of these reagents consist of chlamydia antisera conjugated
with a fluorescent dye used to identify chlamydia directly
from clinical specimens or cultured isolates derived from
clinical specimens. The identification aids in the diagnosis of
disease caused by bacteria belonging to the genus Chlamydia
and provides epidemiological information on these diseases.
Chlamydia are the causative agents of psittacosis (a form
of pneumonia), lymphogranuloma venereum (a venereal
disease), and trachoma (a chronic disease of the eye and
eyelid).
(b) Classification. Class I (general controls).
11.2.4.2 Canada
• Medical Devices Regulations (SOR/98-282) [9] SCHEDULE 1
(Section 6) Classification Rules for Medical Devices Part 2, in vitro
Diagnostic Devices Use With Respect to Transmissible Agents
• Rule 2(b) (ii):
An IVDD that is intended to be used to detect the presence of, or
exposure to, a transmissible agent is classified as Class II, unless
(a) it is intended to be used to detect the presence of, or exposure
to, a transmissible agent that causes a life-threatening disease
if there is a risk of propagation in the Canadian population, in
which case it is classified as Class IV; or
(b) it falls into one of the following categories, in which case it is
classified as Class III:
(i) it is intended to be used to detect the presence of, or

exposure to, a transmissible agent that causes a serious
disease where there is a risk of propagation in the
Canadian population,
(ii) it is intended to be used to detect the presence of, or
exposure to, a sexually transmitted agent,
(iii) it is intended to be used to detect the presence of an
infectious agent in cerebrospinal fluid or blood,
or
(iv) there is a risk that an erroneous result would cause death
or severe disability to the individual being tested, or to the
individual’s offspring.
11.2.4.3 EU
Directive 98/79/EC [3] — Annex II — List of Devices Referred to in
Article 9(2) and (3)
• Rule: List B
— Reagents and reagent products, including related calibrators
and control materials, for determining the following blood
groups: anti-Duffy and anti-Kidd,
— reagents and reagent products, including related calibrators
and control materials, for determining irregular anti-
erythrocytic antibodies,
and control materials, for the detection and quantification in
human samples of the following congenital infections: rubella,
toxoplasmosis,
and control materials, for diagnosing the following hereditary
disease: phenylketonuria,
 reagents and reagent products, including related
calibrators and control materials, for determining the
following human infections: cytomegalovirus, chlamydia,
and control materials, for determining the following HLA
tissue groups: DR, A, B,
and control materials, for determining the following tumoral
marker: PSA,
— reagents and reagent products, including related calibrators,
control materials and software, designed specifically for
evaluating the risk of trisomy 21,
Medical Device Classifications 109
— the following device for self-diagnosis, including its related

calibrators and control materials: device for the measurement
of blood sugar.
11.2.4.4 Singapore
Health Sciences Authority GN-14 Guidance [4] on the risk classi-
fication of in vitro Diagnostic Medical Devices
• Rule: 2
Tests to detect infection by HIV, HCV, HBV, HTLV. This Rule applies to
first-line assays, confirmatory assays and supplemental assays.
Rule 2: IVD medical devices intended to be used for blood
grouping, or tissue typing to ensure the immunological compatibility
of blood, blood components, cells, tissue or organs that are intended
for transfusion or transplantation , are classified as Class C, except
for ABO system [A (ABO1), B (ABO2), AB (ABO3)], rhesus system
[RH1 (D), RH2 (C), RH3 (E), RH4 (C), RH5 (e)], Kell system [Kel 1
(K)], Kidd system [JK 1 (Jka), JK2 (Jkb0)] and Duffy system [FY1
(Fya), FY2 (Fyb)] determination which are classified as Class D.
Rationale: The application of this rule as defined above should
be in accordance with the following rationale: A high individual risk,
where an erroneous result would put the patient in imminent life-
threatening situation places the device into Class D. The rule divides
blood-grouping IVD medical devices into two subsets, Class C or
Class D, depending on the nature of the blood group antigens the
IVD medical device, is designed to detect, and its importance in a
transfusion setting.
11.3 Medical Device Classification:

Practical Examples
Figures 11.3–11.8 provide examples of the way to use the classifi-
cation decision trees provided in the various guidelines when
classifying a medical device. These examples focus on one type of
medical device (i.e. a syringe). Depending on its intended use, a
simple syringe can be classified in each of the categories, from the
lowest one (lower risk) to the highest one (higher risk). The rules
taken as reference for this case study are the ones from the European
regulation as laid down in Appendix IX of the Medical Devices
Directive 93/42/EEC with the supporting charts from the MEDDEV
2.4/1 Rev. 9 Guidance [6].
110
Syringeȱwithoutȱneedleȱ
Intendedȱuse:ȱchannelȱorȱstoreȱsubstancesȱwhichȱwillȱeventuallyȱbeȱadministeredȱtoȱtheȱ
body;ȱtypically,ȱitȱcanȱbeȱusedȱinȱtransfusion,ȱinfusion,ȱextracorporealȱcirculationȱ
Invasive?ȱȱ
NOȱ
Ruleȱ2:ȱChannellingȱorȱstoringȱforȱeventualȱadministrationȱ
ClassȱIȱ
ȱ
Invasive?ȱȱ
NOȱ
ClassȱIȱ

Figure 11.3
Figure11.3.ȱ
Medical Device Classification
MEDDEV 2.4/1 Rev. 9 — Non-Invasive Devices.

111
112
Intendedȱuse:ȱchannelȱorȱstoreȱsubstancesȱwhichȱwillȱeventuallyȱbeȱadministeredȱtoȱtheȱ
body;ȱtoȱbeȱusedȱonȱinfusionȱpumpsȱ
Invasive?ȱȱ
NOȱ
Itȱmayȱbeȱconnectedȱtoȱanȱactiveȱmedicalȱdeviceȱ(infusionȱpump)ȱ
ClassȱIIaȱ
ȱ
Itȱmayȱbeȱconnectedȱtoȱanȱactiveȱmedicalȱdeviceȱ(infusionȱpump)ȱ
ClassȱIIaȱ
Figure
ȱ 11.4

MEDDEV 2.4/1 Rev. 9 — Non-Invasive Devices
113
114
Intendedȱuse:ȱdeliverȱoralȱmedicationȱ
Invasive?ȱȱ
YESȱ
Invasiveȱinȱbodyȱorifice?ȱ
YESȱ
TransientȱUse?ȱ
YESȱ(theȱtheȱsyringeȱisȱaimedȱtoȱbeȱusedȱforȱlessȱthanȱ60ȱminutes)ȱ
ClassȱIȱ
ȱ
ȱ
ȱ
ȱ
ȱ
ȱ
YESȱ
TransientȱUse?ȱ
YESȱ(theȱtheȱsyringeȱisȱaimedȱtoȱbeȱusedȱforȱlessȱthanȱ60ȱminutes)ȱ
ClassȱIȱ
ȱ
ȱ
ȱ
ȱ
ȱ
ȱ
Figure 11.5
MEDDEV 2.4/1 Rev. 9 — Invasive Devices.

115
116
Syringeȱwithȱneedleȱ
Intendedȱuse:ȱtoȱadministerȱsubstancesȱtoȱtheȱbodyȱ
Invasive?ȱȱ
YESȱ
NOȱ
Surgicallyȱinvasive?ȱ
YESȱ
TransientȱUse?ȱ
for less than 60

YESȱ(theȱsyringeȱisȱaimedȱtoȱinjectȱmedicineȱinȱlessȱthanȱ60ȱ
minutes)ȱ
ȱ ClassȱIIaȱ
ȱ
ȱ
TransientȱUse?ȱ
YESȱ(theȱsyringeȱisȱaimedȱtoȱinjectȱmedicineȱinȱlessȱthanȱ60ȱ
minutes)ȱ
ȱ ClassȱIIaȱ
ȱ
ȱ

Figure11.6.
Figure 11.6 MEDDEV 2.4/1 Rev. 9 — Surgically Invasive Devices.

117
118
Syringeȱwithȱneedleȱ
Intendedȱuse:ȱtoȱadministerȱorȱwithdrawȱsubstancesȱinȱtheȱspineȱ
Invasive?ȱȱ
YESȱ
NOȱ
Surgicallyȱinvasive?ȱ
YESȱ
TransientȱUse?ȱ
YESȱ(theȱsyringeȱisȱaimedȱtoȱbeȱinȱcontactȱwithȱtheȱbodyȱinȱlessȱ
thanȱ60ȱminutes)ȱ
ForȱuseȱinȱdirectȱcontactȱwithȱtheȱCentralȱNervousȱSystemȱ
ȱ ClassȱIII
ȱ
ȱ
ForȱuseȱinȱdirectȱcontactȱwithȱtheȱCentralȱNervousȱSystemȱ
ȱ ClassȱIII
ȱ
ȱ
ȱ

Figure 11.7
Figure11.7.MEDDEV 2.4/1 Rev. 9 – Surgically Invasive Devices.
119
120
Syringeȱwithoutȱneedle,ȱpreȬfilledȱwithȱSodiumȱChlorideȱSolutionȱ
Intendedȱuse:ȱtoȱrinseȱvascularȱaccessȱdevicesȱ
Mechanical?ȱ
ȱ YESȱ(rinsing,ȱflushingȱcatheters)ȱ
Deviceȱincorporatingȱaȱsubstance,ȱwhich,ȱifȱusedȱseparately,ȱcanȱbeȱconsideredȱtoȱ
beȱaȱmedicinalȱproduct,ȱandȱwhichȱactsȱonȱtheȱhumanȱbodyȱwithȱanȱancillaryȱ
actionȱ
ȱ ClassȱIIIȱ
Mechanical?ȱ
ȱ YESȱ(rinsing,ȱflushingȱcatheters)ȱ
Deviceȱincorporatingȱaȱsubstance,ȱwhich,ȱifȱusedȱseparately,ȱcanȱbeȱconsideredȱtoȱ
beȱaȱmedicinalȱproduct,ȱandȱwhichȱactsȱonȱtheȱhumanȱbodyȱwithȱanȱancillaryȱ
actionȱ
ȱ ClassȱIIIȱ
Figure 11.8
Figure11.8.

MEDDEV 2.4/1 Rev. 9 — Special Rules.

121
Note: If the syringe is prefilled with a drug, the entire combination is

reviewed under the pharmaceutical legislation in Europe. If it would
be filled with degradable hyaluronic acid for injections in knees
as lubricant, they would be class III, based on rule 8; filled with
bovine collagen they would be class III under rule 17 and animal
tissue directive would be applicable as well.
References
1. Classification of Medical Devices in Europe — An Overview Dr Jaap

Laufer, President, European Medical Device Consultants (EMDC).
2. Council of the European Parliament (5 September 2007) Directive
2007/47/EC of the European Parliament and of the Council of 5
September 2007 amending Council Directive 90/385/EEC on the
approximation of the laws of the Member States relating to active
implantable medical devices, Council Directive 93/42/EEC concerning
medical devices and Directive 98/8/EC concerning the placing of
biocidal products on the market, Official Journal of the European
Communities OJ L247 p. 21.
3. Council of the European Parliament (27 October 1998), Directive
98/79/EC of The European Parliament and of The Council of 27
October 1998 on in vitro diagnostic medical devices, Official Journal of
the European Communities OJ L331 p. 1.
4. GN-14 Guidance on the Risk Classification of In Vitro Diagnostic
Medical Devices Revision 1 (2008). Medical Device Guidance, Health
Sciences Authority, Singapore.
5. Guidance Notes: GN-01 Overview of the Medical Device Administrative
Control System Government of the Hong Kong Special Administrative
Region, The People’s Republic of China Date of Issue: 1 September
2005, Department of Health.
6. European Commission — DG Health and Consumer — Directorate B,
Unit B2 “Cosmetics and medical devices” — June 2010 MEDDEV 2. 4/1
Rev. 9 — Guidelines Relating to the Application of the Council Directive
93/42/EEC on Medical Devices, OJ L 169, 12.7.1993, p. 1.
7. Principles of IVD Medical Devices Classification SG1 Final Document
GHTF/SG1/N045:2008, Global Harmonization Task Force.
8. SG1(PD)/N77R4 Global Harmonization Task Force — (Revision
of GHTF/SG1/N15:2006) Title: Principles of Medical Devices
Classification — Authoring Group: Study Group 1 of the Global
Harmonization Task Force — Date: October 3, 2011.
References 123
9. Medical Devices Regulations (SOR/98-282) Schedule 1 (Section 6)

Classification Rules for Medical Devices Part 2, in vitro Diagnostic
Devices Use With Respect To Transmissible Agents. Retrieved 06 April
2012, from: http://laws.justice.gc.ca/eng/regulations/SOR-98-282/
page-23.html#h-68.
10. Title 21 — Food And Drugs: Chapter I —Food And Drug Administration
Department Of Health And Human Services Subchapter H—Medical
Devices Part 866 — Immunology And Microbiology Devices Subpart
D — Serological Reagents Sec. 866.3120 Chlamydia Serological
Reagents. Code of Federal Regulations, Revised as of April 1, 2011,
CITE: 21CFR866.3120. Retrieved 06 April 2012, from: http://www.
accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?
fr=866.3120.
Chapter 12
ISO 13485:2003
Medical Devices — Quality Management
Systems — Requirements for Regulatory
Purposes
Ann Goodall and Gert Bos

British Standards Institution (BSI) — Healthcare,
Kitemark Court, Davy Avenue, Knowlhill, Milton Keynes, MK5 8PP, UK
ann.goodall@bsigroup.com, gert.bos@bsigroup.com
This chapter describes the origin, implementation and use of

the quality management system requirements in medical device
globally based on a commonly used standard 13485 [1].
12.1 Introduction
A standard is, in essence, an agreed repeatable way of doing
something. It is a document, published after collective work from
one or more committees, which contains a technical specification
or other precise criteria designed to be used consistently as a
rule, guideline, or definition. Standards help make life simpler
and to increase the reliability and the effectiveness of many goods
and services we use. Standards are created by bringing together
the experience and expertise of all interested parties such as the

www.panstanford.com
126 ISO 13485:2003 Medical Devices — Quality Management Systems
producers, sellers, buyers, users and regulators of a particular

material, product, process or service.
Standards are designed for voluntary use and do not impose
any regulations. However, laws and regulations may refer to certain
standards and make compliance with them compulsory.
The current basis for quality management systems is ISO 9000,
which was first published in 1987. ISO 9001, which was based on the
BS 5750 series of standards from the British Standards Institution
(BSI), was proposed to ISO in 1979. However, Historically, ISO 9000
can be traced back some twenty years before that, to the publication
of the UK Department of Defence MIL-Q-9858 standard in 1959 that
through the NATO AQAP series of standards in 1969, the BS 5179
series of standards (1974), led to the development of BS 5750.
BSI has been certifying organizations for their quality
management systems since 1978, and the first ever issued
certification (FM 00001) still exists.
12.2 Background and Origins of ISO 13485:2003

ISO 13485:2003 is a Quality Management System (QMS) for medical
devices specifically for regulatory purposes and whilst based
upon the ISO9001:2000 quality management system standard is a
standalone standard.
ISO13485:1996 was published by the International Standards
Organisation Technical Committee 210 Working Group 1, following
alignment with ISO9001:1994 — Quality Systems — Requirements.
During December 2000, ISO 9001:2000 was published replacing
the ISO9001:1994 series. There was a three-year transition period
before the 1994 versions (ISO9001:1994 — complete MS-, EN
ISO 9002:1994 — exclusion or design — and EN ISO 9003:1994
— exclusion for design and manufacturing) were withdrawn for
those organisations that were already certified to the standards. The
ISO 13485:1996 standard made reference to ISO9001 throughout
and as such was not a standalone standard, but rather provided
additional requirements for the medical device industry. There
was also ISO 13488:1996, which was aligned to ISO 9002:1994, in
essence focussing on all QMS aspects with the exception of design.
During April 2000, ISO 13485:1996 and ISO 13488:1996 were
adopted as European standards and replaced the then existing
Background and Origins of ISO 13485:2003 127
sector specific European standards (i.e. EN 46001, EN46002,

EN46003). Europe changed the harmonised reference to the
European medical Devices Directives to the ISO series away from
the European Norms.
ISO 13485:2003 is published by various organisations and
when it is published by those organisations, this is recognised by
letters being placed before the ISO 13485:2003. For example in the
United Kingdom it is published by British Standards Institution
(BSI) and this is denoted by the Standard being BS ISO 13485:2003
and as it is also a European Norm it is published as BS EN ISO
13485:2003.
Some of the changes that had been introduced with the
publication of ISO9001:2000, including the reduction in the
number of required documented procedures and the inclusion of
concepts such as customer satisfaction and continual improvement,
were not in alignment with the regulatory requirements for
medical devices. The option of revising ISO 13485 and ISO 13488
in alignment with ISO 9001:2000 was considered but thought not to
be appropriate and so the Technical committee decided that ISO
13485 should become a standalone standard (Fig. 12.1). This meant
that in order to fulfil the regulatory requirements organization did
not have to have certification to ISO 9001 as well as ISO 13485/8.
Figure 12.1 Initiation of a standalone healthcare QMS standard.

The standard ISO 13485:2003 Medical Devices — Quality

Management Systems — Requirements for Regulatory Purposes is
now becoming the certification standard of choice for medical device
manufacturers. The requirements are specific to organisations
that are providing medical devices or services to the medical
device industry and this does not depend on the size or type of the
organisation.
12.3 Management Systems Standard [2]

While ISO 13485:2003 is a standalone standard, it is based on ISO
9001:2000. Sub-Clause 3.1 of ISO 13485:2003 explains that those
(sub-) clauses in ISO 13485:2003 quoted directly and unchanged
from ISO 9001:2000 are in normal font. Where the text of ISO
13485:2003 differs from the text of ISO 9001:2000, the sentence
or indent containing the text as a whole is shown in blue italics.
The nature and reasons for the differences are noted in Annex B of
the standard, providing further insight useful in implementing ISO
13485:2003.
The main difference between ISO 13485:2003 and ISO
9001:2000 is related to customer satisfaction and continuous
improvement. These are not included in ISO 13485:2003. In ISO
13485:2003, processes are required for ensuring continuing
effectiveness of the quality system to meet customer and regulatory
requirements instead of continual improvement. The standard also
promotes active systems for customer feedback related to if the
organization is meeting customer and regulatory requirements.
In addition, the requirements of ISO 13485:2003 include many
more requirements for documented procedures, documented
requirements and records. This is due to the nature of the standard,
i.e., it is there to support meeting regulatory requirements.
The relationship between ISO 9001:2008 and ISO 13485:2003
is evaluated in more detail in ISO/TC 210 N382 — Explanation
of Differences Between ISO 13485:2003 and ISO 9001:2008. In
moving ISO 9001 to the next level, there might well be more
divergence between the two related standards in the future, as
elements of added value auditing that might be introduced in
ISO 9001 would not be directly related to the purpose of meeting
regulatory requirements that forms the basis of ISO 13485.
Quality Management Systems 129
12.4 Quality Management Systems

Quality management systems consist of common elements that are
expressed as the organizational structure, processes, procedures,
work instructions and resources needed to implement quality
management (Fig. 12.2).
Figure 12.2 Essence of quality management system.
Shared elements of the organizational structure, authorities and

responsibilities, methods and processes, data management, resources,
training, maintenance, customer satisfaction/requirements, product
quality and continuous improvement are based on eight principles
of quality management:
(i) Customer and regulatory focus: By understanding current
and future customer needs, organisations can meet their
requirements whilst ensuring that all known applicable
regulations are applied.
(ii) Leadership on purpose and direction: Leaders, by
establishing unity of purpose and direction of the organization,
should create and maintain the internal environment in
which people can become fully involved in achieving the
organizations objectives.
(iii) Involvement of people at all levels: People are the essence

of an organization and their full involvement enables best
performance in the organisation.
(iv) Process approach to resources and activities: This principle
commonly leads to the PDCA approach of Plan–Do–Check–
Act.
(v) Systems approach to management: The core in the system’s
smooth running is identifying, understanding and managing
inter-related processes of a system as it contributes to the
organizations effectiveness and efficiency in achieving its
objectives and reducing overall process risks.
(vi) Factual approach to decision making: Decisions based on
analysis of data and information are typically more effective.
Monitoring and measuring will allow an organization to
understand its ability to supply a safe and effective product
and service.
(vii) Mutually beneficial supplier relationships: An organization
is responsible for ensuring control of its outsourced processes,
and with increasing regulatory pressure, supply chain
management truly becomes one of the keys to success.
(viii) Improvement as an ongoing objective: Long withheld
in medical device industry, legislation is now changing to
stimulate product improvement in a continuous effort.
12.5 ISO 9000 and ISO 13485 Quality

Management System Family of Standards
ISO 13485:2003 is commonly seen as part of the 9000 series of
standards, despite it being a standalone standard. This means that
effective implementation can best be achieved by combining the
requirement of ISO 13485 with the content, views and guidance of a
series of adjacent standards, representing further detail and in some
cases national variations:
(i) BS EN ISO 9000:2000 describes the fundamentals and
vocabulary.
(ii) BS EN ISO 9001:2000 provides the basic QMS requirements.
(iii) BS EN ISO 9004:2000 provides guidelines for performance
improvement beyond general QMS requirements.
ISO 13485:2003 and Regulatory Requirements Around the World 131
(iv) BS EN ISO 19011:2011 provides guidelines for quality and/

or environmental management systems auditing, including
internal audits.
(v) ISO/TR14969:2004 provides guidelines for application of
ISO13485:2003.
In addition there is a standard used to supervise third party
assessment bodies that audit against e.g. ISO13485:2003:
(i) ISO/IEC 17021:2006 provides requirements for bodies
providing audit and certification of management systems.
12.6 ISO 13485:2003 and Regulatory

Requirements Around the World
With the increasing use of ISO13485:2003 by regulatory
authorities worldwide, the use of the standard by manufacturers
and other organizations is increasing. ISO13485:2003 supports
the regulatory compliance in several countries including the
European Union for CE marking, Australia, Canada and Taiwan.
Japanese Ministerial Ordinance (MO) No. 169 is similar to ISO
13485. In Europe it is a harmonised standard for the three
medical devices directives, which means that adhering to it for the
quality management systems aspects identified in these directives
there is a presumption of conformity, details of which are specified
in the so-called annexes Z found at the back of the European
versions of the standards. For the USA ISO 13485:2003 is an option
and may typically be the basis for the QMS that is used by many
manufacturers, but it is not a distinct requirement. It can also be
used for low risk devices manufacturers that are exempt from QSR’s
21 CFR 820. The US FDA has been cooperating closely with the
development of ISO 13485, in the attempt to further align ISO 13485
and QSR (Quality System Regulations) requirements.
With the growing interest in regulatory regimes in the
Middle East, Asia, Africa, and Latin America, many more regulatory
requirements are added to the equation. ISO 13485:2003 certifica-
tion is a great tool to harmonise the various QMS requirements from
all these existing and developing legislations, as it is very easy for
national regulators to add some country specific requirements to
the general framework provided in the global standard.
12.7 Good Reasons to Implement an ISO

13485:2003 Quality Management System
There are various reasons why an organisation implements a certi-
fied ISO13485:2003 quality management system, and this primarily
includes meeting regulatory requirements when registering medi-
cal devices worldwide. In addition, it might help improve customer
confidence and increase the organisation’s competitive edge. As such
it makes good business sense and forms an excellent basis for an effi-
cient and effective business to be certified against ISO 13485:2003.
A well-implemented ISO13485-based QMS supports regulatory
compliance and improves customer confidence. It improves the
consistency and stability of the processes used by the organisation. It
can reduce waste and defects and improve employee motivation and
participation and is a basis for monitoring, managing or potentially
improving the performance of suppliers.
12.8 Process Approach

A process is a set of interrelated or interacting activities that uses
resources to transform inputs into outputs. The process approach
systematically identifies and manages the linkage, combination,
and interaction of a system of processes within an organization, as
depicted in Fig. 12.3, linking the various parts of ISO 13485:2003
in a generic process flow. The QMS documentation will reflect the
actual process flows of the particular organisation.
Figure 12.3 Process interactions as depicted in ISO/TR 14969 [3].

Planning the Implementation 133
The process model of the Plan–Do–Check–Act cycle is used in

the ISO13485:2003 standard to link Clauses 4 to 8 of the standard
(Fig. 12.4). It is used to show how the requirements of customers
and regulatory authorities can be meet.
Figure 12.4 PDCA for your processes.
The process approach considers the importance in understand-

ing and meeting requirements by looking at processes in terms
of the value that they can add, in measuring the performance of
processes, determining if that process is effective and by the use of
the objective measurement of processes to improve that process.
12.9 Planning the Implementation

The implementation process begins with the assumption that the
decision to implement has already been taken. Best practice traces
back the origin of the decision to implement and the underlying
causes or views, such as supply chain requirement, regulatory
requirement, or desire to improve performance, reduce waste, etc.
Some initial general steps for a successful implementation
effort would include knowing how to interpret the ISO 13485:2003
requirements for your system, ensuring team members are
knowledgeable on the current system, arranging management
commitment, and developing a comprehensive project plan which
includes monitoring steps. Where needed training should be

provided to staff to enhance their knowledge and to boost their
commitment which is crucial to the successful implementation
and continuing compliance to the requirements of the standard.
Key elements would include promoting awareness, performing
a critical gap analysis and following effective implementation of
course getting ready for continually improving the system, where
regulatory requirements allow.
The ultimate assessment and verification of the first
implementation is in a round of internal audits followed by a
management review concluding the effectiveness of the QMS.
12.10 Scope, Exclusions and Non-Applicability

ISO 13485:2003 can be applied to any organisation who wishes to
demonstrate the ability to provide medical devices and/or related
services that meet customer and regulatory requirements ISO
13485:2003. ISO13485:2003 can be applied irrespective of type
or size. Providing it is permitted in the regulatory requirements
that apply to the organisation that is implementing ISO13485:2003
exclusions are permitted. Organisations can exclude design and
development controls, Clause 7.3 but the justification for the
exclusions must be clearly documented in the organisations quality
system and must be an appropriate exclusion for any regulatory
system being followed. Other clauses can be excluded if they are not
applicable, e.g. sterilisation if the manufacturer does not produce
sterile medical devices.
12.11 Document Control

To be efficient and effective, an organisation has to manage how
to ensure that those working within that organisation carry out
the process in a consistent way. This includes both large and
small organisations. In a large organisation, this means that tasks
are completed in the same systematic way. Large organisations
or those with complicated processes will benefit significantly
with the adoption and implementation of an appropriate quality
management system.
Management Responsibility 135
Section 4.2 of ISO13485:2003 describes the requirements

for documents and records that are used to support the quality
management system, which very often is divided into four tiers
with their own types of documentation (Fig. 12.5).
Figure 12.5 Typical four-tier quality management system setup.
12.12 Record Completion and Control

Quality records are an important part of any quality manage-
ment system and especially in ISO13485:2003 as they are the
evidence that that activities that are required as part of the qual-
ity management system have been completed. Requirements for
records are referenced in at least 50 places within the standard, but
many organizations will have the need for records for other
aspects of the quality management system due to the nature of the
business.
12.13 Management Responsibility

The emphasis in Clause 5 is on the role of top management of the
organisation within the quality management system in ensuring
that the system remains effective and is maintained and that
customer and regulatory requirements are met by the organisation.
Top management has to ensure that the organisations quality

policy is defined and that this is linked to the quality objectives of
the organisation. A management representative is appointed by top
management.
Reviews are conducted at planned intervals and in the standard
the aspects of the quality management system that should be
considered at these reviews are defined.
12.14 Resource Management

It is important for any organisation to have adequate resources
to be able to meet the customer and regulatory requirements and
these needs to ensure that the requirements of the products are
met. These should include the effective initiation of the resources
and their continued maintenance to support the processes of the
quality management system. It is the role of top management to
ensure that the appropriate resources are available.
There are many aspects to resources they can be people,
infrastructure, work environment, information, suppliers and
partners, natural and financial resources. Even if these resources
are outsourced they have to be managed by the organisation like the
processes that are within the organisation.
12.15 Product Realisation

Product realisation includes all the processes that bring the
product or service to the customer. These include planning,
understanding customer requirements, communicating with
customer, the design and development of the product or service,
purchasing of the materials and services, production/manufacturing,
delivery of the products/service and calibration of any equipment
that is used.
12.16 Risk Management [4, 5]

The only place where risk management is identified within ISO
13485:2003 is under the planning of product realisation. Risk
management is a requirement throughout product realisation.
Design and Development 137
The requirements for risk management must be documented and

records of the risk management must be retained. It ultimately
forms the basis of the decision to place a product on the market or to
refrain from it, depending on the outcome of the final risk to clinical
benefit evaluation (Fig. 12.6).
Figure 12.6 Essential steps in risk management.
There is a standard which gives guidance on risk management:

ISO 14971:2007 Medical Devices — Application of Risk Management
to Medical Devices. Further guidance on how to integrate risk
management throughout the entire QMS can be found in GHTF
guidance from Study Group SG3.
12.17 Design and Development

The design and development process includes all aspects of
the process of bringing the product or service from the original
concept of the idea and ensuring that is in line with the user and
regulatory requirements through to that product or service that
is available to customer and then how any changes to that design
are managed.
In order to do this, there are various aspects that are
identified within the requirements of ISO 13485:2003. These are:
(i) Planning (v) Verification
(ii) Inputs (vi) Validation
(iii) Outputs (vii) Control of change
(iv) Review
12.18 Purchasing and Supplier Control [6]

The management of suppliers and the materials or services
received from those suppliers is critical to the organization and the
quality of the product and service supplied by the organization to
their customers.
The GHTF has published guidance on the Control of Products
and Services Obtained from Suppliers. The guidance describes the
process of establishing controls for products and services obtained
from suppliers. This typically comprises six phases as follows:
(i) Planning
(ii) Selection of potential supplier(s)
(iii) Supplier evaluation and acceptance
(iv) Finalization of controls
(v) Delivery, measurement and monitoring
(vi) Feedback and communication, including corrective action and
preventive action process
When an organization outsources the process, they still
remain responsible for that process. They must ensure that
the processes remain suitable and effect as part of the quality
management system. They need to ensure that that the product
requirements are not effected as a result of outsourcing that process
as the manufacturer is responsible for the product throughout
the time the product is being managed by the subcontractor. For
example, if the design process is being out sourced the business
that is outsourcing the process would need to have involvement
in defining the design inputs to ensure that the customer and
regulatory requirements are met. Other key processes that may be
outsource or subcontracted are sterilization or distribution
12.19 Production and Service Provision

The standard clearly calls out to plan and carry out provisions
under controlled conditions, including availability of information
describing product characteristics, availability of documented
procedures, work instructions, and reference standards, use of
suitable equipment and use of measuring and monitoring devices.
As for controlled environments used, there is no clear guidance,
but applied conditions should be found suitable in the process
risk assessment and appropriate to the final use of the device.
Monitoring and Measuring, Including Internal Audits and Management Review 139
Clearer requirements are provided on the validation need

for the processes for production and service provision (usually
following a master validation plan approach), identification and
traceability, customer property including drawings and IP, and the
preservation of the product.
For many medical devices, ensuring that the device is stored and
handled so that the performance of the device is maintained is im-
portant. Preservation of products covers many perspectives includ-
ing storage at the defined temperature, making sure the product re-
mains sterile, protection of fragile products. In order to be able to do
this, the organisation has to understand the requirements specific
to the product, for example, what temperature range the product
should be stored at and how the product should be protected if it
is fragile. Any special storage conditions have to be controlled and
recorded. What this means is that the area where the product is
stored it need to be known to be capable of maintaining that tem-
perature range throughout whether is it a refrigerator or freezer or
a walk-in freezer and it has to have been qualified to show that it
maintains the temperature range throughout.
12.20 Monitoring and Measuring, Including

Internal Audits and Management Review
The quality management system needs to be implemented to
a high level before internal audits are conducted. Of course, to
conform to ISO 13485:2003, an internal audit program must
be operational, helping the organization investigate any quality
problems and verify solutions are effectively implemented. Periodic
audits also keep the quality awareness level of staff high and foster
improved internal communications.
The internal audits are expected to cover all areas and all shifts,
auditing some areas more often based on previous results, whilst
increasing audit frequency for changed or high-risk areas. ISO 19011
can serve as guidance.
Based on the internal audits and further management
information, top management arranges the management review
to come to a supported conclusion towards the (continuing)
effectiveness of the QMS as well as to ensure continuing suitability.
The standard identifies minimum requirements to be taken into the
review including also any new or revised regulatory requirements
for any country the company sells products or provides service to.
Records of such reviews are kept, including action lists and their
follow up activities.
12.21 Control of Non-Conforming Product

Non-conforming product needs to be identified and controlled to
prevent its unintended use or delivery. Controls and responsibilities
need to be defined in a documented procedure that should arrange
for action taken to eliminate the detected non-conformity and for the
authorization of non-conforming product’s use, release or acceptance
by concession. Such acceptance of non-conforming product by
concession can only be signed off if regulatory requirements,
including a dedicated risk assessment, are met and the identity of
the person authorizing the concession is identified and recorded.
12.22 Analysis of Data

The intent of this section is to stimulate the manufacturer to collect
and analyze data on the quality system, both from the inside (e.g.
production inspections), as well as from external sources which
include complaint handling and more active ways of post market
surveillance. It further supports the demonstration of the suitability
and effectiveness of the QMS. In many cases, a selection of the
analysed data might well be used to stimulate quality awareness and
motivate staff to further improve quality and efficiency.
12.23 Improvement: Corrective Action and

Preventive Action
Following the documented procedure for corrective action
and recording the results of the action taken will allow quick
identification of any findings in one area. This can potentially
help the remaining areas to avoid a similar problem (and reduce
the number of reported non-conformities in ISO 13485:2003
certification assessments). The correction is the immediate remedy
to a non-conformity, e.g. clearing an uncontrolled messy area. The
corrective action, which follows the root cause analysis (e.g. using
Achieving Certification and Continuing to Maintain Certification 141
the five-why method), is the sum of measures that will ensure the
same non-confirming situation does not re-occur. A different part
of the improvement system are the preventive actions, which in a
similar way work to ensure a non-conforming situation does not
occur, but based on rationales and other input, not stemming from
an existing non-conformity.
Clear distinction should be made between cases where some
non-conforming situation was found, where correction and or
corrective action to prevent reoccurrence are warranted, and the
cases where no non-conformity was found but where preventive
action can prevent a non-conformity from happening at all.
12.24 Purpose and Goal of ISO 13485:2003

Certification
Formal certification is achieved only through external (third
party) assessment by a Certification Body. Certification can only be
achieved after correct preparation for the initial audit, which is a
two-stage event comprising a readiness review followed by a
complete in-depth audit of all applicable areas of the standard.
Benefits of certification include expanded access to world
markets, the improved ability to bid for contracts, the use as a
market differentiator. The display of the certification mark (e.g.
a symbol granted by the certification body which usually is a
combination of the registrar’s logo and ISO13485) and the evidence
of independent audits by professional, independent certification
bodies designated by an accreditation agency can help to provide a
much greater trust in the company’s ability to provide a consistent
high quality product or service.
These benefits clearly outweigh the barriers to certification
such as the difficulty to identify and create new processes for
the system, development of the necessary documented procedures
and instructions and the resistance by some employees to change
(and process measurements) that are found in most organisations.
12.25 Achieving Certification and Continuing to

Maintain Certification
For an organization to be ready for certification, it is important that
they have fully implemented an ISO13485:2003 QMS and are using
the system. When the QMS is being assessed for certification, the
certification body considers two aspects:
(i) Are all the requirements included in the QMS? This will be
completed by the review of the QMS as it is documented and
by review of the internal audits and management reviews that
have taken place. This is often called a stage 1 assessment or
document review.
(ii) The second stage of the certification process is to show
the effectiveness of the processes that have been put in
place to meet the requirements of the standard. During this
assessment, the organisation has to demonstrate the continual
improvement of the quality management system. This is stage
2 of the assessment.
An organisation needs to be sure that they are ready to
demonstrate both of these aspects. Often organisations try to
complete the process too quickly and do not have sufficient
evidence of the working of the QMS to demonstrate compliance.
Other pitfalls are as follows:
(i) There is insufficient awareness throughout the organisation.
(ii) Top management have not been sufficiently involved to show
that they are taking top management responsibility seriously.
(iii) There has been insufficient training throughout the
organisation to understand what is required.
(iv) The requirements especially related to Clauses 6 and 7 have
not been related to the products or services that the
organisation is manufacturing or delivering.
(v) Internal audits have not been completed of the whole QMS.
(vi) Appropriate metrics and measures have not been put in place
for the analysis of data.
Once an organisation has received its assessment and
achieved certification to ISO1345:2003, this is not the end of
the process. The continuing process of maintaining certification
begins as part of the continual improvement process.
Becoming certified to ISO13485:2003 is a significant
achievement for an organisation and is a cause for celebration.
When the celebrations are over, it is important for everyone in the
company to realise that maintaining the effective implementation
of the quality management system is just as important. This
includes understanding that it is a continuous process that
References 143
everyone is committed to and involved in to ensure that the

requirements of the quality management system continue to be
met.
References
1. ISO 13485:2003 — Medical Devices — Quality Management Systems

— Requirements for Regulatory Purposes.
2. ISO/TC 210 N382 — Explanation of Differences between ISO
13485:2003 and ISO 9001:2008.
3. ISO /TR 14969:2004 — Medical Devices — Quality Management
Systems — Guidance on the Application of ISO 13485: 2003.
4. GHTF SG3/N15R8/2005 — Implementation of Risk Management
Principles and Activities within a Quality Management System.
5. ISO 14971:2007 — Medical Devices — Application of Risk Management
to Medical Devices.
6. GHTF/SG3/N17:2008 Quality Management System — Medical Devices
— Guidance on the Control of Products and Services Obtained from
Suppliers.
Chapter 13
ISO 14971: Application of Risk

Management to Medical Devices
Tony Chana,b,c and Raymond K. Y. Tongd,e

aVirginiaTech, 21520 Yorba Linda Blvd. Suite G288, Yorba Linda, CA 92887, USA
bUS Co-Chair, ISO TC 210 JWG1 Risk Management
cUS Expert Member, IEC TC 56 WG4 Dependability Management
dHong Kong Polytechnic University, Hung Hom, Hong Kong
eAsia Regulatory Professional Association (ARPA)
chant@vt.edu, tchan@agsm-inc.com, k.y.tong@polyu.edu.hk
13.1 Introduction
The development of ISO 14971 was not carried out in a vacuum
but instead was shaped by precedent activities in the European
Union (EU) to establish risk management standards quite early
in the 1990s. The first step made by the EU was the publication in
1997 of a European Standard, EN (European Norm) 1441 on Risk
Analysis for Medical Devices. The framework focused on using a
specific set of methods called Failure Mode and Effect Analysis
(FMEA), for medical device risk analysis. ISO adopted this European
Standard in 1997, when it essentially duplicated its publication under
the title “Medical Device — Risk Analysis,” ISO 14971-1. This standard
was useful for prioritizing activities but remained incomplete
because of its focus on the particular use of a single approach,

www.panstanford.com
146 ISO 14971
Risk Analysis
• Intended use identification

• Safety characteristics identification
• Hazard identification
• Risk estimation for each hazardous
situation
Risk
Assessment
Risk Evaluation
• Risk acceptability decisions
Risk Control
• Option analysis
• Implementation of risk control
measures
• Residual risk evaluation
• Risk/benefit analysis
• Risk arising from risk control measures
• Completeness of risk control
Risk
Management
Overall Residual Risk Evaluation

• Overall residual risk acceptability
decisions
Risk Management Report
• Documented evidence of risk

management plan & review, etc.
Production & Post-production

Information
• Product & Process Transfer

Experience
• Product experience
• Post-production/Field use
experience
• Review of risk management
experience
Figure 13.1 ISO 14971 Risk Management Process.

Introduction 147
namely FMEA. Thus, a working group was formed to incorporate

risk management practices already defined in the IEC 60601
Standard Series, a set of standards focusing on medical electrical
equipment, into its new international standard, designated as ISO
14971, in 2000. This standard then replaced the ISO/IEC 14971-1
standard and was recognized as both a European-harmonized
standard (GHTF SG3/N15R8:2005 [1]) and an FDA-recognized
standard. It emphasized a more complete risk management
framework, shown in Fig. 13.1.
The ISO 14971 Standard includes all the basic principles of risk
management that are applicable to medical devices. It specifies the
steps required for identifying hazards, estimating risk, evaluating
risk, and controlling risk. A medical device manufacturer’s risk
management process must include these steps. The new standard
has two important aspects that deserve special mention. First,
the standard expands the scope and potential approaches to the
risk management process that enables manufacturers to satisfy
the essential requirements of the medical device directives of
the EU. These directives have similar authorities in the EU as the
US Code of Federal Regulations in the United States. Essential
requirements are necessary elements for protecting the public
interest in the EU, are mandatory for product compliance before
they are put into commerce and must be applied as a function of the
hazards inherent to a given product.
Second, the standard deemphasized the use of FMEA, which
is recommended only if it fulfills appropriately the particular risk
analysis task under study; many other analytical approaches are
acknowledged to potentially be suitable to achieve the same end.
The expanded scope of the standard emphasizes management
responsibilities. The standard stipulates that management
responsibility is the initial and key requirement. More precisely,
management must incorporate the following tasks:
(1) defining policies for determining acceptable risk
(2) ensuring the provision of adequate resources, including the
identification of a risk management team
(3) ensuring the assignment of trained personnel to perform risk
assessment and management activities
(4) reviewing the results of risk management activities at defined
intervals to ensure the effectiveness of the risk management
process
148 ISO 14971
The expanded scope also mandates implementation of the

following records:
(1) risk management plan
(2) risk management file
(3) risk management report
(4) production and post-production information
These requirements are interesting because they draw attention
to the fact that risk management rests on more than having a
framework, but also on a human dimension where the activities of
people must be directed and organized. Currently, the ISO 14971
Standard has just gone through a second edition that incorporated
only minor changes from the initial edition; however, the volume of
explanation of the stipulated framework in the second edition has
increased almost three-fold (from 22 pages to 65 pages). The ISO
14971:2007 “Application of Risk Management to Medical Devices”
[2] stipulates an expectation of a risk management framework
that considers the total lifecycle of the product. It includes a risk
management process, and defines executive responsibilities,
personnel qualifications for performing risk management activities,
and the documentation needed to provide a record of risk
management activities. Some limitations in the document are still
perceived by some to exist. For example, it does not provide guidance
with respect to clinical decisions that may be a significant part of
the risk/benefit analysis. In fact, the EU is currently challenging
the committee on the sufficiency of the guidance with regard to
risk/benefit analysis. In addition, some readers of the standard can
develop the false impression that it only addresses the design control
elements of a quality management system because manufacturing
only appears once in the text although it is in fact mentioned a further
twenty times in the annexes of the document which are provided
for explanations but not requirements.
In summary, the ISO Standard provides a framework to the
medical device manufacturers for effective management of the risks
associated with the use of their products and within which experience,
insight, and judgment are applied systematically to manage these
risks. It also helps practitioners to identify processes by which they
can identify hazards associated with a medical device, estimate
and evaluate the risks associated with these hazards, control these
risks, and monitor the effectiveness of that control.
The Foundation of a Risk Management (RM) Framework 149
13.2 The Foundation of a Risk Management

(RM) Framework: Policy, Plan, Team,
Process, and Documentation
The foundation of an RM framework consists of five elements: (1)
policy, (2) plan, (3) team, (4) process, and (5) Documentation.
13.2.1 Policy
A risk management policy is essential to a company that
operates on RM. This policy should take into account of relevant
international, national, or regional standards and regulations. It
should define how to determine acceptable risk and include the
review of results of risk management activities at defined intervals.
The review ensures the continuing suitability and effectiveness of
the RM process. Moreover, the policy should be established before
or at the time of implementation of the RM process. The RM process
should not begin without such policy in place.
13.2.2 Plan
The company should establish a risk management plan for every
product based on its risk management process. This plan [1] should
(a) identify and describe the product
(b) define a scope
(c) state verification activities
(d) indicate roles and responsibilities of the allocated resources
(e) define intervals for review
(f) specify criteria for risk acceptability
(g) record the plan changes and its revision
13.2.3 Team
A description of each of the RM team members’ roles and
responsibilities should be defined and recorded. It is a part of the
evidence to demonstrate sufficient resource is allocated for risk
management activities.
150 ISO 14971
13.2.4 Process
A medical device company should establish a process describing
how, what, and when risk management activities are carried
out during the entire product life cycle (See Fig. 13.1 and Section
13.3). At the broadest level, the RM process consists of a four-part,
continuous-management process: (1) analyze risk, (2) evaluate risk,
(3) control risk, and (4) get feedback from both production and post-
production information. The next section describes the details of
each major activity of the process.
13.2.5 Documentation
Documentation can be electronically stored records or paper
records. It provides objective evidence for regulatory compliance as
well as for legal purposes. The documentation should include policy,
procedures, plans, and records of all risk management activities
during the entire product life cycle.
13.3 The RM Process

13.3.1 Analyze Risk
This initial task involves the following steps:
(a) Familiarize yourself with the product.
It is important to understand thoroughly the requirements of
developing a product before the start of any risk management
activities. The background understanding of requirements,
such as marketing, performance, functional, regulatory,
legal, etc., would provide a firm foundation for those who are
engaged in the risk management activities.
(b) Understand intended purpose and use.
In addition to aforementioned requirements, the intended
purpose and use of a product provide a boundary and scope for
the subsequently risk management activities. Understanding
the medical purpose, anatomy and/or organs of body affected,
patient profile, user profile, and application environment of
the product forms the basis to initiate hazard identification
and for carrying out further risk management activities.
The RM Process 151
(c) Identify hazards and hazardous situations.

In the framework of the Standard, hazard is defined as the
potential source of harm; harm is physical injury or damage
to the health of people, property, or the environment. Thus,
one should focus on identifying the immediate source or a
situation(s) that causes the hazard that results in harm, i.e.,
the hazard or hazardous situation. It is also beneficial to
distinguish that a failure may not cause harm or directly cause
harm.
(d) Estimate risk.
Once a hazard or hazardous situation is identified, its
consequence or severity of harm and probability of
occurrence of harm need to be estimated. The consequence or
severity of harm of a hazard or hazardous situation could be
assessed directly and immediately. However, the probability
of occurrence of harm may be an indirect assessment since
the harm is related to the hazard and the hazard is related to
the product. The risk level of a hazard or a situation(s) that
initiate the hazard would then be estimated based on the
probability of occurrence and severity of that harm posed by
the hazard or the hazardous situation.
13.3.2 Evaluate Risk

This subsequent activity after risk analysis is to make an
acceptability decision. Consequently, there are many actions need to
be taken depending upon the level of risk on each of the identified
issues. Generally, there are three kinds of actions. First, the risk
could be accepted without further actions. Second, the risk is so
high that control measures must be taken to reduce it to an
acceptable level. Lastly, the risk is at a marginally acceptable or
unacceptable level. It requires further investigation, either conduct
a risk/benefit analysis before making accept or reject decisions, or
implement further risk control measure(s) to reduce the risk to an
acceptable level.
13.3.3 Control Risk

After the initial risk analysis and evaluation, risk control measures
may be deemed necessary to maintain, reduce or eliminate the
152 ISO 14971
risk. In the framework of the Standard, risk has two components:

the probability of occurrence of harm and the severity of that harm.
Therefore, a risk control measure could either affect the probability
of occurrence of the harm or the severity of that harm. Generally, it
is much easier to work on maintaining or minimizing the occurrence
aspect of the harm. It would take relatively much more resources
and efforts in reducing or eliminating the severity of harm. In fact,
risk control is aiming at controlling the identified hazards and the
hazardous situations that are causing harm.
The Standard is very specific about how risk should be controlled.
It stipulates an Option Analysis [1] that requires a hierarchy of
priority order when approach to risk control measures. Risk control
measure(s) should be considered in the following priority order:
(a) inherent safety by design (the most preferred risk control
measure)
(b) protective measures in the product or in the manufacturing
process
(c) information for safety (the last resort for risk control
measure)
It is indispensable to ensure the implementation of these
risk control measures have taken place as well as to demonstrate
their effectiveness after implementation. Objective evidence of
implementation and demonstration of effectiveness of these
measures should be documented.
In practice, risk analysis, risk evaluation, and risk control
are steps of an iterative process. These activities may happen at
least three times in a product development process. Initial risk is
analyzed, evaluated for acceptance the first time and then risk
control measures are considered as necessary for each hazard and
hazardous situation. Then, residual risk needs to be analyzed and
evaluated for acceptance as related to each individual hazard after
the control measures are applied. This process continues until the
residual risk is judged acceptable. Finally, a review of the overall
residual risk, i.e., the accumulation of all the residual risks posed by
each individual hazard after effective control measure(s) is applied,
should take place. This is when a company decides whether a product
is safe for use.
If an individual residual risk or the overall residual risk [1] is
judged unacceptable using the policy or criteria pre-established
by the company and further risk control is impractical, the
The RM Process 153
company may gather and review data and literature on the medical
benefits of the intended purpose and use of the product to
determine if they outweigh the residual risk. If the evidence does
not support the conclusion that the medical benefits outweigh the
residual risk, then the risk remains unacceptable. The project should
be cancelled or the product needs redesign. If the medical benefits
outweigh the residual risk, then the company should document
all the evidence to support the acceptability decision. This
iterative process should continue until all individual residual risk
and the overall residual risk are judged acceptable before the
commercialization of a product.
13.3.4 Feedback from Production and Post-Production

Information
In this part of the risk management process, the focus is on
information received after all risk control measures are deployed.
When considering the entire product life cycle, the company should
establish and maintain a systematic process. It could be a well-
developed information system, to review information gained about
the product after development. This information should include
information from design and process validation, product transfer,
design to production, vendor to company, company to vendor,
outsourced activities, production activities, field use, etc. The
information should be evaluated for possible relevance to safety [1]
especially the following:
(a) if previously unrecognized hazards are present
(b) if the estimated risk(s) arising from a hazard is no longer
acceptable
(c) if the original assessment is otherwise invalidated
If any of the above conditions is satisfied, the results of the
evaluation should be fed back as an input to the risk management
process. A review of the appropriate steps of the risk management
process for the product should be considered. If there is a potential
that the residual risk(s) or its acceptability has changed, the impact
on previously implemented risk control measures should be
evaluated.
The above four risk management activities are integral parts of
a continuous process improvement within a management system.
Certain activities may be initiated out of the aforementioned order.
154 ISO 14971
They are useful if applied appropriately, especially early in the

product development process.
13.4 Conclusion
RM is about focusing on the number of safety issues to the vital
few that will make a difference. A comprehensive RM framework
helps a company gain confidence that it understands those risks
that really matter to avoid unacceptable and unexpected crises or
surprises. The framework also helps the company know how to
avoid, eliminate, or contain the causes or drivers of those significant
risks that may cripple the business if they were neglected. It also
provides a basis for measuring, comparing, controlling, monitoring,
and preventing those risks that have the potential to exhibit
significant negative impact to the company.
In conclusion, RM is a disciplined, structured, and scientific
approach that provides a proactive business strategy to enable
a company to manage and prevent potential crisis and create a
sustainable strategic advantage while maximizing shareholder
value. Through the RM process, a company is better able to protect
and secure its value, guard its growth potential, and hedge against
market, capital, operational, and financial volatility.
13.5 Case Study — An Example to Illustrate

Risk Management on a Medical Device:
Functional Electrical Stimulation System
for Walking
Functional electrical stimulation (FES) is generally referred to as
an artificial electrical stimulation of a muscle that has diminished
nervous control, with the aim of providing muscular contractions
and producing functionally useful movements. The FES is a
technique that uses bursts of short electric pulses to generate muscle
contractions by stimulating motor-neurons or reflex pathways.
A FES system for walking consists of a main unit, a control
sensor, and adhesive surface electrodes connected with wires
(Fig. 13.2). The surface electrodes are located on the surface of the
Case Study — An Example to Illustrate Risk Management on a Medical Device 155
skin, above a targeted muscle or nerve. With regard to the lower

limbs, drop-foot is a common clinical feature of those who have
suffered from stroke, which is characterized by the inability to
dorsiflex the foot during the swing phase of gait. People affected tend
to have a labored and unsafe gait, and compensatory movements
such as hip hiking and limb circumduction may occur. The intended
use of an FES drop-foot stimulator system is to correct the problem
of drop-foot by stimulating the ankle dorsiflexors or the common
peroneal nerve to achieve toe clearance (Fig. 13.3). The stimulation
of the hemiplegic leg can be controlled by a heel-switch worn on
the hemiplegic side. When the switch is on the hemiplegic side,
stimulation is initiated by a heel off and terminated by a heel strike.
The effectiveness of the system is to save effort in walking, increase
the patient’s ability to walk, and reduce spasticity.
Main unit
Main unit
Stimulation
Stimulation
electrodes
electrodes
Foot
Footswitch
switch sensor
sensor
(a) (b)
Figure 13.2 Using FES for walking.

156 ISO 14971
(a) (b)
Figure 13.3 Right hemiplegic stroke patient: (a) without FES and drop
foot on the right side; (b) with FES system to correct drop foot
problem.
13.5.1 Risk Management Process

Step 1: Intended use/intended purpose
• For the particular medical device or accessory being considered,
the manufacturer shall describe the intended use/intended
purpose and any reasonably foreseeable misuse. They should also
have a list of all those qualitative and quantitative characteristics
that could affect the safety of the medical device and, where
appropriate, their defined limits.
The intended use of the FES drop-foot stimulator system is to
correct the problem of drop-foot by stimulating the ankle dorsiflexors
or the common peroneal nerve to achieve toe clearance. The timing
of stimulation is controlled by a heel-switch worn on the hemiplegic
side. Electrical stimulation is initiated by a heel off and terminated
by a heel strike in every walking step on the hemiplegic side.
The FES system only can be applied on stroke patients with drop
foot problem by a trained clinician/rehabilitation engineer. The
patients must be trained by the clinician/rehabilitation engineer
before they can take the device back home for training and daily
use.
The FES stimulation parameters are 40 Hz with adjustable pulse
width of the stimulation pulse (100–500 us) and the maximum
stimulation intensity is 100 mA. These parameters are safe and they
are currently use in clinical/hospital for rehabilitation with FES.
Step 2: Identification of known or foreseeable hazards
• The manufacturer shall compile a list of know or foreseeable
hazards associated with the medical device in both normal
conditions and fault conditions.
Example of Hazards
1. Surface stimulation electrodes are placed on the wrong
position on the skin and cause injury.
2. There are three connection ports on the FES main unit and they
are connected wrongly: one is connected to the stimulation
electrodes, another one is for foot switch and last one is for
computer data transfer.
3. The output electrical stimulation is too high and cause injury.
4. Patient pressed or turned wrong button to change the FES
parameters, which causes injury.
5. There is skin allergy to the surface electrode.
Step 3: Estimation of risks for each hazard
• ISO14971: For each indentifies hazard, the risk(s) in both

normal and fault conditions shall be estimated using available
information or data. The hazard is combined with the hazard
severity and the probability of occurrence (Tables 13.1 and
13.2).
Estimated Risk = (Estimated hazard Severity) × (Estimated
Probability of Occurrence )
Each manufacturer is free to define his own category system
(Tables 13.1 and 13.2) and has to recorded these in the risk
management file.
Table 13.1 Example of five qualitative severity levels (ISO 14971:2007

Table D.3)
Common terms Possible description
Catastrophic Results in patient death
Critical Results in permanent impairment or life-threatening

injury
Serious Results in injury or impairment requiring professional

medical intervention
Minor Results in temporary injury or impairment not

requiring professional medical intervention
Negligible Inconvenience or temporary discomfort

158 ISO 14971
Table 13.2 Example of semi-quantitative probability levels (ISO 14971:

2007 Table D.4)
Common terms Examples of probability range

Frequent ≥10–3
Probable <10–3 and ≥10–4
Occasional <10–4 and 10–5
Remote <10–5 and ≥10–6
Improbable <10–6
Step 4: Risk Evaluation

• For each identified hazard, the manufacturer shall decide
the criteria in the management file to consider whether the
estimated risk(s) is needed to have risk reduction or not (Tables
13.3 and 13.4).
Table 13.3 Estimation of risks for each hazard
Hazards Severity Probability

R1. Surface stimulation electrodes are placed on Serious Remote
the wrong position
R2. The three connection ports on the FES main Minor Probable
unit are connected wrongly with wires
R3. The output electrical stimulation is too high Serious Remote
R4. Patient pressed or turned wrong button to Serious Probable
change the FES parameters
R5. Skin allergy to the surface electrode. Minor Occasional
Table 13.4 Risk evaluation

Qualitative severity levels
Negligible Minor Serious Critical Catastrophic
Semi-quantitative
probability levels
Frequent
Probable R2 R4
Occasional R5
Remote R1, R3
Improbable
Key
Unacceptable risk
Investigate further risk reduction
Insignificant risk
Step 5: Risk Control

• The manufacturer shall identify risk control measure(s) that are
appropriate for reducing the risk(s) to an acceptable level. Risk
control shall use the following in the priority order listed:
(1) inherent safety by design
(2) protective measures in the medical device itself or in the
manufacturing process
(3) information for safety
R2, R3, R4, and R5 are using inherent safety by design to reduce
the risk and R1 are using information for safety.
Step 6: Implementation of risk control measure(s)

• The manufacturer shall implement the risk control measure(s)
selected in step 5.
Implementation of risk control measure(s) (Table 13.5)

R1: A qualified trained clinician/rehabilitation engineer shall
provide information sheet and taught the patients on how to
place the stimulation electrode correctly.
Table 13.5 Table with risk mitigation measures
Qualitative severity levels

Negligible Minor Serious Critical Catastrophic
Semi-quantitative
probability levels
Frequent
Probable
Occasional
Remote R5 R4
Improbable R2 R1, R3
Key
Unacceptable risk
Investigate further risk reduction
Insignificant risk
R2: The connection ports are designed only one plug can fit in one
socket for all the three ports (Fig. 13.4).
160 ISO 14971
R3: The system use standard 9 V battery and the circuit can only
generate maximum 100 mA. And the stimulation pulse width
can be changed by the clinician through an FES program
software only.
R4: Patient can only change the stimulation amplitude in a limited
range, and all the parameters are pre-programmed by the
clinician.
R5: Biocompatible electrode for clinical use on surface electrical
stimulation shall be used. They will receive the biocompatible
standard.
Figure 13.4 The connection ports are designed only one plug can fit in
one socket. And the patient can only adjust the stimulation
intensity in the limited range on a knob from 0 to 10.
Step 7: Residual risk evaluation
• Any residual risk that remains after the risk control measure(s)
are applied shall be evaluated using the criteria defined in the
risk management plan. If the residual risk does not meet the
criteria, further risk control measures shall be applied.
The residual risk is judged acceptable for the FES system.
References 161
References
1. GHTF (2005). SG3/N15R8:2005 Implementation of risk

management principles and activities within a Quality Management
System, Global Harmonization Task Force.
2. ISO14971:2007 — Application of Risk Management to Medical
Devices.
3. ISO/IEC Guide 51:1999 — Safety Aspects — Guidelines for their
inclusion in standards.
Part 3
Harmonization of Medical
Devices in Asia
Chapter 14
Medical Devices in the World Health

Organization
Adriana Velazquez Berumena and Jack Wongb

aHSS/EHT/DIM, World Health Organization,
20 via Appia, 1211 Geneva, Switzerland

bAsia Regulatory Professional Association (ARPA)
velazquezberumena@who.int, speedxquality@yahoo.com
The World Health Organization (WHO) is the directing and

coordinating authority for health within the United Nations system.
It is responsible for providing leadership on global health matters,
shaping the health research agenda, setting norms and standards,
articulating evidence-based policy options, providing technical
support to countries and monitoring and assessing health trends.
The World Health Assembly approved 13 “core functions” for
strategic objectives in 2006, the number 11 is to improve access
to effective, quality and safe medical products.
The medical devices unit of the WHO had been hosted in the
Essential Health Technologies unit since 2006. Then in 2012, with
the dissolution of the Health Technologies Department, the medical
devices unit became part of the Essential Medicines and Health
Products Department under the Health Systems and Innovation
cluster.

www.panstanford.com
166 Medical Devices in the World Health Organization
The World Health Assembly recognized that medical devices

are indispensable for health care delivery under prevention,
diagnostics, treatment and rehabilitation. In response to the
WHA60.29, the health technologies resolution that was approved
by all 194 member states in 2007, it has been developing four major
activities:
1. Assessing the global situation on medical devices
• The first-ever global Baseline Country Survey on Medical
Devices was launched in February 2010. Respondents from
146 countries identified the key areas requiring support;
in 2011, 171 countries responded. This survey contains
information about the health technology policies, lists of
medical devices for reimbursement, and focal points in the
regulatory agency, in the health technology management,
and in the health technology assessment, if they have any of
them. It also includes the census of health care facilities and
of five major medical equipment for diagnosis or treatment,
such as nuclear magnetic resonance (NMR), radiotherapy
or positron emission tomography (PET) scanners.
• All the information is available on the Internet in the
country profiles as well as statistical analysis and maps in
the Global Health Observatory in the WHO web page.
2. Strengthening capacity
• In 2011, the WHO launched the Medical Device Technical
Series. These reference documents provide those in low-
resource settings with information and guidance they
can adapt to their particular situation. Eight reference
documents have been printed that include needs assessment,
procurement, donations, maintenance, inventories, health
technology assessment, and steps on how to develop policies
on medical devices at the country level.
• The Global medical devices information system will be
an online clearing house, requested by the World Health
Assembly Resolution WHA60.29 on Health Technologies,
in providing evidence based, impartial information on
medical devices, tailored to different levels of care and health
interventions.
Medical Devices in the World Health Organization 167
• The Core Medical Equipment Fact Sheets provide technical

information on the devices most commonly used in health
care facilities.
• The e-Documentation Centre is a centralized repository of
more than 300 WHO documents and resources in various
languages that relate to health technologies. These are all
available on the website.
3. Encouraging innovation
• Medical devices currently on the market do not meet all of
the global health needs. The Priority Medical Devices Project
proposes a research agenda to inform innovators how best to
address this gap
• The Compendium of Innovative Health Technologies show-
cases medical devices that address health concerns in low-
resource settings, in order to promote dialogue between
biomedical engineers, ministries of health, donors, innovators,
manufacturers and end users. The compendium and the call
were done in 2010 and 2011; a new update is available and
a 2013 call has been launched.
4. Fostering partnerships
• The WHO Medical Devices Unit coordinates the activities of
non-governmental organizations, academia, professional
societies, governments, health professionals and WHO Colla-
borating Centres, in reference to medical devices.
• In September 2010, over 300 participants from around the
world gathered in Bangkok, Thailand, for the first WHO Global
Forum on Medical Devices, building on three years of intense
activity that followed the adoption of the first resolution
on health technologies by the World Health Assembly in
May 2007. The Second WHO Global Forum on Medical
Devices will take place in 2013 and will address regulations,
innovations and access to medical devices.
• The WHO, APEC, and AHWP discussed the training strategy
and potential needs. The team agreed to work together to
generate a “Pilot Medical Device Regulatory Awareness
Workshop” and develop a “Joint 5 years training strategy/
roadmap”.
168 Medical Devices in the World Health Organization
• WHO is looking into the regulatory convergence and

harmonization as a way to increase access to safe and effective
medical devices, uptake of core essential medical devices,
dissemination of innovation to help target global health
concerns.
• WHO has become official observer of IMDRF, International
Medical Devices Regulators Forum, which will be following
on the implementation of the GHTF documents.
• WHO is working in the update of regulation guidelines, tools,
norms and standards and particularly in capacity building.
• WHO encourages that the Biomedical Engineering pro-
grammes and curricula worldwide addresses regulations
of medical devices, this will then prepare the professionals
that are in Academia, research and development, industry
or in health care services to be aware of the importance of
medical devices regulation, from registration, premarket ap-
proval, standards, requirements, to post market surveillance,
adverse event reporting through continuous technovigilance
monitoring safe and effective use of medical equipment for
the well being of the population.
• WHO has been now an official observer of the IMDRF.
• A global action plan is now being developed to follow a five-
year strategy and invite all stakeholders to participate in order
to increase access to safe, appropriate, and affordable medical
devices, particularly to the population in need.
Chapter 15
Asian Harmonization Working Party
Saleh Al Tayyar
Asian Harmonization Working Party
Saudi Food & Drug Authority, Riyadh, Saudi Arabia
AHWP-Chair@sfda.gov.sa
15.1 Introduction
The Asian Harmonization Working Party (AHWP) has been
established as a non-profit organization. Its goals are to study and
recommend ways to harmonize medical device regulations in the
Asian and other regions and to work in coordination with the Global
Harmonization Task Force, APEC, and other related international
organizations aiming at establishing harmonized requirements,
procedures, and standards. The AHWP is a group of experts from
medical device regulatory authorities and the medical device
industry. Membership is open to those representatives from the
Asian and other regions who support the above-mentioned goals.

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170 Asian Harmonization Working Party
15.2 Future Directions

Organize awareness education, training, and seminars for medical
device regulators and industry in the area of regulatory require-
ments (such as Essential Principles of Safety and Performance of
Medical Devices; Classification Rules and risk-based management
approach) and premarket review processes. One possibility is to
tap the availability of Global Harmonization Task Force (GHTF)
Study Group (SG) resource persons on business trips or visits
to Asia:
• Define the scope and deliverables and tasks of the Technical
Committee, including the conduct and frequency and venue of
meetings;
• Seek budgetary and strategic support for AHWP activities and
programs;
• Establish an effective communication network and presence
among participating Asian economies through scheduled
AHWP meeting, e-mails, correspondence, and Internet-based
access site;
• Plan for the next AHWP Meeting;
• Work toward enlarging the base of participating economies so
as to maximize the benefit of the GHTF harmonization process
to Asia.
I am honored to write on behalf of the Asian Harmonization
Work Party (AHWP) an introductory note to the Handbook of Medical
Device Regulatory Affairs in Asia, as part of the Asia Regulatory
Professional Association (ARPA) initiative.
This handbook is in line with Asian Harmonization Working
Party scope and objectives to harmonize Medical Device
Regulation among member economies. The AHWP is a nonprofit
organization that was formed by a group of regulators in Asia Pacific
around 1996–1997. It aims to develop techniques to harmonize
medical device regulations in Asia and other regions, to work in
coordination with the Global Harmonization Task Force (GHTF),
Asia-Pacific Economic Cooperation (APEC), and other related
international organizations aiming at establishing harmonized
requirements, procedures, and standards.
Future Directions 171
The AHWP is planning to organize awareness education,

training, and seminars for medical device regulators and industry
in the area of regulatory requirements (such as Essential Principles
of Safety and Performance of Medical Devices; Classification Rules
and Risk-Based Management Approach) and premarket review
processes.
The Handbook of Medical Device Regulatory Affairs in Asia is
intended to give an overview of the medical device regulatory systems
in the United States, European Union, Australia, and Japan. It also
looks at regulatory frame work in the AHWP member economies,
(i.e., China, Hong Kong, India, Indonesia, Jordan, Korea, Malaysia,
the Philippines, Saudi Arabia, Singapore, Chinese Taipei, Thailand,
the United Arab Emirates (Abu Dhabi), Vietnam, Laos, Cambodia,
Brunei Darussalam, Myanmar, South Africa, Yemen, Pakistan,
Kuwait, and Chile).
The handbook touches base on important and controversial
issues in medical device regulations such as medical device clinical
trials, labeling, and language complexity in relation to the intended
use, labeling compliance, and access of medical device in developing
countries.
A tremendous effort has been made to cover various topics
related to medical devices to allow regulatory staff from various
levels to benefit from this handbook and consider it one of their
main references. Medical Device Safety and Related Standards have
also been discussed in this handbook. The handbook also looks at
the harmonization of medical devices and examines efforts and
contributions by the AHWP, ASEAN, APEC, and GHTF to the medical
device harmonization.
The handbook is well structured and organized. The
contributions by highly distinguished experts in the field of medical
device regulation from all over the world make this book rich
in knowledge and an important reference. I hope regulators in
developing countries will find it beneficial to them and use it as a
tool for benchmarking and guidance in setting up and/or improving
their medical device regulations.
In conclusion, I would like to thank everyone who contributed to
the development of this handbook.
Chapter 16
Asia-Pacific Economic Cooperation
Lindsay Tao
Corporate Director,
Regulatory Government Affairs at Johnson & Johnson
ltao@jnj.its.com
16.1 Introduction
APEC is the premier forum for facilitating economic growth,
cooperation, trade and investment in the Asia-Pacific region. APEC
is the inter governmental grouping of 21 members as listed below,
which account for approximately 40.5% of the world’s population,
approximately 54.2% of world GDP and about 43.7% of world
trade.
The Asia-Pacific Economic Cooperation (APEC) works in three
broad areas to meet the Bogor Goals of free and open trade and
investment in the Asia-Pacific by 2010 for developed economies
and 2020 for developing economies.

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174 Asia-Pacific Economic Cooperation
Table 16.1 List of member economies constituting APEC
Date of entry Member states

1989 Australia Indonesia
Brunei Darussalam Japan
Canada Republic of Korea
The Philippines Malaysia
Singapore New Zealand
Thailand The United States
1991 People’s Republic of China Chinese Taipei
Hong Kong
1993 Mexico Papua New Guinea
1994 Chile
1998 Peru Vietnam
Russia
Known as APEC’s “Three Pillars,” APEC focuses on three key

areas:
• trade and investment liberalization
• business facilitation
• economic and technical cooperation
The outcomes of these three areas enable APEC Member
Economies to strengthen their economies by pooling resources
within the region and achieving efficiencies. Tangible benefits are
also delivered to consumers in the APEC region through increased
training and employment opportunities, greater choices in the
marketplace, cheaper goods and services and improved access to
international markets.
16.1.1 Trade and Investment Liberalization

Trade and Investment Liberalization reduces and eventually
eliminates tariff and non-tariff barriers to trade and investment.
Protectionism is expensive because it raises prices of goods and
services. Thus, trade and investment liberation focuses on opening
markets to increase trade and investment among economies,
resulting in economic growth for APEC member economies and
increased standards of living for all. This goal is also now furthered
by APEC’s Regional Economic Integration agenda, which includes
Introduction 175
work on model measures for bilateral and regional trade agreements

and an examination of the prospects for a Free Trade Area of the
Asia-Pacific.
16.1.2 Business Facilitation

Business Facilitation focuses on reducing the costs of business
transactions, improving access to trade information and aligning
policy and business strategies to facilitate growth, and free and
open trade. Essentially, Business Facilitation helps importers and
exporters in Asia Pacific meet and conduct business more efficiently,
thus reducing costs of production and leading to increased trade,
cheaper goods and services and more employment opportunities
due to an expanded economy. APEC’s Structural Reform agenda
addresses this area: It focuses on reforming domestic policies and
institutions that adversely affect the operation of markets, and the
capacity of businesses to access markets and to operate efficiently.
16.1.3 Economic and Technical Cooperation

Economic and Technical Cooperation (ECOTECH) is dedicated to
providing training and cooperation to build capacities in all APEC
member economies to take advantage of global trade. This area
builds capacity at the institutional and personal level to assist APEC
member economies and its people gain the necessary skills to meet
their economic potential.
APEC is a unique forum, operating on basis of
• non-binding commitments, open dialogue and equal respect
for views of all participants
• decisions by consensus; commitments undertaken on
voluntary basis
• individual and collective action
APEC Chair rotates annually — host economy (Peru, 2008;
Singapore, 2009; Japan, 2010; the United States, 2011; Russia,
2012).
APEC operates at policy level and working level as shown in
Fig. 16.1.
Leaders Meeting
APEC Business Ministerial Sectoral Ministerial

Advisor Council Meeting Meetings
Senior Officials
APEC Secretariat
Meeting (SOM)
Committee on Budget and Economic SOM Steering

Trade and Management Committee (EC) Committee on
Investment (CTI) Committee (BMC) ECOTECH
Sub-Committees/ Special Task Working Groups

Expert Groups Groups
Policy Level
Working Level
Figure 16.1 Structure of APEC.
16.2 APEC LSIF: Life Sciences Innovation Forum

(Reports to Committee on Trade and
Investment)
Life sciences innovation is critical to growth and socio-economic
development as healthy people produce healthy economies. Efficient
and effective delivery of patient focused products and services
can improve a population’s longevity, wellness, productivity and
economic potential. Established by APEC leaders in 2002, the Life
Sciences Innovation Forum (LSIF) has since grown to become APEC’s
leading initiative on health and health sciences innovation.
It is a tripartite forum that engages representatives from
the highest levels of government, industry and academia to
create the right policy environment for life sciences innovation.
The LSIF brings together scientific, health, trade, economic, and
financial considerations to address the challenges of infectious
and chronic disease and ageing populations. Guiding principles
include transparency, meaningful dialogue with stakeholders and
recognition of due process. The LSIF forum also acknowledges that
capacity building is critical to successful implementation.
Life Sciences Innovation Forum 177
APEC LSIF
RHSC AHC
Figure 16.2 Operational model.
The APEC Life Science Strategic Plan, which was approved by

APEC ministers in 2004, provided recommendations for collective
action and an implementation schedule. The Strategic Plan also
provides recommendations for strengthening the innovative life
sciences sector in the APEC region, placing particular emphasis
on boosting region-wide levels of investment in research
and development for health innovation. In the strategic plan,
regulatory harmonization was highlighted: Toward this end,
leaders also recognized that “Harmonization of standards…
according to international best practices…will give the APEC
region a competitive edge and expand opportunities for the rapid
development of innovation.”
In 2007, the LSIF was tasked to undertake a multidisciplinary
study on the role of and returns to economies from investment in
health innovations that address health and related economic and
fiscal challenges facing the region. It was also mandated to establish
frameworks for public-private sector partnerships to better utilize
resources to meet health needs.
The LSIF has developed an Enablers of Investment Checklist, a
voluntary guidance tool for policy makers in each APEC economy
to assess their investment environment for life sciences innovation.
Singapore volunteered to fill out the implementation of the Checklist
in 2009.
Based on a series of seminars held in 2008–2009 that dealt
with ways to combat the increase in counterfeit medical products,
the LSIF has developed an Anti-Counterfeit Medical Product Action
Plan. The objective is to share best practices in the detection and

prevention of counterfeits to both regulatory authorities and
industry professionals, and to build capacity at the economy level to
combat the threat.
A series of regional seminars for government regulators on
the issue of harmonization of medical device regulation were
held in 2008 and 2009 (Malaysia and Canada). The objective was
to help regulators of medical devices in APEC economies develop
robust regulatory systems. The seminars highlighted the benefits
to patients, regulators, and industry and to global and regional
trade when economies implement a medical device regulatory
system based on harmonization standards and procedures.
Industry representatives were invited to participate. The training
programs were closely coordinated with the medical devices Global
Harmonization Task Force (GHTF) and two regional working
parties: the Asian Harmonization Working Party and the Latin
American Harmonization Working Party.
Workshops aimed at strengthening drug regulatory authorities’
capacity to harmonize regulatory practices relating to drug
development in clinical trials, and to good clinical practice/clinical
research, were also held in Thailand in 2009.
The APEC Harmonization Center (AHC) was launched in Seoul,
Korea, in June 2009. The AHC is an important step toward harmoni-
zing regional regulatory priorities. An LSIF Regulatory Steering
Committee has also been created to advance the harmonization
agenda. The AHC has since organized a series of events, including
an “APEC Harmonization Center Biosimilar Workshop” in September
2009. The workshop focused on the opportunities and challenges
of biological medicines, regulatory issues for Biosimilars and the
regulatory landscape for Biosimilars. A “Good Manufacturing
Practice Pharmaceutical Validation Workshop,” was also held by the
AHC in December 2009 and drew over 450 participants.
16.3 APEC LSIF/RHSC: Regulatory

Harmonization Steering Committee
Regulatory harmonization is identified by the LSIF as strategic
imperative and by its significant contribution to the life science
innovation.
Regulatory Harmonization Steering Committee 179
The LSIF has sponsored successful series of workshops on

anti-counterfeiting, clinical trial evaluation and GCP inspection, ICH
quality guidance, and harmonization of medical device regulatory
approaches based on the GHTF over the years. However, despite the
progress made, the recognition that the LSIF has not been used to its
full potential in promoting a more strategic and effective approach
within the APEC region as a driver of regulatory harmonization and
cooperation has been due to
• insufficient engagement of regulatory authorities in LSIF
process
• clear articulation of how LSIF can take best advantage of
strengths to achieve stated objectives in a more strategic and
coordinated fashion
• diversity of APEC region and lack of well-established network
of subject matter experts have made effective interactions
with harmonization initiatives such as ICH challenging
In August 2007, LSIF VI in Lima, series of recommendations
were made to address these issues, notably the support for the
establishment of the APEC Harmonization Center (AHC) and creation
of a Regulatory Harmonization Steering Committee (RHSC).
The RHSC’s goal is to promote a more strategic, effective, and
sustainable approach to harmonization within the APEC region by
• proactively identifying and prioritizing projects seen to be of
greatest value
• providing direction to the AHC on projects and activities that
best meets these needs
• enhancing the effectiveness of interactions with international
and regional harmonization initiatives
• promoting the establishment of APEC networks of technical
experts and repository of reference materials
• supporting mechanisms for the sharing of regulatory
information and best practices
• seeking, in partnership with the AHC, to establish/strengthen
linkages with harmonization initiatives, training organizations
and other key players in efforts to promote complementary
actions and most effective use of resources
• undertaking activities in accordance with a strategic plan to
be developed by the SC
• ensuring products within the remit of SC: medical life science

products (notably drugs and devices)
The RHSC consists of eight regulatory authorities (the United
States, Canada, China, Japan, Thailand, Korea, Chinese Taiwan, and
Peru), two official regulatory observers (Singapore and Mexico),
four industry representatives (two from the device industry and
two from the pharmaceutical industry), three official observers
(PhRMA, AdvaMed, and RDPAC), and one academic representative
(director of AHC).
The objective of the RHSC is to provide leadership on a strategic
approach on regulatory convergence in APEC region. The RHSC
developed strategic frameworks aiming at achieving regulatory
convergence in APEC region by 2020 and was endorsed by APEC
economies in 2011. It also identified priority regulatory work areas
at
• good review practice
• multi-regional clinical trial
• supply chain integrity
• biologics
• combination products
• advanced therapies
Regulatory authorities take championship of these priority
working areas and develop projects supporting the achievement of
strategic framework.
Development Key Enabler:

(Stds, Guidances) Interface APEC Harmonization Center + RHSC
APEC Economies
and beyond
+ DRAs: Australia, Brazil, China, Chinese Taipei, India, Korea, Russia, Singapore
Figure 16.3 Building a better harmonization model.
Reference 181
Reference
1. Life Sciences Innovation Forum, Retrieved January 2012, from http://

www.apec.org/Groups/Committee-on-Trade-and-Investment/Life-
Sciences-Innovation-Forum.aspx.
Chapter 17
Harmonization of Medical Device

in ASEAN
Petahn McKenna
ASEAN Regulatory Affairs Manager,
PMCKENN1@its.jnj.com
17.1 Introduction
17.1.1 Medical Device Market in ASEAN
ASEAN (Association of Southeast Asian Nations) was founded on
8 August 1967, aimed at accelerating economic growth, social
progress, and cultural development among its members, and to
promote regional peace.
ASEAN has 10 member states, including Indonesia, Singapore,
Malaysia, the Philippines, Thailand, Brunei Darussalam, Cambodia,
Vietnam, Laos and Myanmar. With a combined population of
approximately 600 million and a combined gross domestic product
(GDP) of approximately $2.9 trillion, the ASEAN region represents
a sizable market for medical devices with considerable potential. In

www.panstanford.com
184 Harmonization of Medical Device in ASEAN
comparison, the population of the European Union is 500 million

and a GDP of $14.7 trillion [1]. The average life expectancy of the
ASEAN population is increasing, and consequently, there is a
growing demand for better healthcare. Tied to this is an expectation
to implement tighter regulatory controls for therapeutic products.
17.1.2 Medical Device Regulatory Environment

in ASEAN
The respective Ministries of Health from each ASEAN member
state are facing increasing pressure to implement regulatory
requirements applicable to the therapeutic products supplied in
their respective countries. Patients and surgeons now demand
higher standards of healthcare, and the local industry strives to
participate in globalized trade where the absence of a regulatory
framework would put them at a disadvantage. From the regulator’s
perspective, increased regulatory requirements provide increased
protection for the public against substandard medical devices
by ensuring that the devices meet internationally recognized
standards for safety, quality and efficacy. It is also in the interest
of the local government and trade associations to ensure that
locally manufactured medical devices will not face international
trade restrictions and technical barriers when compared to global
competitors.
The status of medical device regulation in the 10 ASEAN member
states varies considerably: Singapore, Indonesia, Thailand, Vietnam,
the Philippines and Myanmar have implemented mandatory
regulatory requirements, whereas medical device registration is
currently voluntary in Malaysia. Brunei, Cambodia and Laos are
currently developing their requirements.
17.2 ASEAN Medical Device Directive

and Harmonization
As part of the ASEAN Consultative Committee on Standards and
Quality (ACCSQ), the Medical Device Product Working Group
(MDPWG) was established to implement specific measures to
facilitate harmonization of medical device regulations in ASEAN.
Such measures include
ASEAN Medical Device Directive and Harmonization 185
• developing a common submission dossier template for

product approval in ASEAN
• formalizing of a post-marketing alert system for defective or
unsafe medical devices
Both of these goals have been addressed in the ASEAN Medical
Device Directive (AMDD), developed by the MDPWG through
cooperation of all ASEAN member countries, with input from
industry and international regulatory bodies, including the Global
Harmonization Task Force (GHTF), Asian Harmonization Working
Party (AHWP) and World Health Organization (WHO).
Equivalent to the European Medical Device Directive adopted in
the European Union (EU), the AMDD represents a harmonized set
of regulatory requirements for medical devices by which medical
device companies can demonstrate that a medical device meets the
Essential Requirements for safety and performance. The AMDD itself
will not be recognized as legislation; however, all member countries
will be required to harmonize their regulatory requirements with
the provisions of the AMDD. The AMDD states that “Member States
shall undertake all necessary measures to ensure that only medical
devices which conform to the provisions of this Directive and its
Annexes and Appendices may be placed in the markets of Member
States.”
The following sections describe the provisions of the AMDD,
with specific attention to the definition of a medical device, medical
device classification system, Common Submission Dossier Template
(CSDT), and ASEAN post-marketing alert system.
17.2.1 Provisions of the AMDD

The AMDD largely focuses on pre-market regulatory requirements
that a company must adhere to before placing a medical device on
the market. In contrast, post-market regulatory requirements apply
to medical devices which have been granted approved for supply by
the applicable regulatory authority. The AMDD’s 18 articles, which
are generally based on those of the GHTF, are as follows:
1. General provisions
2. Definition and scope of medical devices (including in vitro
diagnostics (IVDs))
3. Essential requirements of safety and performance of medical
devices
4. Classification of medical devices (A–D) according to level of

risk
5. Conformity assessment of medical devices
6. Registration and placement on market
7. Registration of persons responsible for placing medical
devices on the markets of member states
8. Technical documents for medical devices (e.g. CSDT,
Declaration of Conformity)
9. Relevant technical standards (ISO, etc.)
10. Labelling
11. Product claims
12. Post-marketing alert system
13. Clinical investigation
14. Institutional arrangements
15. Safeguard clauses
16. Confidentiality
17. Special cases
18. Implementation
17.2.2 Definition of a Medical Device

The AMDD applies to all products covered by the “definition of
a medical device.” The definition includes (but is not limited to)
medical instruments, machines, in vitro diagnostic (IVD) products
and software which are intended to be used for human beings for a
medical purpose. Critically, for a product to meet the definition of a
medical device, it must not achieve its primary intended purpose by
pharmacological, immunological or metabolic means. A drug product
may be included as a component of the medical device, but can only
act to support the medical device achieve its primary indication.
The definition of a medical device according to the AMDD also
includes “Accessories”, defined as another article which is intended
to be used together with a “parent” medical device to enable that
medical device to achieve its intended purpose. According to the
AMDD, accessories are regulated independently, and according to
the same regulations as the parent medical device. This means that
the accessory may have a different risk classification to the medical
device.
ASEAN Medical Device Directive and Harmonization 187
17.2.3 Medical Device Classification

The AMDD is aligned to the GHTF model of four medical device
classes, defined according to potential risk to the patient.
Class Risk level

A Low risk
B Low-moderate risk
C Moderate-high risk
D High risk
A set of classification rules is provided within the AMDD to

guide Member states and medical device companies in classifying
their medical devices into one of the above categories.
The AMDD sets out that any member state that reclassifies or
differs in its interpretation of the classification rules shall notify
the ASEAN Medical Device Committee (AMDC).
17.2.4 Common Submission Dossier Template

The AMDD sets out the requirements for all Member States to
adopt and implement common technical documents, including the
ASEAN CSDT.
The CSDT outlines the standard data which must be included
in a submission to register a medical device with a regulatory
authority, as follows:
• executive summary
• essential principles and methods used to demonstrate
conformity
• device description
• summary of design verification and validation
• preclinical and clinical data (if necessary)
• device labelling
• risk analysis
• manufacturer information
The purpose of the CSDT is to provide a template to guide
manufacturers and device sponsors to collate documentation which
will be sufficient to demonstrate conformance to the Essential
Principles of Safety and Performance of Medical Devices.
The CSDT largely aligns with the Summary of Technical

Documentation (STED) published by GHTF, with some key
differences such as the Device Description section, which contains
the following additional items: potential adverse effects and
alternative therapies. The benefit of the alignment between
the CSDT and STED is that when adopted by ASEAN member
countries, 80–90% of the documentation submitted to the US
Food and Drug Administration can also be used to complete the
submissions for the local ASEAN Market, thereby reducing time
in preparing the submission dossier. This alignment also provides
regulators of member countries with a level of confidence that
products which have been approved in countries where the
STED has been adopted, that product conforms to the same
standards as the ASEAN Member countries.
The standard language for documentation submitted in the
CSDT will be English.
17.2.5 Post-Market Alert System

ASEAN Member states are required to record and evaluate all
information brought to their attention regarding any malfunction
or deterioration of a device, or inadequacy in the labelling or the
instructions for use which might lead to or might have led to the
death of a patient or user or to a serious deterioration in their state of
health, or any technical or medical reason which may have lead to a
systematic recall of devices of the same type. The AMDD encourages
member states to work with the applicable medical device company
throughout the evaluation.
Furthermore, following the evaluation, member states are
required to immediately inform the other member states of the
incidents referred to above.
17.2.6 AMDD Status

The first version of the AMDD was presented in January 2008 and
has been developed throughout subsequent MDPWG meetings. The
official deadline for all ASEAN members to comply with the AMDD
is 2015. However, the date on which each country will be able to
comply will depend on the priorities and resources of the local
government.
References 189
17.2.7 Future of ASEAN Harmonization

In addition to the development of the AMDD, other points of focus
of the MDPWG include the following [2]:
• exploring the feasibility of an abridged approval process for
medical devices which regulators of benchmarked countries
or recognized regulators have approved
• exploring the feasibility of adopting a harmonized system of
placement of medical devices into the ASEAN markets, based
on a common product approval process
To date, work on these projects has not commenced; however,
similar to the AMDD, they present immense potential to the
advancement of the medical device industry in ASEAN.
References
1. ASEAN Community in Figures, 2010, ASEAN Community in Figures
(ACIF) 2010 Jakarta, ASEAN Secretariat — Retrieved April 2011, from
http://www.aseansec.org/publications/ACIF2010.pdf.
2. Objectives and Scope of the ACCSQ-MDPWG, MDPWG website [Online],
retrieved 16 January 2012, from http://accsq-mdpwg.org/index.
php?option=com_content&view=article&id=19&Itemid=60.
Chapter 18
Regulatory Affairs Professionals Society
Sherry Keramidas and Zachary Brousseau

Regulatory Affairs Professionals Society®
skeramidas@raps.org, zbrousseau@raps.org
18.1 Introduction
Founded in 1976, the Regulatory Affairs Professionals Society
(RAPS) is the largest international organization of and for health-
care product regulatory professionals. RAPS is headquartered in
suburban Washington, DC, with offices in Europe and Asia, and
chapters and affiliates worldwide, and can be found online at
www.RAPS.org. It helped establish the regulatory profession and
continues to promote its identity and prestige, operating outside the
political arena as a neutral, non-lobbying organization.
RAPS members help ensure the safety, effectiveness and
availability of the full range of healthcare products, including
medical devices, pharmaceuticals, biologics and biotechnology
products, and nutritional products, as well as some foods and
cosmetic products. They work in a variety of employment settings,
including the companies that make and sell healthcare products; the
regulatory agencies that oversee them, such as the US Food and Drug
Administration (FDA), the European Medicines Agency (EMA), the

www.panstanford.com
192 Regulatory Affairs Professionals Society
Singapore Health Sciences Authority, Japan’s Pharmaceuticals and

Medical Devices Agency (PMDA) and Ministry of Health, Labour and
Welfare (MHLW), Taiwan Food and Drug Administration and others;
academic institutions; clinical research organizations; and other
companies and organizations where regulatory expertise is needed.
RAPS members and regulatory professionals in general, play a
myriad of vital roles throughout the lifecycle of healthcare products,
from research and development to manufacturing to compliance
and postmarketing.
RAPS supports these individuals and the organizations that
employ them by providing integrated solutions with products and
services that meet the shared needs of regulatory professionals
worldwide, as well as the unique local needs of different countries
and employment settings. This includes education and training,
professional standards, research, knowledge-sharing, publications,
networking, career development opportunities and other valuable
resources. It also provides Regulatory Affairs Certification (RAC), the
only post-academic professional credential to recognize regulatory
excellence (www.RAPS.org/rac).
18.2 Importance in Today’s Global Environment

Around the world, patients, healthcare providers, and payers
increasingly demand safer, more effective healthcare products,
improved outcomes, more-affordable treatments, advanced
diagnostic tools, and better adherence to treatments. In the current
global business environment, regulatory requirements dominate
biopharmaceutical and medical device development and lifecycle
management. Regulatory professionals today are engaged beyond
just submission and compliance. They play integral roles throughout
the product lifecycle (Fig. 18.1) and are increasingly engaged in
critical business functions, including organizational and business
strategy, health technology assessment, comparative effectiveness
research, and even bridging the gap between regulation and
reimbursement.
RAPS’ research shows that together, business and strategy
occupy more than 28% of regulatory professionals’ time, and
more are pursuing business education. These trends underscore
the regulatory profession’s important position at the intersection
of business, emerging healthcare technologies, and government
regulation.
The Global Regulatory Community 193
Regulatory professionals have a unique ability to adapt to

changes in science, technology, manufacturing, business, economics,
and regulatory processes. The role of the regulatory professional
today is more complex and demanding than ever.
Figure 18.1 The healthcare product lifecycle.
18.3 The Global Regulatory Community

RAPS represents 25,000 professionals in the local and global
regulatory communities from 90 countries. At the local level, RAPS
has 14 chapters in North America, one in Switzerland, and one in
Israel, as well as 15 affiliates throughout the world, including Brazil,
Germany, India, Taiwan, and the United Kingdom (Fig. 18.2). RAPS
chapters and affiliates host local educational and networking events
throughout the year.
Figure 18.2 RAPS offices, chapters and affiliates.

RAPS connects regulatory professionals around the world to

the global regulatory community. Through face-to-face meetings,
networking events, and RAPS’ online community, Regulatory
Exchange (connect.RAPS.org), professionals interact with one
another and their broader community to converse, exchange ideas,
ask questions, or weigh in on the latest developments in healthcare
and regulation. The RAPS global network also allows members to
find other RAPS members based on geographic location, regional
interests, or the types of products with which they may be involved.
18.4 Building Knowledge and Competencies

RAPS strives to meet regulatory professionals’ needs for knowledge,
skills and competencies across all career levels and geographies.
It offers a range of high-quality regulatory education and training
options, including workshops, webcasts, online courses and
certificate programs, and the organization’s annual conference
(www.RAPS.org/education-amp-training).
RAPS’ annual flagship conference, dubbed The Regulatory
Convergence, is the largest annual gathering exclusively for the
regulatory profession (Fig. 18.3). It provides a critical opportunity
for regulatory professionals and thought leaders from industry,
regulatory agencies, academia and other stakeholder organizations
to come together to learn, network, and exchange ideas.
Figure 18.3 RAPS annual conference, San Jose, CA, USA.

The RAC Credential 195
At this annual gathering, expert presenters cover the latest

regulatory developments and implications across a range of
healthcare topics in biologics and biotechnology, clinical, compliance,
electronic intervention, health-related foods, medical devices and in
vitro diagnostics, pharmaceuticals, and regulatory business.
Attendees hear from top officials from agencies including the
US FDA, the EMA, the European Commission, China’s State Food
and Drug Administration, Japan’s PMDA and MHLW, the Korea Food
and Drug Administration, Health Canada, Brazil’s Anvisa, and other
regulators from around the globe.
RAPS also hosts regular workshops, meetings and webcasts
covering important topics of interest to the regulatory community.
RAPS Online University (RAPS.org/onlineu) provides self-paced
continuing education for regulatory professionals, making quality
regulatory study available worldwide. Online University courses
reflect the real-world environment of the regulatory profession.
The competency-based learning is designed by regulatory experts,
around the specific responsibilities of regulatory professionals and
delivered through RAPS’ proprietary learning platform for desktop
and iPad. Online University offers more than 35 courses covering
regulatory essentials, clinical, medical devices, pharmaceuticals and
quality, with many more courses in development.
Online University students may also earn a regulatory affairs
certificate by completing customizable curricula of courses
pertaining to the medical device and/or pharmaceutical industries.
Certificates may be earned in pharmaceuticals or medical devices, or
students may choose a dual certificate that covers both areas.
18.5 The RAC Credential

Regulatory Affairs Certification® (RAC) is the only post-academic
professional credential for the healthcare product regulatory field.
The credentialing exam and credential maintenance criteria are
developed, managed, and administered by the Regulatory Affairs
Certification Board (RACB) and supported by RAPS. Since its
inception in 1990, more than 7,000 professionals in 35 different
countries have earned the RAC.
RAC-credentialed professionals are among the current and rising
leaders in the regulatory profession. They work in all parts of the
world and in many settings, including industry, government and
academic organizations.
Earning the RAC demonstrates regulatory knowledge, critical

thinking skills and professional commitment. Professionals with the
credential are highly valued by employers, and RAPS’ own research
shows that those with the RAC earn 6% more than their peers
without the credential.
Candidates for the RAC credential sit for one of the four versions
of the exam — the RAC (US) covering US regulations, the RAC (EU)
covering European regulations, the RAC (CAN) covering Canadian
regulations, and the RAC (General Scope), which covers general
regulatory responsibilities and international standards. The
computer-based exam is administered worldwide and intended
for regulatory professionals with three to five years of regulatory
experience.
Once earned, the RAC is maintained through continuing
professional development and activities, such as attending or
speaking at meetings and conferences, writing for professional
publications, self-paced distance education, university coursework,
earning additional certifications, or professional leadership and
involvement. Recertification is required every three years.
18.6 Professional Knowledge and Standards

RAPS develops the standards for knowledge, competency, and
ethics for the regulatory profession.
Every two years, RAPS conducts the largest, most comprehensive
study of the regulatory profession, the RAPS Global Scope of
Practice & Compensation Survey. RAPS has conducted this research
for more than 20 years, and the data collected help regulatory
professionals benchmark their compensation against others in the
field and better understand the range of responsibilities of their
regulatory peers. This information also helps RAPS support the
development of the profession and create effective tools to support
regulatory professionals’ career development.
The Scope of Practice research has uncovered a number
of important developments over the 20-plus years it has been
conducted. Results have shown increased movement of professionals
across product lines and expanded involvement in combination
products over time, as well as a move away from country-specific
specialization as more professionals now have multinational or
global responsibilities.
News and Information 197
The results have revealed strong similarities in the scope of

practice of professionals around the world, regardless of where they
live and work. And in the past decade, the increased involvement of
regulatory professionals in business and strategic decision making
was identified through the Scope of Practice research.
RAPS also initiated and supported the development of a code of
ethics for the regulatory profession. Following a series of surveys
and focus groups held over two years, a task force of volunteers was
convened in 2003 to craft the Code of Ethics for Regulatory Affairs
Professionals.
The task force identified eight fundamental principles guiding
regulatory professionals in their professional endeavors: duty,
competence, objectivity, integrity, honesty, courage, fairness and
respect. These core values of the profession are detailed in the full
code, available from RAPS.
18.7 News and Information

Since its inception in 1996, RAPS’ Regulatory Focus (RF) has been
the flagship publication for regulatory professionals around the
world (Fig. 18.4). It provides readers an in-depth picture of the global
regulatory environment with features and views from regulatory
experts and professionals in the field.
Figure 18.4 Regulatory Focus.

In 2012, RF moved to an all-digital format, available online at

www.regulatoryfocus.org, allowing RAPS to offer more timely
information and articles, increased accessibility, and greater depth
and breadth of regulatory resources connected with the topics
of interest to readers. RF publishes free online regulatory news
and content, as well as features and other information available
exclusively to RAPS members. In addition, RF is accessible via mobile
application for the iPhone and iPad, and applications for Android
devices will be available in late 2012.
RAPS publishes numerous books and materials to address
specific needs of regulatory professionals at all levels, involved in
all product lines and across the full product lifecycle, including the
highly regarded Fundamentals of Regulatory Affairs series of
reference books, as well as books covering a range of specific
regulatory, medical device and pharmaceutical topics. All are
available from the RAPS Store (RAPS.org/store).
Chapter 19
Expediting Innovation in Singapore

with Regulatory Knowledge
Patricia Ho and Jui Lim

Singapore Stanford Biodesign, 61 Biopolis Drive #01-02,
Proteos, 138673 Singapore
ssbenquiry@scei.a-star.edu.sg
One of the most positive developments for the medical device

industry in Singapore has been, in recent years, the recognition
by innovators, clinicians, engineers, and economic planners of the
regulatory approval process’ centrality in bringing innovation to
the benefit of patients. The recognition that medical technology
innovation cannot exist without the regulatory approval process is,
in the first instance, founded on ethical and medical grounds, but it
also drives economic considerations as embodied by the following
questions: “How do we maximize the effect of R&D investments?,”
and “how do we reduce the attrition rate in medical device
development?” This recognition has spurred into action the panoply
of programs now available in Singapore that raises awareness
of, and builds capabilities in, the regulatory approval process. We
believe that there is heuristic value in the Singapore experience, and
this chapter will outline these programs, highlighting for illustrative
purposes the Singapore-Stanford Biodesign Program [1].

www.panstanford.com
200 Expediting Innovation in Singapore with Regulatory Knowledge
Conjointly with Singapore’s efforts to raise the profile of

“regulatory” knowledge in medical device development, there has
been an equally concerted effort to bring clinicians, engineers, and
business people together to form multidisciplinary teams. These
efforts correctly acknowledge the complexity of medical device
commercialization, as too often good ideas lay dormant for want
of technical expertise to actualize the idea, or projects without
prior financial due diligence lead to the attrition of projects and
consumed resources gone to waste.
Programs are now available from the Ministry of Health, the
Ministry of Trade & Industry, and the Prime Minister’s Office,
either directly or through their organizations and statutory boards,
such as the National Research Foundation (NRF), the Standards,
Productivity, and Innovation Board (SPRING Singapore), the Health
Sciences Authority (HSA), the Economic Development Board (EDB),
the National Medical Research Council (NMRC), and the Agency
for Science, Technology, and Research (ASTAR). These programs
emphasize medical device development using a multidisciplinary
approach that is compliant with quality and regulatory
requirements.
Some of the more energetic and forward-thinking of these
programs are those initiated by ASTAR. Through its Health and
Lifestyle (H&L) Office, ASTAR makes sizeable (S$500,000 to
S$2,000,000) grant calls that require for each qualifying application,
two co-principal investigators, one clinician and one engineer.
There are separate grant calls for diagnostic device projects and
therapeutic device projects. For all project applications, a regulatory
section must be completed, forcing applicants to consider the type
of device they are developing, and its regulatory requirements,
including the associated timeline and budgetary implications of
that device. Writing a research grant is now comparable to writing a
business plan [3].
In addition to making grant calls for medical device development,
ASTAR, through its H&L Office holds bi-monthly forums aimed to
bring clinicians, engineers, business people, and regulators together
to discuss selected clinical themes. Regulatory courses and talks
are also organized at a regular cadence, conducted by practitioners
in the industry. At the time of writing this chapter, ASTAR is even
evaluating the possibility of offering diploma and/or degree courses
in regulatory affairs.
The Biodesign Innovation Process 201
Other government agencies are following suit, especially

grant funding agencies, which now require in their applications
the commercialization plans that acknowledge both quality and
regulatory requirements. Elsewhere, the HSA has recently
announced a multi-year plan to roll out a new approval process for
medical devices, which further raises the importance of regulatory
knowledge. This has been matched by a vigorous and regular
outreach effort to keep all stakeholders informed of the HSA’s
requirements, which has had the effect of raising awareness of
“regulatory” importance for and relevance to medical devices. At the
National University of Singapore, the Medical Engineering Research
and Commercialization Initiative (MERCI) was set up, comprising
engineers and doctors from industry, to provide early inputs on
issues relating to quality and regulatory matters to contemplated
medical device development projects [2].
In 2009, EDB and ASTAR teamed up to advance efforts to train
Singaporean innovators as a way of strengthening its medical
device industry. Through a joint venture with Stanford University’s
Biodesign Program, the Singapore-Stanford Biodesign (SSB) Program
was born and launched in 2010 [1].
19.1 The Biodesign Innovation Process

SSB, like its older sibling in the United States, is predicated on the
belief that innovation can be taught, rather than it being a sudden,
ineluctable, unpredictable, and random “bright idea.” This belief has
now been fully articulated as the “Biodesign Process” and validated
by the phenomenal output of technologies and start-up companies
that have emanated from this “Process.”
The “Biodesign Process” begins by forming teams of people with
differing backgrounds (medical doctors, engineers, and business
backgrounds) to identify unmet clinical needs, brainstorm and
design novel solutions for these needs, and then develop business
proposals to commercialize these innovations. SSB is based on the
three-stage innovation process as shown in Fig. 19.1. In this chapter,
this approach to innovation will be introduced as an example of
how information, such as the regulatory knowledge provided in the
other chapters of this book, helps expedite innovation.
Figure 19.1 The three-stage innovation process used to train innovators .
19.1.1 Identify
In the first stage of the innovation process, our students are tasked
with searching for unmet needs by way of full clinical immersion.
They observe procedures and treatments with an eye to identifying
the shortcomings with current procedures and their implements.
Literature reviews are performed concurrently to understand
the state of the art and its complications. Students interview the
relevant clinician-operators to obtain deeper understanding of any
particular problem and associated need. All observed problems
are then ultimately re-expressed as a need statement, a written
statement concisely defining the need. This may be further refined
over multiple iterations. This stage of defining the need statement
to address is the fulcrum of the innovation process. Thereafter, our
students evaluate their list of need statements, effectively triaging
them to arrive at a shortlist of the top needs. The parameters of this
triage are a deep understanding of the disease process, the treatment
options, the market, and the stakeholders involved.
19.1.2 Invent
After they have shortlisted the top needs, our students, in this second
stage, begin to draw and design various possible solutions to address
The Biodesign Innovation Process 203
a selected clinical need. Innovators also begin to acknowledge and

utilize country-specific regulatory information, such as contained
in this book.
After concluding with some possible designs, a patent search is
done, to see whether or not such solutions already exist and if the
innovator has the freedom to operate. With each possible design,
regulatory pathways are evaluated. Does a predicate device exist?
Early on, the innovator may wish to eliminate device concepts that,
for example, foreshadow an arduous and expensive regulatory
process, in favor of equally effective device concepts that may
undergo expedited approval. Patient flow is examined to see if
the invention would be disruptive to current patient flow, which
would affect key stakeholders. Understanding patient flow and
key stakeholders helps the innovator discern whether the intended
users would be willing to adopt this proposed technology versus
existing technologies, and if so, at what price range. Doctors
may not wish, for instance, to accept such technologies that may
decrease their number of patients or commoditize their expertise.
The commonly used example of the Scribner Shunt highlights
the issues that may arise with a successful novel invention. The
Scribner Shunt, a device used in hemodialysis that allows for the
blood to be filtrated outside of the body, radically changed the
standard of treatment and patient flow [4]. Prior to this invention,
maintenance dialysis for irreversible kidney failure was not done
and end-stage kidney disease was fatal. With its introduction,
the device allowed for the treatment of irreversible chronic renal
failure. To deliver this new treatment, the first outpatient dialysis
centers were introduced with specialized nurses and technicians,
replacing clinics and nephrologists. Now that chronic hemodialysis
had become possible, the expenses of treatment largely increased,
and certain issues, such as reimbursement and who should be
allowed treatment, arose. With key stakeholders identified,
the innovator can identify prices of existing treatments, how
to increase physician adoption, possibilities for government
subsidies and insurance coverage, and determine an estimated
price for their device.
This “invent” stage helps innovators avoid the problem many
failed startups face of leaping from the identification phase to
implementation, only to find there is no market or that regulatory
hurdles are too steep.
19.1.3 Implement
By the time this final stage is reached, the student may have repeated
the previous two stages, refining the need statement and subsequent
prototypes, before selecting a final concept. This third stage
focuses on creating the strategy to execute successful production
and commercialization. Financial models are built to estimate
the amount of funding needed and the associated funding period.
Regulatory issues again take center stage. To address regulatory
issues such as assessing the requirements for regulatory approvals
and consultation with regulatory authorities and consultants may
take place at this stage. This helps the innovator with strategic
decisions, such as determining the requirements for pursuing
regulatory approval in one market and deciding if they are capable
of leveraging the data and approval to expedite regulatory approval
in another market. Potential animal and clinical trials are designed.
Again, as in the invent stage, the innovator must examine the flow
of patient care, whether the device will be accepted by the user
community, and how the device will be sold and distributed. By the
end of this final stage, innovators are left with an estimated cost and
time needed to bring their device to market, followed by a proposed
sales and distribution strategy.
19.2 The Innovator’s Resource

SSB was founded in 2010 as a collaboration among the Singapore
Agency for Science Technology and Research (A*STAR), Singapore
Economic Development Board (EDB), and Stanford University.
In its current form, SSB consists of a fellowship and class, to train
approximately 36 people annually on the innovation process who
are expected to become leaders in the medical device innovation
industry. Although it is primarily a training program, SSB is also
interested in creating a resource for innovators to use, to help
expedite the innovation process and increase the number of
successful innovations in Asia.
Unlike many of the organizations participating in the regulatory
harmonization efforts, SSB is unique as it is neither a governmental
regulatory agency nor a part of industry. This resource SSB is in the
process of compiling will serve as a first-stop for entrepreneurs,
guiding them on who the country’s regulatory authority is, how
healthcare is distributed and paid for, and how their inventions
The Innovator’s Resource 205
can be protected. These entrepreneurs often lack the funding and

resources large multinational companies have, to identify and hire
credible consultants early on in the process. SSB hopes to encourage
more entrepreneurs to come to Asia by filling their gaps of
knowledge, helping to guide them in their early-stage decisions.
The resource for innovators focuses on Regulatory, Reimbursement,
and Intellectual Property (IP), with personal vignettes and case
studies showcasing various experiences.
For example, most innovators are less familiar with knowing,
for example, that the regulatory authority in Singapore is the Health
Sciences Authority (HSA). Figure 19.2 provides a general sample
checklist for innovators to use as to understand the regulatory basics
in Singapore. Similar checklists will hopefully be provided for other
countries and topics such as reimbursement and IP as well.
 Is the innovation a medical device?

o What is the intended purpose of the device? What is its primary
mode of action?
o Where to Look: HSA website, Health Products Act 2007
 Classify the Device
o Follow the rules noted in HSA’s Guidance Document on
Classification
o Where to Look: GN-13-R1 Guidance on Risk Classification of General
Medical Devices and the Singapore Medical Devices Register
(SMDR)
 Prepare Product Registration Application
o For class A device, see if the device is exempt from product
registration
o Prepare the submission dossier based on the ASEAN Common
Submission Dossier Template (CSDT)
o Where to Look: HSA GN-15-R3 Guidance on Medical Device Product
Registration, GN-17 Guidance on Preparation of Product Registration
Submission for General Medical Devices using the ASEAN CST, and
GN-22 Guidance to the List of Medical Devices Exempted from
Product Registration
 Determine the Appropriate Regulatory Pathway
o Has the device been evaluated or approved in at least one of the GHTF
member countries?
o Where to Look: GN-15-R3 Guidance on Medical Device Product
Registration
 Submit Product Registration Application
o Use the online Medical Device Information and Communication
System (MEDICS)
o Where to Look: GN-15-R3 Guidance on Medical Device Product
Registration
 Consult Regulatory experts or consult with a regulator within HSA.
Figure 19.2 Checklist for innovators for Singapore regulatory approval.

Other areas of regulatory useful for innovators to know include

upcoming or new regulations, estimated regulatory approval times
and fees, and what country-specific considerations an innovator
should be aware of. For example, when dealing with Japan’s
PMDA, the innovator could benefit from knowing one key success
factor would include arranging a meeting with the PMDA, with a
consultation fee of thousands of dollars, price-dependent on the
type of consultation.
Intertwined with regulatory issues are other areas important for
innovators to understand, which SSB strives to provide resources
for. In the reimbursement section, SSB hopes to provide a general
overview of healthcare distribution and financing, medical device
procurement, subsidization, and grants. For example, an innovator
interested in entering China would benefit from the knowledge
that the National Development & Reform Commission (NDRC) is
responsible for price supervision policies for medical devices, while
the Ministry of Human Resources and Social Security is in charge of
Urban Employee and Residents Basic Medical Insurance and other
medical insurance findings. Equipped with this knowledge, the
innovator can further investigate the specific government agencies
to understand how prices of devices are determined to assess the
affordability of their proposed device. Further, they should know
whether the local government will provide a subsidy for the device,
whether it be on a list of subsidized devices or simply partially paid
for up to a certain amount. If I had a new device, would I sell the
price through tender? Is the model of consignment often seen in
hospitals? Which types of hospitals are most frequented, and would
they be able to afford the care I am proposing? These are some of the
questions many innovators ask, yet the answers are currently not
provided in a one-stop resource of information.
As with regulatory and reimbursement issues, Intellectual
Property is another section with country-specific knowledge SSB
hopes to highlight for innovators. Innovators must understand
the basics of the legal system, prevailing attitudes, and forms of
available protection. This will help the innovator go about protecting
and maximizing the value of their invention. The innovator faces
questions such as, how do I protect my product’s reputation and
patents, avoiding the potential of counterfeits more easily available
and at a discounted price? How long would it take for the country’s
authority to grant the patent after submitting an application? With
References 207
the answers, the innovator is able to plan his timelines accordingly,

to maximize efficiency while executing regulatory and intellectual
property strategies.
19.3 Current Direction

Innovators are becoming increasingly interested in innovating for
Asia, as they see the potential in creating cutting-edge technology for
the growing middle-class in emerging markets. These devices often
must be priced competitively, limiting the technological capability
or quality of the products. Entrepreneurs with little or no prior to
the medical device environment in Asia arrive, struggling to find the
correct contacts to answer the questions as they subject their ideas to
the innovation process. With the helpful collaborations from people
in government authorities and industry, SSB hopes to compile this
resource for innovators to cultivate the hunger to innovate for Asian
markets and expedite the innovation process.
References
1. Singapore Stanford Biodesign (2010). What the Program Is About.

Singapore Stanford Biodesign. Retrieved March 8, 2012, from http://
www.ssb.a-star.edu.sg/about-program.html.
2. MERCI (n.d.). NUS’s Medical Engineering Research and
Commercialization Initiative (MERCI). Special Feature: Singapore
Medtech Innovations & Initiatives. Retrieved March 20, 2012, from
http://www.medtechsingapore.com/pdf/Universities_A_Source_of_
Innovation_in_the_Medtech_Sector.pdf.
3. A*STAR (3 April 2012). Grants & Sponsorships. Agency for Science,
Technology, and Research. Retrieved March 8, 2012, from http://www.
a-star.edu.sg/tabid/136/default.aspx.
4. Christopher R. Blagg. The Early History of Dialysis for Chronic Renal
Failure in the United States: A View from Seattle. American Journal of
Kidney Diseases, 49(3) (March 2007), 482–496.
Part 4
Medical Device Regulatory System

in the United States and the
European Union
Chapter 20
United States Medical Device

Regulatory Framework
Carole C. Carey
U.S. Food and Drug Administration, Center for Devices and Radiological Health,
10903 New Hampshire Ave., Silver Spring, Maryland, USA
carole.carey@fda.hhs.gov
20.1 Introduction
The United States Food and Drug Administration (USFDA), well
known as the FDA, is an agency within the U.S. Department of Health
and Human Services (HHS). The FDA is a science-based, regulatory
and public health agency. Its statutory mandate is to ensure that
the nation’s food supply is safe and wholesome, products that emit
radiation are safe, and medical products marketed in the United
States are safe and effective. Furthermore, the FDA also regulates
mammography facilities as well as cosmetics and tobacco products.
The FDA does not regulate medical practice. State law regulates
medical practice. The FDA’s regulatory authority extends to the
50 States, the District of Columbia, Puerto Rico, Guam, the Virgin

www.panstanford.com
212 United States Medical Device Regulatory Framework
Islands, American Samoa, and other US territories. The medical

device industry is a highly regulated segment of the US economy. A
report, Medical Device Industry Assessment, Updated March 24, 2010,
(International Trade Administration, US Department of Commerce),
[http://ita.doc.gov/td/health/medical.html] points to the United
States as the leader in the manufacturing of medical devices and the
largest medical devices market in the world. It is roughly 42% of the
world’s total, with an estimated value at more than US$100 billion
in 2008. The report also noted that over the past decade, the value
of exported and imported medical devices steadily increased. Shown
in Table 20.1 is the medical device sector trade flow in 2007 and
2008 based on the North American Industry Classification System
(NAICS) code.
Table 20.1 Medical device sector trade flows by NAICS code in billions of
US dollars
NAICS 2007 2008 2007 2008

code Description exports exports imports imports
334510 Electro- 7.2 8.08 6.8 7.22
medical
apparatus
334517 Irradiation 3.1 3.34 3.6 3.72
apparatus
339112 Surgical 8.8 9.98 8.8 9.14
and medical
instruments
339113 Surgical 6.8 7.39 7.3 9.01
appliances and
supplies
339114 Dental 1.1 1.22 1.2 1.28
equipment
and supplies
339115 Ophthalmic 1.3 1.39 3.3 3.26
goods
Total 28.3 31.4 31.0 33.63
In this chapter, we will focus on the regulatory management

and supervision of medical devices. The learning objective is
to provide students and other interested individuals a concise
Total Product Life Cycle Approach 213
overview of the US regulatory framework, as well as to introduce

the general regulatory requirements, premarket and postmarket,
necessary to legally market medical devices in the United States.
Since the majority of device submissions are classified in Class I and
Class II, there is more effort to clarify the premarket notification
510(k) clearance process and the general regulatory controls
mandatory to all classes (I, II, and III).
20.2 The FDA Center for Devices and

Radiological Health
In the United States, the FDA’s Center for Devices and Radiological
Health (CDRH) is responsible for regulating medical devices and
radiation-emitting products (medical and non-medical). Within
CDRH, the Division of Mammography Quality and Radiation
Programs ensures that a mammography facility must meet the
Mammography Quality Standards Act (MQSA) certification in
providing quality mammography services, and are inspected.
The USFDA CDRH evaluates new medical devices for safety and
effectiveness before they are marketed; and monitors products
already on the market, so that unsafe and ineffective products are
kept out of the market. In addition, the USFDA CDRH regulates
companies that design, manufacture, repackage, relabel, and/or
import medical devices into the United States.
To learn more about the Center’s mission, vision, and shared
values as well as strategic planning, transparency, and innovation
initiatives, the following Web site provides comprehensive
information:
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedical
ProductsandTobacco/CDRH/ucm300639.htm
20.3 Total Product Life Cycle Approach

CDRH’s regulatory paradigm in managing medical devices is
based on risk. That is, the higher the risk of harm to humans, the
greater the level of regulatory control. Further, the integrated
systematic approach of Total Product Life Cycle (TPLC) is applied
in the regulatory oversight of medical devices. Figure 20.1 is a
schematic representation of CDRH’s Total Product Life Cycle (TPLC)

model, a “cradle to grave” concept. It depicts the interconnection
of the continuing stages throughout the different lifecycle phases;
beginning from the initial design concept, prototype, premarket
testing, clinical study, manufacturing, marketing, to widespread use,
and finally to obsolescence of the “old” technology. An attribute of
TPLC is the required interaction among stakeholders. The sharing
of important information on device experience and lessons learned
from a product’s life cycle are applied to the development of the next
phase, and ultimately in the design of the next generation or future
products.
Figure 20.1 FDA’s Center for Devices and Radiological Health Model of
Total Product Life Cycle (TPLC).
20.4 Legislation and Device Laws

The 1968 mandate of the Radiation Control for Health and Safety
Act (RCHSA) required safety standards for electronic products that
give off radiation, such as microwave ovens, x-ray equipment and
others. People should not be exposed to harmful levels of radiation
from these products. A few years later, on May 28, 1976, President
Gerald Ford signed into law the Medical Device Amendments to the
US Federal Food, Drug, and Cosmetic Act (FD&C Act). This was the
result of a US Senate finding that faulty medical devices had caused
10,000 injuries, including 731 deaths. The statute established
Federal regulatory controls for medical devices. It granted FDA the
authority to require premarket testing and submissions of safety
and effectiveness information for FDA review.
The Regulatory Environment for Bringing a Medical Device to Market 215
20.4.1 FDA Law vs. FDA Regulations vs. FDA Guidance

Federal laws establish the legal framework within which FDA
operates. The FD&C Act is a federal law enacted by Congress in 1938
giving authority to the USFDA to oversee the safety of food, drugs,
and cosmetics. The FD&C Act has been amended many times. For
instance, it was amended in 1976 as described above to incorporate
into law the Medical Device Amendments Act.
Based on the laws set forth in the FD&C Act and other federal
laws, the FDA develops regulations. This process is known as “notice
and comment rulemaking.” Hence, FDA regulations are also federal
laws and are commonly referred to as Title 21 Code of Federal
Regulations (CFR). The CFR represents all current regulations and
the volumes are published annually. There are nine volumes; the
volume that contains the medical device and electronic product
regulations is Part 800-1299.
On the other hand, FDA guidance is not law. Guidance describes
the agency’s current thinking on regulatory issues. Guidance is not
legally binding on the public or the FDA but is a very practical and
useful regulatory tool for FDA staff and regulated industry. Guidance
facilitates the regulatory process by providing more information
on the interpretation of medical device regulations. The CDRH
Office of Device Evaluation and Office of In Vitro Diagnostic Device
Evaluation and Safety develop guidance documents to articulate
safety and effectiveness requirements on specific device types.
The guidance documents provide consistency and predictability,
which helps manufacturers gather appropriate non-clinical and
clinical data, plan, and submit an organized and well-thought out
marketing application.
More information on FDA laws, regulations, and guidance is
available at http://www.fda.gov.
20.5 The Regulatory Environment for Bringing a

Medical Device to Market
Anyone who wishes to commercially distribute in the United
States medical devices or electronic products that emit radiation
must comply with applicable US laws and regulations, even if the
product is authorized for marketing in another country. At present,
the FDA does not recognize regulatory marketing approvals from

other countries. However, it will evaluate all safety and effectiveness
information submitted to it in the premarket application, including
foreign clinical data.
Comprehensive information about the Center for Devices and
Radiological Health and the regulation of medical devices can be
found at http://www.fda.gov/MedicalDevices.
It is also important to know that device regulatory topics
discussed in this chapter are accessible from the FDA Medical
Devices homepage, under Medical Device Topics, “Device Advice:
Comprehensive Regulatory Assistance” http://www.fda.gov/
MedicalDevices/DeviceRegulationandGuidance.
20.6 Regulatory Considerations to Market and

Keep Devices in Distribution
20.6.1 Definition of Medical Devices
Section 201(h) of the FD&C Act defines the term “device” as “an
instrument, apparatus, implement, machine, contrivance, implant,
in vitro reagent, or other similar or related article, including a
component part, or accessory which is recognized in the official
National Formulary, or the United States Pharmacopoeia, or any
supplement to them, intended for use in the diagnosis of disease or
other conditions, or in the cure, mitigation, treatment, or prevention
of disease, in man or other animals, or intended to affect the structure
or any function of the body of man or other animals, and which does
not achieve any of its primary intended purposes through chemical
action within or on the body of man or other animals and which is
not dependent upon being metabolized for the achievement of any
of its primary intended purposes.”
The definition above determines whether the product is a
medical device and provides a clear distinction between a medical
device and other FDA regulated products such as drugs or biologics.
In such cases, another FDA Center is responsible for the regulation
of the product.
You may also find the definition of a medical device by entering
in the Search box “medical device definition” at http://www.fda.
gov/MedicalDevices/DeviceRegulationandGuidance.
Regulatory Considerations to Market and Keep Devices in Distribution 217

The FD&C Act also requires FDA to classify all devices intended for
human use into one of three regulatory categories (Class I, Class II,
and Class III). The tiered classification is based on risk. Appropriate
level of regulatory control necessary to assure safety and effective-
ness of each device increases according to its classification. Some
examples of Class I devices are battery-powered ophthalmic
electrolysis units and protective restraints. Examples of Class
II devices include blood pressure monitors, oximeters, and
electrocardiographs. Further, in an effort to reduce regulatory
burden, the FDA judged most Class I devices and some Class II
devices exempt from submitting a Premarket Notification (510(k))
application (discussed below). Examples of Class I Exempt
devices include tongue depressors, elastic bandages, and manual
stethoscopes. Examples of Class II Exempt devices are radiologic
tables and biofeedback devices. Class III devices have the highest
risk and the most stringent regulatory controls. Examples of Class
III devices are implantable cardiac pacemakers, hip joint acetabular
metal cemented prostheses, and heart valves.
Often used in the surgical setting are kits or trays consisting of
two or more separate types of finished devices packaged together
for the convenience of the user and often referred to a convenience
kit. The device classification of the kit is based on the highest
classification of the devices that are provided in the kit.
CDRH makes available to the public several medical device
databases under Tools and Resources at http://www.fda.gov/
MedicalDevices/DeviceRegulationandGuidance/Databases.
The publicly available product classification database (Fig. 20.2)
provides a means for conducting a simple and advanced search.
It contains the medical device name, the associated three-letter
product code unique to CDRH and identifies the device class as
well as the type of premarket submission. Other information also
includes the device definition, the regulation description, any
applicable recognized consensus standard, and other important
regulatory information about the generic device type.
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/
classification.cfm
Figure 20.2 Screen shot of the Product Classification search database.
All classes of medical devices are subject to general regulatory

controls.
The FD&C Act requires baseline controls necessary for market-
ing, proper labeling and monitoring performance once a device is
on the market. All devices must comply with the following General
Controls:
• Adulteration and Misbranding
• Establishment Registration and Medical Device Listing
• Premarket Notification (510(k)), unless exempt
• Labeling requirements
• Quality System Regulation/Good Manufacturing Practices
(GMP)
• Medical Device Reporting (MDR)
More information is available at http://www.fda.gov/Medical
Devices/DeviceRegulationandGuidance/Overview.
20.6.3 Adulteration and Misbranding

Medical devices are subject to the adulteration and misbranding
provisions of the FD&C Act. In Section 501, a device is considered
to be adulterated if it includes any filthy, putrid, or decomposed
substance, or if it is prepared, packed, or held under unsanitary
conditions. The misbranding provisions of various aspects of drug

and device labeling requirements are covered in Section 502. An
example of misbranding violation is if a device labeling is false
and misleading, or if it does not bear adequate directions for use,
warnings, etc.
Particulars are available at http://www.fda.gov/MedicalDevices/
DeviceRegulationandGuidance/Overview/GeneralandSpecial
Controls/ucm055910.htm.
20.6.4 Establishment Registration and Medical

Device Listing
Manufacturers (both domestic and foreign) and initial distributors
(importers) of medical devices must register their establishments
with the FDA and are required to pay a fee and register annually.
The initial registration and/or device listing information must be
submitted within 30 days of an establishment beginning an activity
or placing a device in commercial distribution. Afterwards, the fee-
based registration information must be submitted every year even
if no changes have occurred between October 1 and December 31
of each year. Device listing must also be reviewed at the same time.
However, device listing updates may be submitted at any time without
additional fees. The registration process is done electronically.
In addition, foreign manufacturers must also designate a US
Agent. Most establishments that are required to register are also
required to list the devices that are made in those facilities, as
well as activities that are performed on those devices. If a device
requires 510(k) clearance or PMA approval before being marketed
in the United States, the manufacturer must wait until the FDA has
granted the clearance or approval to market the device. Note that
Registration and Listing is not a marketing authorization, certifica-
tion or license to market a device in the United States. However, one
should be aware that in some regulatory systems in the world, the
term “Registration” may be equivalent to marketing authorization to
sell and distribute a device.
More information on the required fees, how to register, payment
process, US agent, and other important reminders about registration
and listing can be found at http://www.fda.gov/MedicalDevices/
DeviceRegulationandGuidance/HowtoMarketYourDevice/
RegistrationandListing.
20.6.5 Premarket Notification (510(k))

Two of the most common pathways in successfully bringing a
medical device to market are described in this chapter: (1) Premarket
Notification (510(k)) clearance (21 CFR Part 807 Subpart E), and (2)
Premarket Approval (PMA) process (21 CFR Part 814).
The Section 510(k) of the FD&C Act requires device manufactu-
rers to notify FDA, at least 90 days in advance, of their intent to
market a medical device in the United States. The 510(k) regulatory
process requires manufacturers to demonstrate “substantial
equivalence,” that is, the proposed (or new) device is at least as
safe and effective as a predicate device. The predicate device is a
legally marketed device that has previously been cleared to market
through the 510(k) program and serves as a comparator to which
substantial equivalence is claimed. A predicate device cannot be
in violation of the Act. A substantial equivalence determination or
request for additional information is usually made within 90 days
upon receipt of a 510(k) submission.
Special Controls
All Class I and Class II devices, unless exempt, require submission
of a 510(k) application and are subject to General Controls. Exempt
devices are only exempt from a 510(k) submission but are subject to
the requirements of other applicable General Controls (Registration
and Listing, Labeling, GMP). Additionally, Class II devices must
meet the requirements for Special Controls since General Controls
alone are insufficient to assure safety and effectiveness of Class II
devices. Examples of Special Controls include special labeling
requirements, patient registries, mandatory performance standards,
and postmarket surveillance studies. Class II Special Controls
Guidance Documents have been written for some device types (e.g.,
bone sonometers, percutaneous transluminal coronary angioplasty
(PTCA) catheters) or systems (e.g. full field digital mammography
system and instrumentation for clinical multiplex test systems). All
available medical guidance documents, including Special Controls
guidance documents are searchable at the following site: http://
www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments
20.6.5.1 Kits
For a kit to be marketed in the United States as described in the
classification section above, the submission must identify all
devices provided in the kit and document the marketing status of
each device in the kit by including the Kit Certification for 510(k)s.
Certain convenience kits that meet the criteria in the Convenience
Kit Interim Regulatory Guidance are under enforcement discretion
and do not require a 510(k). If a 510(k) is not required, it is
recommended to maintain this information in your files.
The Guidance documents pertaining to convenience kits are
• Convenience Kits Interim Regulatory Guidance
• Sterilized Convenience Kits for Clinical and Surgical Use
There are special considerations for medical device kit that
include gloves and/or sutures. Kit manufacturers and assemblers
should assure that the gloves and/or sutures in their kits are cleared
for marketing in the US additional guidance and other requirements
for medical gloves are available in Guidance for Medical Gloves.
20.6.5.2 Predicate device and substantial equivalence

For purposes of seeking to market a device in US interstate
commerce, the first step is to confirm that the product is a medical
device according to the definition discussed in the section above.
The next step is to determine which regulatory pathway is required.
If the appropriate market application is determined to be through
the 510(k) clearance regulatory process, the manufacturer must
demonstrate that the proposed device is at least as safe and effective,
that is, substantially equivalent to a legally marketed device (21 CFR
807.92(a)(3)) that is not subject to PMA. The legally marketed device
to which equivalence is drawn is also known as the “predicate” device.
Most often devices recently cleared under 510(k) are selected as
the predicate to which equivalence is claimed. However, any legally
marketed 510(k)-cleared device may be used as a predicate.
Demonstration of substantial equivalence does not imply the
new and predicate devices must be identical. Substantial equivalence
is established with respect to intended use, design, energy used or
delivered, materials, chemical composition, manufacturing process,
performance, safety, effectiveness, labeling, biocompatibility,
standards, and other characteristics, as applicable.
A device is substantially equivalent if, in comparison with a

predicate, it
• has the same intended use as the predicate; and
• has the same technological characteristics as the predicate;
or
• has the same intended use as the predicate; and
• has different technological characteristics and the information
submitted to FDA;
o does not raise new questions of safety and effectiveness;
and
o demonstrates that the device is at least as safe and effective
as the legally marketed device.
A device may not be marketed in the United States until the
submitter receives a letter declaring the device substantially
equivalent and “clears” the device for commercial distribution.
Details may be found at http://www.fda.gov/MedicalDevices/
DeviceRegulationandGuidance.
Of the note are the lists of topics that appear on the left side of the
screen (Fig. 20.3) as they provide a detailed explanation of regulatory
topic of interest, often in a tutorial fashion. For example, from the
Device Regulation and Guidance Web site, the link to Premarket
Submissions will then lead to the Premarket Notifications (510(k))
site. Below is an example of the Premarket Notification 510(k) screen
with subtopics on the left hand side such as Submission Process,
510(k) Forms, How to Find a Predicate Device, How to Prepare a
Traditional 510(k), Abbreviated 510(k) or Special 510(k) and many
more topics.
Additionally, an excellent resource for identifying predicate
device(s) and other important regulatory information about a
legally marketed device such as product code, regulation number,
description, and others is to make use of publicly available
search engines under Medial Device Databases, namely: Product
Classification, Premarket Notifications (510(k)), etc. A more recently
added database is the TPLC (Total Product Life Cycle) database that
integrates premarket and postmarket data about a device.
(http://www.fda.gov/MedicalDevices/DeviceRegulationand
Guidance/Databases)
Figure 20.3 Screenshot of the Device Regulation and Guidance Web site
and Premarket Submissions.
20.6.5.3 Planning and assembling the 510(k)

submission process
In the Code of Federal Regulation, 21 CFR 807 Subpart E, describes
requirements for a 510(k) submission. The Office of Device Evalua-
tion (ODE) and the Office of In Vitro Diagnostic Device Evaluation
and Safety (OIVD) within CDRH are responsible for review of
510(k) applications. Within the offices, Divisions and Branches are
organized into sub-units according to medical scientific disciplines
and specialties. The pool of scientific reviewers is multidisciplinary
that include engineers (electrical, software, biomedical, mechanical,
etc.), physicians, physicists, microbiologists, chemists, material
scientists, statisticians and others who perform and evaluate the
safety and effectiveness of 510(k) applications and other regulatory
submissions such as clinical investigations under the Investigational
Device Exemption (IDE) regulation (discussed below). The scientific
reviewer recommends whether a new device is found substantially
equivalent (SE) or not substantially equivalent (NSE).
The 510(k) submission process begins when the application is

received in the CDRH Document Mail Center, date stamped, entered
into the internal FDA database and assigned a unique document
control number that is referred to as the 510(k) number. It begins
with the letter “K” and is followed by 6 numeric digits. Having a
general understanding of the next steps, (i.e., what happens to
the document after the log-in procedure) is helpful knowledge to
acquire before preparing the 510(k) application. It is recommended
that a 510(k) application be administratively complete in order for
the scientific review to proceed. The Web link below explains in
more detail the routing process: Division Acceptance and Review,
Scientific Reviewer Assignment, FDA Requests for Additional
Information, Issuance of the Decision Letter, and Request the Review
Status of the 510(k) submission.
Guidance/HowtoMarketYourDevice/PremarketSubmissions/
PremarketNotification510k/ucm070201.htm)
When writing the 510(k) submission, it is critical to clearly
identify and articulate the “indications for use,” for which, a
substantially equivalent determination is sought. CDRH will
include the indications for use in the clearance letters for devices
found to be substantially equivalent to a legally marketed predicate
device. The confusion between the agency and the 510(k) submitter
is minimized if not eliminated.
Furthermore, it is very important to understand the different
forms associated with premarket notification and comply with the
applicable requirements. This would facilitate the preparation time
and prepare a well-organized submission that meets the essential
administrative elements. An incomplete submission package may
result in FDA “refuse to file” your application.
Following is the list of the forms:
• 510(k) Pre-Review Form
• Exempt Device Review Form
• Screening Checklist for Traditional/Abbreviated Premarket
Notification [510(k)] Submissions
• 510(k) Format Guidance
• 510(k) Review Template
• Premarket Notification [510(k)] Status Request and

Response (PDF-419 KB)
• 510(k) Review Template Instructions
• 510(k) Cover Sheet Memorandum
• 510(k) “Substantial Equivalence” Decision Making Process
• Standards Data Form for Abbreviated 510(k)s
• Sterile Devices in Premarket Notification [510(k)]
Submissions
• Description of 510(k) “Substantial Equivalence” Decision-
Making Process (Accessible Text)
• Premarket Notification Class III Certification and Summary
• Premarket Notification Truthful And Accurate Statement
• Premarket Notification 510(k) Statement
• Required Elements for a Declaration of Conformity to a
Recognized Standard
Moreover, in the premarket phase, it is vitally important for
an applicant to consider the Quality Systems (QS) regulation in
planning and during the 510(k) process. Class II, Class III, and
certain Class I devices are subject to design control requirements of
the QS regulation during the design phase of product development.
The topic is discussed further in Section 20.6.9.
20.6.6 Premarket Approval (PMA)

For new, more innovative, non-substantially equivalent devices,
the pathway to market is the PMA (21CFR Part 814) route. These
devices are the Class III high risk devices, usually those that support
or sustain human life, implanted in the body, or pose a significant
risk of illness or injury. This regulatory process is more involved
and includes submission of clinical data to support medical device
claims. In addition to meeting applicable General Controls and
Special Controls, a PMA application is required. The regulatory time
to review the PMA and for FDA to make a regulatory decision is
180 days.
Details can be found at http://www.fda.gov/MedicalDevices/
DeviceRegulationandGuidance/HowtoMarketYourDevice/
PremarketSubmissions/PremarketApprovalPMA.
20.6.7 Investigational Device Exemption (IDE)

An IDE allows the investigational device to be used in a clinical
study in order to collect safety and effectiveness data. In some cases,
clinical data may be required to support a 510(k) submission. The
studies must be conducted under the principles of medical device
Good Clinical Practices (GCP). The GCP refer to the regulations and
requirements that must be complied with while conducting a clinical
study. These regulations apply to the manufacturers, sponsors,
clinical investigators, institutional review boards, and the medical
device. The primary regulations address the following important
areas: Investigational Device Exemption (21CFR 812); Protection of
Human Subjects (i.e., informed consent) (21CFR 50); Institutional
Review Boards or IRB (21CFR 56); Clinical Investigators’ Financial
Disclosure (21CFR 54); Good Laboratory Practice or GLP for
Nonclinical Laboratory Studies (21 CFR 58); and Design Controls of
the Quality System Regulation (21CFR 820).
Before a significant risk (SR) IDE study can begin, the FDA and
the IRB must review and approve the study. The regulatory time for
FDA to review the IDE and make a determination is 30 calendar days
or it is deemed approved. A non-significant risk (NSR) IDE study
only requires IRB approval before the study can begin but must still
comply with the abbreviated requirements of the IDE regulation.
Under the Pre-IDE Program, manufacturers are encouraged to
have early dialogue with FDA staff on specific aspects of the IDE
application before they submit an official IDE application. An added
benefit for early interactions is the “heads-up” on the new device
investigational technology and/or clinical protocol that this provides
to FDA. The CDRH Office of Device Evaluation conducts the primary
review of the IDE submission. The Bioresearch Monitoring Program
within the CDRH Office of Compliance oversees the IDE enforcement
of good clinical practices.
Details can be found at
http://www.fda.gov/MedicalDevices/DeviceRegulationand
Guidance/HowtoMarketYourDevice/InvestigationalDevice
ExemptionIDE
20.6.8 Labeling
Labeling includes labels on the device as well as descriptive and
informational literature that accompany the device. The general
labeling requirements for medical devices are speciied in 21 CFR

Part 801. These regulations specify the minimum requirements for
all devices. There are additional requirements needed for speciic
categories of devices such as labeling for in vitro diagnostic device,
IDE devices, radiation-emitting products and natural rubber (latex).
20.6.9 Quality System (QS) Regulation/Good

Manufacturing Practices (GMP)
Device manufacturers must comply with the FDA Quality System
Regulation (21 CFR Part 820). The regulation includes requirements
related to the methods used in the facilities and controls used for
designing, purchasing, manufacturing, packaging, labeling, storing,
installing and servicing of medical devices in order to conform to
current good manufacturing practices (GMP). FDA inspects
manufacturing facilities to assure compliance with the QS
requirements. Certain types of devices are exempt from GMP.
However, exemption from GMP requirements does not exempt
manufacturers from keeping complaint iles or from general
requirements concerning records. IDE clinical studies are exempt
from GMP, except for the Design Controls that provide the require-
ment for procedures to control the design of the device in order to
ensure that the speciied design requirements are met.
The International Organization for Standardization (ISO)
developed and published ISO 13485:2003. It is the international
standard relating to Quality Management Systems for organizations
involved in the manufacture of Medical Devices. Although there
are few substantive differences between the FDA Quality System
Regulation and the ISO 13485:2003, there are no conlicting
requirements.
For more information on the FDA Quality System (QS)
regulation, please refer to Quality Systems at http://www.fda.
gov/MedicalDevices/DeviceRegulationandGuidance/Post-
marketRequirements/QualitySystemsRegulations.
20.6.10 Medical Device Reporting (MDR)

Reporting of adverse events is a mandatory postmarketing require-
ment for medical devices. Firms who have received complaints of
device malfunctions, serious injuries or deaths associated with

medical devices are required to notify FDA of the incident. User
Facilities (e.g., hospitals, nursing homes) are required to report
suspected medical device related deaths to both the FDA and the
manufacturers. They report medical device-related serious injuries
only to the manufacturer unless the manufacturer is unknown. In
such instances, the serious injury is reported to FDA.
The MDR regulation is contained in 21CFR Part 803. These
regulations allow a mechanism for FDA and manufacturers to
identify and monitor significant adverse events involving medical
devices. The objectives of the regulation are to detect and correct
problems in a timely manner. Under the Medical Device Reporting
program, incidents in which a device may have caused or contributed
to a death or serious injury must to be reported to the FDA. Further,
certain malfunctions must also be reported. Currently, CDRH has
an electronic medical device reporting program, eMDR. At present,
participation in the eMDR program is voluntary.
For more detailed information on postmarket requirements,
i.e., reporting adverse events, postmarket surveillance studies, and
post-approval studies, go to http://www.fda.gov/MedicalDevices/
DeviceRegulationandGuidance/PostmarketRequirements.
How to report a medical device problem: http://www.fda.gov/
MedicalDevices/Safety/ReportaProblem.
20.6.11 User Fees

Under the 2002 Medical Device User Fee and Modernization Act
(MDUFMA), the FDA began to collect user fees for certain medical
device applications, such as 510(k)s, PMAs and Premarket Reports.
Additionally, the 2007 reauthorization allowed FDA to collect
fees for other types of submissions: 30-day notices, requests for
information regarding classification (513g), annual fees for periodic
reporting on Class III devices and establishment registration. Small
business may be eligible for reduced or waived fees.
For more information on how a firm may qualify for small
business and be eligible for substantially discounted rates as well as
information on the latest reauthorization of the medical device user
fees, go to the medical devices homepage and enter in the search box
“user fees.”
Summary 229
(http://www.fda.gov/MedicalDevices/DeviceRegu-lationand
Guidance)
20.7 Summary
The set of laws in the 1938 FD&C Act, 1968 RCHSA, 1976 Medical
Device Amendments, Title 21 Code of Federal Regulations and
other statutes, regulations, policies remain the underpinnings for
the current US medical devices regulatory framework to protect
public health. The USFDA CDRH is the regulatory authority that
regulates medical devices in the United States. If a product is
labeled, promoted, or used in a manner that meets the definition
of a medical devices defined in section 201(h) of the FD&C Act, it
will be regulated as a medical device and is subject to premarketing
and postmarketing regulatory controls (QS Regulation/GMP
and MDR). Foreign companies that manufacture medical devices
and/or radiation-emitting products that are imported into the
United States must comply with applicable US regulations before,
during, and after their import into the United States or its territories.
It is important to recognize that the same safety and effectiveness
standards apply to all medical devices intended for marketing and
distribution in the United States or its territories irrespective of the
origin of manufacture.
Figure 20.4 is a simple guide in deciding if a 510(k) or a PMA
regulatory route would be the appropriate means to bring a new
medical device to the US market. Note that the 510(k) process
requires a predicate device as discussed in the Premarket Notification
section above.
The FDA Medical Devices Web site (http://www.fda.gov/
MedicalDevices) is very rich in information and the main source
of all published information regarding the regulation of medical
devices in the United States. It is intended to be an intuitive content
management based-format display of information that links to more
specific locations.
The starting point to get information on how to market a medical
device is “Device Advice: Comprehensive Regulatory Assistance.”
Guidance)
All medical devices require General Controls!
Bench Testing Required? No
Yes
Clinical Data Needed?

Submit IDE
(include applicable Yes No
Foreign Clinical Data)
Submit 510k
Submit 510k/PMA
FDA Cleared
FDA Cleared/ Exempt

Approved Market
Figure 20.4 Two most common pathways to market a new medical

device, a 510(k) or PMA route.
References
1. Center for Device and Radiological Health (2012), Food and Drug
Administration. Division for small Manufacturers, International and
Consumer Assistance 10903 New Hampshire Avenue WO66-4621
Silver Spring, MD 20993.
2. Device Advice is an on-line comprehensive regulatory assistance.
Available: http://www.fda.gov/MedicalDevices/DeviceRegula-
tionandGuidance/.
3. CDRH Learn is a Web-based tutorial consisting of a series of training
modules. The different modules describe many aspects of medical
device and radiological health regulation, covering both premarket
and postmarket issues. Some modules are also available in Spanish
and Chinese Mandarin. Available: http://www.fda.gov/Training/
CDRHLearn/.
4. Medical Devices Web site. Access to more information concerning
other medical device topics, including current program initiatives,
device clearances and approvals, recalls and alerts, public databases,
and others; Available at http://www.fda.gov/MedicalDevices/.
References 231
5. Health Industries: Medical Device Industry Web site. U.S. Department

of Commerce, International Trade Administration report, “Medical
Device Industry Assessment Updated March 24, 2010. Available April
17, 2012, at http://ita.doc.gov/td/health/medical.html.
Chapter 21
European Union: Medical Device

Regulatory System
Patricia Teysseyre
No. 2, International Business Park,
pteyssey@its.jnj.com
Disclaimer
The regulatory information contained in this chapter is intended for
market planning and is subject to change frequently. Translations of
laws and regulations are unofficial.
21.1 Glossary of Terms

AIMD Active Implantable Medical Devices Directive 90/385/EEC
BBP Benzyl butyl phthalate
CE European Conformity
CEN European Committee for Standardization
CENELEC European Committee for Electrotechnical Standardization
CMR Carcinogenic, Mutagenic and Toxic to reproduction
COCIR European Coordination Committee of the Radiological, Electromedical
and Healthcare IT Industry
DBP Dibutyl Phthalate
DEHP Di-(2-ethylhexyl) phthalate

www.panstanford.com
234 European Union
EC European Community
EDMA European Diagnostic Manufacturers Association
EEA European Economic Area
EEC European Economic Community
EFTA European Free Trade Association
EMIG European Medical Devices Industry Group
ETSI European Telecommunications Standards Institute
EU European Union
EUCOMED European Medical Devices Technology Industry Association
EUROM VI European Medical Technology Industry
FSCA Field Safety Corrective Action
GHTF Global Harmonization Task Force
The GHTF will evolve in 2012 into the International Medical Device
Regulators’ Forum (IMDRF)
IAF International Accreditation Forum
IEC International Electrotechnical Commission
ISO International Standards Organization
IVD In-Vitro Diagnostics Medical Devices Directive 98/79/EC
MD Medical Device
MDD Medical Device Directive 93/42/EEC
MDEG European Medical Devices Expert Group
MEDDEV Medical Devices Guidance Document
NANDO New Approach Notified and Designated Organizations information
system: database operated by the European Commission that catalogs
all the notified bodies and the directives that the organizations
technically are qualified to review.
NB Notified Body
NB-MED Co-ordination of Notified Bodies Medical Devices on Council Directives
90/385/EEC, 93/42/EEC and 98/79/EC
NBOG Notified Body Operations Group
PMS Post-Market Surveillance
STED Summary Technical Documentation for Demonstrating Conformity to
the Essential Principles of Safety and Performance of Medical Devices
TEAM-NB European Association for Medical Devices of Notified Bodies
UDI Unique Device Identifier
21.2 European Union: History and Structure

The European Community as of 2011 comprises 27 countries, which
represent 830 million people (Table 21.1). The medical device
market is estimated to be of €62 billion.
• 27 members are part of the Council
• Shares responsibility with parliament
• Works in specific areas, such as agriculture, finance etc.
• Passes EU laws: the legislation is called Council Directive or Council Regulation
The Council of the • Coordinates the broad economic policies of EU member countries
European Union
• Signs agreements between the EU and other countries
• Approves the annual EU budget
• Develops the EU’s foreign and defence policies
• Coordinates cooperation between courts and police forces of member countries
• 27 members are part of the Council

• Debates and passes European laws, with the Council
• Scrutinies other EU institutions, particularly the Commission, to make sure they are
working
European • Debates and adopts the EU’s budget, with the Council
Parliament
• Proposes new laws to Parliament and the Council

• Manages the EU’s budget and allocating funding
• Enforces EU law (together with the Court of Justice)
• Represents the EU internationally, for example, by negotiating agreements between
European the EU and other countries
Commission
European Union
Figure 21.1 Structure of the European institutions.

235
236 European Union
Table 21.1 List of member states of the European Union
Year of entry
into the EU Member states
Belgium, France, Germany, Italy, Luxembourg, the
1958
Netherlands
1973 Denmark, Ireland, the United Kingdom
1981 Greece
1986 Portugal, Spain
1995 Austria, Finland, Sweden
Czech Republic, Cyprus, Estonia, Hungary, Latvia,
2004
Lithuania, Malta, Poland, Slovak Republic, Slovenia
2007 Bulgaria, Romania
The European Union member countries facilitate the free

movement of goods and humans. The structure of the European
Institutions is illustrated in Fig. 21.1. Medical devices bearing
the CE mark are considered to be cleared in the European Union
market. The European Economic Area (EEA) was established on 1
January 1994 following an agreement between the member states
of the European Free Trade Association (EFTA) and the European
Community: Iceland, Liechtenstein and Norway are allowed to
participate in the EU’s Internal Market without a conventional EU
membership. In exchange, they are obliged to adopt all EU legislation
related to the single market, for Medical Devices for instance. One
EFTA member, Switzerland, has not joined the EEA; CE marking of
Medical Devices is, however, recognized in Switzerland by means
of a Mutual Recognition Agreement (MRA) between the EU and
Switzerland. CE marking is now also in place in Turley, following
the Ankara Agreement between EU and Turkey. Mutual acceptance
between Turkey and EFTA is arranged in an agreement between
these parties based on CE marking.
The next country currently in the process of entering the EU is
Croatia, expected to be member in 2013.
21.3 New Approach — Global Approach

Concepts
As Foodstuffs, Chemicals and Pharmaceuticals were already regu-
lated in EU, a new legislative and technical frame has been created
in 1985 for the other products circulating in the EU countries.
New Approach – Global Approach Concepts 237
The New Approach concept [8] is a legislative-technical frame

for harmonization in Europe: it is to link industrials and regulators
for harmonization for the elaboration of Directives and Technical
Standards.
Using the New Approach for market access results in most of
the cases by having a product recognized by a European Conformity
(CE) mark. However, among the Directives (around 20; Table 21.2)
which adopt the New Approach, some did without the CE mark like
the Directive 94/62/EC on waste and packaging.
The New Approach concept (Fig. 21.2) was established in
1985 and resulted in the elaboration of European Directives,
which are based on the following principles:
• Only products fulfilling the essential requirements may be
placed on the market and put into service.
• Harmonized standards, the reference numbers of which have
been published in the Official Journal and which have been
transposed into national standards, are presumed to conform
to the corresponding essential requirements.
• Application of harmonized standards or other technical
specifications remains voluntary, and manufacturers are free
to choose any technical solution that provides compliance
with the essential requirements.
• Manufacturers may choose between different conformity
assessment procedures provided in the applicable directive.
NewApproach(1985)
GlobalApproach(1989)
ConsistentApproachforProductConformity
Assessment:Modules
QualityAssurance:ISO
9001
NotifiedBodies:CE
Marking
Figure 21.2 New Approach: Global Approach Diagram.

238 European Union
The Global Approach concept was issued in 1989 and

introduced the following points:
• Modules for each development phase of the product (design/
prototype/manufacture) were established for the conformity
assessment, defining criteria for use and designation of bodies
operating these procedures.
• The use of European standards relating to quality assurance
(EN ISO 9000 series), which by now includes ISO 13485 for
the medical device industry.
• Accreditation systems and use of inter-comparison techniques
were promoted in member states.
• Mutual recognition agreements concerning testing and
certification.
• Programs to minimize the differences between member states
and industrial sectors (quality infrastructures: calibration/
metrology, testing laboratories, certification/inspection/
accreditation bodies).
• Mutual recognition agreements with third countries to
facilitate the cooperation and technical assistance programs.
Table 21.2 List of European directives
Directive
reference Subject of directive
90/396/EEC Appliances burning gaseous fuels
Cableway installations designed to carry per-
2000/9/EC
sons
89/106/EEC Construction products
2004/108/EC Electromagnetic compatibility
Equipment and protective systems in potentially
94/9/EC
explosive atmospheres
93/15/EEC Explosives for civil uses
90/396/EEC Gas appliances
95/16/EC Lifts
2006/95/EC Low Voltage Equipment
2006/42/EC Machinery safety
2004/22/EC Measuring instruments
93/42/EEC Medical devices
90/385/EEC Medical devices: Active implantable
98/79/EC Medical devices: In vitro diagnostic
Harmonized Standards and Presumption of Conformity 239
New hot-water boilers fired with liquid or gase-

92/42/EEC
ous fluids (efficiency requirements)
90/384/EEC Non-automatic weighing instruments
94/62/EC Packaging and packaging waste
89/686/EEC Personal protective equipment
97/23/EC Pressure equipment
Radio and telecommunications terminal equip-
1999/5/EC
ment
94/25/EC Recreational craft
87/404/EEC Simple pressure vessels
88/378/EEC Toys safety
Regulations address essential safety and performance

principles. Detailed technical requirements and characteristics are
provided by voluntary product standards developed by national
and international expert groups (see ISO TR 16142:1999). The
international reference standard for medical device quality systems
requirements is ISO 13485.
21.4 Harmonized Standards and Presumption

of Conformity
A standard stands for an agreed understanding of key words and
terminology and methods, which, when applied by the manufacture,
ensure a common global level of safety of medical care to patient.
The formal definition of a standard is: standards are documented
agreements containing technical specifications or other precise
criteria to be used consistently as rules, guidelines or definitions of
characteristics, to ensure that materials, products, process are fit for
their purpose. Standards can:
• Provide reference criteria that a product, process or service
must meet;
• Provide information that enhances safety, reliability and
performance of products, processes and services;
• Assure consumers about reliability or other characteristics of
goods or services provided in the marketplace [16].
Harmonized standards are European standards prepared
in accordance with the General Guidelines agreed between the
240 European Union
Commission and the European standards harmonization, and follow

a mandate issued by the Commission after consultation with the
member states.
Conformity with a national standard that transposes a
harmonized standard, whose reference has been published, confers
a presumption of conformity with the essential requirements of
the applicable New Approach directive that is covered by such a
standard.
References (such as titles, identification numbers) of harmonized
standards are published in the Official Journal for the directive in
question. Member states must publish the reference of the national
standard that transposes a harmonized standard. The application
of harmonized standards, which give a presumption of conformity,
remains voluntary. Thus, the product may be manufactured directly
on the basis of the essential requirements.
For getting information about standards under review or creation
and for acquisition of the published standard, the manufacturer
has to apply and buy them from the standard organizations at the
European level (Table 21.3) or at the national level.
Table 21.3 List of committees for standardization
Committee
name Scope
CEN CEN is the European Committee for Standardization.
It contributes voluntary technical standards which
promote free trade, the safety of workers and consumers,
environmental protection, exploitation of research and
development programs, and public procurement.
CENELEC CENELEC is the European Committee for Electrotechnical
Standardization and is responsible for standardization in the
electrotechnical engineering field.
ETSI The European Telecommunications Standards Institute (ETSI)
produces globally applicable standards for Information and
Communications Technologies (ICT), including fixed, mobile,
radio, converged, broadcast and internet technologies.
IEC IEC is the International Electrotechnical Commission. It is
the world’s leading organization that prepares and publishes
international standards for all electrical, electronic and
related technologies.
ISO ISO is International Standards Organizatio. It is an inter-
national standard-setting body composed of representatives
from various national standards bodies.
Table 21.4 List of European associations
Association
name Competences/terms of reference Participants
MDEG It is a group of member states, industry and other stakeholder representatives in the area of medical devices for competent authorities, industry
the implementation of the directive. This group is the umbrella group for other working groups in the field and (trade associations), notified
co-ordinates and oversees their activities. bodies, standardisation bodies,
In closed session MDEG is a forum to discuss all issues relating to the implementation of the medical device direc- COM services
tives with member state competent authorities. MDEG also meets in closed
MDEG publishes MEDDEV Guidance Documents. sessions including competent
authorities only.
NBOG Its aim is to contribute to improvement of the overall performance of notified bodies in the medical devices sector Competent authorities/designat-
by primarily identifying and promulgating examples of best practice to be adopted by both notified bodies and ing authorities (experts), COM
those harmonization responsible for their designation and control. services (On focal points, a noti-
They review the “recommendations” issued by the NB-MED (group where all the EU notified bodies participate) fied body representative can be
and act as a “Mirror Group” following GHTF work relating to notified bodies. invited to participate)
NB-MED To share experience and exchange views on application of conformity assessment procedures with the aim of notified bodies, competent
contributing to a better understanding and consistent application of requirements and procedures. authorities (experts), industry,
To draft technical recommendations on matters relating to conformity assessment and build a consensus. standardisation bodies, COM
To advise the Commission, at its request, on subjects related to application of the medical device directives. services
To consider, and if necessary, draft reports on ethical aspects of notified bodies’ activities.
To ensure consistency with standardization work at European level.
To keep informed of harmonization activities at European level.
TEAM-NB A non-profit association of 32 notified bodies under any or all of the three medical device new approach direc- Medical Device notified bodies
tives: 90/385/EEC; 93/42/EEC; 98/79/EC.
The association aims
• to improve communications with the EC Commission, Industry, competent authorities and user
groups by acting as a focal point and the single voice of notified bodies,
• to promote high technical and ethical standards in the functioning of notified bodies, and
• to protect the legal and commercial interests of notified bodies in their vital role in the functioning of
Harmonized Standards and Presumption of Conformity
the three medical device directives
(Continued)
241
242
Table 21.4 (Continued)

Association
name Competences/terms of reference Participants
European Union
EUCOMED It represents the medical technology industry in Europe. Industry representatives

Eucomed members include both national and pan-European trade and product associations as well as medical
technology manufacturers, representing around 22,500 designers, manufacturers and suppliers of medical tech-
nology used in the diagnosis, prevention, treatment and amelioration of disease and disability.
EDMA It is the trade association that represents the In Vitro Diagnostic (IVD) industry active in Europe. Industry representatives
EDMA membership brings together 22 National Associations in European countries and 43 major companies
engaged in the research, development, manufacture or distribution of IVD products. Through its affiliated National
Associations, EDMA represents in total more than 500 companies across Europe.
Since its establishment in 1979, EDMA acts in co-operation with other European and international trade associa-
tions representing medical devices, pharmaceuticals and biotechnology in general, as well as with scientific socie-
ties and patients organisations to make a real difference in health and life quality.
COCIR This non-profit trade association was founded in 1959 and represents the medical technology industry in Europe. Industry representatives
COCIR’s aim is to represent the interests and activities of its members and act as a communication channel
between its members and the European institutions and other regulatory bodies. It also cooperates with other
organisations on issues of common interest.
COCIR seeks to promote the development of harmonized international standards and regulatory control which
respect the quality and effectiveness of the medical devices and healthcare IT systems without compromising the
safety of patients and users and promote the free worldwide trade of these products.
COCIR encourages the use of technology in delivering cost-efficient and state of the art healthcare systems.
EUROM VI- Med- European small and medium enterprises involved in medical devices for surgery (including dental), anaesthesia, Industry representatives
ical Technology respiration and inhalation, operating theatre, gas supply, sterilization, disinfection, internal and external orthopae-
dics, opto-medical and ophthalmology area, rehabilitation and handicaps fields, infusion and transfusion.
Its objectives are to represent the European medical technology industry to promote cooperation between mem-
bers but also with other European organizations; to encourage worldwide trade by being involved in harmoniza-
tion of legislation, standardization, mutual recognition and certification procedures, to be a partner on works with
UE Commission and Standardization Bodies; to defend European industry views on international activities.
EMIG It is a non-profit trade association, and brings together the European medical industry organizations COCIR, Industry representatives
EUCOMED, EDMA, EUROM VI, and a few smaller once, representing a unified European industry voice where pos-
sible.
Overview of Medical Devices Directives 243
21.5 European Associations

The European associations active in Europe which contribute to
shape the regulatory environment and offer platforms for regulators
and industry to communicate with each other and work on
harmonization are shown in Table 21.4.
21.6 Overview of Medical Devices Directives

The European Directives (Table 21.5) have to be transposed
into national law by each member state in order to integrate the
content of these directives into laws and regulations without major
modification (Changes which conflict with EU Directive are not
acceptable).
Table 21.5 List of applicable directives to medical devices
Date of
enforcement Reference Designation Scope Examples
1990 AIMD Directive on Active Active Cardiac
90/385/EEC Implantable Medical Implantable Pacemaker,
Devices Medical defibrillator
Devices
1993 MDD 93/42/ Medical Device Medical Sutures,
EEC Directive Devices syringes
1998 IVD 98/79/ Directive on In Vitro In Vitro Blood
EC Diagnostics Medical Diagnostics collection
Devices Medical system, Petri
Devices dishes
The other products which do not fall under the scope of medical
devices are regulated by different directives such as
• Biocides Directive 98/8/EC
• Directive for Medicinal Products 2001/83/EC, applicable to
drugs
• Directive for Cosmetics Products 76/768/EEC which will
be replaced by the regulation 1223/2009 to be enacted on
July 2013. This change will have an impact on the medical
devices directives, as cosmetics implant will be removed from
cosmetics and included in medical devices
244 European Union
21.7 Guidelines
The interpretation of the Directives is supported by the elaboration
of guidelines entitled “MEDDEV” (Table 21.6) and issued within the
MDEG Group: They are elaborated through a process of consultation
with competent authorities and Commission representatives,
notified bodies, industry and other interested parties in the medical
devices sector. They remain voluntary; however, it is anticipated
that the guidelines will be followed within the member states
and, therefore, ensure uniform application of relevant Directive
provisions. Guidelines are subject of a regular updating process [6].
Table 21.6 Examples of MEDDEV guidelines
Scope Title MEDDEV reference

Application, Definitions Borderline products, drug-delivery products MEDDEV 2.1/3 rev 3
and medical devices incorporating, as integral
part, an ancillary medicinal substance or an
ancillary human blood derivative
2.3: Reference to Publication of titles and references of MEDDEV 2.3/1
standards European harmonized standards under AIMD
and MDD
2.4: Classification of MD Guidelines to the classification of medical MEDDEV 2.4/1 rev.9
devices
Manual Borderline Classification MD MEDDEV ver. 1.8
2.5: Conformity Technical documentation MEDDEV 2.5.1/Rec5
assessment procedure Reporting of design changes and of changes of MEDDEV 2.5.2/Rec2
General rules the quality system
2.5.4: Verification of Homogeneous batches MEDDEV 2.5.4/Rec1
manufactured products Verification of manufacture products for IVD MEDDEV 2.5.4/Rec2
directive
2.7: Clinical Clinical evaluation: Guide for manufacturers MEDDEV 2.7.1 Rev3
investigation, clinical and notified bodies
evaluation Clinical investigations: Serous adverse event MEDDEV 2.7/3
reporting
2.11: Products using Application of council Directive 93/42/EEC MEDDEV 2.11/1 rev.1
materials of biological taking into account the Commission Directive
origin 2003/32/EC for Medical Devices utilizing
tissues or derivatives originating from animals
for which a TSE risk is suspected
2.12: Market Medical devices vigilance System MEDDEV 2.12/1 rev.6
surveillance; vigilance Appendix, list of contact points MEDDEV 2.12/1 rev 4
Clinical Evaluation — Post-Market Clinical MEDDEV 2.12/2
Follow-up
Post-Marketing Surveillance (PMS) post- MEDDEV 2.12/Rec1
market/production
Note: The exhaustive list in their latest revision is available on line on the MEDDEV
website.
Definitions 245
21.8 Definitions
21.8.1 Medical Device
A “medical device” according to 93/42/EEC directive [1] as last
amended in 2007/47/EC [4], means any instrument, apparatus,
appliance, software, material or other article, whether used alone or
in combination, including the software intended by its manufacturer
to be used specifically for diagnostic and/or therapeutic purposes and
necessary for its proper application, intended by the manufacturer
to be used for human beings for the purpose of
• diagnosis, prevention, monitoring, treatment or alleviation
of disease
• diagnosis, monitoring, treatment, alleviation of or compen-
sation for an injury or handicap
• investigation, replacement or modification of the anatomy or
of a physiological process
• control of conception
and which does not achieve its principal mode of action in or on
the human body by pharmacological, immunological or metabolic
means, but which may be assisted in its function by such means.
21.8.2 CE Mark
The CE mark is the proof from the manufacturer that the product is
in conformity with the regulations.
CE marking attests that the products are in conformity with
the essential requirements of the applicable directives and that the
products were subjected to the procedure of conformity evaluation
envisioned in the directives.
CE marking is affixed before marketing the product.
CE marking allows freedom of movement of the medical device
in the territory of the European Union
It engages the responsibility of the manufacturer, on all aspects
relative to the product.
The manufacturer must maintain the technical documentation of
the device and supply it to the proper authorities.
Devices other than those used to measure and those intended
for clinical investigations that are put on the market or brought into
service in Europe must be CE marked.
246 European Union
The manufacturer chooses a procedure for CE marking, whether

or not to utilize a notified body, in particular according to the class of
the medical device (Fig. 21.3).
Ministry of Health
Competent Authority X
Notified
Body Y
Legal Manufacturer Z Authorised Representative [

Located in EU Located in EU
Legal Manufacturer Z
Located outside EU
Figure 21.3 Relation between the different actors.
21.8.3 Competent Authority

The competent authority or regulatory authority is a government
agency or other entity that exercises a legal right to control the use
or sale of medical devices within its jurisdiction. It has the ability to
take enforcement action to ensure that medical products marketed
within its jurisdiction comply with legal requirements.
Its roles and responsibilities are as follows:
• indicates and inspects the notified bodies
• supervises the market
• centralizes and evaluates the vigilance data
• takes suitable medical measurements of police force
Following are the examples of competent authority:
• United Kingdom: MHRA (Medicines and Healthcare Products
Regulatory Agency)
• France: AFSSAPS (Agence Francaise de Securite Sanitaire des
Produits de Sante)
Definitions 247
• Ireland: IMB (Irish Medicines Board)

• Germany: BfArM (Bundesinstitut für Arzneimittel und
Medizinprodukte)
21.8.4 Notified Body: Conformity Assessment Body

A notified body (as per Medical Devices Directives terminology)
is a certification organization authorized by the relevant member
state’s competent authority to perform conformity assessment tasks
specified in the Directives.
The notified body is responsible to evaluate the conformity of
the product with the essential requirements and issues the CE mark
certificate.
The notified body is an organization indicated and supervised by
the proper authority of the member state and must meet the criteria
of Annex IX of Directive 93/42/EEC for medical devices, criteria
of Annex IX of Directive 98/79/EC for in vitro diagnostic medical
devices and criteria of Annex 8 of the Directive 90/385/CE to be
notified for active implantable medical devices.
A Conformity Assessment Body (CAB from the GHTF termin-
ology) is a body engaged in the performance of procedures for
determining whether the relevant requirements in technical
regulations or standards are fulfilled. A CAB is authorized to
undertake specified conformity assessment activities by a regulatory
authority that will ensure performance of the CAB is monitored and,
if necessary, withdrawal of designation.
The manufacturer calls upon the notified body of choice: among
the 76 registered notified bodies in Europe, of which 5 are in
Switzerland and 1 in Australia at the time of this publication.
Nando (New Approach Notified and Designated

Organisations) Information System
Notification is an act whereby a member state informs the Comm-
ission and the other member states that a body, which fulfils the
relevant requirements, has been designated to carry out conformity
assessment according to a directive. Notification of notified
bodies and their withdrawal are the responsibility of the notifying
member state.
The lists of notified bodies can be searched on the NANDO
website. The lists include the identification number of each notified
248 European Union
body as well as the tasks for which it has been notified, and are
subject to regular update.
Table 21.7 Examples of notified body
Identification
Designation Body type number
Laboratoire national d’essais/G-MED, France LNE/G-med 0459
British Standards Institution, United Kingdom BSI 0086
National Standards Authority of Ireland, Ireland NSAI 0050
TÜV SÜD Product Service GmbH, Germany TÜV 0123
21.8.5 Legal Manufacturer

The legal manufacturer means the natural or legal person with
responsibility for the design, manufacturing, packaging and labelling
of a device before it is placed on the market under his own name,
regardless of whether these operations are carried out by that
person himself or on his behalf by a third party, as defined in each
relevant section of the Directives: Medical Devices Directive 93/42/
EEC-Article 1.2.(f), In-Vitro Diagnostic Devices 98/79/EC-Article
1.2.(f) and Active Implantable Medical Devices 90/385/EEC Article
1.2.(i).
The manufacturer must ensure that it is manufactured to
meet or exceed the required standards of safety and performance.
This includes the three phases (design/development/testing,
manufacturing, packaging and labelling) that lead to a product being
ready for the market. The legal manufacturer is responsible of all
the operations necessary to design, manufacture, label and package
the product throughout its lifecycle from design to distribution to
the final customer. The legal manufacturer is responsible to choose
the notified body and affixing the CE mark on the product once it
is obtained. Depending on the organization, the legal manufacturer
can be the design centre but not necessarily.
A manufacturer, in the meaning of New Approach, is the person
who is responsible for designing and manufacturing a product with
a view to placing it on the Community market on his own behalf.
The manufacturer has an obligation to ensure that a product
intended to be placed on the Community market is designed
and manufactured, and its conformity assessed, to the essential
requirements in accordance with the provisions of the applicable
New Approach directives.
Classification 249
The manufacturer may use finished products, ready-made parts

or components, or may subcontract these tasks. However, he must
always retain the overall control and have the necessary competence
to take the responsibility for the product.
21.8.6 Authorized Representative

The authorized representative means any natural or legal person
established in the Community who, explicitly designated by the
manufacturer, acts and may be addressed by authorities and bodies
in the Community instead of the manufacturer with regard to the
latter’s obligations under this Directive as stipulated in each relevant
section of each Directive: Medical Devices Directive 93/42/EEC
Article 1.2.(j), In-Vitro Diagnostic Devices 98/79/EC-Article 1.2.(g)
and Active Implantable Medical Devices 90/385/EEC Article 1.2.(j).
The manufacturer may appoint any natural or legal person to act
on his behalf as an authorized representative.
For the purposes of New Approach directives, the authorized
representative must be established inside the Community.
The authorized representative is explicitly designated by the
manufacturer, and he may be addressed by the authorities of the
member states instead of the manufacturer with regard to the latter’s
obligations under the New Approach directive in question.
The manufacturer remains generally responsible for actions
carried out by an authorized representative on his behalf.
21.9 Classification
21.9.1 Medical Devices
The EU Classification of Medical Devices is based on the risk of the
device and follows the GHTF classification [14].
The classification is made based on the rules laid down in
Appendix IX of the Medical Devices Directive 93/42/EEC. Annex IX
classification is based on a risk assessment of the product, when
used as intended. The “risk” is composed of the duration of use and
the level of invasiveness, as defined by the intended purpose stated
by the manufacturer (see examples in Table 21.8). The “Intended
purpose” means the use for which the device is intended according
to the data supplied by the manufacturer on the labelling, in the
instructions and/or in promotional materials.
250 European Union
Medical devices are divided into four classes — Class I, Class IIa,
Class IIb, and Class III — according to the level of risk the device as
based on the following criteria [9]:
• duration of use (transient, short term, long term)
• invasiveness (invasive devices, body orifice, surgically invasive
device)
• active/non-active
• implantable
• specific hazards (e.g. contact with the central nervous system,
animal tissues, absorbable material, ionizing radiation,
medical device with ancillary pharmaceutical substance)
Table 21.8 Examples of medical devices per class
Class Risk Examples

Class I Moderate risk Surgical instruments
Non-invasive tubing to evacuate body liquids
Examination gloves
Hospital beds
Class Is Moderate risk (sterile) Sterile body liquid collection devices
Sterile absorbent pads
Class Im Moderate risk (with a Syringe without needle (graduated barrel)
measuring function) Device for measuring body temperature
Non-active device for measuring intra-ocular
pressure
Class IIa Moderate–average risk Syringe with needle
Tubing intended for use with an infusion pump
Non-medicated impregnated gauze dressings
Short term corrective contact lenses
Class IIb Average–elevated risk Hemodialysers
Long term corrective contact lenses
Urinary catheters intended for long term use
Insulin pens
Class III Elevated risk Neurological catheters
Prosthetic heart valves
Aneurysm clips
Pre-filled syringe for vascular access device
flushing
Spinal needle
Absorbable sutures
21.9.2 Active Implantable Medical Devices

The active implantable medical devices are at maximum risk: by
definition they are any active medical device which is intended to
be totally or partially introduced, surgically or medically, into the
human body or by medical intervention into a natural orifice, and
which is intended to remain after the procedure [2].
Classification 251
Examples of active implantable medical devices

• Implantable cardiac pacemakers
• Implantable defibrillators
• Leads, electrodes, adaptors for above examples
• Implantable nerve stimulators
• Bladder stimulators
• Sphincter stimulators
• Diaphragm stimulators
• Implantable active drug administration device
By default, all accessories to AIMDs are covered under AIMD
themselves. They cannot be classified separately under the MDD.
21.9.3 In vitro and Diagnostics Medical Devices

The classification of in vitro and diagnostics medical devices is based
on the risk of of usage (see examples in Table 21.9): If they are to be
used by healthcare professionals, they are classified with lower risk,
and thus exempt from independent pre-market approval and placed
on the market based upon the manufacturer’s self-declaration that
the device comply with the requirements of the Directive 98/79/
EC [3]. When they are of higher risk and/or intended to be used by
home user for self-testing, they require a premarket design
examination from a notified body.
Table 21.9 Examples of in vitro diagnostic medical devices per class
Class Risk Examples

List A Highest Reagents, calibrators, control materials for
including Risk • Determining blood groups: e.g. ABO system, rhesus,
self-test anti-Kell
• Detection, confirmation, quantification in human
specimens of markers: e.g. HIV infection, hepatitis
Self-tests Interim Risk Pregnancy tests
List B Interim Reagents, calibrators, control materials for
Risk • Detection, quantification in human samples of congenital
infections: e.g. rubella and toxoplasmosis
• Diagnosing hereditary disease
• Determining human infections: e.g. Chlamydia
• Determining tumoral marker
Software for evaluating the risk of trisomy 21
Self-diagnosis device for blood sugar measurement
(Continued)
252 European Union

Class Risk Examples
Self- All others, Instrument, intended by the manufacturer, specifically to
certifiable lowest risk be used for in vitro diagnostic procedures;
Microbiological culture medium
Reagents, calibrators, control materials for:
• Detection of angina pectoris, heart failure and atrium
fibrillation: e.g. Hb, TSH, Gluc
• Determining subfertility
• Diagnosis cardiovascular disease markers: e.g.
troponine, CK/CK-MB, lipidsm Km creatinine
• Diagnosis of rheumatoid arthritis
• Detection and differentiation of leucocytes
• Diagnosis of allergies
Specimen containers, transport media
21.10 Conformity Assessment Procedures

Figure 21.4 shows the different steps a manufacturer has to
go through from the device classification through the notified
body selection to the final CE mark certificate and declaration of
conformity issuance:
Medical Device
By the Classification
Legal Manufacturer
MDD: Class
MDD: Class Is,
Is,Im,
Im,IIa,
IIa, By the Legal Manufacturer MDD: Class
MDD: ClassI I
IIb,III
IIb, III IVD: Self-tests,
IVD: Self-tests,
AIMD: High
AIMD: High Risk
Risk Self certifiable
Self certifiable
IVD:list
IVD: list A
A and
andBB
Notified Body Selection
Notificed Body Selection Self
SelfCertification
Certificationby the
byLegal
the
LegalManufacturer
Manufacturer
Conformity Assessment Procedure

Conformity Assessment Procedure
Selection by the Legal Manufacturer
Selection by the Legal Manufacturer
Batch Technical Documentation review by the Notified body

Batch Technical Documentation review by the Notified body
Verification
Verfication
by the
by the
Notified body
Notified body
for IVD List A Quality Management System audit by
Quality Management System audit bythe Notified
the bodybody
Notified
for IVD List A
CE Mark Certificate
CE Mark Certificate
Delivered by Notified body
Delivered by Notified body
Class
Class Is,Is,Im,
Im,IIa,
IIa, IIb,
IIb,IIIIII
Class II
Class
XXXX*
XXXX*
*identification number of the
Notified Body
Continued Batch Verification by the CE Declaration of Conformity

Continued Batch Verfication by CE Declaration of Conformity
Notified body Issued by the Legal Manufacturer
the Notified bodyforfor
IVDIVD
List A
List A Issued by the Legal Manufacturer
Figure 21.4 Flow chart representing steps to be followed for CE marking.

Conformity Assessment Procedures 253
The Conformity Assessment Procedures correspond to modules

described in the Medical Device Directives (Table 21.10), which
the manufacturer has to follow in order to affix the CE mark on the
device. The procedures may be used single or in association and are
aimed to cover the Design and the production quality of the device.
The possible procedures are defined in the annexes of each
Directive (Tables 21.11–21.13):
• Annex II: CE Declaration of Conformity (Full Quality
Assurance)
o Roles and responsibilities of the manufacturer
 maintain a complete system of quality assurance
including the design, manufacture and control
 provide appropriate information about the product,
and documentation about the quality system
 maintain the design file
o Roles and responsibilities of the notified body: quality
system verification
 study the file
 inspect the buildings and monitoring
 examine the design of the product for class III
devices
• Annex III: CE Type Examination (Certificate by the notified
body that a sample representative of production satisfied the
essential requirements)
o Roles and responsibilities of the manufacturer
 provide the documentation about the design,
manufacture, and performance of the product and a
sample
o Roles and responsibilities of the notified body
 examine and evaluate the documentation
 verify that the sample is manufactured in conformance
with the documentation
 perform, or subcontract suitable inspections and
necessary tests
• Annex IV: CE Verification
• Annex V: CE Declaration of Conformity (quality assurance of
production): approval of the production quality system by the
notified body (Quality Management System with exception of
design)
254 European Union
• Annex VI: CE Declaration of Conformity (quality assurance of

the products, Quality Management System without design and
manufacturing)
• Annex VII: CE Declaration of Conformity without recourse at a
competent organization
Table 21.10 Overview of the relevant annexes per Directive
Title MDD 93/42/EEC IVDD 98/79/EC AIMD 90/385/EEC

Internal Control VII III —
of Manufacturing,
EC Declaration of
Conformity
EC Type Examination III V 3
Production Quality V VII 5
Assurance
Product Quality VI — —
Assurance
Product Verification IV VI 4
Full Quality Assurance II IV 2
Table 21.11 Combination of procedures for CE marking of Medical

Devices as per MDD 93/42/EEC
Class I Annex VII: Auto-certification (no intervention

of a notified body)
Class Is (sterile device) Annex II, except point 4 (Design examination)
Class Im (measuring Annexes VII and IV
function) Or Annexes VII coupled with V
Or Annexes VII coupled with VI
Class IIa Annex II, except point 4 (Design examination)
Or Annexes VII coupled with IV
Or Annexes VII coupled with V
Or Annexes VII coupled with VI
Class IIb Annex II, except point 4 (Design examination)
Or Annexes III coupled with IV
Or Annexes III coupled with V
Or Annexes III coupled with VI
Class III Annex II, including point 4 (Design
examination)
Or Annexes III coupled with IV
Or Annexes III coupled with V
Essential Requirements 255
Table 21.12 Combination of procedures for CE marking of in vitro

diagnostic medical devices as per IVD 98/79/EC
List A Annex IV including points 4 (Design

examination) and 6 (Batch verification)
Or Annex V coupled with Annex VII
List B Annex IV, except points 4 and 6
Or Annex V coupled with Annex VI
Or Annex V coupled with Annex VII
Self-Test Annex III including point 6
Others: not for self- Annex III excluding point 6 (no intervention of a
testing notified body)
Table 21.13 Combination of procedures for CE marking of active

implantable medical devices as per IVD 90/385/EEC
All Annex 2I
Or Annex 3 coupled with Annex 4
Or Annex 3 coupled with Annex 5
Table 21.14 provides more practical information about how to

apply and choose a conformity assessment procedure per product
class: it shows the most widely used combinations and their
implications and consequences in terms of Audit and Technical
Documentation.
21.11 Essential Requirements

The essential requirements lay down the necessary elements for
protecting the public interest: they are mandatory. Only products
complying with essential requirements may be placed on the market
and put into service.
Essential requirements must be applied as a function of the
hazards inherent to a given product: they correspond to the technical
requirements with which a device must comply in terms of safety
and performance in order to be CE marked: they are to be met to
demonstrate the safety and functionality of a device and are defined
in the Annex I of each applicable Directives (Medical Device Directive
93/42/EEC as amended, In-Vitro Diagnostic Medical Devices 98/79/
EC, Active Implantable Medical Device Directive 90/385/EEC as
amended).
256
Table 21.14
Device Conformity assessment procedure: Intervention of notified body
Examples of most widely used conformity assessment procedures for MDD in EU at this stage
class quality system in quality system Technical documentation CE certificate

European Union
I Systematic procedures in place None Maintained on site None

Is Systematic procedures in place to cover Limited to the securing and Maintained on site CE Certificate of Conformance
provisions laid down in Annex VII and in maintaining sterile conditions for sterility
Annex II or V aspects
Im Systematic procedures in place to cover Limited to the metrological Maintained on site CE Certificate of Conformance
provisions laid down in Annex VII and in requirements for the measuring function
Annex II or V
IIa Annex II Audit of Submitted upon request CE Certificate of Conformance
Excluding Point 4 (Design)

Full quality assurance system Quality System Can be reviewed by notified body on a for Annex II
by notified body statistical basis
Or Annex V Audit of Submitted upon request CE Certificate of Conformance
Production quality assurance Quality System Can be reviewed by notified body on a for Annex V
by notified body statistical basis
IIb Annex II Audit of Systematically reviewed by notified CE Certificate of Conformance
Excluding Point 4 (Design)

Full quality assurance system Quality System body for Annex II
by notified body
Or Annex V Audit of Systematically reviewed by notified CE Certificates of Conformance
Production quality assurance Coupled with Quality System body for Annex III and Annex V
Annex III EC Type examination by notified body
III Annex II Audit of Design Dossier Systematically CE Certificate of Conformance
including point 4 Quality System reviewed by notified body for Annex II
Full quality assurance system by notified body
Or Annex V Audit of Design Dossier Systematically CE Certificates of Conformance
Production quality assurance Coupled with Quality System reviewed by notified body for Annex III and Annex V
Annex III by notified body
EC Type examination
Labelling 257
The essential requirements checklist is divided into the foll-

owing sections:
• Safety and performance
• Design and construction
o Chemical, physical and biological properties
o Infection and microbial contamination
o Construction and environmental properties
o Devices with a measuring function
o Protection against radiation
o Requirements for medical devices connected to or
equipped with an energy source
o Information supplied by the manufacturer
21.12 Labelling
The labelling of medical devices in very important for the product
identification and tracaebility. The Manufacturer must meet the
requirements from the Annex I of the Essential Requirements of
each applicable Directive:
• Annex I section 13 “Information supplied by the manufacturer”
of the Medical Device Directive 93/42/EEC
• Annex I section 8 “Information supplied by the manufacturer”
of the In-Vitro and Diagnostic Medical Device Directive 98/
79/EC
• Annex 1 sections 14 and 15 of the Active Implantable Medical
Device Directive 90/385/EEC
National regulations in the European Community may require
the information referred to in the device label and Instructions for
Use to be in their national language(s) or in another Community
language when a device reaches the final user, regardless of whether
it is for professional or other use (Article 4, paragraph 4 in each
respective Directive (MDD, AIMD, IVD)). The use of symbols that
conform to harmonized standards ensures consistency throughout
the European Community and means that there is no need to
translate certain information (ISO 15223-1 [13]).
258 European Union
21.13 Technical Documentation

The technical documentation must allow assessment of the
conformity of the product with the requirements of the Directive.
Its content is described in each Annex of the Directive, depending
on the Conformity Assessment route chosen by the manufacturer
to demonstrate conformity of the device with the provisions of the
Directive.
Depending on the medical device class, a Notified body is
involved for the quality system review or technical documentation
review [15]. The technical documentation can be reviewed either
during an audit on site by a notified body or as part of the CE
certification, depending on Notify Body’s practice. For instance, some
notified bodies would only accept their own template as part of a CE
certification; some would accept a cross-reference to the location of
the evidences within the full technical documentation.
Table 21.15 provides some guidance about how to design the
layout of a technical documentation for CE marking: it details the
level of information which should be covered in a Technical File for
low-moderate risk devices (Class I, Is, Im, IIa and IIb from MDD;
List B, Self-test from IVD) and in a Design File for high risk devices
(Class III from MDD; List A from IVD; AIMD). The STED (Summary
Technical Documentation for Demonstrating Conformity to the
Essential Principles of Safety and Performance of Medical Devices)
requirements from GHTF are given as reference.
21.14 Quality Management System

A quality system implemented on the basis of the ISO 13485 [11]
standard gives a presumption of conformity with the respective
conformity assessment procedures with regard to the provisions in
the modules that these standards cover, and provided that the quality
system enables the manufacturer to demonstrate that the products
fulfil the essential requirements of the directive in question. This means
that the manufacturer must specifically address regulatory needs
when implementing and applying a quality system, in particular:
• The quality objectives, quality planning, quality manual
and control of documents must fully take on board the
objective of delivering products that conform to the essential
requirements;
Quality Management System 259
• The manufacturer must identify and document the essential

requirements that are relevant for the product and the
harmonized standards to be used or other technical solutions
that will ensure fulfilment of the essential requirements;
• The identified standards or other technical solutions must be
used as design input, and as verification that design output
ensures that the essential requirements will be met;
• The measures taken by the organisation to control production
must ensure that the products conform to the identified safety
requirements;
• The organisation in its measurement and control of the
production process and finished products must identify
and use methods which are identified in standards or other
appropriate methods to ensure that the essential requirements
are met; and
• Quality records, such as inspection reports and test data,
calibration data, qualification reports of the personnel
concerned, must be suitable to ensure the fulfilment of the
applicable essential requirements.
• The manufacturer has the responsibility to implement and
continuously operate the quality system in such a way that
regulatory needs are respected. The notified body must ensure
in its assessment, approval and continued surveillance, that
this is the case.
The objective of ISO 13485 is to set out requirements for a Quality
Management System that is capable of consistently providing safe
and effective medical devices and consistently meeting customer
requirements (including regulatory requirements).
The Quality Management System has to be evaluated by a third
party [10] (notified body or general registrar) through periodic
surveillance inspections (audit). The quality system certificates
which are issued by a notified body have a limited validity and must
be renewed every 3 years. (only exception of 5 years is Germany,
which is not part of the global IAF organization) IAF is International
Accreditation Forum: this is the global organization where member
states discuss and review ISO accreditation rules, which they then
use to supervise notified bodies issuing ISO certificates. They for
instance provide a document which identifies how many audit days
are needed for what size of organization, issue guidance on how
many days for surveillance versus renewal versus initial audits, etc.
260
Table 21.15 Guideline on content of technical documentation
Technical Documentation
CE Documentation Sted
European Union
Technical File Design Dossier

Low-Moderate High Risk
Risk
REGULATORY INFORMATION
Sites identification and addresses:
Manufacturer name and address X X X
If necessary
Authorized Representative name and address X X X
If necessary
Design site name and address X X
If necessary
Manufacturing site name and address X X
If necessary
Assembly Site name and address: X X
Sterilization Site name and address X X
Class of device and justifications X X X
GMDN information X X X
Notified body name and address X X X
Conformity Assessment Procedure X X X
Statement that no other application lodged with another notified body X X
Statement on the use of material of animal origin X
Statement on the device including a medicinal substance X
Risk
Statement on the device including human blood derivative X
PRODUCT DESCRIPTION/INTENDED USE
Intended use X X X
If necessary
Description of the device and its variants X X X
If necessary
Drawings X X
If necessary
Method of use X X
Description of the packaging configuration X X
Product Historic – Previous existing legislation X X
COMPONENTS/MATERIALS/PACKAGING COMPOSITION
Device Components and Materials description X X X
Suppliers name and address and quality certificates X X
Packaging composition X X X
DESIGN VERIFICATION
Results of Design Calculation X X
PRODUCT REALIZATION
Quality Management System
(Continued)
261
262
European Union

Risk
Manufacturing description/flow chart X X X
Subcontractors name X X
Subcontractors quality details X
Method and validation of processes X X
(e.g.: primary packaging/cleaning/disinfection/decontamination
Quality Control: description of Incoming/In-process/Final inspections X X X
Environmental controls X X X
STERILIZATION
Method/Appropriate standards X X X
Sterilization Validation X X X
Summary
STABILITY DATA
Physical, chemical and functional stability (shelflife demonstration) as X X
If necessary
applicable
Transportation and Storage conditions if applicable X X
RISK MANAGEMENT
Risk
Summary
Summary
Risk Management Report – ISO 14971 requirements X X
Post-market Analysis – Complaint Data X X
Conformity when connected to other medical devices as applicable X X
BIOCOMPATIBILITY
Pre-clinical evaluation/Biocompatibility data X X X
Summary
CLINICAL EVALUATION
Summary
Scientific literature review X X
Summary
Clinical data assessment X X
Summary
POST-MARKET SURVEILLANCE
LABELLING
Labelling content description (Labels from all level of packaging and X X X
Instructions for Use)
LIST DEMONSTRATING COMPLIANCE TO STANDARDS X X X
Quality Management System
ESSENTIAL REQUIREMENTS CHECKLIST X X X

263
264 European Union
21.15 Risk Management

The ISO 13485 recognizes that risk management is a key quality
system element that pervades the entire life cycle of a medical
device.
The ISO 14971 [12] sets for guidance related to risk management.
The manufacturer shall establish, document and maintain
throughout the life-cycle an ongoing process for identifying hazards
associated with a medical device, estimating and evaluating the
associated risks, controlling these risks, and monitoring the
effectiveness of the controls. This process shall include the following
elements:
• risk analysis
• risk evaluation
• risk control
• production and post-production information
The risk/benefit analysis is the basis to be conducted to ensure a
high level of protection of health and safety: its purpose is to assess
the acceptable risks when weighted against benefits to the patient.
The risk reduction is then the elimination or mitigation as far as
possible of the risks for a safe design and construction. It addresses
protection measures to be taken and information to be provided the
user and patient for each residual risk.
21.16 Clinical Evaluation

The clinical evaluation corresponds to the medical assessment
of a medical device: The aim is to demonstrate that the intended
purpose and claim of the device are achieved and to confirm that the
device is safe and performs as expected. In this aim, the conformity
of the device characteristics and performances as defined in the
essential requirements, needs to be assessed, based on the evaluation
of the side-effects and the acceptability of the benefit/risk ratio.
Clinical data is data which is relevant to the various aspects of
the clinical safety and performance of the device. This may include
data from prospective and retrospective clinical investigations of
the device concerned as well as market experience of the same or
similar devices and medical procedures and information from the
scientific literature.
Clinical Evaluation 265
Clinical data evaluation is the process by which clinical data

from all selected sources (literature, results of clinical investigations
and other) is assessed, analysed and deemed appropriate and
adequate to establish conformity of the device with the pertinent
essential requirements of the Directive as they relate to safety
and performance, and to demonstrate that the device performs
as intended by the manufacturer. The outcome of this process is a
report which includes a conclusion on the acceptability of risks
and side effects when weighed against the intended benefits of the
device.
The clinical data evaluation report should be made based on the
risk of the product and based on the assessment of the combination
of several of the following critical evaluation:
• Relevant scientific literature currently available relating to
the safety, performance, design characteristics and intended
purpose of the device where the data adequately demonstrate
compliance with the relevant essential requirements
• Results of existing clinical investigations issued from clinical
studies
• Data from market experience of same/similar devices already
regularly placed on the market
• Additional requirements of applicable standards and guidance
documents
• Performance claims
• Risk analysis report
The conclusion should compile all risk/benefit assessment from
each part: the rationale should be included to justify the acceptability
of each remaining risk when weighted against the intended benefits
from use of the device. Statements concerning the field of use of the
device and its indications and contraindications, effects and side
effects, should be consistent with the device labelling, including
the instructions for use.
Where demonstration of conformity with essential requirements
based on clinical data is not deemed appropriate, adequate
justification has to be given based on risk management output and
under consideration of the device/body interaction, the clinical
performances intended and the claims of the device.
The clinical evaluation should be reviewed, signed and dated by a
dully qualified medical practitioner or other expert (medical expert:
medical director or associate).
266 European Union
21.17 CE Mark Certificate and Declaration

of Conformity
The CE marking symbolizes the conformity of the product with the
applicable European Community requirements imposed on the
manufacturer.
The CE marking affixed to products is a declaration by the person
responsible that the product conforms to all applicable European
Community provisions, and that the appropriate conformity
assessment procedures have been completed.
A CE mark certificate indicating the procedure of evaluation
applied and the range of the products is established by the notified
body. It is valid for a maximum of 5 years, and can be renewed.
During its validity it can be amended to allow for changing products
and line-extensions.
If the selected procedure utilizes a notified body, then the
product labelling has to include on all levels of labelling/packaging
the following symbol:
XXXX, where XXXX is the identification number of the

notified body
In the case of self-certification (Class I, non-sterile, without a

measuring function), the labelling of the product comprises the CE
Symbol only:
The declaration of conformity is the final step in the relevant

conformity assessment procedure for all Medical Devices, which fall
under the scope of one of each of the Directives and is incumbent
to the Manufacturer: this is whereby the Manufacturer ensures and
declares that the products concerned meet the provisions of the
Directives.
The declaration of conformity is a mandatory document which
must imperatively be established and signed before any product
release for sale and which must be kept at regulators disposal.
A CE Declaration of conformity is established by the manu-
facturer whatever the class of the device. It ends any conformity
assessment procedure.
Post-Market Surveillance 267
21.18 Post-Market Surveillance

The post-market surveillance (PMS) is an information gathering
process to ensure that any problems or risks associated with the
use of a manufacturer’s medical device, once freely marketed, are
identified, reported to national competent authorities and corrective
actions are taken to mitigate the problem or risk.
The post-market surveillance plan includes post-market clinical
follow-up, reporting of serious incidents to competent authorities
(Vigilance System), application of Field Safety Corrective Actions
(FSCA, previously named Recall). A Field Safety Corrective Action is
an action taken by the legal manufacturer to reduce a risk of death
or serious deterioration in the state of health associated with the
use of a medical device that is already placed on the market. Such
actions should be notified via a Field Safety Notice, which is the
communication of a Field Safety Corrective Action to users.
The post-market surveillance system is based on the information
received from the field in the post-production phase, which is the part
of the life-cycle of the product after the design has been completed
and the medical device has been manufactured. The post-market
surveillance system shall consist of the review and assessment for
effectiveness and or further action of the following:
• Corrective and preventive actions associated with the
Complaints, Medical Device Vigilance Reports and Field Safety
Corrective Action activity
• The results of customer surveys
• Feedback from manufacturing plant surveillance activities
• Output reports from post-market clinical evaluation studies
• Feedback from users via sales representatives
• Reports and or interactions with regulatory authorities
• Literature reviews and media analysis where applicable
• Output from expert user/focus groups if applicable to the
product platform
The post-market surveillance activities are aimed at obtaining
some of the following types of knowledge or feedback:
• Detection of manufacturing problems and detection of needs
for product quality improvement
268 European Union
• Confirmation of risk analysis

• Knowledge of performance of the device in different user
populations and on ways in which the device is misused
• Feedback on indications for use, on Instructions for Use,
training needed for users, use with other devices, customer
satisfaction and on continuing market viability
21.19 Recent Changes of MDD 93/42/EEC

and Impacts
In 2007 the European Commission issued Directive 2007/47/EC,
which EU member states implemented by amending national laws
implementing the Medical Device Directive (MDD) and Active
Implantable Medical Devices 90/385/EEC. On 21 March 2010, the
2007/47/EC amendments came into full force and manufacturers
MUST comply fully with the amended Medical Device Directive by
this date.
The 2007/47/EC [7] impacts the competent authorities’ roles and
responsibilities: the Competent Authorities are expected to increase
their communication for better co-operation, consistency and
transparency; they have to take some arrangement to assess drug-
device combination in a more established way. In terms of Vigilance,
the measures taken to impose field safety corrective action are now
subject to scrutiny by the European Commission. The Competent
Authorities are allowed to request information about ALL Medical
Devices classes, including Class I because of counterfeit/market
surveillance. One authorized representative only is now allowed
per Medical Device/products family in order to avoid confusing
situations: the role of the Authorised Representative has been better
defined as it acts as the communication interface with EU regulatory
bodies and is fully responsible of regulatory compliance.
The 2007/47/EC has some impacts as well on notified bodies, as
it requires Competent Authorities to increase their control of notified
bodies for more consistency across the European Community. It
brought greater clarity in the processes and nature of assessments
and a closer scrutiny of design validation: the notified body has now
to evaluate the ability of Manufacturers to produce appropriate
Recent Changes of MDD 93/42/EEC and Impacts 269
Technical Files (including Technical Files of Class IIa and IIb Medical
Devices) and to evaluate a representative sample of a Technical File
elaborated by a Manufacturer.
The changes of the Medical Device Directive 93/42/EEC as
amended by the Directive 2007/47/EC are as follows:
• Classification of some Medical Devices:
o The modifications in the annex related to the classification
system bring products for the disinfection of invasive
devices into Class IIb.
o The rule for the determination of the time of contact of
invasive products was modified and impacts some invasive
devices.
o Surgically invasive devices intended specifically for use
in direct contact with the central nervous system are in
Class III
o Software are considered as active Medical Devices
o Where a device is intended by the manufacturer to be
used in accordance with both the provisions on Personal
Protective Equipment in Council Directive 89/686/EEC
and the MDD 93/42/EEC as amended, the relevant basic
health and safety requirements of Directive 89/686/EEC
shall also be fulfilled
• When a Manufacturer is not located in a member state, a
single authorized representative must be designated in the
European Union: this must be clearly defined on the product
labelling and in the declaration of conformity.
• The technical documentation and solutions adopted to meet
the essential requirements have to integrate the following
points:
o The Design of the Medical Device shall take into account
the expected skills and knowledge of the user (reduction
of use error)
o The demonstration of conformity shall include a clinical
evaluation for every class of Medical Device
o The Software must be validated according to the state of
the art
270 European Union
• The declaration of conformity needs to provide a clear

description of the medical device(s).
• Single-use product.
o The labelling has to be consistent throughout the European
Union, using a single symbol.
o Information must be provided as to the risks posed if the
device is reused: in the instructions for use and/or on the
outer packaging of the medical device.
• Identification and risk management on toxic substances:
o Special reference is made in the Essential Requirements
Checklist, Section 7.5, to phthalates and manufacturers
to add suitable specific label for phthalate-containing
devices.
o Phthalates plasticizers are added to the typically rigid
plastic to make it pliable (plastic softeners). Their low
molecular weight makes them prone to migration from
the plastic to the contained product; the PVC (polyvinyl
chloride) remains the most widely used plastic in single
use medical applications.
o This applies [5] when parts of a device (or a device itself)
are intended to administer and/or remove medicines, body
liquids or other substances to or from the body, or devices
intended for transport and storage of such body fluids or
substances and when the intended use of such devices
includes treatment of children or treatment of pregnant
or nursing women, and when substances are classified as
Carcinogenic, Mutagenic and Toxic to reproduction (CMR)
Class I and II in accordance with Annex I to Directive
67/548/EEC.
o No specific phthalates are listed in the MDD 93/42/EEC as
amended; however, it can be noticed that 3 phthalates are
mainly and widely considered in most of the texts (DEHP,
DBP and BBP).
The changes from the 2007/47/EC which impact both the
Medical Device Directive 93/42/EEC and the Active Implantable
Medical Devices (90/385/EEC) concern the clinical evaluation:
Trends 271
• Clinical evaluation:
o The new Directive expresses the need for clinical
evidence (Essential Requirements, Section 6a) for all
Medical Devices (93/42/EEC) and section 5a for Active
Implantable Medical Devices (90/385/EEC).
o The clinical evaluation is the process by which clinical data
from all selected sources (information from the scientific
literature, data from prospective and retrospective clinical
investigations, market experience of the same or similar
devices) is assessed, analysed and deemed appropriate
and adequate to demonstrate that the device performs as
intended by the manufacturer.
21.20 Trends
The European Commission is seeking to improve some areas in the
European regulatory frame such as for the following topics:
• Designation and monitoring of the notified bodies
• Common codification and simplification of the Medical Devices
Directives
• Post-market safety improvement for more consistent and
timely reactions to safety issues coming from outside the
European Community: implementing a better coordination
with other authorities such as the United States Food and Drug
Administration or the State Food and Drug Administration in
China
• Clinical Safety improvement with the scrutiny of clinical
evaluation and data and the strengthening of the Vigilance
and post-market surveillance systems
• Transparency of the devices, with the implementation of the
Summary Device Information and Unique Device Identifier
for traceability of devices (UDI)
• Control the product information disclosure: enhance
consistency of device information between its Instructions for
Use, Internet information and marketing materials
272
PREͲMARKET PLACINGONTHEMARKET POSTͲMARKET
Manufacturer Vendor User

European Union
RegularAssessmentby
NotifiedBody(Audit)—
ISO13485
Conception&Development
Competent
Ͳ MedicalDeviceClassification Authority
Ͳ DesignVerification&Validation Notified
Ͳ Standards Body
Ͳ ClinicalTrialsISO14155
Terminology
Ͳ PreͲclinical ¾ EssentialRequirements
Tests/Biocompatibility ¾ ClinicalEvaluationReport
Ͳ ScientificLiteratureReview ¾ RiskManagementReport
¾ TechnicalDocumentation
1. Compilationforinitial CEMark
Manufacture approval Certificate
2. Updateforsubstantial
Ͳ QualityManagementSystem changes
Ͳ ProductValidation Ͳ DeviceLaunch
Ͳ QualityControls Ͳ MarketingMaterials UserDisposal
Ͳ Traceability Ͳ UserTraining
Ͳ BatchVerificationIVDListA Ͳ TraceabilityͲDistribution
Records
Labeling&Packaging Ͳ CustomerComplaints
System
Ͳ ProductLabel/IFUͲLanguagesͲ
Ͳ PostͲMarketSurveillance
Symbols
Ͳ FieldSafetyCorrective
Ͳ Storage,Handling,Distribution.
Action
Ͳ VigilanceSystem
21.21 Overview of All Interactions and Key
PostͲmarketanalysisofdeviceitselfor
equivalentdevice
References 273
References
1. Council of the European Parliament (12 July 1993) Council Directive

of 14 June 1993 concerning Medical Devices (MDD 93/42/EEC), as
amended by Directive 2007/47/EC of the European Parliament and
of the Council of 5 September 2007, Official Journal of the European
Communities OJ L169 p1.
2. Council of the European Parliament (20 June 1990) Council Directive
90/385/EEC of 20 June 1990 on the approximation of the laws of the
member states relating to active implantable medical devices (AIMD),
Official Journal of the European Communities OJ L169 p1.
3. Council of the European Parliament (27 October 1998) Directive
98/79/EC of The European Parliament and of The Council of 27
October 1998 on in vitro diagnostic medical devices, Official Journal of
the European Communities OJ L331 p1.
4. Council of the European Parliament (5 September 2007) Directive
2007/47/EC of the European Parliament and of the Council of 5
September 2007 amending Council Directive 90/385/EEC on the
approximation of the laws of the member states relating to active
implantable medical devices, Council Directive 93/42/EEC concerning
medical devices and Directive 98/8/EC concerning the placing of
biocidal products on the market, Official Journal of the European
Communities OJ L247 p21.
5. EUCOMED (30 October 2009) Guidance on the information requirements
of the revised Medical Devices Directive 93/42/EEC concerning certain
phthalates.
6. European Commission Online- DG Health & Consumers — Public health
Medical devices — Documents Guidelines — Guidance MEDDEVs.
Retrieved December 2011, from http://ec.europa.eu/health/medical-
devices/documents/guidelines/index_en.htm.
7. European Commission — Enterprise and Industry Directorate
— General — Consumer goods — Cosmetics and Medical Devices (5
June 2009) — Interpretative document of the Commission’s services
— Implementation of Directive 2007/47/EC amending Directives
90/385/EEC, 93/42/EEC AND 98/8/EC, Brussels ENTR/F3/PBE/
D(2009)19003.
8. European Commission (2000) Guide to the Implementation of Directives
based on the New Approach and the Global Approach — Luxembourg:
274 European Union
Office for Official Publications of the European Communities — ISBN

92-828-7500-8.
9. European Commission DG Health and Consumer Directorate B, Unit
B2 “Cosmetics and medical devices” (June 2010) MEDICAL DEVICES:
Guidance document — Classification of medical devices — guidelines
relating to the application of the Council Directive 93/42/EEC on medical
devices — MEDDEV 2. 4/1 Rev. 9.
10. NBOG’s Best Practice Guide applicable to MDD (July 2009) Guidance
on Notified Body‘s Tasks of Technical Documentation Assessment on a
Representative, NBOG BPG 2009-4.
11. ISO 13485:2003 — Medical devices — Quality management systems
— Requirements for regulatory purposes.
12. ISO 14971:2007 — Medical devices — Application of risk management
to medical devices.
13. ISO 15223-1:2012 — Medical devices — Symbols to be used with
medical device labels, labelling and information to be supplied — Part
1: General requirements.
14. G1(PD)/N77R4 Global Harmonization Task Force — (Revision of GHTF/
SG1/N15:2006) Title: Principles of Medical Devices Classification
— Authoring Group: Study Group 1 of the Global Harmonization Task
Force — Date: October 3, 2011.
15. Technical Secretariat NB-MED (03 February 2000) Coordination of
Notified Bodies Medical Devices on Council Directives 90/385/EEC,
93/42/EEC and 98/79/EC Recommendation NB-MED/2.5.1/Rec5 —
Technical Documentation — 2.5.1 Conformity assessment procedures;
General rules.
16. World Health Organization Geneva (2003) Medical Device Regulations
Global overview and guiding principles Medical device regulations:
global overview and guiding principles, WHO Library Cataloguing-in-
Publication Data ISBN 92-4-154618-2.
Chapter 22
Regulation of Combination Products in

the United States
John Barlow Weiner and Thinh X. Nguyen

Office of Combination Products, Food and Drug Administration,
WO32, Hub/Mail Room #5129, 10903 New Hampshire Avenue,
Silver Spring, MD 20993, USA
John.Weiner@fda.hhs.gov, THUYNTT@its.jnj.com
Disclaimer
This chapter represents the views of the authors in their personal
capacities. It does not represent an official statement by the US Food
and Drug Administration.
22.1 Introduction
This chapter addresses the regulation of combination products in
the United States. As the discussion below indicates, combination
products present particular challenges. For example, issues may
arise with respect to premarket data requirements and postmarket
regulatory requirements, as well as associated practical considerations
such as information technology needs and collaboration with other
regulated entities.
The following topics are addressed: what products are
considered “combination products”; the standards for determining

www.panstanford.com
276 Regulation of Combination Products in the United States
whether a product is a combination product and for determining

which component of the US Food and Drug Administration (FDA)
has primary responsibility for the regulation of a combination
product; how to obtain a formal product classification or assignment
determination from the FDA; premarket review and post-market
regulatory considerations for combination products; the role of the
FDA’s Office of Combination Products (OCP); examples of expected,
near-term regulatory developments in the US that may be of interest
to combination product developers; international harmonization
and coordination activities with foreign counterparts; and FDA
resources for obtaining additional information.
22.2 What Products Are Considered

Combination Products
In the United States, the term “combination product” refers to a
product comprising any combination of a drug and a device; a device
and a biological product; a biological product and a drug; or a drug,
a device, and a biological product (21 CFR 3.2; see 21 USC 353(g)).
Types of combination products include physically or chemically
combined products (such as drug-eluting stents or syringes marketed
prefilled with a drug or biological product); co-packaged products
(such as an ampule of a drug packaged together with a delivery
device, first aid kits that include bandages and drugs to treat wounds
and other injuries, or surgical kits that include devices and drugs
that might be used for a particular type of surgical procedure); and
certain separately marketed but “cross-labeled” products (such as a
laser and a light-activated drug that are marketed separately from
one another but labeled specifically for use with one another). See
21 CFR 3.2(e).
22.3 The Standards for Determining If a Product

Is a Combination Product
Because a combination product comprises two or more different
types of medical products (constituent parts), a determination of
whether a product is a combination product begins with determining
the classification of the articles of which it is comprised. If the
product includes at least two, distinguishable medical products
FDA Component with Primary Responsibility for Regulating a Combination Product 277
that are classified differently from one another, it is a combination

product. Generally, it may be fairly obvious whether a product is
a combination product. A prefilled syringe, for example, clearly
consists of a device (the syringe) and the drug or biological product
contained in the syringe. In some cases, classification may be more
difficult to determine. Regardless of how apparent the classifications
may be, the answer depends on an assessment of which of the
statutory definitions — that for biological product, device, or drug
— best applies to each article of which a product is comprised.1
22.4 The Standards for Determining Which FDA

Component has Primary Responsibility for
Regulating a Combination Product
The FDA has three components, called “Centers,” that regulate
medical products for humans: the Center for Biologics Evaluation
1Section 201(g) of the Federal Food, Drug, and Cosmetic (FD&C) Act (21 USC 321(g))
provides that the term “drug” means:
(A) articles recognized in the official United States Pharmacopoeia, official
Homoeopathic Pharmacopoeia of the United States, or official National Formulary,
or any supplement to any of them; and (B) articles intended for use in the diagnosis,
cure, mitigation, treatment, or prevention of disease in man or other animals; and
(C) articles (other than food) intended to affect the structure or any function of the
body of man or other animals; and (D) articles intended for use as a component of
any articles specified in clause (A), (B), or (C)… .
Section 201(h) of the FD&C Act (21 USC 321(h)) provides that the term “device”
means:
… an instrument, apparatus, implement, machine, contrivance, implant, in vitro
reagent, or other similar or related article, including any component, part, or
accessory, which is—
(1) recognized in the official National Formulary, or the United States Pharmacopeia,
or any supplement to them,
(2) intended for use in the diagnosis of disease or other conditions, or in the cure,
mitigation, treatment, or prevention of disease, in man or other animals, or
(3) intended to affect the structure or any function of the body of man or other
animals, and which does not achieve its primary intended purposes through
chemical action within or on the body of man or other animals and which is not
dependent upon being metabolized for the achievement of its primary intended
purposes.
Section 351(i) of the Public Health Services Act (42 USC 262(i)) provides that:
The term “biological product” means a virus, therapeutic serum, toxin, antitoxin,
vaccine, blood, blood component or derivative, allergenic product, protein (except
any chemically synthesized polypeptide), or analogous product, or arsphenamine
or derivative of arsphenamine (or any other trivalent organic arsenic compound),
applicable to the prevention, treatment, or cure of a disease or condition of human
beings.
Figure 22.1 FDA chart.

FDA Component with Primary Responsibility for Regulating a Combination Product 279
and Research (CBER); the Center for Devices and Radiological

Health (CDRH); and the Center for Drugs Evaluation and Research
(CDER). Section 503 of the FD&C Act requires that the determination
of which Center will have primary responsibility for the regulation of
a combination product be based upon the “primary mode of action”
(PMOA) of the combination product. See 21 USC 353(g). There are
three modes of action for purposes of this analysis, that of a biological
product, a device, or a drug. See 21 USC 353(g); 21 USC 3.2(k). If
the PMOA is provided by a biological product constituent part, the
combination product is typically assigned to CBER. If the PMOA is
provided by a device constituent part, the combination product is
typically assigned to CDRH, and if the PMOA is provided by the drug,
the combination product is typically assigned to CDER. See 21 USC
353(g)(1); 21 CFR 3.4(a).
PMOA is defined as the mode of action that provides the greatest
contribution to the overall therapeutic effect of the combination
product. See 21 CFR 3.2(m). Like classification, the PMOA may be
obvious in some cases. For example, the drug or biological product
provides the PMOA for a prefilled syringe because the syringe serves
merely to deliver the drug or biological product that then treats
the disease or condition the combination product is intended to
address. In other cases, PMOA may be more difficult to determine,
for example, if more than one constituent part of the combination
product directly contributes to the treatment effect. In such cases,
data on the relative contribution of the different constituent parts
may be needed to make the determination.
Further, in some cases, it may not be possible to determine PMOA
directly. For example, a product may consist of two articles that
address different diseases or conditions, so that there is no overall
therapeutic effect to which either contributes more than the other.
In such circumstances, PMOA is determined indirectly through the
use of an algorithm. See 21 CFR 3.4(b). The first step of the algorithm
asks whether one of the Centers already regulates a combination
product that raises similar questions of safety and effectiveness to
those raised by this combination product. If there is one such Center,
the combination product will be assigned to that Center. If there is
not such a Center, the second step of the algorithm applies. Under the
second step, the combination product is assigned based on which
Center has the most experience with the most significant safety and
effectiveness issues presented by the combination product.
22.5 Requests for Designation

Section 563 of the FD&C Act provides that a request for designation
(RFD) may be submitted to obtain a formal, binding determination
from the FDA as to the classification or Center assignment for a
product. 21 USC 360bbb-2. The FDA is required to respond to RFDs
not later than sixty days after they are filed. See 21 USC 360bbb-
2(b). If the agency does not respond within that time-frame, the
classification or assignment recommended by the RFD submitter
applies. See 21 USC 360bbb-2(c). A classification or assignment
made through the RFD process can only be changed either with the
consent of the RFD submitter or for public health reasons based on
scientific evidence. See 21 USC 360bbb-2(b),(c); see 21 CFR 3.9.
RFDs are submitted to OCP, which is charged with determining
whether products should be classified as biological products,
devices, drugs, or combination products, and with assigning
them to the appropriate Center. The FDA permits and encourages
sponsors to seek guidance from OCP before submitting an RFD, to
confirm whether one is needed and to help ensure that the RFD will
be complete for filing. Among other requirements, an RFD must
describe the product, its components and ingredients; state the
product’s intended use; provide the submitter’s understanding of
how the product works; and provide a justification for the product’s
PMOA if the product is a combination product. See 21 CFR 3.7. For
further guidance see How to Write a Request for Designation (RFD),
Guidance for Industry (http://www.fda.gov/RegulatoryInformation/
Guidances/ucm126053.htm).
22.6 Premarket Review Considerations

There are no special premarket standards or requirements
specifically for combination products. The basic concern for them, as
for all medical products, is to ensure that they are safe and effective
for their intended uses. While the lead Center for a combination
product is determined based on the PMOA of the product as
discussed above, other Centers may participate in the premarket
review of combination products, bringing to bear their expertise
and informing the review process. See, e.g., 21 USC 360bbb-2(g)(1),
(4)(C).
Post-Market Regulatory Considerations 281
A principal consideration for combination products is to

ensure that product development and testing addresses all
relevant considerations relating to each constituent part and
their interactions. Accordingly, for example, in assessing whether
a syringe is an appropriate delivery device for a particular drug,
relevant considerations would include whether the syringe interacts
with the drug, whether it will deliver the correct drug dosage, and
whether the integrity of the syringe material can be maintained in
accordance with the combination product’s shelf-life. Similarly, in
the case of a drug-eluting stent for example, considerations for the
drug constituent part would include (in addition to its effectiveness
to achieve its intended therapeutic purpose) such factors as whether
the formulation of the drug is appropriate in light of the need to
control the elution rate and resist flaking from the stent.
Strong, clear business arrangements between regulated entities
can be important to obtaining marketing authorization. Access
to third-party proprietary data submitted by one manufacturer,
for example, can reduce data development demands and expedite
product review and approval, including with respect to post-market
changes. A related issue with regard to cross-labeled combination
products in particular, is whether it makes better sense to seek a
single marketing authorization for the combination product or to
seek separate marketing authorizations for each of the separately
marketed constituent parts of the combination product. Separate
applications may facilitate further development of these constituent
parts for independent uses not involving the other constituent
part. However, reliance upon separate applications may also pose
challenges, for example, with respect to coordination of post-
market modifications to either constituent part, particularly if
the applications are held by different sponsors. The FDA has the
authority to require two applications in appropriate cases for
combination products. See 21 CFR 3.5(c).
22.7 Post-Market Regulatory Considerations

In the context of two rulemakings, for postmarketing safety
reporting (PSR) and for current good manufacturing practices
(CGMPs) for combination products, among other contexts the
FDA has stated that combination products are subject to the
legal requirements applicable to their constituent parts, and that
combination products comprise a distinct category of medical

products that can be regulated in light of the distinct regulatory
considerations they raise. See Current Good Manufacturing Practice
Requirements for Combination Products (final rule), 78 FR 4307
(https://www.federalregister.gov/articles/2013/01/22/2013-
01068/current-good-manufacturing-practice-requirements-for-
combination-products); Postmarketing Safety Reporting for Combi-
nation Products (proposed rule), 74 FR 50,744 (http://edocket.
access.gpo.gov/2009/pdf/E9-23519.pdf).
The FDA has taken a similar approach in both rulemakings
for PSR and for CGMPs. Specifically, for each topic the agency re-
viewed the regulations applicable to biological products, drugs, and
devices, and assessed in which ways those sets of regulations overlap
and in which ways they may be distinct. Based on this review, the
FDA developed approaches it states are intended to enable regulated
entities to comply with the multiple sets of regulations applicable
to their combination product without unnecessary redundancy
of requirements or burden. In both cases, the FDA has pursued an
approach under which some regulations applicable to constituent
parts of the combination product must be implemented in their
entirety while only specified provisions of other such regulations
need to be met. These two rulemakings offer some insight as to the
FDA’s thinking regarding what requirements apply to combination
products and how to clarify and streamline appropriate measures
to comply with them. Further insight can be expected from the
finalization of the PSR rule and other policy initiatives announced
by the FDA such as those noted in the discussion of near-term
developments below.
As in the premarket context, various staff from Centers other than
the lead Center and from other FDA components may participate in
post-market regulatory activities for combination products. Such
coordination may be appropriate, for example, to ensure staff with
appropriate expertise participate in site inspections and the review
of post-market changes to products.
22.8 Role of Office of Combination Products

OCP is a statutorily mandated office whose responsibilities include
ensuring the timely, effective premarket regulation of combination
products and their consistent and appropriate post-market
regulation. See 21 USC 353(g)(4). OCP undertakes a wide range of

OfficeoftheCommissioner
Office of the Commissioner
OfficeofMedicalProductsandTobacco
Office of Medical Products and Tobacco
OfficeofSpecialMedicalPrograms
Office of Special Medical Programs
Officeofcombination
Office of Combination OfficeofPediatric
Office of Paediatric OfficeofGoodClinical
Office of Good Clinical OfficeofOrphanProduct
Office of Orphan Product AdvisoryCommittee
Advisory Committee
products
Products Therapeutics
Therapeutics Practice
Practice Development
Development Oversight&Management
Oversight & Management
Figure 22.2 The OCP chart.

Role of Office of Combination Products
283
activities in accordance with this mandate, including: responding

to RFDs as discussed above; facilitating the consultation process
between Centers on combination product regulatory issues; offering
input on product-specific regulatory issues; convening working
groups and coordinating initiatives to develop policies; participating
in agency working groups and initiatives that may affect regulation
of combination products; and resolving disputes within the FDA
and between FDA and regulated entities. In addition, OCP acts as
a resource to combination product developers and manufacturers
to answer regulatory questions and facilitate interactions with the
agency, including Center review staff, field staff, and enforcement
and inspectional personnel.
22.9 Near-Term Developments That May Arise

in the US
OCP and other FDA components have announced various
projects for combination products that may be of particular interest
to combination product developers and manufacturers. These
include: continued development of product-specific guidance for
imaging products, injectors, and companion diagnostics. In addition,
OCP has announced plans to develop further general guidance for
combination products on post-marketing changes, registration and
listing, and cross-labeled combination products. Also, the FDA is
continuing efforts to finalize guidance on standards to determine
whether medical products should be classified as biological products,
devices, drugs, or combination products.
22.10 International Harmonization and

Coordination Activities with Foreign
Counterparts
The FDA has expressed interest in working with foreign counterpart
agencies to promote harmonization and coordination of activities
with respect to combination products. Some preliminary discussions
have taken place with Australian, Canadian, European, and Japanese
regulators regarding identification of topics of shared interest.
In addition, OCP continues to work with and provide technical
FDA Resources for Obtaining Additional Information 285
assistance to foreign counterparts throughout the world. A practical

consideration is that harmonization and coordination with respect
to combination products largely depends on related efforts with
respect to biological products, devices, and drugs. Accordingly,
progress on some topics may depend on preliminary work with
respect to each of these types of products from which combination
products are comprised.
22.11 FDA Resources for Obtaining Additional

Information
For further information, OCP’s Web page on the FDA Web site is an
excellent resource: http://www.fda.gov/CombinationProducts/
default.htm. In addition, as noted above OCP itself is an important
resource to address questions and obtain assistance for engaging
with the FDA on regulatory issues for combination products and
medical product classification issues. Contact information for OCP is
available on its Web page.
Chapter 23
Regulation of Combination Products in

the European Union
Janine Jamieson and Elizabeth Baker

Licensing Division, Medicines and Healthcare Products Regulatory Agency,
London SW1W 9SZ, UK
janine.jamieson@mhra.gsi.gov.uk, elizabeth.baker@mhra.gsi.gov.uk
23.1 Introduction: Legal Basis

In Europe, there are two regulatory routes for drug–device
combination products, either as medical devices incorporating
ancillary medicinal substances or as medicinal products utilizing a
delivery device.
Following are the regulations covering these two options:
• Medical Devices Directive 93/42/EEC (MDD)/Active Implan-
table Medical Devices 90/385/EEC (AIMDD)
• Medicinal Products Directive 2001/83/EC (MPD)
As a general rule, a combination product is regulated either by
the MDD/AIMDD for the conformity assessment procedure relevant
to medical devices or by the MPD for the marketing authorization

www.panstanford.com
288 Regulation of Combination Products in the European Union
procedure applicable to medicinal products. The procedures of

both Directives do not apply cumulatively; however, some cross-
references are made within one regime to specific requirements of
the other regime.
The two procedures have different requirements and the
correct classification is crucial for development and regulatory
approval of a combination product in Europe.
The appropriate regulatory procedure depends upon the
principal mode of action of the combination product.
• Drug-delivery products presented as an integral combination
with a medicinal product are regulated as medicinal
products.
Example: pre-filled syringes
See Section 1.2.
• Drug-delivery products presented separately from the
medicinal product are regulated as medical devices.
Example: drug delivery pump
See Section 1.3.
• Medical devices incorporating, as an integral part, an ancillary
medicinal substance are regulated as medical devices but
with additional requirements for the ancillary medicinal
substance.
Example: drug-eluting stent
See Sections 1.4, 1.5 and 1.6.
Guidance on which regulations are applicable, particularly in
cases where the principal mode of action is not clear, can be found in
the MEDDEV 2.1/3: EC Guidance document on “Borderline products,
drug-delivery products and medical devices incorporating, as an
integral part, an ancillary medicinal substance or an ancillary human
blood derivative”. See the European Commission website [1].
The information provided in the following sections is based,
to a large extent, on the text of the MEDDEV 2.1/3 document. The
reader is directed to this document for more detailed information
and examples of drug–device combination products.
23.1.1 Definitions
23.1.1.1 Medical device
Article 1(2) (a) MDD defines a medical device as
Introduction 289
Any instrument, apparatus, appliance, software, material or

other article, whether used alone or in combination, including
the software intended by its manufacturer to be used specifically
for diagnostic and/or therapeutic purposes and necessary for its
proper application, intended by the manufacturer to be used for
human beings for the purpose of:
of disease,
• diagnosis, monitoring, treatment, alleviation of or compen-
sation for an injury or handicap,
• investigation, replacement or modification of the anatomy or
of a physiological process,
• control of conception,
and which does not achieve its principal intended action in
or on the human body by pharmacological, immunological or
metabolic means, but which may be assisted in its function by
such means.
The medical device function is usually achieved by physical
means (including mechanical action, physical barrier, replacement
of or support to organs or body functions).
23.1.1.2 Medicinal product
Article 1(2) MPD defines a medicinal product as follows:

(a) Any substance or combination of substances presented as
having properties for treating or preventing disease in human
beings; or
(b) Any substance or combination of substances which may be
used in or administered to human beings either with a view
to restoring, correcting or modifying physiological functions
by exerting a pharmacological, immunological or metabolic
action, or to making a medical diagnosis.
This definition comprises two limbs, one relating to presentation
and the other to function. A product constitutes a medicinal product
if it is covered by one or other or both of those limbs.
The definition of a medicinal product is applied on a case by
case basis and determination takes into account current European
Case Law. The Medicinal Products Directive (MPD), Article 2(2), is
clear that, in cases of doubt, taking into account all of a product’s
characteristics, if a product meets both the definition of a medical

device and a medicinal product, then the MPD will apply.
23.1.1.3 Combination products: Principal mode of action

The principal intended action of a combination product is deter-
mined based on the mechanism of action of the device and medicinal
substance aspects.
The manufacturer’s labelling and claims are also taken into
account, but they should be in line with, and not contradict, current
scientific data. The product manufacturer should be able to justify
scientifically their rationale for the design and classification of the
combination product.
Useful definitions from MEDDEV 2.1/3

“Pharmacological means” is understood as an interaction between
the molecules of the substance in question and a cellular constituent,
usually referred to as a receptor, which either results in a direct
response, or which blocks the response to another agent. Although
not a completely reliable criterion, the presence of a dose-response
correlation is indicative of a pharmacological effect.
“Immunological means” is understood as an action in or on the
body by stimulation and/or mobilisation of cells and/or products
involved in a specific immune reaction.
“Metabolic means” is understood as an action which involves
an alteration, including stopping, starting or changing the speed of
the normal chemical processes participating in, and available for,
normal body function.
Medical devices may be assisted in their function by phar-
macological, immunological or metabolic means, but as soon as
these means are not ancillary with respect to the principal intended
action of a product, the product no longer fulfils the definition of
a medical device and the product will be regarded as a medicinal
product.
Examples
Bone cements and gentamicin-loaded polymethylmethacrylate
(PMMA) beads are useful examples of combination products for
illustration of the classification rules:
• Plain bone cement without antibiotics is a medical device
since it achieves its principal intended action (the fixation of
prosthesis) by physical means.
Combination Products Regulated as Medicinal Products 291
• Bone cements containing antibiotics, where the principal in-

tended action remains fixation of prosthesis, are also medical
devices. In this case the action of the antibiotic, which is to
reduce the possibility of infection being introduced during
surgery, is clearly ancillary.
• If, however, the principal intended action of the combination
product is to deliver the antibiotic (for example, gentamicin-
loaded beads for insertion into and withdrawal from an
infected bone cavity), this will be regarded as a medicinal
product with the beads acting as a delivery device for local
action of the gentamicin.
23.1.1.4 Borderline products: MEDDEV 2.1/3

The EC guidance document MEDDEV 2.1/3 is an extremely useful
document which provides detailed information on the classification
criteria between medical devices and medicinal products. In cases
where it is not clear which regulatory regime applies, numerous
examples and explanatory notes are provided to aid in the decision
making process.
23.1.1.5 Borderline products: Manual of decisions

There have been a number of cases of disagreement about classi-
fication over the years, between manufacturers and notified bodies
and also between different notified bodies and competent authori-
ties (the EU national regulatory bodies for medicines). A Medical
Device Expert Group (MDEG) on Borderline and Classification issues
has been set up to discuss products where there is a divergence of
opinion across Europe. The Expert Group meets regularly to help
reach agreement on classification issues. The decisions of the
MDEG on Borderline and Classification are published in the Manual
of Decisions available on the European Commission website [2].
However, the manual is designed to aid case-by-case application
of the legislation by the competent authorities and is not a legal
document itself.
23.2 Combination Products Regulated as

Medicinal Products
This classification refers to devices that are intended to administer
a medicinal product in the case where the device and the medicinal
product form a single integral product, which is intended exclusively

for use in the given combination and which is not reusable.
According to the MDD, this single product is governed by the
MPD but the relevant essential requirements of Annex I to the MDD
apply as far as the safety and performance-related device features
are concerned.
23.2.1 Examples of Combination Products Regulated as

Medicinal Products
• Pre-filled syringes
• Aerosols containing a medicinal product
• Patches for transdermal drug delivery
• Implants containing medicinal products in a polymer matrix
whose primary purpose is to release the medicinal product
• Intrauterine contraceptives whose primary purpose is to
release progestogens
• Temporary root canal fillers incorporating medicinal products,
whose primary purpose is to deliver the medicinal product

Medical Devices
This category refers to devices that are intended to administer a
medicinal product, but are not combined with a specific medicinal
product. They may be re-useable and may be used with different
medicinal products.
In this case, that device is governed by the MDD or the AIMDD.
23.3.1 Examples of Combination Products Regulated as

Drug-Delivery Devices
• Drug delivery pump
• Implantable infusion pump
• Iontophoresis device
• Nebulizer
• Syringe, jet injector
• Spacer devices for use with metered dose inhalers
• Port systems
Devices Incorporating Ancillary Medicinal Substance as Integral Part 293

Devices Incorporating, as an Integral Part,
an Ancillary Medicinal Substance
These relate to a device that incorporates, as an integral part, a
medicinal substance which, if used separately, may be considered
to be a medicinal product and which is liable to act upon the body
with action that is ancillary to that of the device.
In this case, the principal mode of action is attributable to the
device element and the medicinal substance has a lesser, secondary
effect.
The device is assessed and authorised in accordance with the
MDD or the AIMDD, with additional requirements in line with MPD
applied to the medicinal substance component.
According to the directives, the substance incorporated in the
device must meet the three following conditions:
• The substance, if used separately, may be considered to be a
medicinal product.
• The substance is liable to act upon the human body.
• The action of this substance is ancillary to that of the device.
In addition, a medical device incorporates a medicinal substance
as an integral part, within the meaning of the directives only if the
device and the substance are physically or chemically combined at
the time of administration (i.e., use, implantation, application, etc.)
to the patient.
23.4.1 Examples of Devices Incorporating an Ancillary

Medicinal Substance
• Drug eluting stents
• Catheters coated with heparin or an antibiotic agent
• Bone cements containing antibiotic
• Root canal fillers which incorporate medicinal substances
with ancillary action
• Bone void filler intended for the repair of bone defects where
the primary action of the device is a physical means or matrix,
which provides a volume and a scaffold for osteoconduction
and where an additional medicinal substance is incorporated
to assist and complement the action of the matrix by enhancing

the growth of bone cells
• Condoms coated with spermicides
23.4.2 Examples of Drug Substances Incorporated

into Devices
• Antibiotics, e.g. gentamicin, vancomycin
• Other anti-microbials, e.g. silver, chlorhexidine, rifampin
• Anti-proliferatives, e.g. paclitaxel, sirolimus
• Heparin
• Dexamethasone
• Nonoxinol
• Benzocaine
23.4.3 Assessment of the Medicinal Substance Aspects

of a Device Incorporating an Ancillary Medicinal
Substance
For devices incorporating, as an integral part, an ancillary medicinal
substance, the notified body should first of all verify the usefulness
of the substance as part of the medical device themselves. They
must then seek a scientific opinion from one of the EU competent
authorities for medicines on the quality and safety of the substance
including the clinical benefit/risk profile of the incorporation of the
substance into the device.
The aspect of “usefulness” is interpreted as the rationale for using
the medicinal substance in relation to the specific intended purpose
of the device. It refers to the suitability of the medicinal substance to
achieve its intended action, and whether the potential inherent risks
(aspect of “safety”) due to the medicinal substance are justified in
relation to the benefit to be obtained within the intended purpose of
the device.
23.5 The Consultation Process

The notified body and the manufacturer may choose the EU
competent authority with whom they consult. However, the Euro-
Information to Be Provided on the Ancillary Medicinal Substance 295
pean Medicines Agency (EMA) must be consulted for all medical

devices incorporating ancillary human blood derivatives, e.g. human
albumin or medicinal products manufactured using biotechnological
processes (i.e., those falling within the scope of Annex I to Regulation
(EC) No. 726/2004 [1]).
In accordance with MEDDEV 2.1/3, Section C, the notified body
should ensure that data supplied by the manufacturer in relation to
the device and its intended use includes a specific segment regarding
the medicinal substance being incorporated with ancillary purpose.
Detailed submission guidance is available on the websites of EMA,
MHRA and other competent authorities.
23.6 Information to Be Provided on the

Ancillary Medicinal Substance
23.6.1 General
Information addressing the safety, quality and usefulness of the
medicinal substance should be prepared by the manufacturer,
submitted to the notified body, and then forwarded by the notified
body to the competent authority (MHRA in UK). In addition, a report
on the usefulness of the medicinal substance should be prepared by
the notified body and included with the application form.
Because of the wide range of medical devices which incorporate,
as an integral part, an ancillary medicinal substance, a flexible
approach to the data requirements is necessary. However, the
information should be based in principle and to the relevant extent
on Annex 1 to Directive 2001/83/EC (MPD).
23.6.2 Quality, Safety, Usefulness (Clinical Benefit/Risk)
23.6.2.1 Quality
Relevant information should be provided on both
• the drug substance itself and
• the drug substance as incorporated into the medical device.
With regard to the drug substance, evidence should be provided
that the drug substance is manufactured to a high, reproducible
quality and is suitably controlled by an appropriate specification.
Where a European Pharmacopoeia (PhEur) monograph exists

for a substance, the specification should be that of the PhEur as a
minimum.
With regard to the combination product, information relevant to
the medicinal substance should be provided, i.e. on the quantitative
composition, details of manufacture, control of critical excipients,
and control of intermediate and finished products. Validation data
should be provided where appropriate, in particular for analytical
methods. The data submitted should demonstrate that the amount
of medicinal substance incorporated is based on safety and efficacy
considerations, that it can be suitably controlled within specified
limits, that it is evenly distributed within/across the device as
necessary and maintains satisfactory performance over the shelf-life
of the product.
23.6.2.2 Safety and usefulness (clinical benefit/risk)

There should be a clear rationale and safety consideration for
including the ancillary medicinal substance at the proposed dose.
Where well-known medicinal substances for established
purposes are involved, original data on all aspects of safety and
usefulness may not be required and many of the headings of
Annex 1 to Directive 2001/83/EC will be addressed by reference
to literature sources, including standard textbooks, experience and
other information generally available. However, all headings should
be addressed, with either relevant data or justification for absence of
data, based on the manufacturer’s risk assessment.
For new active substances and for known medicinal substances
for a non-established purpose, comprehensive data is required
to address the requirements of Annex 1 to Directive 2001/83/
EC. The evaluation of such active substances would be performed
in accordance with the principles of evaluation of new active
substances.
23.6.2.3 Guidance
MEDDEV 2.1/3, Section C, provides guidance on the consultation
procedure for devices incorporating ancillary medicinal substances
or ancillary human blood derivatives [1]. In addition, the EMA and
national competent authorities publish guidance on procedures and
documentation requirements for the consultation.
References 297
There are also a number of useful European guidelines relating

to the quality, safety and efficacy of medicinal substances as used in
medicinal products which can be found on the EMA website [3] and
in these consultation guidance documents.
It is not intended that the guidelines should be strictly adhered
to for ancillary medicinal substances used in devices, however, as
for medicinal product evaluation, justification for the use of different
approaches should be provided.
23.7 Other Combination Products

This chapter has focused on the combination of medical devices with
chemical medicinal substances. There are also other combination
products in the early developmental stage, e.g. gene therapy, cell
therapy, tissue engineered products combined with medical devices
such as scaffolds, implants, stents and extracorporeal circuits.
These combinations are regulated as advanced therapy
medicinal products (ATMP) and are assessed centrally by the
Committee for Advanced Therapies (CAT) at EMA.
In this case, consultation with a notified body is required on
the device aspects in a similar manner to consultation with a
competent authority on the medicinal substance aspects of devices
incorporating an ancillary medicinal substance.
More information on ATMP products can be found on the EMA
[3] and MHRA websites [4].
References
1. MEDDEV 2.1/3: “EC Guidance document on ‘Borderline products,

drug-delivery products and medical devices incorporating, as an
integral part, an ancillary medicinal substance or an ancillary human
blood derivative,” retrieved (April 2012) from http://ec.europa.eu/
health/medical-devices/documents/guidelines/index_en.htm.
2. Medical Devices Expert Group on Borderline and Classification: Manual
of Decisions, retrieved (April 2012) from http://ec.europa.eu/health/
medical-devices/documents/borderline/index_en.htm.
3. European Medicines Agency website: Ancillary medicinal substances:
Regulatory and procedural guidance, retrieved (April 2012) from
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/
document_listing/document_listing_000133.jsp&mid=WC0b01ac0
5800267b9&jsenabled=true; Advanced therapies, retrieved (April
2012) from http://www.ema.europa.eu/ema/index.jsp?curl=pages/
regulation/general/general_content_000294.jsp&mid=WC0b01ac05
800241e0.
4. MHRA website: Borderline with Medicines, retrieved (April 2012)
from http://www.mhra.gov.uk/Howweregulate/Devices/Medical
DevicesDirective/Borderlinewithmedicines/index.htm; Consultation
with MHRA on Devices incorporating an ancillary medicinal
substance, retrieved (April 2012) from http://www.mhra.
gov.uk/Howweregulate/Devices/MedicalDevicesDirective/Drug-
deviceconsultations/index.htm; Regulation of Advanced Therapy
Medicinal Products, retrieved (April 2012) from http://www.mhra.
gov.uk/Howweregulate/Advancedtherapymedicinalproducts/
Aboutadvancedtherapymedicinalproducts/index.htm.
Part 5
Medical Device Regulatory System in

Asia-Pacific Region
Chapter 24
Australian Medical Device Regulations:

An Overview
Petahn McKenna
ASEAN Regulatory Affairs Manager,
PMCKENN1@its.jnj.com
24.1 Medical Device Market in Australia

One of the wealthiest healthcare markets in Asia-Pacific, Australia’s
spending on health is at par with European markets such as
Finland, Norway, and the United Kingdom. Similar to many other
developed countries in the world, increased life expectancy,
income, and demands for a higher quality of life are driving an
increase in health expenditure.
Healthcare provision in Australia is made up of public and
private funding: Public expenditure is funded by the Commonwealth
(central) Government under a health care system called Medicare:
Australia’s universal, tax-financed insurance scheme covering
medical, pharmaceutical, and public hospital services. Private

www.panstanford.com
302 Australian Medical Device Regulations
expenditure is largely funded through insurance. However, Medicare

also pays 75% of the schedule fee for services and procedures
provided in private hospitals.
Australia’s medical device manufacturing industry is also
growing: There were 655 medical devices companies in Australia
in 2007, 30 more than the previous year. In 2009, Australia had
domestic medical device sales of AUD 6 billion and earned export
revenue of AUD 1.7 billion, employing at least 17,500 people.
Table 24.1 Australian health demographics

Population (June, 2011) [1] 22,620,600
Population Growth Rate (over previous 1.4%
year) [1]
Life Expectancy (years) [2] 82
Economics
GDP Per capita (USD) [3] 39,975
GDP Growth Rate [2] 2.5%
Healthcare statistics
Total expenditure on health as percent 8.5% (2009) 8.4% (2009)
of gross domestic product (2009) [3]
Per capita total expenditure on health 3,382 (2009) 2,980 (2005)
(PPP int. $) [3]
24.2 Medical Device Regulations

24.2.1 Overview
In Australia, medical devices are regulated by the Therapeutic Goods
Administration (TGA). The Australian medical device regulatory
requirements, which were implemented in 2002, are largely based
on the European Council Medical Device Directive (MDD) 93/42/
EEC (1). Since July 2010, In vitro diagnostic devices (IVDs) have also
been regulated as a subset of medical devices.
The TGA regulates medical devices via the following platforms:
(i) pre-market assessment
(ii) post-market monitoring and enforcement of standards
(iii) licensing of Australian manufacturers and verifying overseas
manufacturers’ compliance with the same standards as their
Australian counterparts
Definition of Medical Device 303
The following text will concentrate on pre-market assessment

and the requirements that must be fulfilled in order to place a
medical device on the Australian market. Much of the information
within this section has been extracted from the Australian
Regulatory Guidelines for Medical Devices (ARGMD), accessible
via the TGA website. Wherever any more detail or clarification is
required, readers should always refer to the TGA website or contact
the TGA directly.
For details of the Australian post-market vigilance and moni-
toring requirements, please refer to Section 22 of the ARGMD.
24.2.2 Regulating Authority

The body responsible for regulating medical devices in Australia is
the Office of Devices Authorisation, within the Therapeutic Goods
Administration (TGA). The TGA is a division of the Australian
Government Department of Health and Ageing.
24.2.3 Legislation and Guidance

All regulatory decisions applicable to medical devices are made
using legislation as set out in the Therapeutic Goods Act 1989,
Therapeutic Goods Regulations 1990, and the Therapeutic Goods
(Medical Devices) Regulations 2002.
The TGA, in collaboration with the medical devices industry
sector, has developed a consolidated reference document detailing
the Australian regulatory requirements for medical devices. This
document is called the Australian Regulatory Guidelines for Medical
Devices.
24.3 Definition of Medical Device

The Therapeutic Goods Act 1989 defines a medical device as
any instrument, apparatus, appliance, material or other
article (whether used alone or in combination, and including
the software necessary for its proper application) intended
by the person under whose name it is to be supplied, to be
used for human beings for the purpose of one or more of the
following:
(i) Diagnosis, prevention, monitoring, treatment or alleviation of
disease;
(ii) Diagnosis, monitoring, treatment, alleviation of or

compensation for an injury or handicap;
(iii) Investigation, replacement or modification of the anatomy or
of a physiological process; control of conception;
and that does not achieve its principal intended action in or on
the human body by pharmacological, immunological or metabolic
means, but which may be assisted in its function by such means*;
or
(i) an accessory to such an instrument, apparatus, appliance,
material or other article.
*There are therapeutic goods that have both a medicine and
a medical device component, and it is the combination of the two
components that deliver the desired therapeutic effect. In deciding
how these products are regulated, the TGA considers
(i) the primary intended purpose
(ii) the mode of action of the product
as they relate to the definition of a medicine and a medical device.
Further guidance is provided in Section 14 of the ARGMD: Medical
Devices Incorporating a Medicine.
The regulations define a medical device to be an IVD if it satisfies
the following criteria:
(i) It is a reagent, calibrator, control material, kit, specimen
receptacle, software, instrument, apparatus, equipment or
system, whether used alone or in combination with another
diagnostic product for in vitro use; and
(ii) It is intended by the manufacturer to be used in vitro for the
examination of specimens derived from the human body,
solely or principally for
(a) giving information about a physiological or pathological
state or a congenital abnormality; or
(b) determining safety and compatibility with a potential
recipient; or
(c) monitoring therapeutic measures.
24.4 Classification of Medical Devices

Medical devices are classified on the basis of risk, through consid-
eration of the manufacturer’s intended use, degree of invasiveness
Classification of Medical Devices 305
in the human body, and duration of use. The classification follows

the EU system except that the Australian system includes a separate
class for active implantable medical devices. The classification levels
are shown in Table 24.2.
Table 24.2 Classification of medical devices
Classification Level of risk
Class I Low
Class I—supplied sterile Low–medium
Class I—incorporating a measuring function
Class IIa
Class IIb Medium–high
Class III High risk
Active implantable medical devices (AIMD) High risk
Note: Differences between the Australian and European classification systems are
detailed in Section 8 of the ARGMD.
The TGA has adopted a risk-based approach to regulation of
medical devices, through consideration of the risk to the patient,
versus potential benefit of the device. The level of TGA regulatory
control increases with the level of risk of the medical device.
24.4.1 Classification of IVD Medical Devices

The Australian medical device regulatory framework has a
separate classification system for IVD medical devices (IVDs). The
manufacturer is responsible for determining the class of an IVD
(as described in Table 24.3) using a set of classification rules with
regard to
(i) the manufacturer’s intended use of the device; and
(ii) the level of risk to the patient and the public (taking into
account the likelihood of harm and the severity of that harm).
Table 24.3 Classification of IVD medical devices
Classification Level of risk
Class 1 IVD No public health risk or low personal risk
Class 2 IVD Low public health risk or moderate personal risk
Class 3 IVD Moderate public health risk or high personal risk
Class 4 IVD High public health risk
Note: The same classification rules apply to both commercial IVDs and in-house IVDs.
24.5 Inclusion of Medical Devices on the ARTG

The majority of medical devices must be included in the Australian
Register of Therapeutic Goods (ARTG) before being made available
for supply in Australia. Exceptions to this requirement are devices
that are supplied through one of the four mechanisms for supplying
medical devices in Australia not included in the ARTG:
(i) clinical trials in Australia
(ii) authorised prescribers
(iii) Special Access Scheme
(iv) personal importation
(v) custom-made medical devices
For a medical device to be included in the ARTG, the TGA must
be satisfied that available evidence demonstrates that the device
is safe and effective and that an appropriate system is in place for
monitoring the ongoing performance and safety of the device. As
such, a sponsor can only apply to include a medical device in the
ARTG if
(i) the device complies with the Essential Principles
(ii) appropriate conformity assessment procedures have been
applied to the device
Applications for inclusion of a medical device in the ARTG are
submitted through the TGA eBusiness (eBS) services, accessed via
the TGA website, http://www.tga.gov.au.
There are different levels of access for registered users and the
general public. Only an Australian sponsor can apply to include a
medical device in the ARTG.
Following the inclusion of a medical device in the ARTG, the TGA
issues a Certificate of Inclusion, which can be downloaded by the
Sponsor from the eBS.
Class 1–3 in-house IVD medical devices are required to be
entered on an in-house IVD database that is separate from the ARTG
— For more information, please refer to Part 6A, Schedule 3, of the
Regulations.
24.5.1 Process for Supplying a Medical Device

in Australia
The following processes must be followed in order to include a
medical device on the ARTG:
Inclusion of Medical Devices on the ARTG 307
(i) process for all Class I non-sterile and non-measuring devices

(ii) process if the medical device is manufactured in Australia
(other than Class 1)
(iii) process if the medical device is manufactured overseas (other
than Class 1)
(iv) process if the device contains a medicine or materials of
animal, microbial recombinant, or human origin
This chapter only outlines the latter two processes as these will
be of most interest to the majority of readers. Please refer to the
ARGMD on the TGA website for a detailed description of the up-to-
date processes.
• Class I sterile
x Class I sterile Manufacturer
Manufacturer determines
determines classification of
x Class I measuring device
• Class I measuring classification of device
x Class IIa
• Class IIaIIb
x Class
• Class IIbIII
x Class
x AIMD
• Class III
Manufacturer obtains conformity assessment
• Class IIb Manufacturer obtains
evidence from the TGAconformity assessment
or EU Notified Body
evidence from the TGA or EU Notified Body
Manufacturer prepares Australian Declaration of

Manufacturer prepares Australian
Conformity
Declaration of Conformity
Sponsor submits Manufacturer’s evidence to the

Sponsor submits TGA
Manufacturer’s
evidence to the TGA
IfIf necessary
necessary
x Amendments are
• Amendments made
made
x Further information
• Further informa- No
No
Submission
is provided Submission
successful?
tion is provided
x Application is successful?
withdrawn
• Application is
withdrawn
Yes
Yes
Some applications are

Sponsor lodges application to include the device
Sponsor lodges application to Some applications are
selected for detailed
in the ARTG selected
applicationfor detailed
audit
include the device in the ARTA application audit
No
No
Application
Application
successful?
successful?
Yes
Yes
DeviceDevice included in the ARTG and sponsor can
included in the ARTG and spon-
supply the device in Australia
Ongoing monitoring
Ongoing monitoringof the of
while on the market
device
the
sor can supply the device in Australia device while on the market
Figure 24.1 Process to supply a medical device in Australia if the medical

device is manufactured overseas.
The following processes must be followed in order to include an

IVD medical device on the ARTG:
(i) process for including Class 1 IVD medical devices (other than
export only) in the ARTG
(ii) process for including IVD medical devices (other than Class 1)
in the ARTG
For most Class I and II devices, successful electronic submission
of the medical device application form is followed by inclusion of the
device in the ARTG.
Applications for Class III, AIMD, and certain Class IIb devices
(refer to Section 11, ARGMD) are subjected to a mandatory Level
2 application audit prior to inclusion in the ARTG whereby all
supporting documentation will be submitted to the TGA for
evaluation.
In addition, any application for a medical device of any Class may
be randomly selected for a Level 1 Application Audit. In such cases,
the sponsor is required to provide the requested documentation to
the TGA within 20 working days.
Since the Australian regulatory system is closely aligned with
the European system, evaluation requirements for all devices (other
than those containing a medicine or material of animal, human or
microbial origin) are significantly reduced for products which have
already been approved for CE Marking by a European Notified
Body. Products which have not been CE Marked must go though full
Conformity Assessment evaluation by the TGA.
Additionally, an abbreviated approval route through the Aust-EC
Mutual Recognition Agreement (MRA) is available for devices other
than those containing a medicine or material of animal, human or
microbial origin, which are substantially manufactured within the
European Community (and have a EC legal manufacturer). Devices
with MRA certificates issued by a European Notified Body may be
approved by the TGA within 1 week.
Full TGA Conformity Assessment evaluation is required for
devices that include human blood or plasma derivative, derivatives of
animal or microbial origin, or incorporate a medicine. TGA approval
for such products may involve a TGA audit of the manufacturing
facility.
Once issued, TGA Conformity Assessment certificates are valid
for 5 years.
• xClass III
Class III Manufacturer
Manufacturerdetermines classification of
determines
x AIMD device
• AIMD classification of device
Manufacturer decides the procedures to be used

Manufacturer decides
to demonstrate devicethe procedures
meets to be used
relevant Essential
to demonstrate device
Principles meetsnecessary
and prepares relevant Essential
documentation
Principles and prepares necessary documentation
Manufacturer applies
Manufacturer for TGA for
applies Conformity
TGA
Assessment Certificate
Conformity Assessment Certificate
No
No Application
Application
successful?
successful?
Yes
Yes
Manufacturer prepares Australian Declaration of
Manufacturer prepares Australian
Conformity
Sponsor
Sponsorsubmits Manufacturer’s
submits evidence to the
Manufacturer’s
TGA
evidence to the TGA
IfIfxnecessary
necessary
Amendments made
• Amendments made
x Further information is
provided
• Further informa-
No
No Submission
Submission
x Application is successful?
tion is provided
withdrawn successful?
• Application is
withdrawn Yes
Yes
Sponsor lodges application

Sponsor lodges to include the device
application to
in the ARTG
include the device in the TGA
No
No
Application
Application
successful?
successful?
DeviceDevice included
included ininthe
the ARTG
ARTG andandsponsor can
sponsor Ongoing monitoring of the device
Ongoing monitoring of the
supply the device in Australia while on the market
can supply the device in Australia device while on the market
Figure 24.2 Process to supply a medical device in Australia if the device

contains a medicine or materials of animal, microbial
recombinant, or human origin.
24.5.2 Process for Including Class 1 IVD Medical Devices

(Other Than Export Only) in the ARTG
The flowchart in Fig. 24.3 summarises the steps for including in
the ARTG a Class 1 IVD that is to be supplied in Australia:
Sponsor lodges
application to include
device in ARTG via
TGA eBs
Application
selected for a Yes TGA conducts
Technical File Technical File Review
Review?
No
Application satisfactory?
Auto-inclusion
Yes No Application will not be

approved if the
information is deficient
IVD medical device ARTG entry may be

included in ARTG and selected for post market
TGA notifies sponsor review
Sponsor prints
Certificate of Inclusion
from eBS
Figure 24.3 Steps for including in the ARTG a Class 1 IVD that is to be
supplied in Australia.
24.5.3 Process for Including IVD Medical Devices (Other

Than Class 1) in the ARTG
The flowchart in Fig. 24.4 summarises the steps for including in the
ARTG an IVD that is to be supplied in Australia, other than a Class 1
IVD:
Sponsor to ensure that

Manufacturer’s Evidence
has been submitted and
accepted by the TGA
Sponsor lodges
application to include
device in ARTG via
TGA eBs
Application TGA conducts
Yes
selected for a Technical File Review
Technical File
Review? (TFR)
No
Application satisfactory?
No
Application will not be
approved if the
Yes information is deficient
IVD medical device

included in ARTG and
TGA notifies sponsor
ARTG entry may be

selected for post market
Sponsor prints review
Certificate of Inclusion
from eBS
Figure 24.4 Steps for including in the ARTG an IVD that is to be supplied
in Australia, other than a Class 1 IVD.
24.6 Same Kind of Medical Device (SKMD)

In the case of Class I, Class I sterile, Class I measuring, Class IIa,
and Class IIb medical devices, and Class 1, Class 2, Class 3 IVDs and
Class 4 immunohaematology reagents (IHRs), one medical device
is considered to be of the “same kind” as another medical device, if
both devices
(i) have the same manufacturer
(ii) have the same sponsor and
(iii) are the same classification
(iv) have the same GMDN code
Medical devices which are identical in respect to these criteria
can be grouped under one ARTG inclusion. There is no record kept in
the ARTG of the product family name, model numbers, or catalogue
numbers for these classes of device.
For Class III and Class AIMD medical devices, and Class 4 IVDs
(that are not IHRs) a further requirement is added to the definition
of same kind of medical device — they must have the same Unique
Product Identifier (UPI), described in the following section.
24.7 Unique Product Identifier

As specified in Regulation 1.6, of the Therapeutic Goods (Medical
Devices) Regulations 2002, the unique product identifier (UPI) is
the combination of words, numbers, symbols, or letters assigned
by the manufacturer to uniquely identify the device and any of its
variants. The UPI is distinct from the catalogue identifier assigned
to the device.
The TGA recognizes that different manufacturers identify their
product lines in different ways such as
(i) using family names to identify a range of similar devices
(ii) uniquely identifying each device with a model number
(iii) adopting a combination of both of these approaches
Figure 24.5 explains UPI showing the example of a family of
prosthetic heart valves, as provided within the ARGMD. In this
example, the family name does not uniquely identify all of the device
models in the product range. Therefore, the term “Globus prosthetic
heart valves” is not considered a UPI, because it does not distinguish
In vitro Diagnostic UPIs 313
between the different intended purposes of each model in the

product range — atrial-versus mitral-valve replacement.
However, the model names
(i) Globus atrial prosthetic heart valve
(ii) Globus mitral prosthetic heart valve
are considered UPIs because the model/catalogue numbers are
only variations of the diameter of the device that do not change its
intended purpose.
Family Name Globusprostheticheartvalves
Model Names Globusatrial Globusmitral

prostheticheartvalve prostheticheartvalve
A123Ǧ13 M123Ǧ13
Denotes13mmdiameter Denotes13mmdiameter
Model/ A123Ǧ15 M123Ǧ15

Catalogue
Numbers
A123Ǧ17 M123Ǧ17
A123Ǧ19 M123Ǧ19
Figure 24.5 Example of a UPI provided within the ARGMD.
24.8 In vitro Diagnostic UPIs

The UPI for an IVD uniquely identifies an individual IVD, or a
combination of IVDs which together constitute an IVD closed system
(a combination of reagents, calibrators and quality control materials
that share a common intended purpose; and are to be used only in
combination with each other as components of a single assay).
24.9 Renewal
In Australia, the requirement for sponsors to renew or resubmit
their regulatory approvals on a periodic basis is restricted to those
supported by a TGA Conformity Assessment certificate, which
requires renewal every 5 years.
Once a medical device is included in the ARTG, the sponsor is
obligated to ensure the medical device remains in compliance with
the Essential Principles and that changes are submitted to the TGA
for evaluation as required.
Sponsors are required to pay an annual fee for each ARTG
inclusion, equivalent to the original fee for inclusion on the ARTG.
24.10 Documentation Requirements

24.10.1 Conformity Assessment Applications
Manufacturers who apply for a TGA Conformity Assessment
Certificate are required to prepare technical documentation to
demonstrate that the medical device complies with the Essential
Principles. This will vary on a case by case basis, depending on
the, type of device, risk associated with its manufacture and use,
and period that it has been on the market. However, the minimum
technical documentation will always include the elements described
in Fig. 24.6.
Documentation Required
Conformity Assessment
Copy of all current conformity assessment evidence for the medical device and/or
manufacturer
Clinical evidence
Risk management records (ISO 14971)
Essential Principles compliance summary (e.g., Essential Principle checklist or
similar)
Evidence to support compliance with any standards or test methods utilised
for compliance (for example, test reports or assessment reports, labels and
Instructions for Use)
Microbial, or recombinant origin; or medicinal substances
Evidence to support the quality and safety of animal derived material, in accordance
with the TGA approach to minimising the risk of exposure to Transmissible
Spongiform Encephalopathies (TSEs) through medicines and medical devices,
available on the TGA website.
Drug Master File and GMP Clearance for medicine manufacturer.
Figure 24.6 Minimum documentation required, applications for Confor-

mity Assessment Certificate.
Application Audits 315
The TGA refers sponsors to the GHTF Summary Technical

Documentation for Demonstrating Conformity to the Essential
Principles of Safety and Performance of Medical Devices (STED), for
guidance on the technical documentation that should be assembled
and submitted to demonstrate conformity to the Essential
Principles.
Devices containing materials of human blood or plasma
derivatives, animal, microbial or recombinant origin or medicinal
substances are regulated more stringently by the TGA. As such, the
TGA reserves the right to conduct an on-site audit of manufacturing
facilities as part of the application process if they are not completely
satisfied with the supporting documentation.
At a minimum, the TGA requires evidence to support the quality
and safety of animal derived material, in accordance with the TGA
approach to minimising the risk of exposure to Transmissible
Spongiform Encephalopathies (TSEs) through medicines and
medical devices, available on the TGA website.
24.11 Application Audits

The TGA will write to the sponsor requesting the information that
is required to conduct the application audit. The TGA may ask for
any documentation relating to the device and/or manufacturer
(Fig. 24.7).
Level 1
• Original or correctly notarised copy of the manufacturer’s Australian
• Copy of the latest and current conformity assessment evidence for the
medical device and/or manufacturer
• Information about the device, including copies of the
label
instructions for use
advertising material such as brochures, web pages, advertisements
Level 2
• All the documentation listed above for a Level 1 audit
• Risk management report
• Clinical evaluation report
• Efficacy and performance data for medical devices that disinfect including
sterilisation of other medical devices
Figure 24.7 Minimum documentation requirements for each level of an

application audit.
24.12 Access to Unapproved Medical Devices

There are four mechanisms for accessing unapproved medical
devices in Australia which do not require inclusion in the ARTG prior
to supply:
(i) clinical trials in Australia
(ii) authorised prescribers
(iii) the Special Access Scheme
(iv) personal importation
Importantly, these schemes cannot be used to facilitate the
commercial supply of therapeutic goods.
Further information on these mechanisms is available on a web
page titled “Accessing unapproved products”, on the TGA website,
http://www.tga.gov.au/hp/access.htm.
References
1. Australian Demographic Statistics (June 2011). Australian Bureau of

Statistics. Retrieved (18 May 2012) from http://www.abs.gov.au/.
2. AusMedtech (28 Nov 2011). Retrieved (22 February 2012) from
http://www.ausbiotech.org/ausmedtech/.
3. Department of the Treasury. Australia to 2050: Future Challenges,
January 2010 (Intergenerational Report 2010).
4. TGA. Australian Regulatory Guidelines for Medical Devices (ARGMD)
(May 2011). Therapeutic Goods Administration Version 1.1. Retrieved
(25 January 2012) from www.tga.gov.au.
5. TGA. Accessing unapproved products. Therapeutic Goods Adminis-
tration. Retrieved (25 January 2012) from http://www.tga.gov.au/hp/
access.htm.
6. World Health Organisation. Global Health Observatory (GHO)(2011).
Country Statistics 2011. Retrieved (18 January 2012) from http://
www.who.int/gho/countries/en/.
7. Year Book Australia (2008). Australian Bureau of Statistics. Retrieved
(22 January 2012) from http://www.abs.gov.au/ausstats/abs@.
nsf/0/A50BD9743BF2733ACA2573D2001078D8?opendocument.
Chapter 25
China: Medical Device Regulatory

System
Jack Wong
Disclaimer
25.1 Introduction
China’s overall registration framework is under revision and
amendment, and certain regulation outlined below may have been
revised recently. Certain explanation of the regulation may also be
updated accordingly. Please refer to the most updated regulation
from the State Food and Drug Administration’s (SFDA) official
website or consult your local regulatory affairs staff/consultant for
up-to-date explanation and practice.

www.panstanford.com
318 China
25.2 Market Overview

China’s medical device market is forecasted to have a value of
US$23.2 billion in 2011 with strong growth in two-digit annual
growth rate. China has the world’s largest population.
In 2009, the Chinese government committed 850 billion yuan
(US$124 billion) to develop/enhance the country healthcare system
over a three-year period. The plan is to create a platform for universal
healthcare access for all by 2020. The prospects for medical device
spending are huge. The government has committed heavily in the
construction of thousands of hospitals, healthcare centres and
clinics, and this will inevitably lead to spending on capital goods,
most notably medical devices.
25.3 Overview of Regulatory Environment

and What Laws/Regulations Govern the
Medical Devices
China’s regulatory system for medical devices is still in its rapid
development phase, which unavoidably leads to a certain degree of
difficulty to catch up on the latest regulatory requirement. Language
can also be a major problem for foreign manufacturers as most of
regulation and product standards are in Chinese. Product registra-
tion submission files are also required to be in Chinese as well
There are three levels of legislation, all of which are considered
mandatory and apply to both local and foreign manufacturers:
• Regulations for the Supervision and Administration of Medical
Devices, which were promulgated by the State Council on 4
January 2000 and came into force on 1 April 2000;
• SFDA Orders, which provide the detail for implementing the
Regulations
• Normative documents of the central or local FDAs, which are
similar to standards
Regulations for the Supervision and Administration of Medical
Device basic content include
• Chapter I: General Provisions
Overview of Regulatory Environment 319
o Scope: All units or individuals engaged in the research and

development, production, distribution, use, supervision
and administration of medical devices within the territory
of P.R. China
o Definition of medical device
o Competent authority : SFDA
o Classification: Class I, II and III
• Chapter II: The Administration of Medical Devices
o Registration
o Requirements of clinical trial
• Chapter III: Administration of Production, Distribution and
Use of Medical Devices
• Chapter IV: Supervision of Medical Devices
• Chapter V: Penalties
• Chapter VI: Supplementary Provisions
The English version of the China regulations for the supervision
and administration of medical devices can be found at the following
link: http://eng.sfda.gov.cn/WS03/CL0767/61641.html.
25.3.1 Measuring Function

Medical devices produced and used for the purpose of providing
concrete measuring values shall comply with the requirements
of the metering law. The detailed product list shall be formulated
and promulgated by the drug regulatory authority under the State
Council, jointly with the metering authority.
25.3.2 Standards
China has National Standard for medical device. A medical device
must follow China National Standard specification. More than 35%
of all IEC and ISO standards have now been adopted by China,
but many are not direct transpositions and contain China-specific
requirements. Table 25.1 lists some of the main medical device-
related international standards and their Chinese equivalents. The
standards ISO 14155 and ISO 13485: 2003 have also recently been
adopted.
320 China
Table 25.1 Primary medical device related international standards and

their Chinese equivalents
International standard Chinese equivalent

ISO 13485/13488 YY/T0287/0288
ISO 14971: 2000 YY/T0316 – 2003
IEC 60601-1: 1988 GB 9706.1 – 1995
National medical devices standards can be found at National

Standardisation Technical Committee’s website (www.sac.gov.cn).
Industry standards can be found at the websites of the SFDA (www.
sfda.gov.cn) and the Centre for Medical Device Evaluation (www.
cmde.org.cn).
The SFDA recognizes products’ country-of-origin approval to
kick off imported product registration.
25.4 Regulatory Body

The SFDA is directly under the State Council, which is in charge of
comprehensive supervision on the safety management of medical
device, drug, food, health food and cosmetics and is the competent
authority of drug regulation.
The drug regulatory authority under the State Council is
responsible for supervision and administration of medical devices
nationwide. The drug administration of the local government
at county level and above is responsible for supervision and
administration of medical devices in each administrative region. The
drug regulatory authority under the State Council shall coordinate
with other departments under the State Council, responsible for
comprehensive economic administration, in the implementation of
policies for the medical device industry
The detailed organization chart of the SFDA can be found at
http://eng.sfda.gov.cn/WS03/CL0763/.
SFDA contact details

State Food and Drug Administration
26 Xuanwumen Xidajie, Beijing, 100053, P.R. China
Fax: +86-010-68310909
Email: inquires@sda.gov.cn
Regulatory Overview 321
25.5 Regulatory Overview

25.5.1 Definition of Medical Device
The definition of a medical device that is used in China is very
similar to the definition provided by the GHTF, although there are
some differences in interpretation of the definition (e.g. spectacles
are not medical devices in China). The definition given in the
Regulations is any instrument, apparatus, appliance, material, or
other article whether used alone or in combination, including the
software necessary for its proper application. It does not achieve its
principal action in or on the human body by means of pharmacology,
immunology or metabolism, but which may be assisted in its function
by such means; the use of which is to achieve the following intended
objectives:
1. Diagnosis, prevention, monitoring, treatment or alleviation of
disease;
2. Diagnosis, monitoring, treatment, alleviation of or comp-
ensation for an injury or handicap conditions;
3. Investigation, replacement or modification for anatomy or a
physiological process;
4. Control of conception.
25.5.2 Classification of Medical Device

Medical devices are classified according to the risk level associated
with their intended use. In general, the risk level depends on the
design of a medical device as well as its intended use.
The State shall classify medical devices and administer them on
the basis of the following classification:
• Class I medical devices are those for which safety and
effectiveness can be ensured through routine administration.
• Class II medical devices are those for which further control is
required to ensure their safety and effectiveness.
• Class III medical devices are those which are implanted into
the human body or used for life support or sustenance or pose
potential risk to the human body and thus must be strictly
controlled in respect to safety and effectiveness.
The classification catalogue for medical devices shall be stipu-
lated, adjusted and promulgated by the drug regulatory authority
322 China
under the State Council, in accordance with classification principles

after consulting with health authority under the State Council.
These class definitions are not the same as those used in the
European Union or by the GHTF, and the Class III classification is
much broader than many manufacturers may be used to. There are
many reasons for these classification differences in China. The two
key reasons are
1. Historical reason, i.e. some devices are classified as different
classification or even as drug even before medical device
regulation came into being and hence the device may follow
the old classification
2. Social reason, i.e. the SFDA may consider some device to have
higher risk in China, e.g. after some adverse events
For further information on the classification of devices, readers
are referred to “The Provisions for Medical Device Classification
(SFDA Order No 15)”.
The handling of administration matters relating to medical
devices is also determined by the device’s classification. For locally
produced devices
 Class I devices are administered by a city level regulatory
authority.
 Class II devices are administered by a provincial/municipal
regulatory authority.
 Class III devices are administered by the central SFDA.
All imported medical devices are administered by the central

SFDA.
25.5.3 Registration Process

25.5.3.1 Medical devices registration certificate
Each medical device or medical device family should have a Medical
Devices Registration Certificate before it can be placed on the
market in China. The certificate is owned by the local manufacturer
or the distributor and must be renewed every four years (the new
regulation will suggest the expiry after a five-year term). The precise
requirements for product registration vary depending on the device
class but can include sample testing, clinical evaluation/investigation
and site inspection.
A simplified flow chart depicting the process for product

registration is shown in Fig. 25.1. For every imported medical
device, before registration, the applicant should write a product
standard which follows China National Standard as the first step.
The manufacturer can use an ISO/IEC standard as product standard,
but the standard should be translated into Chinese. The applicant
should arrange product testing by the national Testing Centre to
ensure that the product passes the test as per the China National
Standard. Once the SFDA Application Receiving Office has all the
required information, the application is passed to the Medical
Devices Evaluation Centre, then to the Department of Medical
Devices Registration at the SFDA, then to the Director of the Medical
Devices Department, and then to the Director General of the SFDA
for final approval. Finally, the result of the application and certificate
of approval is sent back to the Application Receiving Office for
collection by the applicant.
Applicant
Other information
as specified in the
application form
Class I, II and III devices
Development of a
product standard
Class I devices
Class II and III devices
Preparation of self- Sample testing to Clinical evaluation

testing report against product standard (first registration only)
product standard
Clinical
Pass
evaluation
report
SFDA Application
Receiving Office
Figure 25.1 Procedure for obtaining a Medical Devices Registration

Certificate.
25.4.5.2 Product testing

Testing is performed by a local testing centre.
No product testing is required for the following types of devices:
(1) Among the laboratory equipment, the electrophoresis
apparatus “centrifuge” ultra low temperature refrigerator,
324 China
paraffin slicing machine, paraffin embedding machine, cell

centrifuge smearing machine, and full automatic dying
machine no clinical trial reports and Product Type Test
Reports issued by the medical devices quality test agency and
recognized by the State Drug Administration are required to
be provided .
(2) The products of Class I in accordance with catalogue of
classification of the medical device products of China.
(3) As for the medical devices in conformance with both of the
following conditions, the application for exemption from test
may be made if
(a) The domestic enterprise has received the authentication
certificate of GB/T19001+YY/T0287 or GB/T19002+YY/
T0288 issued by the quality system authentication agency
recognized by the State Drug Administration, and the
quality system concerned has covered the products for
application.
(b) The product abroad has received the authorization of
launching from the competent department of the country
of origin, and the certificate is still valid, and the enterprise
has been authenticated in accordance with the ISO 9000
Serial Standards (or equivalent).
(c) The difference between the structure and performance of
the products for application and those of the registered
products of a kind is insignificant in terms of safety and
effectiveness.
(d) The products for application are not implantable devices.
(e) No radioactive sources exist in the products for
application.
(f) In case of any malfunction, no grave injury accidents such
as death of and body injury of the user or operator will be
caused.
25.5.3.3 Clinical trials

In application for medical device registration, Class III medical
devices are subject to clinical trials, Class II medical devices are
generally subject to clinical trials, and Class I medical devices are
exempt from clinical trials.
This is very significant for Class III medical device manu-
facturers that are looking to register their products in China.
Currently, the only Class III devices that absolutely require clinical
trials are long-term implantable devices. This language implies that
clinical trials will be required for all Class III devices. While the final
regulations have yet to be released, this change could greatly affect
the time to entry for foreign Class III products.
25.5.3.4 Exemption of clinical trial data for Class II devices

In November 2011, the SFDA issued Decree 475, exempting several
types of domestically produced Chinese products from clinical trial
requirements. These clearances are very similar to the exemptions
listed in Section 510(k) of the US Food, Drug, and Cosmetic Act.
During the application process, a manufacturer may request
exemption from clinical trial data requirements by demonstrating
the similarity of their device with an approved product already on
the market. The list of products that qualify for this exemption is
currently limited to 21 device groups, including medical surgery
tools, syringes, thermometers, ECG machines, ophthalmic equipment,
nebulisers, electrodes, sterilisers, protective clothing, dentures,
cryogenic tools and single-use urology equipment.
While at first glance this exemption seems like a big advantage
for domestic companies, most foreign firms that register Class II
devices are already exempt from clinical trials as they can provide
safety data from their home countries. In addition, once a company
has an approved product on the market, it is typically exempt from
clinical trial requirements for similar future products. In the short
term, these exemptions will likely be most advantageous for start-
up Chinese companies that wish to quickly bring new devices to the
market; in the long term, however, these regulations may facilitate
the de novo development, manufacture and distribution of medical
devices in China by foreign companies.
25.5.3.5 Enforcing GMPs

With Decree 54, the SFDA officially implemented the new medical
device GMP regulations.
The GMPs are divided into 13 chapters covering general risk
management procedures, management responsibilities, resource
management, documentation, procurement and other sections
equivalent to international GMP requirements.
The most detailed sections of the new regulations cover
production management. The production management guidelines
326 China
require manufacturers to devise, implement and document

production processes at all steps under their control and formulate
guidelines for each device they manufacture. Each product must
be marked and monitored during the entire production process to
identify and prevent improper use of the device prior to or after
official release.
To enforce the new GMPs, the SFDA is using a risk-based
approach similar to that used by its US counterpart. This means that
high-risk devices such as Class III and sterile Class II devices are
being prioritised for SFDA review during the initial inspection and
review process. After the SFDA has expanded its inspection teams
and processed the backlog of high-risk inspections required during
the first phase of this endeavour, other manufacturers can expect to
be visited.
25.5.3.6 Timeframes
Table 25.2 lists the timeframes involved in each activity for obtaining
registration of a product and its distributor.
Table 25.2 Timeframes
Class II and III
Process Class I First registration Re-registration
Dossier compilation by 2–3 2–3 months 2–3 months

the manufacturer and his months
distributor
Translation into Chinese, 1–2 1–2 months 1–2 months

product standard months
compilation, modification
of the Instructions for
Use (manufacturer and
distributor)
Sample tested by national n/a 3 months 3 months

Testing Centre*
Clinical trial or clinical data n/a To be determined n/a

evaluation*†
On-site inspection at overseas n/a To be determined To be

manufacturing site (Class III determined
only)*
Registration dossier 5 months 8 months 8 months

submission to, and approval
by, the SFDA plus review and
approval of the Instructions
for Use by the SFDA
Total ~9 months 12–14 months 12–14 months

* These stages may be performed in parallel.
† May not be needed for some Class II devices (e.g. if equivalent to an approved,
marketed product).
More registration guidelines can be found at http://eng.sfda.gov.

cn/WS03/CL0770/61661.html.
25.5.3.7 The CCC mark

The CCC mark is an additional product testing mark for some
medical devices. Products that do not bear the CCC mark may be
held at customs; the mark applies to the following eight categories
of medical devices:
• rubber condoms (under latex products)
• medical diagnostic x-ray equipment
• haemodialysis equipment
• hollow fibre dialysers
• extra-corporeal blood circuit for blood purification equipment;
• electrocardiographs
• implantable cardiac pacemakers
• artificial heart-lung machines
The CCC mark is issued by the China Quality Certification Centre
(CQC), a parallel department to the SFDA.
CCC testing for medical devices is usually based on national
standards such as GB 9706 (the Chinese equivalent of IEC 60601).
The testing is usually performed at the same testing centre and
at the same time as the testing for a Medical Devices Registration
Certificate. Two separate test reports are issued (one is sent to the
SFDA and one to the CQC) and the fees are charged separately.
There has been a concern about and opposition to this
duplicative testing and certification of medical devices. Despite a
formal announcement by the SFDA and the General Administration
328 China
of Quality Supervision, Inspection and Quarantine (AQSIQ) that

duplicative testing is no longer allowed, in reality this has yet to be
implemented.
25.6 Monitoring Adverse Events

Tracking adverse events and reporting them in a timely manner
has been the driving force behind the issuance of Decree 425 from
the SFDA. The 45-page guidance document issued in 2011 details
requirements for personnel, documentation, reporting times and
annual reports. All medical devices that are registered for sale in
China will have to comply with these new requirements. Foreign
firms that do not have a China office and are working through
local third-party agents and distributors should ensure that their
local representatives are aware of, and can comply with, these
new regulations.
Each company must have designated staff for reporting adverse
events in at least a part-time capacity and a system to properly track,
collect and analyse the root cause of an adverse event. Depending on
the severity of the incident, and prior to a cause being discovered, the
sale of the device may be suspended and could require co-ordination
with hospitals and clinics that dispense the device.
For Class III devices, a system must be in place to collect global
adverse event data from wherever the device is sold. Severe adverse
events must be reported to the SFDA within 15 days irrespective of
its location in the world.
The SFDA sets forth detailed requirements for all stakeholders,
from device manufacturer personnel to distributors and patients.
Any company whose medical devices are sold in China should
carefully review the guidance to ensure that they are in compliance
with the guidelines; otherwise, they risk running foul of the SFDA and
possible blockage of their product’s sale due to improper adverse
event monitoring, reporting or response.
25.7 Managing Recalls

If an adverse event investigation warrants the recall of a medical
device, then the company should follow the Medical Device Recall
Managing Recalls 329
Management Guidelines laid out in SFDA Decree 82. The decree

contains 38 articles laying out the requirements that should be
followed in case of a recall.
A recall notice should have
• name, batch and other basic information
• reasons for the recall
• recall requirements, such as an immediate moratorium on the
sale and use of the product
Everyone in the process, from the manufacturer to the distributor,
shares the liability for medical device problems. Foreign companies
that are working through local Chinese distributors and agents,
therefore, must also ensure that all regulations are being followed
properly.
There are three levels of recalls as determined by the SFDA:
• Recalls are classified as Class I if use of the medical device
has caused, or may cause, serious health hazards that are of a
permanent nature.
• Recalls are classified as Class II if a medical device may cause
a health issue of a temporary nature.
• Class III recalls are the least stringent and are used for devices
that are not likely to cause harm but are still defective.
These recalls can be of a voluntary nature or ordered by the
SFDA.
In carrying out a medical device investigation and evaluating its
defects, an analysis should be done to determine
• whether the use of the medical device caused the adverse
event
• whether there is relevant scientific literature, research, testing
or validation to explain the causes of injury
• the geographical area effected by the damaged device and its
population characteristics
• the extent of the damage to human health
• the probability of injury
• the short-term and long-term consequences of the injury
• other potential harm to human health
330 China
References
1. SFDA website: http://www.sfda.gov.cn.
2. S. Goldenberg, E. Zhao (13 April 2012), The Implications of Medical
Device Regulatory Change in China, RAJ Pharma.
Chapter 26
Hong Kong: Medical Device Regulatory

System
Jack Wong
Disclaimer
market planning and is subject to change frequently. Translations
of laws and regulations are unofficial.

26.1.1 Market Environment
(i) Hong Kong is a prosperous economy and acts as a hub for trade
throughout Asia.
(ii) The population is about 7 million and very receptive to use
of advanced medical products. All medical and healthcare

www.panstanford.com
332 Hong Kong
products, subject to the China and Hong Kong Closer Economic

Partnership Arrangement’s (CEPA) rules of origin, are able to
enjoy duty-free access to the China mainland.
MedicalDeviceMarketinHongKong

Importers/Exporters LocalManufacturers
(~750–1000) (~75–150)
Imports DomesticManufacturing
(~HK$12billion) (~HK$0.25billion)
ReͲexports DomesticExports
(~HK$11billion) (~HK$0.2billion)
LocalConsumption
(~HK$1.05billion)
Figure 26.1 Medical device market in Hong Kong.
26.2 Overview of Regulatory Environment and

Devices
Medical device regulation is developing in Hong Kong. The new
regulatory system will largely be based on the recommendation
of the Global Harmonization Task Force (GHTF). The GHTF is a
voluntary consortium with representatives from the trade and
regulatory authorities from the United States, Canada, Australia,
Japan, and the European Union formed in 1992 to harmonize the
standards and principles of regulating medical devices
Currently, the import or sale of medical devices in Hong Kong
except those containing pharmaceutical products or emitting
ionizing radiation does not require registration.
An “irradiating apparatus” is defined by the Radiation Health
Unit as one intended to produce or emit ionizing radiation, or capable
of producing or emitting ionizing radiation at a dose rate exceeding
5 microsievert per hour at a distance of 5 cm from any accessible
point of the surface of the apparatus. The Radiation Health Unit’s
Irradiating Apparatus Licence Section processes applications for
and handles renewal of licences required to import, sell, manufacture,
Regulatory Body 333
produce, deal in/with, possess and/or use irradiating medical

equipment.
The Consumer Goods Safety Ordinance (Cap.456) provides
protection against the supply, manufacture or import of unsafe
products, including some medical devices that can be regarded
as consumer goods, unless otherwise specified in the Schedule.
The Electrical Products (Safety) Regulation (Cap.406G) provides
protection against the supply of unsafe electrical products including
medical devices designed for household use except those products
specified otherwise. Details are available at: http://www.justice.gov.
hk/home.htm.
The statutory regulation of certain health care professionals,
whereby the practitioners are required to ensure the safe and
appropriate treatment for patients, also provides incidental control
on the use of medical devices.
The Undesirable Medical Advertisements Ordinance (Cap.231)
prohibits advertisements related to the curative or preventive effects
of products on diseases listed in the Ordinance. Details are available
at: http://www.justice.gov.hk/home.htm.
To raise public awareness on the safe use of medical devices
and enable traders to familiarize themselves with the future
mandatory requirements, the Medical Device Control Office
(MDCO) was established in July 2004. Its mission is to set up a
risk-based and cost-effective regulation on the supply and use
of medical devices with reference to harmonized standards
and procedures recommended by the GHTF. The government
launched a Medical Device Administrative Control System
(MDACS) on 26 November 2004. The first phase of MDACS starts
with voluntary listing of Class IV (High Risk) Medical Devices.
The second phase of MDACS, which includes voluntary listing of
Class II and Class III (medium risk) medical devices, was launched
on 14 November 2005.
26.3 Regulatory Body

The MDCO is the regulatory body in Hong Kong.
Contact information for medical devices
Medical Device Control Office,
Department of Health,
334 Hong Kong
The Government of Hong Kong SAR,

31/F, Hopewell Centre,
183 Queen’s Road East,
Wan Chai, Hong Kong
Website: http://www.mdco.gov.hk/
Contact information for irradiating apparatus

Electrical & Mechanical Services Department (EMSD),
Health Sector Division,
16/F Multi-Centre Block A,
Pamela Younde Nethersole Eastern Hospital,
Chai Wan,
Hong Kong
Website: http://www.info.gov.hk/emsd/english/about/organisa-
tion/index.html
DepartmentofHealth
DirectorofHealth
Consultanti/c DeputyDirector
ControllerCHP
DentalService ofHealth
Administration Enforcement Specialized

Services
Admin& Finance Health Boards& Chinese SpecialHealth Family Specialized

Policy & Admin& Councils Medicine Service and Services
Division Supplies Planning Office Division •Pharmaceutical Elderly •Clinical
•COSH Division Division Service Health Genetic
•FPA •Narcotics •PortHealth Services Service
•SARDA, and Office •Child
etc. Drugs •Radiation Assessment
•TCO HealthUnit Service
•MedicalDevice •Student
ControlUnit Health
•IT Service
•Forensic
Pathology
Service
Figure 26.2 Organizational Chart of Medical Device Control Office

(MDCO) in the Department of Health.

26.4.1 Definition of Medical Device (It Follows GHTF)
Medical devices range from sophisticated equipment such as
cardiac pacemakers used by health care professionals to simple
products such as bandages and thermometers bought over the

counter.
In essence, a medical device refers to any instrument,
apparatus, appliance, material or other article, excluding drugs,
used for human beings for diagnosis, prevention, treatment and
monitoring of diseases or injuries; for rehabilitation purposes; or
for the investigation, replacement or modification of body structure
or function. In addition, it includes devices used for examination of
human specimens.
An accessory to a medical device is subject to the same
regulations that apply to the medical device itself. However, devices
designed for the treatment or diagnosis of diseases and injuries
in animals are outside the scope of the proposed regulatory
framework.
An “irradiating apparatus” is defined by the Radiation
Health Unit as one intended to produce or emit ionizing radiation,
or capable of producing or emitting ionizing radiation at a dose
rate exceeding 5 microsievert per hour at a distance of 5 cm from
any accessible point of the surface of the apparatus. The Radiation
Health Unit’s Irradiating Apparatus Licence Section processes
applications for and handles renewal of licences required to import,
sell, manufacture, produce, deal in/with, possess and/or use
irradiating medical equipment.
26.4.2 The Classification of Medical Devices

The Principle
Medical devices are classified according to the risk level associated

with their intended use. In general, the risk level depends on the
design of a medical device as well as its intended use. The actual
classification of each device also depends on several factors, such
as the duration of device in contact with the body, the degree of
invasiveness, whether the device delivers medicines or energy to the
patient, whether they are intended to have a biological effect on the
patient and local versus systematic effects (e.g. conventional versus
absorbable sutures). These factors may, alone or in combination,
affect device classification. For details, please refer to rules of
classification in the MDCO’s guidance document called GN-01
(Overview of the Medical Device Administrative Control System).
336 Hong Kong
Details are available at http://www.mdco.gov.hk/english/mdacs/

mdacs_gn/files/gn_01.pdf.
(Note: The “Classification Rules for Medical Devices” given in
Appendix 1 of this guidance document may be updated from time
to time. You may wish to refer to the most updated version included
in the Technical Reference [TR-003] Classification Rules for Medical
Devices published by Department of Health.)
Table 26.1 Classification of medical devices according to the risk level

associated with their intended use.
Classification Risk level Examples of medical devices

I Low Tongue depressor, bandage, dressing
II Medium–low Suction pump, gastroscope, transdermal
stimulator
III Medium–high Lung ventilator, orthopaedic implant,
X-ray machine, medical laser
IV High Prosthetic heart valve, implantable cardiac
pacemaker, heparin-coated catheter
Note: 1. The classification is in accordance with the Principles of Medical Devices
Classification proposed by the GHTF.
2. Class IV medical devices bear the highest risk, whereas Class I medical
devices bear the lowest risk.
Similar to Europe, it is the manufacturer’s responsibility to

assign the classification of their medical devices.

The local responsible person (LRP) is the one who applies for the
inclusion of a medical device into the List of Medical Devices under
the MDACS. They have the following roles related to the device in
the list:
(i) effective communication with the manufacturer, importers,
users, the public and the Department of Health
(ii) keeping of distribution records
(iii) arrangement of maintenance and services
(iv) tracking of specific medical devices
(v) management of alerts and recalls
The reporting of adverse incidents follows MDCO guidance

document [GN-03] Guidance Notes for Adverse Incident Reporting by
Local Responsible Persons.
It is the manufacturer’s responsibility to assign the classification
of their medical device. The LRP should understand the classification
rationale. More than one LRP for the same product is allowed in
Hong Kong, but the manufacturer needs to have a proper recall
system to identify which LRP should recall which batch of the same
product. Details on the LRP’s roles can be found in the MDCO’s
Code of Practice Document — [COP-01] Code of Practice for Local
Responsible Persons.
26.4.4 Product Registration or Conformity Assessment

Route and Time Required
The MDACS is basically divided into three parts: Pre-market

Approval, Post-market Surveillance and Recognition of Conformity
Assessment Bodies.
Pre-market Approval is in the form of voluntary listing of
medical devices, importers and local manufacturers complying
with specific requirements. They will be listed in one of the following
lists:
• The List of Devices, including Class IV, Class III and Class II
• The List of Importers
• The List of Local Manufacturers
Post-market Surveillance is the review of the experience of
using those devices that have been placed on the market. The
surveillance system would monitor and co-ordinate the management
of adverse incidents, safety alerts and recalls related to the use of
medical devices.
Recognition of Conformity Assessment Bodies (CAB) is the
acceptance of a list of agencies from which manufacturers could
ask them to assess their medical devices for compliance with the
requirements related to safety and performance. BSI Product Service
is the first CAB approved in Hong Kong on 13 April 2007. TUV SUD
and SGS were also approved as CAB afterwards.
338 Hong Kong
Table 26.2 Summary of the requirement for product registration
Class I Class II Class III Class IV
Product registration Not required Required Required Required
Registration of local Required Required Required Required

manufacturers
Registration of overseas Not required Required Required Required
manufacturer or its local
representative
Registration of importer Required Required Required Required
Registration of retailer Not required Not Not Not

required required required
26.4.4.1 Suggested registration routes/steps

(i) The manufacturer understands the essential principles and
gets quality system certification, e.g. ISO 13485.
(ii) The manufacturer appoints an LRP.
(iii) The LRP submits product registration to the MDCO or the CAB.
(iv) A review is conducted by the MDCO or the CAB.
(v) The documentation receives acknowledgement, and the
application number is given two weeks after submission.
(vi) The MDCO takes about 12 weeks for review after getting all
required documentation.
26.4.4.2 Technical material requirement

For Classes II to IV, please follow [GN-02] Guidance Notes for Listing
Class II, III and IV Medical Devices (July 2011 Edition).
26.4.4.3 The labelling requirement of medical device

Please follow Technical Reference document on the MDCO website:
[TR-005] Additional Medical Device Labelling Requirements.
26.4.4.4 Post-marketing surveillance requirement

Please follow the MDCO’s guidance document [GN-03] Guidance
Notes for Adverse Incident Reporting by Local Responsible Persons.
Commercial Aspect 339
26.4.4.5 Manufacturing-related regulation: Do manufacturers

need registration/authorization?
Voluntary listing is recommended. For details, please see [GN-08]
Guidance Notes for Listing of Local Manufacturers.
26.4.4.6 Clinical trial-related regulation: Are medical device

clinical trials regulated?
No, medical device clinical trials are not regulated at the moment,
but a consultation document had been released in the past. The
process is very similar to pharmaceuticals. Details are available at
http://www.mdco.gov.hk/english/mdacs_gn/files/dgn_eng.pdf.
26.4.4.7 Is there a procedure for mutual recognition of

foreign marketing approval or international
standards?
Yes, Hong Kong recognizes ISO standards. Product registration
approvals in GHTF countries will simplify the registration process.
26.5 Commercial Aspect

Currently, there is not any control over the price of a medical
device.
Are parallel imports allowed?
As the MDACS is only a voluntary system, there is no regulatory
requirement on parallel imports. However, only those products
supplied through (or with consent of) the LRP can use the
assigned listing number, as it is impractical, if not impossible, to
verify whether a parallel-imported product is of the same quality
and performance as those listed products supplied through
the LRP. In this way, the LRP can effectively control and recall the
product when required.
Is there any regulation regarding the advertisement of a medical

device?
The Undesirable Medical Advertisements Ordinance (Cap.231)
prohibits advertisements related to the curative or preventive
340 Hong Kong
effects of products on diseases listed in the Ordinance. Details are

available at http://www.justice.gov.hk/home.htm.
26.6 Next Steps

The government launched the MDACS on 26 November 2004. The
MDACS has been implemented in different phases as follows: The
first phase started with the voluntary listing of Class IV (high risk)
medical devices. The second phase, launched on 14 November
2005, continued with the voluntary listing of Class II and Class III
(medium risk) medical devices. Phase III, which commenced on 13
October 2006, involved the recognition of designated Conformity
Assessment Bodies (CAB), in which BSI was the first designated HK
CAB. In phase IV, which began on 23 March 2007, local (Hong Kong)
manufacturers were listed, and phase V, which began on 17 July
2007, listed importers of medical devices (except Class I devices).
Since 2009, Class D in vitro diagnostic medical devices have been
listed.
We expect the listing of medical device distributors and Class 1
medical device products in the future.
Chapter 27
India: Medical Device Regulatory System
Kulwant S. Saini
Johnson & Johnson Medical, India,
A division of Johnson & Johnson Ltd,
9/43, Kirti Nagar, New Delhi 110015, India
ksaini@its.jnj.com, kulwantsaini@hotmail.com
Disclaimer
The regulatory information contained in this report is intended for

• India, a parliamentary democracy and an emerging market in
Asia Pacific, is the most populous (1.24 billion) democracy in the
world.

www.panstanford.com
342 India
• India’s next five-year plan is poised to increase the healthcare

expenditure to 3% of GDP and to 5% by 2020. Nearly 60 million
middle-class households get added every 10 years, and this
increased affordability and access would drive the 75% of
the growth in healthcare. Healthcare remains in the top three
categories in terms of consumption growth. India has the
potential to show the fastest growth over the next 30–50 years
and slated to be third largest economy by 2030.
• The total healthcare expenditure per capita has grown from
US$ 28 in 2000 to US$ 43 in 2010 at a compound annual growth
rate of 4.4% pa. The medical device industry is estimated to
be approximately US$ 3.0 billion and the medical equipment
industry is around half a billion. The medical device industry
is growing at a rate of over 15%. India has been recognized for
its quality pharmaceuticals and is largely self-sufficient, but for
medical devices it is mostly dependent on imports (65–75%).
There are a lot of local manufacturers that are also exporting
their products worldwide, but barring a few simpler medical
devices, most of the advanced medical devices and implants are
being imported into India.
• Healthcare spending trends
 Self-pay will continue to be major part of healthcare spend
(currently at 58% going down to ~50% by 2017).
 Increased penetration of insurance (no. of insured [private] to
grow at 15% over the next seven years).
27.1.2 Overview of Regulatory Environment and What

Laws/Regulations Govern Medical Devices
Currently, there are no separate medical device (MD) regulations in
India, and there is a serious mix up of drug and device regulations.
The MD regulations are evolving and the direction is that the MD
regulations would shape up in line with Global Harmonization Task
Force (GHTF) guidelines.
The Drugs and Cosmetics Act 1940 (Act) and the Drugs and
Cosmetics Rules 1945 are currently applicable to drugs as well as
medical devices. In addition to the aforementioned act, following
other acts and rules also are applicable to regulate the drugs.
Market Overview 343
• Pharmacy Act, 1948

• Drugs and Magic Remedies (Objectionable Advertisements)
Act, 1954
• Narcotic Drugs and Psychotropic Substances Act 1985
• Medicinal and Toilet Preparations (Excise Duties Act, 1955
• Drugs (Price Control) Order, 1995 (under the Essential
Commodities Act)
Following are the other laws that have a bearing on the
manufacture, distribution and sale of drugs and cosmetics:
• Industries (Development and Regulation) Act, 1951
• Trade and Merchandise Marks Act, 1958
• Indian Patents and Design Act, 1970
• Factories Act, 1948.
• Legal Metrology Act 2009 (in force from 1.4.2011),
• Draft Legal Metrology Packaged Commodities Rules 2011
The Drugs and Cosmetics Act 1940 regulates the import,
manufacture, distribution and sale of drugs and cosmetics (and
medical devices). It is a comprehensive act for the requirements
applicable for the drugs and cosmetics but not yet for the medical
devices (except for Schedule M III, provisions applicable to
hypodermic needles and syringes) which have been mentioned in
some sections (drug definition, labelling, standards for MDs) under
drugs.
When we talk of MD regulations in India, we talk of two different
periods, one before October 2005 and the other after October
2005, when 10 categories of medical devices were notified by the
Government of India (MOH) through Gazette notification SO No.
1468(E) and GSR 627(E).
Before 2005, the following medical devices were regulated as
drugs as these fall under either the definition of the drug or were
part of the monograph of a Pharmacopoeia or were of a biological
origin (Schedules C and C1):
• Blood grouping sera
• Ligature, surgical sutures (and staplers)
• Intra uterine devices
• Condoms
• Tubal rings
344 India
• Surgical dressings
• Umbilical tapes
• Blood/blood component bags
• Disposable hypodermic syringes and needles, disposable
perfusion sets (GSR 365(E), dated March 17, 1989)
• In vitro diagnostic devices for HIV, HBsAg and HCV
The first major notification on medical devices was released in
October 2005 post court intervention in one of the case (filed by the
Maharashtra FDA), involving a Mumbai hospital using unapproved
drug-eluting stents (classification issue, drug or device) which were
not approved in country of the origin. The court directed the Drugs
Controller General of India (DCGI) to regulate these critical medical
devices. The following list of categories of sterile products, intended
for internal or external purpose, was notified:
• Cardiac stents
• Drug-eluting stents
• Catheters
• Intra ocular lenses
• IV cannulae
• Bone cements
• Heart valves
• Scalp vein sets
• Orthopaedic implants
• Internal prosthetic replacements
Later, in August 2006, a clarification was issued that the devices
which are imported non-sterile and sterilized by the hospitals before
use would also fall under the ambit of the October 2005 notification
(SO No 1468(E)).
Each brand under the aforementioned categories of notified
medical device needs to be registered with the regulators before
these can be imported into India.
Post October 2005 notification, other lists of products and
accessories were put on the Central Drugs Standard Control
Organization (CDSCO) website (September 2007) but were never
implemented or notified through a gazette notification, as the act
states under the definition of drug. Hence, those were still being
freely imported. On 5 March 2012, the DCGI sent a circular to
State Drug Controllers and CDSCO branch offices categorizing
Market Overview 345
11 products from the aforementioned list into various notified

categories of the main gazette notification of products notified in
October 2005. This correlation of additional products to notified
categories eliminates the need for a tedious gazette notification
process. Table 27.1 shows a list of these products:
Table 27.1 Additional medical devices classified under categories

notified in October 2005
Name of devices Class of notified devices

Spinal needle Disposable hypodermic needle
Insulin syringes Disposable hypodermic syringes
Three-way stop cock as an accessory Disposable perfusion set
of IV cannula/catheter/perfusion set
Introducer sheath IV cannula
Cochlear implant Internal prosthetic replacement
Close wound drainage set Catheter
AV fistula needle Disposable hypodermic needle
Extension line as an accessory of Disposable perfusion set
infusion set
ANGO kit/PTCA/cath lab kit IV cannula/disposable perfusion
set
Measure volume set Disposable perfusion set
Flow regulator as an accessory of Disposable perfusion set
infusion set
Another requirement for drug-eluting stents was put in

September 2007, which stated that before approval/registration,
a manufacturer needed to perform a clinical trial in India on 100
patients for six months (products already in use and approved by
USFDA or CE marked) or 12 months (new products and not yet
approved elsewhere). Through this clarification, peripheral stents
were also brought under the list of regulated products.
Radiation-emitting devices need to be approved by the Bhabha
Atomic Research Centre for the radiation safety.
Operationally, the regulatory mechanism in India consists
of a two-tier system, one in the centre, the DCGI, and one each in
the states (total 28) and in the union territories (total 7). These
two regulators operate independently, and the DCGI reports to the
central government and the state regulators (the Food and Drug
346 India
Administration or the Drugs Control Department) report to their

ministry of health. Both the central regulator and the state regulator
are responsible for the implementation of the Drugs and Cosmetics
Act provisions. Their major responsibilities are listed in the following
subsections.
Under the Drug and Cosmetics Act, the regulation of the
manufacture, sale and distribution of drugs is primarily the concern
of the state authorities, while the central authorities are responsible
for approval of new drugs, clinical trials in the country, laying down
the standards for drugs, control over the quality of imported drugs,
coordination of the activities of state drug control organizations and
providing expert advice with a view to bringing about uniformity in
the enforcement of the Drugs and Cosmetics Act.
27.1.3 Functions Undertaken by DCGI and Central

Government
27.1.3.1 Statutory functions
• laying down standards of drugs, cosmetics, diagnosis and
devices
• laying down regulatory measures, amendments to acts and
rules
• regulating market authorization of new drugs
• regulating clinical research in India
• approving licenses to manufacture certain categories of drugs
as the Central License Approving Authority, i.e. for blood banks,
large-volume parenterals and vaccines and sera.
• regulating the standards of imported drugs
• carrying out tasks relating to the Drugs Technical Advisory Board
(DTAB) and Drugs Consultative Committee (DCC)
• overseeing testing of drugs by central drugs laboratories
• overseeing publication of Indian Pharmacopoeia
27.1.3.2 Other functions

• coordinating the activities of the State Drugs Control Organization
to achieve uniform administration of the act; policy guidance
• providing guidance on technical matters
• participating in the WHO GMP certification scheme
• monitoring adverse drug reaction (ADR)
Market Overview 347
• conducting training programs for regulatory officials and

Government Analysts
• looking after the distribution of quotas of narcotic drugs for use
in medicinal formulations
• screening drug formulations available in the Indian market
• evaluating/screening applications for granting no-objection
certificates for the export of unapproved/banned drugs
27.1.4 Functions Undertaken by the FDA and State

Governments
27.1.4.1 Statutory functions
• licensing of drug manufacturing and sales establishments
• licensing of drug testing laboratories
• approval of drug formulations for manufacture
• monitoring of quality of Drugs and Cosmetics, manufactured by
respective State units and those marketed in the State
• investigation and prosecution in respect of contravention of legal
provisions
• administrative actions
• pre- and post-licensing inspection
Importers and manufacturers face difficulties in compliance
and registration of their products as there had been no separate
regulations written and implemented for MDs. For the registration
of MDs, the drug registration/approval process has been followed
since 2006 although a brief list of contents of the technical dossier
was published in 2006, which was modified later and published (last
quarter of 2010) on the website (http://cdsco.nic.in/).
To streamline the work for designing proper MD regulations,
a core group of industry members and regulators was constituted.
Various industry agencies (Federation of Indian Chambers of
Commerce and Industry [FICCI], Confederation of Indian Industry
[CII], American Chamber of Commerce in India [AMCHAM],
Advanced Medical Technology Association [ADVAMED]) were also
involved into the process through their MD regulatory subgroups.
The efforts of this core group during 2009 and 2010 culminated
into the compilation of a base document (Schedule M III) which
was based on the European Medical Device Directive and the GHTF
guidelines. This comprehensive document was submitted to the
348 India
DCGI office at the end of 2010 and the highlights of this document
are as follows:
1. includes the GHTF definition of a medical device
2. based on the risk-based (GHTF) classification of medical
devices
3. includes the QMS certification (ISO 13485) and Conformity
Assessment Procedures (MDD and GHTF) involving notified
bodies and the regulators (for Class C and D products)
4. post marketing surveillance (PMS)
Schedule M III document need to be wetted by the legal ministry
and has to be linked with various sections of Drugs and Cosmetics Act
in such a way that it becomes a standalone guideline for MDs within
the act. Currently there is no proper definition of the MD in the Drugs
and Cosmetics Act, which is the main hindrance in the inclusion of
the MD guidelines/regulations in the act. A Drugs and Cosmetics
(Amendment) Bill was introduced in the Parliament in 2007. This
bill has been modified in the last four years to amend the act with
respect to the provisions for the drugs as well medical devices. It
includes a proper definition for the MD and separate provisions for
MDs in the act. It even recommends the change of the name of the
Act to “Drugs, Cosmetics and Medical Devices Act” so as to provide
proper recognition to MDs. This bill, which is now pending approval
by the Parliament, would enable the government to make rules for
MDs and inclusion of the Schedule M III into the act.
As the passing of the aforementioned bill by the Parliament
is a time-consuming exercise, as it is busy with other priorities,
in the meantime the DCGI office has come out with guidelines to
streamline the process of registration, manufacture, PMS and clinical
trials. These guidelines have been published on the CDSCO website.
A dialogue is going on between the DCGI and industry members to
further refine these interim guidelines.
27.1.5 Guidance Documents

• Guidance Document on Common Submission Format for
Registration of Medical Devices in India (4 August 2010)
• Guidance Document on Common Submission Format for Import
License in Form 10 of Medical Devices in India (25 August
2010)
• Requirements for Conducting Clinical Trial(s) of Medical
Devices in India (4 August 2010)
Market Overview 349
• Guidance document on application for grant of License in Form-

28 for manufacture of Medical Devices in India under Central
Licensing Authority Scheme (12 August 2010)
• Guidance on clinical trial inspection (1 November 2010)
• Guidance Document on Common Submission Format for
Registration of Notified Diagnostics Kits in India (5 January
2011)
License of Notified diagnostics kits in India (5 January 2011)
License of Non-Notified diagnostic kits in India (5 January
2011)
27.1.6 Indian Pharmacopoeial Commission

The Indian Pharmacopoeial Commission (IPC) is an autonomous
institution under the Ministry of Health and Family Welfare,
Government of India, dedicated to laying down standards for drugs,
pharmaceuticals and healthcare devices/technologies besides
providing reference substances and training.
27.1.7 Detail of Key Regulator(s)

The CDSCO headquarters are located in New Delhi, and it functions
under the Directorate General of Health Services (see Figs. 27.1–27.3
for details).
GovernmentofIndia
MinistryofHealthandFamilyWelfare
DirectorateGeneralofHealthServices
CentralDrugsStandardControlOrganization
DrugsControllerGeneralofIndia
Figure 27.1 The Central Drugs Standard Control Organization: The central
agency.
350 India
DIRECTORATEGENERALOFHEALTHSERVICES
CENTRALDRUGSSTANDARDCONTROLORGANISATION
DRUGSCONTROLLERGENERAL(INDIA)

HEADQUARTERS ZONALOFFICES(4)
SUBZONAL PORT/AIRPORT LABORATORIES(6)
OFFICES(3) SERVICE(7)

• Jt. Drugs • Dy. Drugs • Asst. Drugs • Asst. Drugs • Director
Controller (I) Controller (I) (I)
Controller Controller (I) • Dy. Director
• Dy. Drugs • Asst. Drugs • Technical • Technical • Sr. Scientific
Controller (I) Controller (1) Officer Officer Officer—I
• Asst. Drugs • Drugs • Sr. Tech. • Sr. Tech. Asst • Sr. Scientific
Controller (I) Inspector Staff • Supporting Officer—II
• Technical • Sr. Tech. • Supporting Staff • Research
Officer Asstt. Staff Officer
• Sr. Tech. • Supporting • Sr. Scientific
Asstt. Staff Asst.
• Jr. Scientific
• Supporting
Asst.
Staff
• Supporting
Staff
North Zone: Ahmedabad, Ahmedabad, CDL, Kolkata

Ghaziabad Hyderabad Chennai, CIPL,
South Zone: Delhi, Kochi, Ghaziabad
Chennai Kolkata,
CDTL, Mumbai
East Zone: Nhava Sheva,
Mumbai CDTL, Chennai
Kolkata
RDTL,
Guwahati
CDL, Kasauli*
*Not under CDSCO. IVRI,
**To start shortly. Izzatnagar*
NIB, Noida*
*Not under CDSCO. RDTL,
**To start Shortly. Chandigarh**
Figure 27.2 Organization Chart — CDSCO.

Market Overview 351

Organization, Medical Device Division, CDSCO (HQ)
DrugsControllerGeneralofIndia(Dr

Drugs Controller General of India
(Dr. G N Singh)

Deputy Drugs Controller (India)

(Mrs. Shanti Gunashekaran)

Assistant Drugs Controller (India)
(Dr. S. Eswara Reddy)

Diagnostics Cell

Tech. Data Associates
Drugs Inspector

Mr. Sella Senthil Mr. Manish Ragtah
Mrs. Sunitha Singh

Medical Devices Cell

Drugs Inspectors Tech. Data Associates

Mrs. Anju Kushwaha Mrs. Ashoniya Sheer
Mr. Ashish Rai Ms. Kavita Jayswal
Mr. Krishan Bhardwaj Ms. Nisha Kaushik
Mr. S. N. Saini Mr. Pradeep Verma

Mr. Sanjay Agarwal Ms. Pragalva Mishra

Figure 27.3 Organization chart: CDSCO — Medical Devices Division.
Figure27.3Organizationchart:CDSCO—MedicalDevicesDivision.
352 India
Contact Information
Drugs Controller General of India
Dr. G. N. SINGH
FDA Bhawan, Kotla Road, New Delhi 110002
Phones: +91 11 23236965 (D)
Fax: +91 11 23236973.
Email: dci@nb.nic.in
CDSCO website: http://cdsco.nic.in/
Medical Device Division website: http://cdsco.nic.in/Medical_div/
medical_device_division.htm

Medical devices are partially regulated in India and some (as listed
Section 27.1.2) of the critical devices have been notified as drugs and
regulated as drugs. Rest of the devices are still being freely imported
into India.
Currently, the MD has been defined under the definition of
the drug in Section 3(b)(iv) of the Drugs and Cosmetics Act. This
definition is not close to GHTF definition and requires a gazette
notification for any addition of MD to the list of notified devices:
3 (b) (iv)
… such devices intended for internal or external use in the diagnosis,
treatment, mitigation or prevention of disease or disorder in
human beings or animals, as may be specified from time to time by
the Central Government by notification in the Official Gazette, after
consultation with the board.
In view of the partial and incomplete MD regulations, currently,
there is no definition of the accessory in the Drugs and Cosmetics
act.
The proposed definition of the MD in the Drugs and Cosmetics
Amendment bill is based on the GHTF definition of the MD. This
bill still awaits the approval by the Parliament before these new
provisions can be made part of the Act. Similarly, the Schedule M
III (document compiled for base regulations for MDs) now available
with the regulator also has a GHTF definition of MD. The contents
of the bill and the base regulations would become part of the act in
due course after review and approval by the Parliament and other
ministries involved in the process. This complete definition would
eliminate the need for the involvement and review by the advisory
board in future.

In absence of the base medical device regulations, currently, there is
no system for the risk-based classification of MDs. Medical devices
have been notified from time to time as per the recommendation of
the Advisory Board although the last notification contained mostly
the critical and implantable MDs.
The proposed base MD regulations in the comprehensive
Schedule M III document are in line with the GHTF and the European
MD Directives. A comprehensive risk-based classification on the
lines of GHTF (Class A, B, C, D) requirements has been included in
this document. This considers various factors such as the duration
of contact, degree of invasiveness, biological origin and combination
with drugs. Once implemented, this document also proposes a
phased implementation of regulations starting with Class D devices.
27.2.3 Role of Distributors or Local Subsidiaries (LRP)

A notified MD can be sold in India by a local manufacturer (having
a manufacturing license) or the foreign manufacturer or importer
(licensee), after registration of the manufacturing site and obtaining
an import license for the products manufactured at that particular
site, either by the manufacturer himself or by an affiliate of the
manufacturer having an office in India or by an agent/importer/
distributor. This person is responsible for the compliance to the
provisions (also the GMPs) of the Drugs and Cosmetics Act in India
on behalf of the manufacturer (if situated outside India):
• An authorization from the manufacturer to be its agent in
India in the form of a Power of Attorney.
• Need to have a valid wholesale license for sale and distribution
of products in any state of India, issued by the state’s FDA/
DCA.
• Make sure the premises where the imported products are to
be stocked are equipped with proper storage accommodation
and equipment (temperature/humidity).
354 India
• The importer is a link between the regulators and the source

company for compliance:
 Customer complaints management in coordination
with manufacturer and adverse incident reporting; also
responsible for the reporting of the MDR to the regulator
in India
 Management of the field actions as communicated by the
manufacturer
• The manufacturer shall at all times observe the undertaking
given by them or on their behalf in Form 9.
• The licensee shall allow any inspector authorized by the
licensing authority to enter with or without notice any
premises where the imported products are stocked, to inspect
and to take samples, if required, for testing.
• If the licensing authority directs, the licensee shall not sell or
offer for sale any batch of the products.
• For traceability, the licensee shall maintain a record of all
sales showing particulars of the products and of the person to
whom products have been sold.
27.2.4 Product Registration or Conformity Assessment

Route and Time Required
The pre-market product and site registration process currently
followed in India is based on the drug regulations. Figure 27.4
illustrates the process of the registration of the site and product
(mandatory for Notified MDs). The evaluation process as defined for
MDs in 2006 for expedited review is based on the prior approval
(USFDA, CE Mark or Conformity Assessment Procedure, approval
in any of the GHTF countries) of the products. A new product not
approved previously in any of the countries may be asked to go
for the clinical trials for the generation of evidence for any of the
new indication and then would go for an additional complete
evaluation (for Form 45 new product approval). Almost all of the
MDs approved by DCGI office since year 2006 have gone through
the “Me Too” route, which involves two steps:
• Application in Form 40 and DCGI approval in Form 41
(Registration Certificate)
• Application in Form 8 and DCGI approval in Form 10 (Import
License)
Figure 27.4 Manufacturing site and product registration: process flow

chart.
This evaluation for the indigenous manufacturers involves

DCGI as well as the state FDAs. For foreign manufacturers, it involves
only the DCGI office. The process also involves a site inspection by
the joint team of CDSCO and FDA for indigenous manufacturers. If
required (as per conditions of the license), a site inspection may
be performed for a foreign manufacturer, although such inspection
has not been performed since 2006. Generally, the Conformity
Assessments Procedures performed by the NBs are acceptable for
this purpose.
For in vitro diagnostics (IVDs) (non-critical), only the second
step is required and no site registration is needed. A registration
certificate (RC) for a particular site is generally valid for three years
and then re-registration is required. The import license is valid
till the registration certificate is valid. During the currency of the
Registration Certificate, additional products from the same site can
be endorsed on the RC. The import license in this case would be valid
for the remaining period of the RC. The manufacturing license issued
to an Indian manufacturer is valid for five years.
The dossier format (various forms), contents and submission
process is defined in the guidance documents listed in
356 India
Section 27.2.8 and also available on the CDSCO site and the
Drugs and Cosmetics Act. In case of “Me Too” products, the DCGI
office evaluation process/documentation review takes about
6–9 months to issue the RC and the import license. In case of a
new product/new indication, performing a clinical trial and the
issue of Form 45 may need additional cycle time. In such cases, the
technical dossier may also be additionally referred to an expert
committee for review/comments.
27.2.5 Quality System Regulation

Currently as MDs are notified as drugs, it is expected that the local
manufacturer will comply with Schedule M GMPs (Drugs and
Cosmetics Act). Source companies situated outside India, generally,
comply with ISO 13485, or USFDA QSRs or the QMS requirements
in the country of origin. These are also acceptable, currently, as
part of the submission for the registration certificate to be issued
by the Indian regulators. The Plant Master file required in India is
generally replaced by the Quality Manual of the source company for
the submission.
Future proposed regulations in the Schedule M III draft would
be based on ISO 13485 requirements as per GHTF.

Regulation for Combined Device–Drug Product
As mentioned above, there are no base MD regulations yet in place
in India. MDs are notified and regulated as drugs. Hence, there
is no definition of combination product and no specific requirements
laid down for the combination products.
Proposed Schedule M III has provisions similar to GHTF and
would require such combination products to be evaluated by drug
as well as device section of the CDSCO depending on the status
of approval of drug in India. Combination product definition is
proposed to be similar to GHTF and the product as such would be
treated as MD.
27.2.7 Registration Fee

Table 27.2 shows the fees that are applicable for the various
activities/submissions/functions carried out by the CDSCO, state
FDA and test laboratories.
Table 27.2 Fees applicable for various activities/submissions/functions

carried out by CDSCO, state FDA and test laboratories
Form name as Type of registration/

Type of license per D&C Act activity Fee
Registration and re- Form 40 Mfg. site registration US$ 1,500
registration Product registration US$ 1,000
(per product)
Import license Forms 8 and 9 With one product INR 1,000
Subsequent additional INR 100
Product
Foreign As per conditions GMP inspection US$ 5,000
manufacturer site of license (if required)
inspection with
respect to site
registration
Clinical trials Form 122A INR 50,000
Manufacturing Form 27 (Sterile) Site fees INR 6,000
licenses Product fees INR 1,250
(per product)
Form 24 Site fees INR 3,750
(non-sterile) Product fees INR 750
(per product)
Renewal of plant INR 5,000
layout
Test license Form 12 1st product INR 100
Subsequent product INR 50
Government lab Rule 7, 48 and Product testing Refer to
testing fees 168-F Schedule B,
B-1 of Act
Abbreviation: INR, Indian rupee.
27.2.8 Technical Material Requirement
The dossier submissions for the site and medical device product
registration follow the guidance document available on the CDSCO
website under the MD section (Guidance Document on Common
Submission Format for Registration of Medical Devices in India (4
August 2010), Guidance Document on Common Submission Format
358 India
for Import License in Form 10 of Medical Devices in India (25 August

2010)). These are also listed in section 27.1.5 for MDs and IVDs.
27.2.9 The Labelling Requirement of Medical Device

The labelling requirements for drugs (and MDs) are defined under
Rule 96 (Manner of Labelling) of the Act. Additional labelling
requirements for the Non-Sterile Surgical Ligatures and Sutures
are provided under Rule 102. For special products, the labelling
requirements are provided under Rule 109-A, wherein it is stated
that the labelling of MDs shall conform to “Indian Standard
Specifications” laid down from time to time by the “Bureau of Indian
Standards” in addition to other requirements.
Generally, for imported medical devices, ISO or GHTF guidelines
are considered sufficient, but they are occasionally superseded by
Indian regulations.
According to the Drugs and Cosmetics Act, it is a mandatory
requirement that the product should have 60% residual shelf-life
period as on the date of import.
Additionally, as per “Legal Metrology Act, 2009” (Declaration on
Pre-packaged Commodities), all products sold in retail must carry
the following information prior to commercial access:
(a) name and address of the importer
(b) generic or common name of the product
(c) net quantity in terms of standard units of weights and
measures
(d) month and year of packing in which the product is
manufactured or packed or imported
(e) maximum retail sale price (inclusive of all taxes) at which
the product in packaged form may be sold to the ultimate
consumer
(f) the approval number (import license number) for the notified
devices category
(g) customer contact number
This labelling is generally done (if not labelled by the
manufacturer) in warehouses in India by the importers before the
product can be sold in the market.
Recent requirements by the Ministry of Health specify the
inclusion of the GS1 bar code and serialization on products supplied
to the MOH. The Director General of Health Services also specified

the products to be exported from India for the purpose of tracking
products and to identify counterfeits.
27.2.10 Post-Marketing Surveillance Requirement

The Drugs and Cosmetics Act specifies the reporting requirements
for the Complaints and Adverse Reactions for drugs under Schedule
M (GMPs) and additionally, under the Schedule Y for the new drug
clinical trials. There are currently no specific requirements for MDs.
The proposed Schedule M III has a separate section on PMS and
is based on the GHTF guidelines.
27.2.11 Manufacturing-Related Regulation

The manufacturing site and the product (if notified) need to be
registered in India with the regulators. Licenses to manufacture
medical devices in India can usually be obtained from the state
FDA/DCA, after joint inspection from State FDA and CDSCO.
However, for recently notified devices (see the list of 10 categories
of MDs, Section 27.1.2), DCGI approval is needed. The required
information for a device manufacturing license includes the
implementation of Good Manufacturing Practices (GMP), as well as
some other requirements. Licensing usually involves an inspection
by the CDSCO and the state FDA. The license is valid for five years
and is renewable.
GMPs are provided under Schedule M of the act. As with the
product registration process, much of its requirements were
prepared with drugs in mind. Its provisions include the adequacy
of the manufacturing site, production area, quality control process,
record keeping, testing and adverse event and recall handling
system. Schedule M also calls for the maintenance of a Site Master
File, as well as a self-inspection to be conducted before the official
inspection. For the companies having CE-marked products, the
QMS as per ISO 13485 is considered. Schedule L-1 lays down the
“Good Laboratory Practices and Requirements of Premises and
Equipment”.
Future proposed regulations (Schedule M III) are based on
the Conformity Assessment Procedures (GHTF) involving notified
bodies and the CDSCO (Class C and D MDs).
360 India
Finally, if a product such as a drug-eluting stent contains a

patented or proprietary drug, a good deal of information on the
drug being manufactured must be submitted with a manufacturing
license application.
After the DCGI office formulated guidelines for the import and
manufacture of medical devices in the country, it also specified
that all importers, stockists and retailers of medical devices will
have to obtain sales licenses from the state FDAs within three
months.
27.2.12 Clinical Trial-Related Regulation

The requirements for the new drugs and clinical Trials are provided
under Part X-A of the act (Import or Manufacture of New Drug for
Clinical Trials or Marketing). Rule 122 and its various subparts
specify the process of Application for Permission to Import New
Drug (and device) and to obtain permission for conducting the
clinical trials. The details of requirements for the clinical trials
are provided in Schedule Y of the act. These requirements are
written basically for drugs/pharmaceuticals.
Following are the clinical trial draft guidelines specific to MDs,
available on the CDSCO website under MDs section:
Requirements for Conducting Clinical Trial(s) of Medical Devices in
India (4 August 2010)
Guidance on clinical trial inspection (1 November 2010)
Following additional clarification was issued on 5 September
2007 pertaining to the clinical trial requirements for drug-eluting
stents:
• In case of manufacturers whose stents are already in use
abroad and they wish to introduce the same in India, a six-
month clinical trial has to be carried out on 100 patients.
• In case of stents which are new in nature and have not been
used anywhere, a 12-month clinical trial has to be carried out
on 100 patients.
• Global clinical trials: Whenever a firm applies only for a
global clinical trial to be carried out in the country, this can
be permitted as per the present norms followed in case of
drugs. However, if the same company wishes to also market
the product in India, it has to comply with the aforementioned
norms.
Commercial Aspect 361
• It is clarified that “All Peripheral Stents” are covered under

the provisions of the Drugs and Cosmetics Rules and, hence,
need to be registered for import and licenses approved by
Central License Approving Authority (CLAA) for indigenous
manufacture.
27.2.13 Is There a Procedure for Mutual Recognition

of Foreign Marketing Approval or International
Standards?
There are no mutual recognitions currently in place with any
countries, but India recognizes ISO standards. Product registration
approvals by the USFDA or in GHTF countries and the CE mark are
recognized, and these have formed the basis for the site and product
registrations since 2006. The proposed Schedule M III regulations
are based on the GHTF guidelines and European regulations.

27.3.1 Any Price Control of Medical Device
MDs are notified and regulated as drugs in India. For drugs,
there are price control requirements (Drugs (Prices Control) Order
1995) in India. The National Pharmaceutical Pricing Authority
(Department of Pharmaceuticals, under the Ministry of Chemicals
and Fertilizers) is an organization responsible for the price controls
(to fix/revise) and availability of medicines in India. In the last three
years, there have been some attempts by the authority to bring
MDs under the price control, due to high visibility of the prices of
stents and orthopaedic implants. There have been many interactions
and representation on this subject from the industry to dissuade
the agency from implementing the manufacturing cost-based price
controls on MDs.
In the mean time, the Ministry of Health and Family Welfare has
put certain ceiling limits for reimbursement of stents (drug-eluting
stents, bare-metal stents and non-coronary stents) for its Central
Government Health Scheme beneficiaries. These are based on the
type of approval the product has in India (approved by DCGI) or in the
country of origin (USFDA approved or CE marked). There has been
362 India
strong representation from importers as well as local manufacturers

on this ad-hoc approach to pricing.
27.3.2 Are Parallel Imports Allowed?

For importing the notified MDs, one needs to have an import
license from the DCGI. This is issued on the basis of the Registration
Certificate for a manufacturing site of a foreign company. These
licenses can be used by the authorized agent to whom these have
been issued. An importer may authorize another importer to use
its Registration Certificate and allow the issue of another import
license to the latter by the DCGI. Both of these need to maintain the
distribution records as per the requirements of the act.

Device?
MDs are regulated as drugs in India. Rule 106 A states,
No drug (or MD) may purport or claim to prevent or cure or may
convey to the intending user thereof any idea that it may prevent
or cure, one or more of the diseases or ailments specified in
Schedule J.
The Drugs and Magic Remedies (Objectionable Advertisement)
Rules, 1955: This Act is meant to control the advertisements related
to drugs (or MD).
27.4 Upcoming Regulation Changes

Since the notification (October 2005) of 10 categories of MDs, the
registration and product approval process followed by the DCGI
office has been the same as followed for drugs. This has led to a
mix-up of the drug and device regulations. The industry and the
regulators in India have realized this, and some attempts have been
made by them collectively to resolve this in the near future. Some of
the things are listed below:
• Currently there is no proper definition of a medical device in
the act. A complete definition of the MD (in line with GHTF) has
been proposed in the Drugs and Cosmetics amendment Bill.
Upcoming Regulation Changes 363
This bill was reviewed by Parliament Standing Committee in

2009–2010, and the bill after modification was re-submitted to
the Parliament again in October 2010. This bill is now pending
the Parliament approval. The Parliament’s approval of this bill
will lead to the inclusion of the definition of a medical device
and related regulations/guidelines in the Drugs and Cosmetics
Act. Following are the features of the bill:
 The bill proposes a proper definition of a medical device
and a clinical trial and also proposes separate chapter II A

in the Act for the provisions related to MDs.
 The preamble changes in the act have been proposed,
and the proposed name would be “Drugs, Cosmetics and

Medical Devices Act”.
 The bill proposes the Powers of Central Government to
make rules regarding classification, pre-market evaluation,

standards, conformity assessment procedures, labelling
and registration of MDs, etc.
• A core industry–regulator group has compiled (during 2008–
2010) a comprehensive document Schedule M III containing
MD regulations. These can form part of the Drugs and
Cosmetics Act once the MD definition becomes part of the act
through the passage of the aforementioned bill by Parliament.
Schedule MII is based on the following:
 the GHTF guidelines and the European Medical Device
Directive
 risk-based classification of MDs as per GHTF guidelines
 the conformity assessment procedures involving the
notified bodies
 the adverse event reporting in line with GHTF guidelines
 requirements for the clinical trials
• As the aforementioned bill approval by Parliament and

finalization of the Schedule M III is a time-consuming process,
the DCGI office has come out with MD-specific interim
guidelines. These guidelines cover the registration of the
site/product and import license submission requirements
(common submission dossier) and approval process for MDs
and in vitro devices, clinical trials, etc. These are available on
the CDSCO website under the MDs section.
364 India
27.5 Related Agencies/Departments and

Ministries
• Ministry of Health (MoH)
 Directorate General of Health Services (DGHS)
 Central Drugs Standards Control Organization (CDSCO)
• Ministry of Chemicals and Fertilizers
 Department of Pharmaceuticals (DoP)
 National Pharmaceutical Pricing Authority (NPPA)
• Department of Science and Technology (DST)
• Federation of Indian Chambers of Commerce and industry
(FICCI)
• Confederation of Indian Industries (CII)
Chapter 28
Indonesia: Medical Device Regulatory

System
Mita Rosalina
PT. Johnson & Johnson Indonesia
mrosalin@its.jnj.com
Disclaimer
28.1 Introduction
Indonesia, with a population of more than 220 million, is a
medical device market that has a large potential. However, foreign
manufacturers of medical devices have always been faced with
numerous obstacles and challenges in entering this market. This is
despite the fact that Indonesia relies mainly on imported medical
devices due to the lack of any established local manufacturer. 4

www.panstanford.com
366 Indonesia
Penetrating this huge market of medical devices is difficult due to

the wide and extensive geographical boundaries in the country. Also,
highly bureaucratic medical device import and trading regulations
have made it more difficult for foreign manufacturers to enter the
market. Indonesia also imposes tariffs of up to 30% on imported
medical devices depending on the type, use, and value of these
devices.4
Indonesia has a centralized healthcare system, headed by the
Ministry of Health (Kementerian Kesehatan R.I.). The Ministry of
Health purchases most of the medical disposables and hospital
equipment for the 900 public hospitals around the country. Due
to the highly rigid nature, there is limited budget for most of the
hospitals in the country. Recent changes, however, have been
encouraging in de-centralizing healthcare services in the country.
This will spur the growth of the medical devices market in the
country as individual regions collect and plan the healthcare budget
individually themselves.4
There is a market disparity in the standard of healthcare
between rural and urban areas. The capital city, Jakarta, enjoys
relatively good levels of primary care as well as a range of modern
private specialist facilities, while healthcare coverage in remote
regions tends to be insufficient.
The majority of the Indonesian medical device market is
supplied by imports, which dipped by 1.5% over the previous year
to US$ 348.4 million in 2009. Imports have grown at a CAGR of
35.2% in 2005–2009.5 During the 24th ASEAN Consultative
Committee on Standards and Quality Meeting on August 3–4, 2004,
the formation of a Product Working Group on Medical Device
(ACCSQ-MDPWG) was proposed to implement specific measures
on medical device under the road map for healthcare integration.
This is to be in line with the ASEAN leaders’ decision on the
establishment of the ASEAN Economic Community (AEC) by 2020
and fast-track integration of the 11 priority sectors, including
the healthcare sector. Therefore, as one of ASEAN member
country, Indonesia is committed to the implementation of ASEAN
Harmonization in 2014.
To welcome it, at this time, Indonesia has some regulations
relating to medical devices:
Definition of Medical Device 367
• Ministerial Regulation of Health Republic Indonesia No. 1189/

MENKES/Per/VIII/2010. Production of Medical Devices and
Household Device. Issued on August 23rd, 2010.
• Ministerial Regulation of Health Republic Indonesia No. 1190/
MENKES/Per/VIII/2010. Marketing Authorization Medical
Devices and Household Device. Issued on August 23rd, 2010.
• Ministerial Regulation of Health Republic Indonesia No.
1191/MENKES/Per/VIII/2010. Distribution Medical Devices
and Household Device. Issued on August 23rd, 2010.
28.2 Regulating Authority

Medical devices in Indonesia are regulated by the Ministry of Health
of the Republic Indonesia; Directorate of General Pharmaceutical
Service and Medical Device; and Directorate of Medical Device
Production and Distribution Development with the following
address of office:
Kementrian Kesehatan RI
Jl. H.R. Rasuna Said Blok X-5
Kav No. 4–9; Jakarta 12950
Indonesia
Web site: www.binfar.depkes.go.id

A medical device means any instrument, apparatus, implement,
machine, appliance, implant, in vitro reagent, software, material, or
other similar or related article
(a) intended by the manufacturer to be used, alone or in
combination, for human beings for one or more of the specific
purpose of
• diagnosis, prevention, monitoring, treatment, or
alleviation of disease
• diagnosis, monitoring, treatment, or alleviation of or
compensation for an injury
• investigation, replacement, modification, or support of
the anatomy or of a physiological process
368 Indonesia
•
supporting or sustaining life
•
control of conception
•
disinfection of medical device
•
providing information for medical or diagnostic purposes
by means of in vitro examination of specimens derived
from the human body
(b) that does not achieve its primary intended action in or on the
human body by pharmacological, immunological or metabolic
means, but may be assisted in its intended function by such
means.

Medical devices are classified into three classes based on risk2:
• Class I: In case of malfunction or misuse, these low-risk devices
would not cause serious harm. The evaluation of these health
instruments shall focus on the quality and the product.
• Class IIa: In case of failure or misuse, these medical devices can
result in a significant impact on the health of patients, but not
a serious accident. Before distribution, such health instruments
will have to comply with a sufficient requirement for evaluation,
but they do not require a clinical test.
• Class IIb: In case of failure or misuse, these medical devices can
have significant effect on the health of patients, but not a serious
accident. Before distribution, these health instruments shall
have to comply with a complete requirement for evaluation,
including a risk analysis and security facts for the evaluation, but
they do not require a clinical test.
• Class III: The failure or misuse of these medical devices can
result in serious implications for patients or nurses/operators.
Before distribution, these health instruments shall have to
comply with a complete requirement for evaluation, including a
risk analysis and security facts for the evaluation, and they also
require a clinical test.
Currently Indonesia does not have any guidelines on combina-
tion products. Therefore, it is strongly recommended that prior to
the registration process, the product specification, intended use,
Registration of Medical Devices 369
and product claims be discussed with the Ministry of Health staff

to ensure the classification of the product. Attached classification
of product from legal manufacturer on application is recommended
as reference.
28.5 Registration of Medical Devices

All medical devices (for all classes) with each code should be
registered with the Ministry of Health before they can be freely
imported, distributed, and sold in the market. Unit package that
needs to be registered depends on unit sales.
Safety, quality, and efficacy of the product will be considered
during evaluation to grant marketing authorization.
Abridged evaluation is not recognized by Indonesia authority.
A full assessment is required for all classes of product. Approval
status from others countries serves only as reference for the
Ministry of Health staff in the reviewing process.
28.5.1 Process
The application must have distribution license “IPAK” from the
Ministry of Health and the company that as applicant officially
appointed by the source company or the legal manufacturer
as the sole agent. This letter of appointment from source/legal
manufacturer explains that the representative company in Indonesia
has authorization to register, import, and distribute the product
in Indonesia. The minimum appointment granted by the source
company is two years, and this document needs to be legalized by
the Indonesian embassy. It should be noted that the company that
has the right to import the product is the same company that is the
license holder for the products.
Currently, application is done by submitting the hard copy of
registration documents and follow-ups directly to the Ministry of
Health. English and Indonesian are the acceptable languages for the
documents.
All classes of medical devices follow the registration process as
shown in Fig. 28.1.
370 Indonesia
Figure 28.1 Medical device registration process followed by the Ministry

of Health.
28.5.2 Documents Required

Please refer to Appendix 1.
28.5.3 Official Registration Fee
Type of medical New registration Re-registration/variation/

device (mio rp) renewal (mio rp)
Class III 5 1
Class II 3 1
Class I 1.5 0.5
Explanation letter: 0.5 Mio Rp
28.5.4 Time Line

The time frame needed to get approval is as follows:
• Class I: 30 working days after pre-registration
• Class II : 60 working days after pre-registration
• Class III: 90 working days after pre-registration
In general, it takes around six to nine months from the date of
submission to get approval. This applies for new registration, re-
registration, variation, and renewal.
28.5.5 Validity of Product License

The product license issued by the Ministry of Health will be effective
for five years or in accordance with the term of validity of the letter
of appointment. The certificate of license needs to be renewed three
months before the expiry date.
28.5.6 Indonesian Labeling Requirement

Refer to Ministerial Regulation of Health Republic Indonesia No.
1190/MENKES/Per/VIII/2010: Marketing Authorization Medical
Devices and Household Device; article 26.
Following is the minimum information that needs to be stated on
the labeling:
• trade name/brand name/product name
• name and address of legal and physical manufacturer
• name and address of importer
• product component, formula (household device)
• active ingredient with percentage (household device)
• intended use and direction for use (must be in Indonesian)
• warning, precaution, and adverse effect (must be in
Indonesian)
• expiry date
• batch number/production code/serial number, registration
number, and net quantity of the product
28.5.7 Regulatory Action for Changes and Device

Modifications
This is not specified in the regulations. Changes can be registered
via a data amendment process, variation, or re-registration, and the
requirements are judged on a case-by-case basis.
Any changes that have an impact on the following should be
considered:
(1) size
(2) packaging specification
(3) LABELING
(4) tax payer number (NPWP)
372 Indonesia
28.6 Post Market Surveillance System

There can be severe consequences of faulty or substandard
medical devices for public health and safety. Regulatory bodies
all over the world are thus striving to achieve an optimal system
of medical device controls that accommodates a device in all its
permutations and combinations, balancing quality and safety
with faster access to the market.
Regulatory systems need to be in place to manage the
potential residual risks posed to the intended user. Because of this,
the Indonesia authority is developing a post market surveillance
process for medical devices. Post market surveillance mechanisms
are required to monitor the medical devices already in the
market. This is essential for such devices. In the event of any
complications, the authorities are able to direct swift corrective
actions.
In Indonesia, post market surveillance is still voluntary.
However, it has been recommended by the authority for cases that
have adverse health consequences for the patient or cause death.
In such cases, it is mandatory for the company to report to the
authority in 24 hours with details of the corrective action.
References
1. Ministerial Regulation of Health Republic Indonesia No. 1189/

MENKES/Per/VIII/2010. Production of Medical Devices and Household
Device. Jakarta, August 23, 2010.
MENKES/Per/VIII/2010. Marketing Authorization Medical Devices and
Household Device. Jakarta, August 23, 2010.
MENKES/Per/VIII/2010. Distribution Medical Devices and Household
Device. Jakarta, August 23, 2010.
4. Wee, A. (2006). Medical Device Distribution in Indonesia-Partnering
Established Companies for Optimum Penetration. Retrieved March 7,
2012, from http://www.frost.com/prod/servlet/market-insight-top.
pag?docid=72640483.
5. Espicom (2012). The Medical Device Market: Indonesia. Retrieved
March 7, 2012, from http://www.espicom.com/prodcat2.nsf/Product_
ID_Lookup/00000554?OpenDocument.
Appendix 1
Indonesia CSDT Format
Attachment A: Administrative Documents
Sections Documents required Details Class I Class II a Class II b Class III

Administrative
Documents Licence as Medical Devices
1. Copy of Local Company – No need to do addendum process to add new * * * *
Distributor
principle in distribution license as long its products
category already available in the list
– If product category has not yet in the list, addendum
process will be needed
– JJMI will provide this himself.
2. Power of Attorney POA (Power of Attorney) from the legal manufacturer * * * *

to local company as sole agent or sole distributor in
Indonesia — Need ID embassy legalization from the
country of legal manufacturer
3. Certificate of Free Sale No need ID embassy legalization * * * *
Endorsed by regulatory body in country of physical

manufacturer or country of legal manufacturer,
including the following information: product name,
product code, description and the manufacturing site
Appendix 1
(Continued)
373
374

Attachment A (Continued)
Indonesia
4. Executive A. Overview
Summary
*Brief description of device * * * *
*Intended uses and indications for use
B. Commercial Marketing
*Any novel features
History
*Date of first introduction and use * * * *
C. Intended Use and

*List of countries where it is marketed
Indications
*Instructions for Use (IFU) * * * *
D. List of regulatory
approval or marketing
*Registration status in reference agencies * * * *
clearance obtained and

status of any pending
*Copies of certificates or approval letters from the
request for market

reference agencies (approval certificates from the 5
clearance
benchmark countries)
*Declaration on labeling, packaging and instructions
E. Important safety/
for use (IFU)
performance related
*Summary of adverse events and recalls * * * *
information
*Description of the following (if the medical device
contains these items):
1. Drugs ( description about safety and efficacy drugs
usage, doses, adverse effect, pharmacology, etc.) If
applicable
2. Animal or human cells, tissues and/or derivatives
thereof, rendered non-viable (e.g. porcine heart
valves, catgut sutures, etc.); If applicable
3. Cells, tissues and/or derivatives of microbial or
recombinant origin (e.g. dermal fillers based on
hyaluronic acid derived from bacterial fermentation
processes); If applicable
4. Irradiating components, ionizing (e.g. x-ray) or non-
ionizing (e.g. lasers, ultrasound, etc.). If applicable
5. Essential Essential principles

Principles conformity checklist
*Essential Principles of Conformity Checklist for * * * *
the device. This checklist should contain all of the
essential principles described in the Guidance on
Essential Principles for Safety and Performance of
6. Evidence Evidence conformity with

Medical Devices
conformity the standard

*Certificate of Analysis (COA) of products. COA should * * * *
with the
be matched with product specification. The template
standard
should mention about parameter, limitation and
nominal result of test. COA should mention name of

product that we register, batch/lot no.
*ISO 13485 from Physical manufacture and legal

manufacture

*IEC 60-601 for electrical safety – if applicable
Appendix 1
*Declaration of conformity
375
376
Attachment B: Information of Device

Indonesia
Device 1. Description ABCD

Description
Description about: * * * *
– Direction for use
– Indication
– Brochure
– Raw material specification
– Expiry date (only for sterile products)
2. Device Description and

– JJMI will provide this himself.
Features
*Description and principles of operation * * * *
*Risk Class and applicable classification (If Appli- (If Appli- (If Appli- (If Appli-
rules cable) cable) cable) cable)
*Description of accessories and other devic-

es to be used with the medical device
*Description of key function elements of the
medical device
*Labeled pictorial representation (product
drawing, picture, photo)
3. Intended use, 4. Indications,

*Explanation of any novel features
5. Instructions of Use,
*Information typically found in the Instruc- * * * *
6. Contraindications,
tions for Use (IFU); for electromedic-->
7. Warnings,
Manual book should be provided. These in-
8. Precautions and
formation should be provided in Indonesia
9. Potential Adverse Effects

language as well.
10. Alternative Therapy *Description of any alternative practices or * * * *
procedures for diagnosing, treating, curing
or mitigating the disease or condition for
11. Materials
which the device is intended
*List of materials of the medical device * * *
making direct contact (e.g. with the mucous
membrane) or indirect contact (e.g. during
extracorporeal circulation of body fluids)
with a human body.
* Include information regarding chemical * * *
material, biological and physical characteri-
zation of the medical devices
*For medical devices intended to emit ion- * * *
izing radiation, information on radiation
source (e.g. radioisotopes) and the material
used for shielding of unintended, stray or
12. Other Descriptive

scattered radiation – if applicable
Information-manufacturer
*Description of any other important char- * * * *
information
acteristics of the medical device that is not
addressed in the preceding sections.
*Finished product specification test (pro-
tocol and result) – example PPQ protocol
and result
Appendix 1
(Continued)
377
378
Attachment B (Continued)

Indonesia
13. Manufacturing Process Must-cover method of manufacturing * * * *

process, condition, environment, facilities
and controls used for process, packaging,
labeling and storage devices.
This process can be represent by flow chart
of manufacturing process.
Include a summary of methods and sterili-
zation processes (for sterile products)
*Identify all sites (name and full address)

for design and manufacturing activities
(including contract manufacturers and
contract sterilizers)
1. Identify the activities conducted at differ-

ent manufacturing sites
2. Provide Quality Management System

(QMS) certificates for all design and manu-
facturing sites (including contract manufac-
13a. Sterilization validation *

turers and contract sterilizers)
(for sterile products)

*Information on the sterilization validation * * *
method used, sterility assurance level (SAL)
attained; standards applied, sterilization
protocol, summary of validation results
*Initial sterilization validation including * * * *
bioburden testing, pyrogen testing, testing
for sterilant residues (if applicable) and
packaging validation. If initial steriliza-
tion validation is not performed, adequate
* * * *
justification must be provided
*Evidence of the ongoing revalidation of the
process (e.g. evidence of revalidation of the
* * * *
packaging and sterilization processes)
*Post-sterilization functional test on the
* * * *
medical device
*If the sterilant is toxic or produces toxic
residuals, test data and methods that dem-
onstrates the post-process sterilant and/or
13b. Stability Studies (for de- * * * *

residuals are within acceptable limits
vices with a shelf life)

*Data demonstrating that the relevant
performances and characteristics of the
medical device are maintained throughout
the claimed shelf life which the “expiry”
* * * *
date reflects, including:
1. Prospective studies using accelerated
ageing, validated with real time degrada-
tion correlation; or
Appendix 1
(Continued)
379
380
Attachment B (Continued)

Indonesia
2. Retrospective studies using real time * * * *

experience, involving e.g. testing of stored
samples; review of the complaint history or
published literature etc.; or
3. A combination of (1) and (2). *(If *(If *(If *( If
* * * *
applicable) applicable) applicable) applicable)
*Summary of stability studies conducted,
stability protocols used, results of studies.
This summary should include conclusions
with respect to storage conditions and shelf
life, and, if applicable, in-use storage condi-
13c. Projected Useful Life (for * * * *

tions and shelf life.
devices without expiry dates)

* For devices that do not have expiry dates
(e.g. infusion pump, digital thermometer),
the projected useful life of the medical de-
vice must be provided. Manufacturers may
refer to TS/ISO 14969 (Medical devices
– Quality management systems – Guidance
on the application of ISO 13485:2003) for
information on how to determine the pro-
jected useful life
Attachment C: Specification and Quality Assurance Device

Specification and 1. Specification * * * *
Quality Assurance
Finished product specification: functional
Device
characteristics and technical performance
specifications for the device including, as
relevant, accuracy, sensitivity, specificity of
measuring and diagnostic devices, reliability
and other factors; and other specifications
including chemical, physical, electrical,
mechanical, biological, software, sterility,
stability, storage and transport, and packaging
to the extent necessary to demonstrate
conformity with the relevant Essential
2. Other Relevant * * *
Principles.
Specifications
List of features, dimensions and performance
attributes of the medical device, its variants
and accessories that would typically appear in
the product specification made available to the
3. Summary or * * *
end user, e.g. in brochures and catalogues
reference or design
This section should summarize or reference
verification and
or contain design verification and design
design validation
validation data to the extent appropriate to
the complexity and risk class of the device:
Such documentation should typically include:
declarations/certificates of conformity to the
“recognized” standards listed as applied by the
Appendix 1
manufacturer; and/or
(Continued)
381
382

Attachment C (Continued)
Indonesia
– summaries or reports of tests and

evaluations based on other standards,
manufacturer methods and tests, or
alternative ways of demonstrating compliance.
The data summaries or tests reports
and evaluations would typically cover, as
appropriate to the complexity and risk class of
the device: a listing of and conclusions drawn
from published reports that concern the safety
and performance of aspects of the device with
reference to the Essential Principles;
• engineering tests;
• laboratory tests;
• biocompatibility tests;
• animal tests;
• simulated use;
Clinical Study * *
• software validation

4. Pre-clinical Studies *Biocompatibility Testing (Protocol and result)

*Physical Testing (Protocol and result)

*Animal Testing (Protocol and result)
*Software validation Studies (Protocol and
5. Devices containing * * * *
result)
Biological material
* results of studies in relation to the risks
(if applicable)
associated with transmissible agents. (If (If (If (If
Statement letter for disease and virus free Applicable) Applicable) Applicable) Applicable)
6. Software * *
verification and
*Manufacturer should give design validation
validation studies
and software development. The manufacturer
(if applicable)
and/or device sponsor must provide evidence
that validates the software design and
development process. This information should
include the results of all verification, validation
and testing performed in-house and in a user’s
environment prior to final release, for all of the
different hardware configurations identified
in the labeling, as well as representative data
7. Clinical Evidence * *
generated from both testing environments.
* *
*Clinical evaluation report of the device
*Full reports of all studies referenced in clinical
evaluation report
Note: The documented evidence submitted
should include the objectives, methodology
and results presented in context, clearly and
meaningfully. The conclusions on the outcome
of the clinical studies should be preceded by
a discussion in context with the published
literature.
Clinical evidence of effectiveness may comprise
device-related investigations conducted dome-
stically or other countries. It may be derived
from relevant publications in a peer-reviewed
scientific literature
Appendix 1
(Continued)
383
384

Attachment C (Continued)
Indonesia
Use of Existing Bibliography Copies is

required of all literature studies, or existing
bibliography, that the manufacturer is using
to support safety and effectiveness. These will
be a subset of the bibliography of references.
General bibliographic references should be
device-specific as supplied in chronological
order. Care should be taken to ensure that
the references are timely and relevant to the
current application
Clinical evidence can be obtained from
publications relating scientific literature
Risk Management 8. Risk Management * *

which has been discussed with the experts.
Documents
*Risk Management report for the design of the
device and its manufacturing process
*Accompanying documents referenced in the
report, including the risk management plan,
Raw material raw material * *

results of risk assessment and risk control
specification specification
Specification of raw material or components
Packaging Mate- Packaging Material * *

of product.
rial Specification Specification (for

Packaging Material Specification (for
(for diagnostic diagnostic product)

diagnostic product),
product)
Analysis Test Analysis Test Report * *
Report
Analysis Test Report and or clinical study for
reagent/in vitro diagnostic product
Attachment D: Labeling and Intended of Use
Device Labeling 1. Device Labeling
*Labels are
* * * *
required for
*Copies (in original color) of:
each and every

1. Labels on the device and its packaging (primary
product codes * * *
and secondary levels)
which are to be
2. Instructions for use/IFU (including operating
registered.
manual and user manual) –> Should be
* * *
Indonesian language
* * * *
3. Patient information leaflet (where applicable)
4. Product picture with address of manufacture
for Electromedic device
*Promotional material (including brochures and
catalogues)
Note: These following information must be avail-
able:
– Name and address physical manufacturer medi-
cal devices and/or Household Medical Supply
– IFU need to be translated in Indonesian
language, at least with below information:
– Indication and Direction of use must be in the
Indonesian language
– Adverse effect-warning signs must be in the In-
donesian language
– Importer-name and address as well as
Lot Numbering * * * *
marketing authorization number
system
Lot numbering system or explanation letter
Appendix 1
regarding the lot system

385
386
Attachment E : Post Market Evaluation

Indonesia
ation
Post Market Evalu- 1. SOP about handling product This SOP should come from the legal * *
complaint, recall and stop manufacturer/source and local as
shipment applicant
Chapter 29
Japan: Medical Device Regulatory

System
Atsushi Tamura
Pharmaceuticals & Medical Devices Agency,
Shin-Kasumigaseki Bldg., 3-3-2 Kasumigaseki, Chiyoda-ku Tokyo, JAPAN
tamura-atsushi@pmda.go.jp
Disclaimer
29.1 Introduction
Japan is an island nation in East Asia, located in the Pacific
Ocean, with a population of over 127 million. Regarding the
international harmonization of medical device, Japan has been
a founding member of the Global Harmonization Task Force and
currently is a member of the International Medical Device Regulators
Forum. Production, import and export values of medical devices
have been 1713 (1576), 1055 (1074) and 453 (475) billion yen,
respectively, in FY2010 (FY2009).1

www.panstanford.com
388 Japan
29.2 Regulatory Agency in Japan

29.2.1 The Ministry of Health, Labour and Welfare
The Ministry of Health, Labour and Welfare (MHLW) designs and
implements social systems and structures that are closely related
to people’s lives throughout their lifetime and entire life cycle. The
MHLW covers a wide range of areas from medical care to employment
and childcare support and each department of the ministry serves
“for people, for life, and for the future” on a daily basis.2 Figure 29.1
shows the key organization chart of the MHLW.
The Pharmaceutical and Food Safety Bureau
The Pharmaceutical and Food Safety Bureau sets consistent
regulations from production to sales and post-marketing safety
measures based on the Pharmaceutical Affairs Act, in order to ensure
the efficacy and safety of drugs, medical devices, etc. The Bureau is
also working on various issues that are directly linked to people’s
lives and health, including blood projects such as blood donation,
and measures against drug abuse.
29.2.2 Pharmaceuticals and Medical Devices Agency

The Pharmaceuticals and Medical Devices Agency (PMDA) is the
Japanese regulatory agency, working together with MHLW. The
PMDA’s obligation is to protect the public health by assuring safety,
efficacy and quality of pharmaceuticals and medical devices. The
PMDA conducts scientific reviews of marketing authorization
application of pharmaceuticals and medical devices, monitoring
of their post-marketing safety. The PMDA is also responsible for
providing relief compensation for sufferers from adverse drug
reaction and infections by pharmaceuticals or biological products.3
The organization chart of the PMDA is shown in Fig. 29.2.
29.2.3 Shared Responsibility of MHLW and PMDA on

Medical Device Regulation
The MHLW has ultimate responsibilities in policies and adminis-
trative measures, for example, the final judgment on approval,
product withdrawal from market, and so on. On the other hand, the
PMDA plays the role of a technical arm of the MHLW, through an
actual review, examination, data analysis, etc., to assist the MHLW’s
MinisterofHealth,LabourandWelfare
Minister’s
Secretariat
Health and Equal
Employment Health
Pension Welfare Employment,
Security Service
Bureau Bureau Children and
Bureau Bureau
y
for the Elderly Families Bureau
Social Welfare Human

Health Labour Health
and Resources
Insurance Standards Policy
War Victims’ Development
Bureau Bureau Bureau
Relief Bureau Bureau
Minister’sSecretariatCouncillor
PharmaceuticalandFoodSafetyBureau
GeneralAffairs Evaluation &

Evaluation& Compliance&
p Blood&Blood
Safety
Safety
Div. LicensingDiv. Narcotics Products
Div.
Div. Div.
Office of
Officeof International
International
MedicalDevice PlanningDirector
Evaluation (Pharm.Affairs)
Regulatory Agency in Japan
Figure 29.1
389
Organization Chart of MHLW.

390 Japan
InformationȱTechnologyȱ
ProtectionȱGroup
Seniorȱ
Executiveȱ Offi
OfficeȱofȱSafetyȱI
fS f I
Director Chiefȱ
Safetyȱ OfficeȱofȱSafetyȱII
Officer
OfficeȱofȱGMP/QMSȱInspection
OfficeȱofȱGeneralȱAffairs
Chiefȱ
Managementȱ OfficeȱofȱFinancialȱManagement
Officer
OfficeȱofȱPlanningȱandȱCoordination
Executive
ChiefȱActuary
Director
ChiefȱReliefȱ
Officer OfficeȱofȱReliefȱFunds
Associateȱ OfficeȱofȱRegulatoryȱScience
Executiveȱ
Director OfficeȱofȱReviewȱAdministration
Chiefȱ
OfficeȱofȱReviewȱManagement
Executive
Associateȱ OfficeȱofȱStandardsȱandȱGuidanceȱ
Executiveȱ Development
Director
Auditor OfficeȱofȱInternationalȱPrograms
InternationalȱLiaisonȱOfficers
Auditor
OfficeȱofȱNewȱDrugȱI
Associateȱ
Centerȱ OfficeȱofȱNewȱDrugȱII
Directorȱofȱ Director
OfficeȱofȱNewȱDrugȱIII
Executive Centerȱforȱ
Director Productȱ
Evaluation
OfficeȱofȱNewȱDrugȱIV
OfficeȱofȱNewȱDrugȱV
Auditȱ Associateȱ OfficeȱofȱNewȱBiologicsȱI

Office Executiveȱ
Director OfficeȱofȱNewȱBiologicsȱIȱI
OfficeȱofȱOTC/GenericȱDrugs
OfficeȱofȱMedicalȱDeviceȱI
Associate
Executive OfficeȱofȱMedicalȱDeviceȱII
Director
OfficeȱofȱMedicalȱDeviceȱIII
OfficeȱofȱConformityȱAudit
SeniorȱScientists
Figure 29.2 Organization chart of PMDA (as of 1 November 2011).
measures, for instance, approval review of medical devices, quality

management system (QMS)/good laboratory practice/good clinical
practice inspection, and collection and analysis of adverse event
(AE) reports.
Legislation of Medical Devices 391
29.3 Legislation of Medical Devices

Medical device administration in Japan is maintained in accor-
dance with a number of laws concerned as shown in Fig. 29.3 and
Table 29.1. Among them, the Pharma-ceutical Affairs Law (PAL) is the
supreme law. Some related cabinet ordinance, ministerial ordinance
and ministerial notification are issued for enforcement of the PAL.
Furthermore, notifications by the director general of bureau and/
or notifications by director of division/office are also published as
guidance documents for smooth enforcement of the PAL.
Hierarchy of legislation
Pharmaceutical
Diet Law (houritsu ἲᚊ) Affairs Law
Cabinet Cabinet Ordinance ((seirei ᨻ௧))
Minister Ministerial Ordinance (syorei ┬௧)

Ministerial Notification (kokuji ࿌♧)
Ministry
Legally binding
Æ
DG of B
Bureau
rea Notification (tsuchi ㏻▱)
Director of Division/ (Notification which shows an interpretation by the
Office Ministry of higher legislation could have compelling
y g g g
force.)
Figure 29.3 Hierarchy of legislation.
Table 29.1 Key pharmaceutical legislation

Law (houritsu) Pharmaceutical Affairs Law (PAL, 1960)
Cabinet Ordinance (seirei) Cabinet Ordinance on PAL, 1961
Cabinet Ordinance on PAFSC, 2000
Ministerial Ordinance (shorei) Ministerial Ordinance on PAL, 1961
GCP for pharmaceuticals, 1997, for MD, 2005
Good Vigilance Practice (GVP), 2004
Good Quality Practice (GQP), 2004, etc.
Ministerial Notification (kokuji) Essential Principles
Certification standards for class II devices
Classification of medical devices
List of orphan designation, etc.
Notification (tsuchi) by Director Information on application procedures
General of Bureau or Director of Guidelines for clinical evaluation, etc.
Division/Office
392 Japan
Medical devices are defined under Article 2, Paragraph 4, of the PAL,

as follows:
The term “medical device” in this Law refers to instruments and
apparatus intended for use in diagnosis, cure or prevention of
diseases in human or other animals; intended to affect the structure
or functions of the body of man or other animals, as designated by
cabinet ordinance, The Pharmaceutical Affairs Law, Enforcement
Ordinance.
All medical devices have a generic name, which is called the
Japanese Medical Device Nomenclature (JMDN). In JMDN, not only
single product but also some grouping products such as surgical
kit and ablation system are defined. At this moment, there is no
clear definition of a product comprising two or more regulated
components, a so-called combination product.
In order to bring medical devices into the Japanese market,
under the PAL a legal procedure is required for products, companies
and manufacturing sites, as shown in Table 29.2.
Table 29.2 Prerequisites to bring MDs into the Japanese market
Product Minister’s Approval (shonin) (Art. 14)
or 3rd party Certification (ninsho) (Art. 23-2)
or Marketing Notification (todokede) (Art. 14-9)
Company License for Marketing Authorization Holder (Seizohanbai-
gyo-kyoka) (Art. 12)
Manufacturing Site/ License for Manufacturer
Manufacturer (seizo-gyo-kyoka) (Art. 13)
or Status as Recognized Foreign Manufacturer (gaikoku
seizo-gyosya nintei) (Art. 13-3)
For medical devices, at least the following should be indicated on

the device itself, wrappers or containers clearly in Japanese: name
and address of the market authorization holder, brand name, generic
name, serial number or manufacture sign, and device category. Since
there are the other labelling requirements depending upon the
type of the devices, the use of the specific materials and so on, it is
necessary to check carefully the PAL and related regulations.

The classification identifies the level of regulatory control that is
necessary to assure the safety and effectiveness of a medical device.
In Japan, medical devices are classified mainly into four classes, on
the basis of risk-based system following the Global Harmonization
Task Force (GHTF) rule as shown in Table 29.3.4
Table 29.3 Overview of classification and pre-market regulation for

medical devices
Risk-based Technical stds. Type of Reviewed

Category classification for certification regulation by QMS
General MDs Class I NA Self- MAH * Some

Extremely declaration (report to exception
Low Risk PMDA)
Cont- Designated Class II YES 3rd Party Registered Applied

rolled Controlled Low Risk Certification Certification
MDs Medical Body
Devices
Others NO Minister’s PMDA and

than above Approval MHLW
Specially Controlled Class III NA

MDs Medium Risk
Class IV
High Risk
29.3.2 Type of Product’s Registration

29.3.2.1 Notification
Class I medical devices are categorized as “General Medical Devices”
by PAL. A marketing authorization holder (MAH) who intends to
market a “general medical device” is not required to obtain the
minister’s approval and is allowed to launch a medical device onto
the Japanese market by submitting the marketing notification for
the medical device to the PMDA.
29.3.2.2 Pre-market certification (third-party certification)
Class II medical devices are called “Controlled Medical Devices”

in PAL. Among the controlled medical devices, medical devices to
which there is the certification standard applicable are recognized
as “Designated Controlled Medical Devices”. To register and market
a designated controlled medical device, the MAH needs to file pre-
market certification application with a registered certification body
(third-party certification body) and obtain their certification.
Application dossiers for pre-market certification have to
be written in Japanese and the technical data and supporting
information have to be submitted following the summary technical
documentation (STED) format.
394 Japan
29.3.2.3 Pre-market approval

Class III and IV medical devices are defined as “Highly Controlled
Medical Device” in PAL. When an MAH intends to launch a “specially
controlled medical device” onto the Japanese market, the minister’s
approval to market the medical device is required. The minister’s
approval is granted on the basis of the scientific review at the
PMDA.
Class II devices other than Specified Controlled Medical Devices
are also subject to pre-market approval. In the case that no applicable
certification standard has been established or that the product is
deemed as a new medical device, the MAH is required to submit an
application to the PMDA to obtain the minister’s approval for the
product.
Application dossiers for pre-market approval have also to
be written in Japanese and the technical data and supporting
information have to be submitted following the STED format, as
shown in Fig. 29.4.
Attachments
A) Origin or history until
STED (Gaiyo) discovery and regulatory
♦ Device Overview status in foreign countries
Shonin Documents
1. Category ♦ Essential principle & Evidence of B) Reason/Background for
Conformity specification
2. Name
C) Stability & Endurance
3. Purpose of Use, Efficacy/ ♦ Device description
4. Shape, Structure or Principle D) Document for compatibility
♦ Summary of preclinical design with Essential Principle
5. Raw materials or Components verification and validation
6. Specifications E) Performance
♦ Labelling (draft) F) Risk Analysis
7. Operation for use/Procedure
8. Manufacturing Process ♦ Risk analysis G) Manufacturing (Process,
9. Storage or UBD ♦ Manufacturing information QC, Sterilization)
10. Site for Manufacturing H) Clinical data
11. Manufacturing site for Raw Materials
12. Remarks: Package Insert etc
Figure 29.4 Application documents set for high-risk device.
29.3.3 Marketing Authorization Holder

To market, lease and/ or grant the products (which are manufactured
or imported), it is necessary to have the appropriate class of MAH
license, as shown in Table 29.4. Additionally, to obtain approval
(certification) for a medical device, the appropriate class of MAH
license is also needed (PAL Article 12, 14).
• MAH has to be responsible for the product distribution.

• MAH is required to be responsible for the quality of the
product and manufacturing.
• MAH has to have an MAH general manager, a quality assurance
manager and a post-marketing safety manager.
Table 29.4 Type of License for MAH (Art. 12)
Classification of medical device Type of license needed

Highly controlled medical device Type 1 MAH License
Controlled medical device Type 2 MAH License
General medical device Type 3 MAH License
29.3.4 Manufacturer License (Art. 13)/Accreditation of

Foreign Manufacturer (Art. 13-3)
It is required by PAL that any person who intended to manufacture
medical devices by professional shall obtain a license for each
manufacturing facility from the heads of prefectures and the
heads of regional bureau of health and welfares (RBHW) (Art. 81
and 81-4). Licenses are valid for five years and are renewable. If
the manufacturing facilities are located outside of Japan, these
foreign manufacturing facilities are required to obtain the Foreign
Manufacturer Accreditation instead of a Manufacturer License.5
Four categories of the accreditation, same as the License for
Manufacturers, are valid for five years and are renewable. Application
for the accreditation should be submitted to the PMDA, as shown in
Table 29.5.
Table 29.5 Types of licenses for the manufacturer
Category Operation Authority

Biological (1) All/Part of processes of Head of Prefecture
manufacturing and quality (except for
management for MDs manufacturers of Specific
designated by the Minister Biological Products etc.
(e.g. biological product) Their licenses are issued
by Head of RBHW)
Sterilization (2) Sterilizing process
(other than 1)
(Continued)
396 Japan

Category Operation Authority
General (3) All/Part of processes of
manufacturing and quality
management for general MDs
(other than 1 and 2)
Packaging, etc. (4) Only packaging, labelling
and storage
29.4 Related Requirements

29.4.1 Quality Management System
In Japan, manufactures for Class II–IV medical devices and Class I
devices which are designated by the MHLW must demonstrate QMS
compliance. Ministerial Ordinance 169 was issued in December 2004
and is the standard of manufacturing control and quality control for
both medical devices and in vitro diagnostic reagents, known as the
QMS Ordinance. This ordinance is the main regulation specifically
listing QMS requirements. Japanese QMS fundamentally refers to
ISO 13485, but there are some differences. These differences are
including document control, record control, responsible engineering
manager, infrastructure, etc. For example, there may be different
requirements for the length of time required to keep copies of
documents.
29.4.1.1 QMS conformity as an essential requirement

QMS conformity is an essential requirement for product approval/
certification and for retention of approval/certification under the
PAL. As requirements for product approval/certification, during the
examination of application documents for approval/certification, a
QMS conformity inspection is performed by the relevant review body.
Approval/certification is granted only after conformity is established.
As requirements for retention of approval/certification, approval/
certification holders are obliged to undergo a QMS inspection every
five years. If the approval/certification holder does not fulfil this
obligation or does not follow improvement instructions resulting
from the QMS inspection, approval/certification may be withdrawn
by the relevant authorities.
MAH’S Obligations during Post-Market Phase 397
29.4.1.2 QMS inspections

QMS inspections are conducted for medical device manufacturing
facilities in Japan and in other countries based on the requirements
set by the QMS Ordinance. The on-site and document-based
inspections of manufacturing sites are performed by the PMDA,
applicable prefecture or the RCB (registered certification body),
according to its application category or other issues.
29.4.2 Good Quality Practices
The Good Quality Practices (GQP) specified in MHLW Ministerial

Ordinance No. 136, 2004, are requirements for the MAH located in
Japan. The MAH has to comply with the GQP, which is the standard
of quality control of a medical device. GQP requires shipping control
supervision of manufacturer handling of defective products etc.
The assessment of compliance to the GQP, for each MAH, is
conducted by the prefectural government where the MAH has their
registered place of business. Every manufacturer should familiarize
themselves with the requirements of this ordinance, because of the
specific requirements stipulating the cooperation between the MAH
and the medical device manufacturer.
29.5 MAH’S Obligations during Post-Market

Phase
Requirements for MAH (Art. 12-2)
The MAH has also to comply with the Good Vigilance Practice
(GVP), which is the standard of post-marketing safety management
of a medical device (issued as MHLW ordinance No. 135 dated 22
September 2004). In GVP requirements, the MAH must continue
controlling risks by conducting investigation/consideration of
information related to post-marketing safety management, planning/
implementation of safety measure, and provision of information
appropriately and smoothly. GVP includes standards concerning
organization and staff engaged in post-market surveillance
measurement, collection of safety information, internal audit and
so on. Figure 29.5 shows the typical flow of an adverse event report.
398
Japan
Figure 29.5 Flow of adverse event report.

MAH’S Obligations during Post-Market Phase 399
29.5.1 Collection, Analysis and Reporting of Safety

Information
When the MAH learns of adverse events, etc., suspected to be related
to the efficacy and safety of medical devices, they must report the
information to the PMDA within a certain period of time stipulated
in MHLW ordinance (Tables 29.6 and 29.7).
Table 29.6 Report due date: malfunction, failure, breakage, leak, fault,
etc. (in case it may cause health damage)
Description to package
inserts (IFU) Report’s due date
Serious Unknown (unanticipated) 30 days
Known (anticipated) 15 days (when the incidence rate of AE
understood beforehand increase)
30 days (except reports shown above)
Non-Serious Unknown Annual reports
Known —
Table 29.7 Report due date: health DAMAGE (death, injury, etc.)
Description to package
inserts (IFU) Report’s due date
Serious Death Known/unknown 15 days
Except death Unknown 15 days
Known 15 days (When the incidence
rate of AE understood
beforehand increase)
30 days (except reports shown
above)
Non-serious Unknown Annual report
Known —
29.5.2 Recall
When the MAH undertakes recalls (including repairs) of medical
devices, they must report to the governor of the prefecture where
the company is located.
400 Japan
29.5.3 Post-Marketing Safety Management

The MAH must continue controlling risks by conducting investi-
gation/consideration of information related to post-marketing
safety management, planning/implementation of safety measure,
and provision of information appropriately and smoothly.
The MAH must make efforts to collect information related to the
eficacy and safety of medical devices and provide it to healthcare
professionals (user).
When the MAH learns that the use of medical devices may cause
the onset or spread of hazards, the necessary measures for safety
should be taken, including recall, repair, discontinued distribution
and provision of information to prevent such hazards.
The MAH must employ a person (“general marketing compliance
oficer”) to undertake quality control and post-marketing safety
control of medical devices.
The general marketing compliance oficer must conduct the work
concerning quality control and safety management impartially and
appropriately.
When it is conirmed to be necessary for impartial and appro-
priate conduct of the work, the general marketing compliance
oficer must present to the MAH (head of the company) opinions
in writing.
29.6 PMDA’s Obligations during Post-Market

Phase
The PMDA collects safety information promptly and eficiently;
safety staff receive reports from companies when cases of adverse
events and infections caused by drugs as well as malfunctions of
medical devices are detected during the development and post-
marketing periods.
The PMDA also consolidates all essential safety information
reported by healthcare professionals, information from international
sources, and conference papers and research reports. The collected
information is then promptly compiled into a database and shared
with the MHLW.
PMDA’S Obligations during Post-Market Phase 401
29.6.1 New Challenge

To improve and enhance safety measures, the PMDA takes various
approaches such as the introduction of data mining methods (which
allow statistical analyses of information on adverse drug reactions as
reported by companies or medical institutions and the detection of
cases to be investigated), promotion of the application of electronic
medical records to safety measures in order to establish evaluation
methods of safety (known as the MIHARI Project), building of a
system for evaluating medical device malfunctions, and building
of a system for gathering and evaluating data from medical devices
subject to tracking.
29.6.2 Information Services

The PMDA makes available a wide range of information on the
quality, efficacy, and safety of drugs and medical devices, such as
the package inserts for drug products and medical devices, recalls,
and urgent safety information (“Dear Healthcare Professional”
Letters), on the Medical Product Information page on its website
(http://www.info.pmda.go.jp). All cases of adverse drug reactions
and malfunctions reported by companies on or after 1 April 2004
(the date the PMDA was established) are posted on the same Web
page.
The PMDA provides information not only to healthcare
professionals but also to the general public, such as the Drug Guide
for Patients, which is an easy-to-understand explanation for patients
to teach them about prescription drugs with warnings labels, and
the Manuals for Management of Individual Serious Adverse Drug
Reactions (for the general public), which outline individual ADRs,
initial symptoms and key points for early detection and treatment in
an easy-to-understand manner.
In addition, the agency offers a free email information service
called “PMDA medi-navi” (available in Japanese only), through
which important safety information is distributed to healthcare
professionals who subscribe to the service.
402 Japan
References
1. Yearbook of Statistics of Production by Pharmaceutical Industry (in

Japanese), retrieved (15 March 2012) from http://www.mhlw.go.jp/
topics/yakuji/2010/nenpo/index.html.
2. Organization of the Ministry of Health, Labour and Welfare, retrieved:
(9 March 2012) from http://www.mhlw.go.jp/english/org/detail/
index.html.
3. Organization of the Pharmaceuticals and Medical Devices Agency,
retrieved (9 March 2012) from: http://www.pmda.go.jp/english/
about/organization.html.
4. Summary Technical Documentation for Demonstrating Conformity to
the Essential Principles of Safety and Performance of Medical Devices
(STED), retrieved (9 March 2012) from http:// http://www.ghtf.org/
sg1/sg1-final.html.
5. Application for Accreditation of Foreign Manufacturers, retrieved (9
March 2012) from http://www.pmda.go.jp/english/service/pdf/
application.pdf.
Chapter 30
Jordan: Medical Device Regulatory

System
Anan Abu Hassan

Medical Devices and Cosmetics Section,
Jordan Food and Drug Administration
anan.abu_hassan@jfda.jo
Disclaimer
30.1 Jordan Food and Drug Administration:

Introduction
30.1.1 Vision
• To be the leading regulatory institution for the safety and
quality of food and drugs at national and regional levels and
well recognized at the international level.
• To gain the trust and confidence of citizens and institutions
of Jordan through the exercise of efficient and effective

www.panstanford.com
404 Jordan
scientifically based decisions that ensure public health safety

and welfare.
30.1.2 Mission
The Jordan Food and Drug Administration (JFDA) is an indepen-
dent public sector regulatory institution whose main objectives
are to ensure the safety and efficiency of drugs and food and the
safety of products, including infant milk formula and its special
formula, supplementary food, medicinal plants, natural products,
disinfectants and antiseptics, medical equipment and supplies,
pharmaceutical preparations containing vitamins and minerals,
cosmetic preparations and any other substances related to treatment
of diseases in human beings.
30.1.3 Overview of Structure of Jordan Food and Drug

Administration
Medical devices sector in Jordan: The directorate of controlled
MDs and Cosmetics controls medical devices, including antiseptics
and disinfectants (see Fig. 30.1). In the past, the JFDA used to depend
only on catalogues, free sale certificate (FSC), and some internal
instructions to custom release for medical devices.
30.2 Medical Device Market in Jordan

The medical device market in Jordan comprises imported products
and also products from local sources, including dental products,
haemodialysis solutions, antiseptics, disinfectants, infusion set,
plasters and surgical sutures. Local manufacturers should submit
their site master file to the JFDA in order to be studied and to get an
approval for manufacturing products.
30.3 Overview of Regulatory Environment

and What Laws/Regulations Govern the
Medical Devices
• Medical Device Importation Directives, Including antiseptics
and disinfectants.
Figure 30.1
Overview of Regulatory Environment
Organizational structure of JFDA.

405
406 Jordan
• Issued in accordance with Article No. (5) of the Drug &

Pharmacy Law No. 88
• Law No. 80 for the year 2001 & its relevant amendment law
No. 30 for the year 2003
• Article 1: These Directives are called Medical Devices Directives
including antiseptics and disinfectants. Effective Date was its
publication date in the official Gazette
• Article 2: For the purpose of implementing these Directives,
the terminology is set as mentioned in accordance with
Article No. 2 of the law in addition to certain explanations for
certain terminology such as
Article 1
These directives are called Medical Devices Directives, including
antiseptics and disinfectants. The date from which they have been
effective is the date of its publication in the official gazette.
Article 2
For the purpose of implementing these directives, the terminology
is set in accordance with Article 2 of the law in addition to certain
explanations for certain terminologies such as
1. Definition of a medical device: It is each device of substance,
whether used alone or associated with others, including the
software necessary for its use, prepared by the manufacturer
to be used for a person in order to achieve any of the following
goals:
• diagnosis, prevention, monitoring, treatment, alleviation
of disease
• diagnosis, monitoring, treatment, alleviation and/or
compensation for any injury or disability.
• disclosure, compensation, or amendment from/to the
anatomical situation.
2. Accessories: Devices/tools prepared by the manufacturers
for use with medical devices in particular class/category
3. Medical device classification: Following are the groups
under which medical devices are classified with regard to
safety/invasiveness, and these are classified in accordance to
what is mentioned in the “Medical Devices Directives 93/42/
EEC:
• Class I
• Class IIA
Overview of Regulatory Environment 407
• Class IIB
• Class III
• Active Implants Class
• Active Implantable MDD 90/385/EEC.
4. Laboratory: FDA Drug Laboratory Control Department
5. Committee: The Medical Device Committee, covers both
antiseptics and disinfectants
Article 3
A. It is allowed to import and freely use medical devices with
the exception of what is stated in (B) after obtaining the
approval of the Director General or its appointed personnel in
accordance with Addendum Nos. 1, 3 and 4.
B. It is allowed to import and freely use the medical devices in
the pharmaceutical forms and those whose components may
be considered pharmaceutical/drug after obtaining the prior
approval of the Medical Device Committee according to the
items referred to in Addendum Nos 1, 3 and 4.
C. It is allowed to import antiseptics and disinfectants in
accordance with the contents of Addendum Nos 2, 3 and 4
D. It is prohibited to import used or refurbished medical devices
for all the health sectors in HKJ.
Article 4
The Medical Device Committee evaluates the importation requests
for the items referred to in Items B and C pertaining to Article No. 3
and decisions regarding the same should be taken within a period of
30 working days from the date of the applicant initial importation
request .
A. The applicant has the full right to submit an objection to
the Medical Device Committee within a period of 30 working
days from being officially notified in written.
B. The Medical Device Committee re-studies and re-evaluates the
submitted objections, and decisions should be taken regarding
the same within a period of 30 working days from date of
submission to the Jordan Food and Drug Administration.
Article 5
The Director General of Jordan Food & Drug Administration has the
full right to prohibit (based on the decision and recommendation
of the Medical Device Committee) importation or marketing or
408 Jordan
to cancel previous approvals or call for recalls of medical devices,

including antiseptics and disinfectants.
Article 6
It is obligatory to obtain the approval of the Medical Device Commi-
ttee regarding any changes/updates to medical devices, antiseptics
and disinfectants prior to implementation.
Article 7
The Director General of Jordan Food and Drug Administration
issues Special Inspection Instructions for manufacturers/importers
and distributors of medical devices, antiseptics and disinfectants
and places/institutes where medical devices, antiseptics and
disinfectants are being used, such as hospitals.
Article 8
The Director General submits all debatable issues which may rise in
favour of the implementation of such importation directives to the
Medical Devices Committee and take the necessary decisions and
actions.
Article 9
Customs Authorities Employees are not allowed to clear any
consignments of medical devices/antiseptics and disinfectants or
any of their raw materials for the local manufacturers unless they
obtain the prior approval of the Director General.
Article 10
It is prohibited to advertise any medical devices or antiseptics
or disinfectants through any advertisement tools (audio/video
advertisement) unless they have been officially approved by the
Director General in accordance with the Medical Device Committee
Recommendation.
The only exception to this is publication in specialized medical
magazines.
Article 11
Post–Marketing surveillance requirement: All hospitals/clinics/
medical institutes centres should report to the JFDA any damage
(whether serious/fatal incurred from the use of the medical devices/
antiseptics/disinfectants).
Priorities 409
30.4 Data about Jordan

Table 30.1 MD&D market information
Number of imported Number of registered medical

Year invoices/year devices/year
2006 12,000 104
2007 15,500 111
2008 17,900 285
2009 13,462 262
2010 18,91 390
Table 30.2 Clinical trials
Type of medical device Clinical trial’s name

Drug-eluting stents 1. Patient-related outcomes with endeavour vs.
Cypher stenting trial
Prospective, multi-centre, randomized, two-arm,
open-label trial
Clinical Investigation Plan
2. A post-market registry of the BioMatrix drug-
eluting stent. Prospective, multi-centre registry
to be conducted at 40 European interventional
cardiology centres
30.5 Price Control of Medical Device

At the moment, there is no control over the prices of medical devices
by the JFDA in Jordan.
30.6 Priorities
Following is a brief summary of key priorities and focus of the JFDA
for MDD in Jordan:
• Supplying the local market with safe, effective and qualified
medical devices.
• To expand the scope of current regulation to cover other
categories, including IVDs.
• Increasing public and private sectors’, consumers’ and
manufacturers’ awareness of the JFDA’s role in medical
devices regulations and defining the role of the JFDA in health
technology assessments.
• Collaboration of JFDA with all involved sectors (customs, royal
medical services, Ministry of Health, private hospitals)
• Allocating financial and human resources at the national level
in order to support proper implementation of plans
410 Appendix 1
Appendix 1
Importation/Registration Requirements for Medical
Devices
General Conditions for the Importation of Medical Devices/
First Time
• The applicant should submit all of the following documents to

the JFDA:
1. The Applicant Commercial Registry Certificate issued by the
Ministry of Industry & Trade.
2. The original copy of any of the following certificates or a freshly
signed notarized valid copy of the certificate (Notary Public
Stamp on each page if more than one page) (the aforementioned
certificate should be valid at the time of shipping):
2.1 FDA Certificate (Certificate to Foreign Government) issued
by the USA Dept. of Health and Human Services
2.2 A Notarized CE Certificate issued by any authorized
accredited EU notified body in accordance with the
• Medical Devices Directives 93/42/EEC.
• Active Implantable MDD 90/385/EEC and their
amendments.
2.3 A Free Sale Certificate issued by the health authorities in
the country of origin in addition to a Free Sale Certificate
from any of the following countries approved by the JFDA:
Switzerland, Australia, Japan, Canada, and Norway. In case
the origin of the medical device origin is none of these
countries, following conditions should be met:
2:3:1 To indicate that the medical equipment is allowed
to be freely sold in the country of origin, any of the
following statements can be applied:
• freely marketed
• freely sold
• may be sold
• may be marketed
• allowed to be sold
• authorized to sell
Appendix 1 411
• no legal objection against the sale

• any other statement accredited by the Medical
Device Committee
2:3:2 The certificate should state a validity period. A
validity period of five years is considered valid from
its initial date of issuance.
2:3:3 The name and the address of the manufacturer
or the marketing authorization holder should be
mentioned.
3. If the medical device is in the form of a pharmaceutical dosage or if
it contains drugs, the following documents must be submitted:
3.1 Original catalogue containing the full information about the
medical device composition, indication/contraindication/
warnings, etc.
3.2 Commitment from the manufacturer clarifying the validity
period of the medical device and its storage conditions and
a stability statement guarantee regarding these conditions.
3.3 Outer pack and inner pack and insert leaflet (if available).
3.4 Finished product specifications and method of analysis of
the medical device (with the exception of the medical device
which contains drugs in its ingredients where Article No. 5/
Addendum 4 should be applied.
3.5 For all medical devices which contain ingredients of
animal origin, the TSE/BSE (transmissible spongiform
encephalopathy)/(bovine spongiform encephalopathy)
Certificate should be submitted.
412 Appendix 2
Appendix 2
General Conditions for the Importation of Antiseptics
and Disinfectants
The applicant should submit the following:
1. Applicant/Importer Registry Certificate, issued by the
ministry of industry and trade.
2. The original free sale certificate issued by the health
authorities in the country of origin, which should include
the name of the product, composition, number and date of
the certificate, name and address of the manufacturer and
a statement showing that the product is freely sold in the
country of origin according to the statement mentioned in
Appendix 1, point 2.3.1, and the said certificate should have
a validity period of five years. A validity period of five years is
considered valid from its initial date of issuance.
3. Declaration from the manufacturer clarifying the validity
period of the antiseptic and disinfectant and its storage
conditions and a stability statement guarantee regarding
these conditions.
4. Finished sample and insert leaflet (if available).
5. Finished product specifications.
6. Method of analysis.
7. For all antiseptics and disinfectants which contain ingre-
dients of animal origin, the TSE/BSE Certificate should be
submitted.
Appendix 3 413
Appendix 3
Labelling Requirements for Medical Devices
1. Single-use medical device outer packs should clearly show

(a) Batch or lot number
(b) Expiry date
(c) Name of the manufacturer or the Marketing Authoriza-
tion Holder
(d) Country of origin
(e) Storage conditions
(f) Sterilization method (in case the product is sterile);
otherwise the applicant should show a certificate from
the manufacturer showing the sterilization method used,
with the exception of antiseptics and disinfectants.
2. If the medical device is CE marked, the CE mark should be
present as a part of the label and it should be
• clear
• readable
• irremovable
3. The medical device should pass the analysis test performed
at the JFDA Lab if available in a pharmaceutical dosage form.
This incudes the following products categories:
• antiseptics, contact lenses solutions, haemostatic, vaginal
douches, lubricants, IUDs.
• mouth washes, infusion sets, bone cement, syringes,
surgical gloves, condoms, surgical sutures (surgical
sutures of bovine origin are prohibited)
• dressings, cotton, plaster, hyaluronic acid, solutions that
are used to keep/preserve Human body parts
Other categories of products will be refered to the Medical Device
committee to decide whether analysis would be required.
414 Appendix 4
Appendix 4
Importation Requirements for Medical Devices,
Antiseptics and Disinfectants
1. Two copies of the invoice showing the following:

1:1 Name of the manufacturer or the Marketing Authorization
Holder
1:2 The country of origin
1:3 Names of the medical devices requested for importation,
their models and catalogue numbers
1:4 Names of antiseptics and disinfectants
1:5 Batch number and expiry date for each item requested to
pass the JFDA/Lab/Dept. analysis as per Addendum No. 3
2. Any of the accredited certificates by JFDA which compile with
the specific class/category of the imported medical devices
according to the following conditions:
2:1 Medical Device Class I
2:1:1 If it is sterile or calibrated for measuring: a
general certificate issued in the name of the whole
group/class.
2:1:2 If differs from the above, then a declaration from
the manufacturer stating that it is manufactured in
accordance to worldwide specifications.
2:2 Medical Devices Class IIA
General certificate in the name of the group class/category
should be submitted.
2:3 Medical Device Class IIA
General certificate in the name of the group with the
exception of implants, where a separate certificate should
be submitted.
2:4 Medical Devices Class III
A comprehensive/detailed certificate showing the trade
name and models should be submitted.
2:5 Medical Devices (Active Implants)
A separate comprehensive detailed certificate showing the
trade name and models should be submitted.
Appendix 4 415
2:6 Free Sale Certificate showing the name of the anti-

septic/disinfectant
1. Catalogue or brochure from the manufacture showing
the name of each imported antiseptic/disinfectant.
2. Certificate of analysis for each imported batch of the
(IVF media) materials used in the dentistry, such as
filling, sticklers or others.
3. Quality Control Release certificate for each imported lot
of the medical device which contains drugs in any of its
ingredients.
4. Medical device containing human albumin requires
certificate according to the current regulations. For
imported batches, lot numbers should be submitted.
5. For devices which contain ingredients of animal origin,
the TSE/BSE-Free Certificate should be submitted for
the imported batches/lots.
416

Appendix 5
Appendix 5
JFDA Adverse Incident Report Form

Report
Reporting body ...................... hospital ...................... health care center ...................... pharmacy ...................... others ....................................
Address ............................................................................................................................................................................................................................................
Report name ..................................................................................................................................................................................................................................
Position ............................................................................................................................................................................................................................................
Telephone number .....................................................................................................................................................................................................................
Consultant-in-charge (if known) .........................................................................................................................................................................................

This report confirms a telephone report a fax report neither
Type of device: (tick one only)

Active implantable devices External defibrillators & pacemakers Physiotherapy equipment
Administration & giving sets Feeding tubes Radiotherapy equipment
Anaesthetic machines & monitors Gloves Radionuclide equipment
Anaesthetic & breathing masks Guidewires Resuscitators
Autoclaves Hearing aids Staples & staple guns
Bath aids Hypodermic syringes & needles Stretchers
Beds & mattresses Implant materials Surgical instruments
Blood pressure measurement Infant incubators Surgical power tools
Breast implants Infusion pumps, syringe drivers Sutures
Cardiovascular implants & device Insulin syringes Thermometers
Commodes Intravenous catheters & cannulae Ultrasound equipment
Contact lenses & care products Joint prostheses Urinary catheters
CT systems Lasers & accessories Ventilators
Dental materials & appliances Magnetic resonance equipment & accessories Walking sticks / frames
Dialysis equipment Mobile x-ray systems Wound drains
Diathermy equipment & accessories Monitors & electrodes X-ray equipment, systems &
accessories
Dressings Non-active implants Other (please specify)
Dressings Non-active implants Other (please specify)
Endoscopes & accessories Ophthalmic equipment ................................................
Further details can be given on additional sheets if necessary

Endotracheal tubes & airways Patient hoists
(Continued)
Appendix 5
417
418
Appendix 5 (Continued)
MEDICAL DEVICES
Appendix 5
Details of device: Invoice No.

Product Catalogue No.
Model Serial No.
Manufacture
Telephone No.
Supplier
Batch No. Expiry date
Date if mfr Quantity defective
Location of device now
Is there a CE-mark/or FDA? YES NO If YES, was the manufacturer or supplier contacted? YES NO
Consequences of Product problem (s).

Was there a fatality? YES NO Was an injury caused? YES NO
Serious: Yes No. If serious please indicate the seriousness of reaction (s).
Death (Date of death ……………................. Cause of death ………………………………….)
Life threatening Hospitalization – initial or prolonged Leading to congenital anomaly
Persistent disability Required intervention to prevent impairment/damage (Device)
Other serious consequences (important Medical events …………………)
Nature of defect/details of incident:
Contact name for further details
Action taken by staff / manufacturer / supplier:

Telephone number
.......................................................................……………………………..................................................................................
Signed .............................................................................. Date ..............................................................
TELEFAX : + 962 – 6- 4
Please send completed form to JORDAN FOOD AND DRUG ADMNISTRATION AMMAN-JORDAN TEL. 4602000
Appendix 5
419
Chapter 31
Republic of Korea (South Korea):

Medical Device Regulatory System
Peter Lee
Korea Testing Laboratory
kmlee1452@hanmail.net
Disclaimer
The regulatory information contained in this report is intended for mar-
ket planning and is subject to change frequently. Translations of laws
and regulations are unofficial.

31.1.1 Facts about South Korea
The Republic of Korea, commonly known as South Korea, is a
sovereign state in East Asia, located in the southern portion of the
Korean Peninsula. It is neighboured by the People’s Republic of
China (Mainland China) to the west, Japan to the east, North Korea

www.panstanford.com
422 Republic of Korea (South Korea)
to the north, and the East China Sea and Republic of China (Taiwan)
to the south. South Korea lies in the North Temperate Zone with a
predominantly mountainous terrain. Its territory covers a total
area of 99,392 square kilometres and has a population of
50,515,000 (in 2010). The capital and largest city is Seoul, with a
population of 10,421,782.
South Korea has the highest healthcare expenditure of all
the “Asian Tigers”, with an estimated 55% funded by the public
sector. The government has been forced to implement cost-cutting
measures in recent years, owing to a large deficit faced by the
healthcare system. Healthcare costs continue to rise, with the
country’s rapidly aging population adding upward pressure to
total spending. In the first half of 2009, for example, senior citizens
accounted for 31.7% of costs covered by the National Health
Insurance Corporation [18].
31.1.2 Medical Device Market Scale in South Korea

The medical device market scale in South Korea was $3.4 billion
in 2010 as shown in Table 31.1, and the market scale has shown
average annual growth rate of 9.0% after 2005. Also, the scale has
occupied 1.3% of global market scale, ranking 14th in the world [17].
Table 31.1 Market scale
Divisions Status in 2006 Status in 2008 Status in 2010

Manufacturers 1,624 1,726 1,857
Manufacturing $1,772,962,000 $2,295,639,000 $2,563,822,000
Exports $710,039,000 $1,234,670,000 $1,454,360,000
Importers 1,281 1,456 1,496
Imports $1,563,020,000 $2,128,000,000 $2,265,035,000
Source: Korea Medical Device Industrial Association Bulletin (November 2011).

According to South Korea’s regulation, medical devices are classified
as medical instruments, medical supplies, dental materials, and
Market Overview 423
in vitro diagnostic (IVD) device reagents and are identified as the

products used to diagnose, cure, alleviate and treat illness, injuries
or disabilities; to prevent illness or to complement injuries or
disabilities; to test, replace or alter structures or functions of the
bodies; or for birth control [1, 2].
Also, medical devices are grouped into four classes according
to the risk level associated with their intended use. IVD Devices are
classified as Class I products mostly. But IVD Device reagents are
classified as Class I to IV according to their risk level (Table 31.2).
Table 31.2 Classification
Classification Risk level Examples of medical devices

I Low Tongue depressor, bandage, dressing,
splints
II Medium–low Suction pump, gastroscope, transdermal
stimulator, X-ray machine
III Medium–high Lung ventilator, orthopaedic implant,
defibrillator, medical laser
IV High Prosthetics heart valve, implantable
cardiac pacemaker, heparin-coated
catheter
Source: KFDA Notice (December 2010).
31.1.4 Detail of Key Regulator

The Ministry of Health and Welfare (MOHW) is the primary
healthcare agency in Korea and regulates the Law and Enforcement
decrees. However, the KFDA, an agency under the MOHW,
independently regulates all medical devices according to the
Medical Device Act; only when the KFDA asks the legislation to fulfil
its mission, the agreement with the MOHW is required. Details can
be found at KFDA home page: http://www.kfda.go.kr/eng/index.
do?nMenuCode=12.
The working level organization of KFDA is the Medical Device
Safety Bureau, which consists of one department and seven
divisions, including two task forces (Fig. 31.1 and 31.2) [11].
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site, November 2011).
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Figure 31.2 Medical Device Safety Bureau Affairs duties (KFDA Web site,
November 2011).
31.2 Introduction to Korea Medical Device

Regulatory System
31.2.1 History
Since 1997, medical devices have been regulated by the KFDA,
which is an independent agency under the supervision of the
Introduction to Korea Medical Device Regulatory System 425
MOHW. Previously, the governing law for medical devices was the
Pharmaceutical Affairs Act, which also had mainly covered drugs
since 1953. However, to better cover medical devices and speed
international harmonization, the new Medical Device Act was
announced on 29 May 2003. It went into implementation and full
enforcement began on May 30, 2004 with the requirement that all
medical devices to be sold in South Korea meet the requirements of
Korea Good Manufacturing Practices (KGMP), mostly identical with
ISO 13485:2003 standard [9, 10].
31.2.2 Procedures
All foreign suppliers of medical devices must apply for either a
manufacturing or import business license in order to enter the
South Korean market. To obtain an import business license, an
importer must provide a copy of KFDA-recommended format to
one of the regional KFDAs with a health certificate of the company
representative (not for a corporation), a copy of the registered
legal entity (only for a corporation) and a list of facilities (in case
of conditional application). An importer can have more than
one distributor, but each distributor must either register as an
importer or have an independent consultant holding the product
approval so each importer has equal access to it.
Under Korean regulations, a foreign manufacturer without
an office in Korea cannot directly submit a device registration
application to the KFDA; therefore, the company may allow its
importer to do the registration. The foreign manufacturer also
may hire an independent third party based in Korea to make the
registration in its own name.
All medical devices require the pre-market registration from
the KFDA before they can be manufactured locally or imported
into Korea. There are two types of pre-market licenses. One is the
pre-market approval for Class II, III and IV devices and the other
is the pre-market notification for Class I devices except those that
have sterile and/or measurement function.
Pre-market approval for Class II, III and IV devices requires
a Technical File Review, Safety and Efficacy Review (SER may be
required for devices with new to market features) and Type Testing,
while pre-market notification requires only an upload the to KFDA
Electronic Filing System (KiFDA system, only Korean version) with
product information (no testing is required).
A Technical File Review is a general technical file review,

similar to the common submission dossier template (CSDT) or
summary technical documentation (STED), for those products
that are basically the same as an already approved product,
whereas a Safety and Effectiveness Review (SER) is required
for devices unlike those currently available on the market. The
KFDA now conducts a Technical File Review on all Class II, III
and IV products and excludes Class I devices. However, the KFDA
authorized the rights to conduct a Technical File Review to six
reviewing agencies — Korea Testing Laboratory (KTL), Korea
Testing Certification (KTC), Korea Conformity Laboratories (KCL),
Korea Testing & Research Institute (KTR), TÜV SÜD Korea and SGS
Korea — for all Class II devices from 8 April 2012.
Also, the KFDA has registered 13 domestic laboratories, including
KTL, to perform “Type Testing” on medical devices for electrical
and mechanical tests, electromagnetic compatibility (EMC) test
and/or bio-compatibility tests (in vivo, in vitro). However, they have
limitations regarding the scope of medical devices they can test;
so identifying laboratories appropriate for testing specific devices
is essential. The 13 laboratories are listed in Section 31.2.11.
Furthermore, the KFDA may accept other laboratories’ type test
reports if the test has been carried out at the laboratory accredited
by International Laboratory Accredition Cooperation (ILAC),
Asia Pacific Laboratory Accredition Cooperation (APLAC), Korea
Laboratory Accreditation Scheme (KOLAS) and similar schemes
under ISO/IEC 17025 Standard from 8 April 2012 [10].
Details can be found at the KFDA English home page:
http://www.kfda.go.kr/eng/index.do?nMenuCode=7.
31.2.3 KGMP: Quality Management System

The KFDA had operated KGMP audit system, almost identical to
the ISO 13485:2003 requirements, utilizing four audit agencies,
including the KTL and the Medical Device Quality Division of
the KFDA, to oversee the medical device manufacturer’s quality
management system for manufacturers of all classes of products,
and the Korea Good Importing Practices (KGIP) had been applied
to the importer using limited requirements of ISO 13485 up
to now. However, to fulfil the requirements of Medical Device Act,
the KFDA conducted the pilot KGMP audit at sites of foreign
manufacturers in 2010 to 2011 and started the expansion of
the KGMP audit to foreign manufacturing sites except those

manufacturing Class I devices. Then, the audit began for Class IV
device manufacturing sites on 8 April 2012. It will be extended to
Class II and III devices subsequently. However, 66 Class I devices,
including single-use urine flow meter, shall fall under KGMP, and
KGIP for importers has included in the instructions for importer
obedience.
An Asian company that wants to obtain KGMP certification
shall apply to the one of the four third-party quality system audit
agencies. These agencies do not solely perform the entire audit
but accompany the KFDA medical device surveillance officer
during much of their work. The GMP Certificate is issued by official
seals of the audit agency president and KFDA commissioner.
The process takes about one month from application and costs
approximately $500/man-day, depending on the size of the
manufacturing site. The certificate is valid for three years. Expenses
for overseas travel and interpreters for KGMP auditors will
be borne by the beneficiary (manufacturer or importer).
Three documents are required to get a device registered in
Korea:
1. A product license;
2. KGMP certification;
3. Business license (manufacturing and/or importing),
Of these, the KGMP certification must be renewed every three
years, and the other two are valid permanently, although major
changes may require re-registration. But, the KFDA is considering
the induction of license renewal system according to the Medical
Device Act. Despite this, it is still a matter of dispute between
the KFDA and industries.
As of December 2011, KGMP requirements have been changed.
The program features include a requirement that manufacturers
need KGMP certification for each product group shown in
Table 31.3, and the certification will be in effect for three years.
Importers should apply for GMP certification on behalf of overseas
manufacturers if they have new development devices or new
manufacturing site or if there were quality issues. The audit agency
expects to take one month from the date of initial application
to coordinate and schedule an audit, accompanied by a medical
device surveillance officer from the KFDA. The KGMP audit is
carried out on the following 25 product groups [1]:
428
Table 31.3 Product groups for which KGMP certification is required
1 General 6 Diagnostic device 11 In vitro 16 Sight corrective lens 21 In vitro medical

treatment diagnostic supplies
device device
Republic of Korea (South Korea)
2 Surgical device 7 Stimulating device 12 Speculums for 17 Hearing aid 22 Contraceptive device
for medical use medical use
3 Medical 8 Operational device 13 Treatment 18 Medicinal sub- 23 Alloy for dental use
chamber device for stance producing
medical use equipment
4 Life-sustaining 9 Patient transport 14 Syringe and 19 Implants 24 Treatment material for

device puncture dental use
5 Artificial 10 Measuring 15 Treatment 20 Human tissue or 25 Analyzing products

internal organ equipment device for organ substitute (reagents) for in vitro
apparatus for biological dental use diagnosis
phenomena
Source: KFDA Notice, December 2011.

Medical devices are divided into four classes, with Class I

being lowest risk and Class IV being highest risk, a strict system
of 2,139 classifications segments devices, including 64 IVD device
reagents and 16 U-healthcare. If a product is not listed in the Korean
system, the company should contact the Medical Device Evaluation
Department of the KFDA and ask for a classification determination
via the website or phone. KFDA may take up to 10 days to process
the request (http://emed.kfda.go.kr) [16].
Table 31.4 Treatment days for the services performed by KFDA
Services Treatment days

Manufacture (import) business license 25
Technical file review 55
Technical file change review 32
Safety-efficacy review 70
Manufacture (import) product license 10
Manufacture (import) product notification 10
Clinical trial plan recognition 30
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Figure 31.3 Flow chart of medical device-related affairs [11].
31.2.4 Product Notification: Class I Devices

The procedure for Class I devices is relatively simple: only
notification is required, not approval. The applicant simply submits
a standard notification to the one of the six regional KFDAs,
depending on the applicant’s residential district. This notification

includes information on the product, its manufacturer or importer,
its classification, purpose of use, instructions for use, raw materials
and specifications, dimensional drawings, precautions and the
labelling to be used. Once it is submitted, the regional KFDA
will issue an acceptance letter, which is equivalent to a product
license in this case [2].
(Processing time: 10 days, fee: approximately $35)
31.2.5 Product License: Class II, III, and IV Devices

Class II, III, and IV devices need to go through a full review and
approval process. Approval in the country of origin can speed up
the process somewhat but is not sufficient for product registration
in Korea. On the other hand, some progress in efficiency has been
made by the admission of third-party review organizations into
the process. The two main requirements for a product license
are a technical file and type testing. In case of Class II devices,
the six regional KFDAs can issue the product license beginning
17 June 2011 [9, 10].
31.2.6 Technical File

The first requirement for a product license in case of Class II, III, and
IV devices is the submission of a technical file, which falls into two
categories:
• The general technical file’s requirements are broadly similar
to the CSDT or STED requirements. It is used when a similar
device already has been approved. There is a one-page
application form that contains much of the same material as
in the notification form for Class I devices, but others require
additional attachments detailing further information. These
attachments include information on physical and chemical
characteristics, electrical safety and performance, among
others, all supported by test reports.
• The SER technical file is required for more novel devices.
Besides the general file requirements, it includes information
on the development process, stability reports and comparative
analysis with other devices. In addition, it requires clinical
study reports [16].
31.2.7 Clinical Trials

The KFDA accepts foreign clinical trials for approval, perhaps
not necessarily needing local ones, but there are criteria for
consideration of these trials. They must be published in a prominent
medical journal (the Science Citation Index is one arbiter of
prominence), or else they must have been accepted by the govern-
ment of the country of manufacture for its own approval procedure.
In the latter case, documentation of that acceptance in the foreign
country should be attached [16].
Figure 31.4 Clinical trial process.

Clinical trials are only required as a rule for SER technical files,
but the KFDA also may require them at its discretion for general
technical files.
31.2.8 Device Notification/License

The technical file must be reviewed and approved before go through.
If it is a Class II device and does not require an SER file, a third-party
organization can do this. A review by the third-party organization
takes only about one month (about $1,200/item). However, the
technical file of Class III and IV devices shall be reviewed by the
KFDA, not any third-party organization (about $150/item).
Following are general requirements for registering all medical
devices in Korea:
• local distributor (Korean importers or Korea registered
subsidiary of the foreign supplier rather than the foreign
manufacturer/supplier) shall apply for and serve as legal
holders of the registration
• technical file
• notarized GMP certificates for the time being (sooner and
later KGMP needed)
• raw material specifications and standards
• catalogues/brochures
Additional requirements, according to product class, are as
follows:
Class I medical devices require only pre-market notification,
which involves
• classifying the device
• the submission of form (to be completed by Korean importer)
including
 local importer information (company name, address and
device business license number)

 local company representative and his/her resident
registration number
 trade name, product name and classification name of
device
 raw materials
 manufacturing methods
 dimensional drawings
 specifications of finished product

 packaging unit
 instructions and precautions for use
 labelling
 foreign manufacturers’ company name
The notification process would be completed easily if the above
information is uploaded to KiFDA online system on the KFDA
home page (no English information service currently) (http://emed.
kfda.go.kr).
Class II, III, and IV medical devices require pre-market
approval, which involves
• classifying the devices
• refer to following items
31.2.9 Technical File Review

• Prepare a Form of Medical Device Technical File Review
Request including
 local importer’s company name, address and device
business license number; local company representative

and his/her resident registration number
 foreign manufacturer’s company name, address and
country of manufacture
 product, model, and classification names of devices
 external appearance, internal structure, size
 manufacturing methods
 effectiveness, performance and purpose of use
 packaging units
 storage conditions, validity period
 standard and test standard
 labelling
In addition to submitting the form to the KFDA for Class III and
IV devices and to one of the six technical file review (TFR) agencies,
including the KTL for Class II device, a cover page and an attachment
with a description of each supporting document are required. These
documents include
• bench test reports
• clinical trial reports
• reference photocopies
• relevant literature
• information on physical/chemical characteristics
• information on electric/mechanical safety
• information on biological safety
• information on radiation safety
• information on electromagnetic compatibility
• rationales and test reports to confirm safety and product
performance
During the technical file review, the KFDA may require a Safety
and Efficacy Review (SER) for products with new-to-market
features in terms of materials, mechanisms of action, usage or
effectiveness.
An SER application includes the following additional in-
formation:
• information on origin, discovery, and background of
development
• characteristics of devices
• stability data
• information on use in foreign countries
• comparative analysis with similar products previously
approved in the market
• clinical study report (most important part of SER)
Other items:
• The local clinical study is not important if foreign clinical data
is strong enough to demonstrate safety and efficacy.
• The KFDA will accept foreign clinical data if published in a
Science Citation Index (SCI) listed journal of if the foreign
government regulator has approved the clinical report, and
documentation is provided [6].
31.2.10 Type Testing (Mandatory for Class II, III, and IV

Devices)
Besides the technical file, the other important requirement
for a product license is type testing. Only third-party laboratories
do this, not the KFDA. It requires submission of samples and the
technical file. Although the technical file has not yet been officially
approved, a draft technical file can be submitted instead. Type testing

takes from one to three months, with fees ranging from $3,000 to
$10,000, all depending on the type of device. At the completion of
testing, the laboratory issues a test report to show its compliance
with the requirements of the technical file to the applicant.
To lower fees and review time, it also is possible to submit
equivalent test reports done abroad and have them validated for a
fee of approximately $800. However, the foreign testing must meet
certain international standards and should come from the laboratory
accredited by ISO/IEC 17025 standard according to ILAC, APLAC or
IECEE/CB Scheme [2].
Once the product passes the technical file review, the technical
review phase, it must undergo type testing (i.e. a KFDA-registered
laboratory tests the product or makes a determination that, based
on acceptable foreign data, the product does not require local testing
in Korea):
• A firm can initiate type testing before or during the technical
file review process.
• The testing must be done by a KFDA-registered third-party
laboratory or accredited laboratories.
• Generally it takes one to three months, depending on the
nature of type testing done.
• The Company must submit a copy of the draft or approved
technical file, foreign test results (if available) and test
sample(s) to the laboratory.
• Importers must file Form to receive exemption to import
unapproved devices for testing.
Required information includes
• candidate importer and manufacturer
• product name
• necessary quantity
• name of test laboratory asked to carry out testing
Type test reports requested
• bio-compatibility tests
 Tests conducted must be carried out to meet ISO, ASTM
and GLP standards.

• electrical and mechanical safety tests
 All testing must meet IEC standards.
 To be exempted from local testing, IEC test reports must

be submitted in the “IECEE-CB Scheme” TRF.
 CB certificate and test reports must be certified by a
national certification Body and CB testing laboratory.

• EMC tests
 All testing must meet IEC/CISPR standards.
 To be exempt from local testing, IEC test reports must be
submitted in the “IECEE-CB Scheme” TRF.
 CB certificate and test reports must be certified by a
national certification body and CB testing laboratory.

• performance tests
 A full description of test protocols, acceptance criteria,
etc., is required.
 Raw data may be required on a case-by-case basis.
 Signatures of laboratory technicians and supervisors are
required.
 Notarized test reports are required.
31.2.11 KFDA-Registered 13 Laboratories

Table 31.5 List of KFDA-registered laboratories
No. Registered laboratory Areas of expertise

1 Korea Testing Laboratory (KTL) All medical devices
2 Korea Testing Certification (KTC) 34 product groups,

including implants and supplies
3 Korea Testing & Research Institute 39 product groups,
(KTR) Except EMC test for only X-ray
equipment
4 Korea Conformity Laboratories (KCL) 13 product groups, including medical
supplies
5 Seoul National University Hospital 13 product groups, including implanted
Clinical Research Institute medical devices and supplies
6 Yonsei University Hospital Medical 11 product groups, including implanted
Technology Evaluation Center medical devices and supplies
7 Yonsei University Dental College Dental materials only
Dental Devices Testing & Evaluation
Center
8 Kyung-Hee University, Testing & Dental materials only

Development Center for Dental
Materials.
9 Kyungpook National University

Institute for Bio Materials Research Dental materials only
and Development Dental Materials
Testing & Evaluation Center
(KDMTEC)
10 Seoul National University, Dental Dental materials only

Hospital, Clinic Dental Research
Institute
11 Korea Workers’ Compensation & 6 product group, including wheelchairs

Welfare Service
12 Korea Institute of Medical Technology 19 product group, including medical

(KIMT) instruments
13 Korea Institute of Medical Device 13 product group, including medical

Assessment (KIMDA) instruments
Source: KFDA Web site, November 2011.
31.2.12 Applying for a Product License

Once both technical file review and type testing are complete, the
approved technical file and a certificate of KGMP or application copy
of KGMP must be submitted to the KFDA or regional KFDA using
Appendix No. 3 KFDA form. After reviewing all of these, the KFDA
issues a product license, which does not expire. The submittal is
available to use the KFDA Internet, KiFDA system (Korean version)
(http://emed.kfda.go.kr)
(Duration of processing: 10 to 80 days; fee: about $42 to $400:
depending on the case) [2]
31.2.13 Business License

There are two types of product license for the manufacturer and the
importer, and this business license can be obtained by submitting
one product license and other information on the company
(business registration and health certificate for its representative)
to one of the six regional KFDAs beginning 17 June 2011. The
form is required to receive a certificate of product approval from
the KFDA. It does not expire. Of course, an importer typically would

have such a license already for other products.
(Processing time: 25 days; fee: approximately $140) [2]
31.2.14 Audit of Quality Management System (KGMP

Certification)
Manufacturers of Classes II, III, and IV devices must be audited
and certified by category for their quality management system
according to KGMP requirements, mostly identical with ISO 13485,
before entering into the Korean market. Class I device manu-
facturers are excluded from the KGMP certification, with effect
from 8 April 2012, except 66 products. Instead of that, foreign
manufacturers of Classes II, III, and IV devices should be audited on
site by Korean auditors for their quality systems from 2012. Then,
the manufacturers must be re-certified every three years.
Twenty-five KGMP product groups are listed in Section 31.2.3.
Firms apply for KGMP certification using one of the KFDA-designated
quality system audit agencies (KTL, KCL, KTC, and KTR). The third-
party organization coordinates with the KFDA and sets audit dates.
The agency normally takes one month from the application date to
audit a firm [1, 3, 8].
31.2.15 Post-Market Surveillance System

The regulatory areas of post-market surveillance currently being
performed by the officials of the Medical Device Management
Division of the KFDA include plans for periodic re-testing, re-
evaluation, re-call, control of advertisement contents and adverse
events caused by a certain device in the market.
The KFDA is operating the PMS connect with the GMP audit
basically, which is called the regular monitoring system. The
GMP auditor may can pick up the sample, if it is doubtful, at the
manufacturing site and then request that it be tested at one of the
registered laboratories.
As the tracking and the management criteria, a person who
intends to report matters concerning adverse side effects of the a
medical device under Paragraph 1 and 2 of Article 31 of the Medical
Device Act shall report within seven days, if the medical device
caused death or a life-threatening adverse event. In this case, details
Importer’s Note 439
shall be additionally reported within eight days from the date of

initial reporting. Also, according to criteria and procedure for the
recall of harmful medical devices requiring recall, the required
recaller shall may submit a recall plan to the KFDA within 5–15 days.
The expected end date of the recall shall be within 30 days from the
start of recall [5].
31.3 Importer’s Note

31.3.1 Import Labelling
Key information that must appear on the device container in Korean
includes
• business name and address of a manufacturer or importer
• source of origin (name of manufacturer(s) and the country of
manufacture) in case of an imported device
• product name, type name (model name), product license or
notification number
• manufacturing (lot or batch) number and date of
manufacture
• weight or packing unit
31.3.2 Import Packaging

Key information that should appear on the outside packaging
is the same as on the product label; packaging inserts should
have the following information:
• directions and precautions for use
• information on technical maintenance
• information required by the KFDA commissioner
• other information required in the Ministerial Decree of the
MOHW
31.3.3 Import Documentation

All application forms submitted to the KFDA and to testing
laboratories must be written in Korean.
In addition, developing a constructive relationship with an
experienced Korean importer is also important, as most res-
ponsible Korean officials do not understand English well. It is
also necessary to cultivate solid relationships with experienced

regulatory professionals and government officials during the
approval process.
All medical device classes require the following:
• device business license (either for local manufacturer or
import distributor)
• KGMP certification except for Class I device
Class I medical devices also are required the notification to
the regional KFDA and the submission of a form via KiFDA online
system of the KFDA home page (see Section 31.2.8). Once product
approval is received and a business license is obtained, the device
can be introduced into the Korean market. If an importer has already
obtained a business license for a company, it does not have to go
through the process again for subsequent medical devices brought
into Korea.
Class II, III, and IV devices must go through the following
additional steps:
• Technical file review; two types are possible:
 Technical file review, when a device is basically same as
previously approved products

 Safety and efficacy review, when a device significantly
different from previously approved products
• Type testing, by KFDA-registered laboratories; test reports by
accredited laboratories may also be accepted
Once these things are completed, a product license is issued,
either a manufacturer license or an importer license.
31.3.4 Other Agencies

• The Health Insurance Reimbursement & Assessment
Service (HIRA), which accepts and reviews applications for
reimbursement approvals submitted by device manufacturers
(http://www.hira.or.kr/cms/rb/rbb_english/12/12_01/
social.html)
• The National Health Insurance Corporation (NHIC), which
collects premiums and pays hospitals and pharmacies (http://
www.nhic.or.kr/english/main.html)
• The Korea Testing Laboratory, which is the only accredited
laboratory performing type testing for all 39 categories of
Importer’s Note 441
medical devices available in the marketplace (http://www.

ktl.re.kr/eng/team/medical.asp)
31.3.5 Medical Device Advertisements
The Korea Medical Device Industry Association (KMDIA) has

conducted the screening of medical device advertisements on
behalf of the KFDA according to Article 25 of the Medical Device Act
and Article 29 of the Enforcement Regulation from April 2007. The
Screening Committee of medical device advertisement reviews and
deliberates on the advertisement contents, if in general, they are
accessible by the general public through newspapers, the Internet,
magazines, TV and radio on every 10 days according to the request
of clients. The review fee is approximately $88/item (http://eng.
kmdia.or.kr/) [17].
31.3.6 Contacts
Asian firms wishing to learn more about regulatory issues related
to medical devices in Korea are encouraged to contact the following
agencies for additional information:
Korea Food and Drug Administration
Policy part: Medical Device Policy Division
Medical Device Safety Bureau
Osong Health technology Administration
Complex,
187 Osong saengmyeong 2-ro, Gangoe-myeon,
Cheongwon-gun, Chungcheongbuk-do, 363-951,
Republic of Korea
http://www.kfda.go.kr/eng/index.do
Phone: +82 43 719 3704/Fax: +82 43 719 3700
Technical part: Cardiac Vascular Device Division
Medical Device Evaluation Department
Medical Device Safety Bureau
Osong Health technology Administration
Complex,
187 Osong saengmyeong 2-ro, Gangoe-myeon,

Cheongwon-gun, Chungcheongbuk-do, 363-951,
Republic of Korea
http://www.kfda.go.kr/eng/index.do
Phone: +82 43 719 3902/Fax: +82 43 719 3900
Once the Device Business License, Product License and KGMP
Certification have been obtained, it is finally legal to market a medical
device in South Korea. Beyond the regulatory permission, there are
other important processes as well, such as obtaining reimburse-
ment from Korea’s national health insurance system, as well as
post-market surveillance requirements.
Dealing with the Korean regulatory structure can be tricky
and requires expertise on the ground. Communication and
consultation with officials is necessary at many processing
stages, and officials will not well discuss applications in English
directly. However, these are not reasons to stay away — but reasons
to be deliberate and patient in entering this active market.
Also, Asian applicants can find the Korean laws and regulations
(English version) at http://www.kfda.go.kr/medicaldevice/index.
do?nMenuCode=104.
Asian companies also may contact to following address for the
regulations-related policies and technical parts:
Medical Device Evaluation Center
Medical Device Group
Korea Testing Laboratory (KTL)
87, Digital 26-gil, Guro-gu, Seoul, 152-718, Korea
http://www.ktl.re.kr/eng/
Phone: + 82 2 8601 620/Fax: +82 2 8601 619
References
1. KFDA (2012.1), Training textbook for newly changed Medical Device

Regulations, KFDA.
2. KFDA (2012.1), Commentary for KFDA Notice of Medical Device
License, Notification and Audit.
3. KFDA (2011.12), Revised Notice for Medical Device Manufacturing,
Importing and Quality System Requirements, KFDA.
4. KFDA (2011.4), Medical Device Act, KFDA.
5. KFDA (2011.4), Enforcement Regulation of the Medical Device, KFDA.
References 443
6. KFDA (2010.12), KFDA Notice for Medical Device Product and

Classification, KFDA.
7. Dal-Ho Lim (2011.12), Principal Researcher of KHIDI, The analysis
report of medical device industry on 2011, Korea Health Industry
Development Institute (KHIDI)/Korea.
8. Peter Lee (2011.12), KTL, The understanding for the global GMP
system, Korea Testing Laboratory.
9. Sang-Soo Park and Peter Lee (2011.12), Eulji University/KTL, Korea
Medical Device Regulations learning by English, Publisher A-Chim/
Korea.
10. Sang-Soo Park and Peter Lee (2009.8), KTL, Korea Medical Device
Regulations, Jungmungak/Korea.
11. Yang-Ha Cho (2010.11), KFDA, Medical Device License Review &
Improvement status in Korea.
12. Ji-Un Choi (2010.11), KFDA, 2010 Medical Device Safety Policy in
Korea.
13. Ames Gross and John Minot, Medical Device Registration in Korea:
An Overview. Retrieved December 2011, from http://www.mpo-mag.
com/articles/2007/05/medical-device-registration-in-korea-an-
overview.
14. Emergo Group, Retrieved: December 2011, from: www.emergogroup.
com.
15. International Trade Administration, Medical Device Regulatory
Requirements for South Korea. Retrieved December 2011, from
http://www.ita.doc.gov/td/health/korearegs.htm.
16. KFDA, Retrieved December 2011, from http://www.kfda.go.kr/
medicaldevice/index.do.
17. Korea Medical Device Industry Association. Retrieved December 2011,
from http://eng.kmdia.or.kr.
18. Wikipedia. Retrieved December 2011, from http://en.wikipedia.org/
wiki/Korea.
Chapter 32
Malaysia: Medical Device Regulatory

System
Yean Ting Ong

Johnson & Johnson Sdn Bhd, G.01, Block B, 10 Jalan Bersatu 13/4,
46200 Petaling Jaya, Malaysia
yong1@its.jnj.com
Disclaimer
The regulatory information contained in this chapter is intended
for market planning and is subject to change frequently. Translations of

Malaysia’s medical devices and supplies are mainly imported,
especially the more technologically advanced items. The Malaysian
Information for this section was generously provided by Johnson & Johnson Medical,
Malaysia.

www.panstanford.com
446 Malaysia
market for medical equipment and supplies was estimated to be

worth US$ 1,089 million in 2010. Malaysia spends 11.6% of total
health expenditure on medical equipment and supplies — around
0.5% of GDP.
Malaysia’s major natural resource is rubber, and the country’s
exports are dominated by latex products such as surgical gloves and
catheters, which together accounted for around 47.0% of the export
total in 2008. The share of these two sub-categories have slowly
started to diminish with the steady growth of diagnostic imaging
exports in recent years, particularly electrocardiographs and other
electrodiagnostic apparatus.
There is currently no mandatory registration for medical devices,
but this is expected to change by end of 2012, along with the other
related regulations involving production and importation of medical
devices, including surveillance and monitoring with the gazettement
of the Medical Device Act 2012 (Act 737) and the Medical Device
Authority Act 2012 (Act 738) on February 9, 2012. Accordingly, this
act will come into operation on a date to be appointed by the Minister
of Health Malaysia as provided under Section 1 (2) of the Medical
Device Act 2012 by way of a notification in the Gazette.
32.2 Regulating Authority

The Medical Device Authority Act 2011 provides for the establish-
ment of the Medical Device Authority to control and regulate
medical devices and the medical device industry and its activities
and to enforce the medical device laws, and for related matters.
The authority shall consist of the following members:
(a) the Director General of Health as the chairman
(b) the chief executive
(c) a representative of the Ministry of Finance
(d) a representative of the Ministry of Health
(e) not more than five persons with expertise and experience
in medical device-related matters to be appointed by the
Minister
Classification of Medical Devices 447

A “medical device” means
(a) any instrument, apparatus, implement, machine, appliance,
implant, in vitro reagent or calibrator, software, material or
other similar or related article intended by the manufacturer
to be used, alone or in combination, for human beings for the
purpose of
(i) diagnosis, prevention, monitoring, treatment or alleviation
of disease
(ii) diagnosis, monitoring, treatment, alleviation of or
(iii) investigation, replacement or modification, or support of
(iv) support or sustaining life
(v) control of conception
(vi) disinfection of medical device
(vii) providing information for medical or diagnostic purpose
from the human body,
which does not achieve its primary intended action in or on the
means, but that may be assisted in its intended function by such
means and
(b) any instrument, apparatus, implement, machine, appliance,
implant, in vitro reagent or calibrator, software, material or
other similar or related article, to be used on the human body,
which the Minister may, after taking into consideration issues
of public safety, public health or public risk, declare to be a
medical device by order published in the Gazette.

Medical Devices are classified into four classes based on risk. The
classification is aligned with the Global Harmonization Task Force
(GHTF) classification system and is determined from
448
Malaysia
Figure 32.1 Registration route.

• the manufacturer’s intended purpose for the medical device

• a set of classification rules; these rules will classify medical
devices into one the four classes of medical devices
Table 32.1 General classification system for medical devices for the four
risk classes of devices
GHTF Malaysia class Risk level Device examples

I A Low risk Surgical retractors/tongue
depressors
II B Low-moderate risk Hypodermic needle/suction
equipment
III C Moderate-high risk Lung ventilator/orthopedic
implants
IV D High risk Heart valves/implantable
defibrillator
Note: The examples given are for illustration only and the manufacturer must apply
the classification rules to each medical device according to its intended purpose.
32.5 Registration of Medical Devices

An abridged process is available for devices that have been approv-
ed by recognized regulatory bodies such as US Food and Drug
Administration, European Union, Therapeutic Goods Administration
(Australia), Therapeutic Products (Canada), and Japanese
authorities. These devices will still need to go through the local
registration process via the abridge evaluation route. Registration is
online; however, hardcopies of documents may have to be provided
if requested. Time to approval has not been determined.
Medical devices that have not been approved by the recognized
authorities/regulators have to go through a conformity assessment
process. The risk level of the device determines the stringency
of the conformity assessment.
450 Malaysia

There is a wide range of medical devices, from a simple medical
device to a highly complex and sophisticated medical device. The
various components can be sold as a separate component, individual
customized pack, or group and can be categorized as SINGLE, FAMILY,
IVD TEST KIT, SYSTEM, and SET. Each of the categories mentioned
can be submitted in the medical device registration application.
Medical devices that can be grouped into one of the following
five categories can be submitted in one application for product
registration and listing in the Malaysia Medical Device Register
(MMDR):
• SINGLE
• FAMILY
• IVD TEST KIT
• SYSTEM
• SET
Three basic rules must all be fulfilled for the grouping to apply:
• one generic proprietary name

• one manufacturer
• one common intended purpose
For the purpose of grouping, the corporate headquarters may
be regarded as the manufacturer for its subsidiaries and regional
manufacturing sites.
For example, TRS MDB ORTHOPAEDIC SYSTEM consists of the
following constituent components (see Fig. 32.2):
• Instruments from ABC Bhd (a subsidiary of TRS MDB

Malaysia)
• Instruments from XYZ Bhd (a subsidiary of TRS MDB
Mexico),
• Plates from TRS MDB Mexico; and
• Screws from TRS MDB China
For the purpose of grouping, the manufacturer of TRS
ORTHOPAEDIC SYSTEM will be TRS MDB Malaysia (Headquarters).
Figure 32.2
Registration of Medical Devices
Example of referencing the headquarters as the manufacturer for the purpose of grouping.
451
452
Table 32.2 Requirements

Malaysia
Class (Full QMS or QMS-design Product Technical Declaration of Registration

+ PMS system) or verification documentation conformity and licensing
(Full QMS + PMS system)
Class A Establish and maintain Prepare and make Prepare (and sign) Perform according to
available upon and submit for requirements
request review/verification
Class A (S) Establish and maintain Prepare and Prepare and make Prepare (and sign) Perform according to
make available available upon and submit for requirements
upon request request review/verification
Class A (M) Establish and maintain Prepare and Prepare and make Prepare (and sign) Perform according to
make available available upon and submit for requirements
upon request request review/verification
32.5.2 Conformity Assessment Process
Class B Establish and maintain Prepare (and sign) Prepare (and sign) Perform according to
and submit for and submit for requirements
review/verification review/verification
Class C Establish, maintain, and Prepare (and sign) Prepare (and sign) Perform according to
make available for audit and submit for and submit for requirements
Class D Establish, maintain, and Prepare (and sign) Prepare (and sign) Perform according to
make available for audit and submit for and submit for requirements
Post-Market Surveillance and Vigilance 453
32.5.3 Combination Products

Definition: A combination product includes
• a product comprising two or more regulated components,
i.e., drug/device, biological/device, drug/biological, or drug/
device/biological, that are physically, chemically, or otherwise
combined or mixed and produced as a single entity
• two or more separate products packaged together in a
single package or as a unit and comprising drug and device
products, device and biological products, or biological and
drug products
• a drug, device or biological product packaged separately that
according to its investigational plan or proposed labeling is
intended for use only with an approved individually specified
drug, device, or biological product where both are required to
achieve the intended use, indication, or effect and where upon
approval of the proposed product the labeling of the approved
product would need to be changed, e.g., to reflect a change in
intended use, dosage form, strength, route of administration,
or significant change in dose
• any investigational drug, device, or biological product
packaged separately that according to its proposed labeling is
for use only with another individually specified investigational
drug, device, or biological product where both are required to
achieve the intended use, indication, or effect
For combination products, both the National Pharmaceutical
Control Bureau and the Medical Device Authority will evaluate the
relevant sections.
32.6 Post-Market Surveillance and Vigilance

32.6.1 Mandatory Reporting
An establishment shall report to the Authority any incident that
comes to the establishment’s attention occurring inside or outside
Malaysia that
(a) is related to the failure of the medical device or a deterioration
in its effectiveness, or any inadequacy in its labeling or in its
454 Malaysia
instructions for use and such report shall be made within

thirty days from the discovery
(b) has led to the death or serious deterioration in the state of
health of a patient, user or other person, or could do so were
the incident to recur and such report shall be made within
10 days from the discovery
(c) is a serious threat to public health and such report shall be
made within 48 hours from the discovery.
Any person who contravenes subsection (1) commits an offence
and shall, on conviction, be liable to a fine not exceeding 200000
ringgit or to imprisonment for a term not exceeding two years or to
both.
32.6.2 Field Corrective Action

An establishment shall undertake corrective or preventive action
in relation to a medical device imported and placed in the market
which may include
(a) the return of the medical device to the establishment
(b) modification of the medical device
(c) exchange of the medical device
(d) destruction of the medical device
(e) specific advice on the use of the medical device
32.6.3 Recall
An establishment may recall any defective medical device at any
time. The establishment shall, on or before undertaking a recall
of the medical device, provide information as may be specified by
the Authority. The establishment shall, as soon as possible after
the completion of a recall, report to the Authority the results of
the recall and any action taken to prevent a recurrence of the
problem. Notwithstanding the above, the Authority may order the
establishment to recall any medical device at any time due to patient
safety and public health.
References 455
32.6.4 Labeling
No guidelines have been announced for labeling requirements as
yet.
32.7 Regulatory Action for Changes and Device

Modifications
No guidelines have been announced for changes and device
modifications as yet.
References
1. Laws of Malaysia Act 737 Medical Device act 2012.

2. Espicom Business Intelligence (Quarter II 2010) A World Medical
Device Market Report, Malaysia Medical Device Market Intelligence
Report, ISSN 2043–9792.
3. Medical Device Bureau, retrieved January 2012, from http://www.
mdb.gov.my/mdb/.
Chapter 33
Philippines: Medical Device Regulatory

and Licensing
Mary Claire Cacanindina and Jennifer Cheahb

aJohnson & Johnson Medical Philippines
bJohnson & Johnson Medical Singapore
Ccacani1@its.jnj.com
Disclaimer
The information contained in this chapter is derived from public
sources and is current to the best of our knowledge. For detailed
and definitive information about a country’s laws and policies,
the government of the country concerned should be consulted.

Currently, the Philippines medical device market is valued at
approximately $200 million. The Philippines’s medical device
market is predicted to increase at about 8–10% over the next
several years. This growth will be mainly driven by imports,

www.panstanford.com
458 Philippines
healthcare expenditures, medical tourism, and the private sector.

The largest buyers of medical devices are private hospitals.
While the country has some capacity to produce domestic
products, imports account for 97% of the medical device market
in the Philippines. Almost all sophisticated medical equipment is
imported.
Industry sources indicate that the most popular products in
the Philippines medical device market are in the diagnosis and
treatment of heart and lung diseases, strokes, and kidney failures.

By virtue of the Republic Act 3720 of 1963, known as the Food, Drug
and Cosmetic Act, the Bureau of Food and Drugs was mandated
to regulate the manufacture and distribution of food, drugs and
cosmetics. In 1987, the President of the Philippines issued Executive
Order No. 175, which amended RA3720, to include the regulation
of medical devices in the mandated function of the Bureau of Food
and Drug Administration (BFAD).
To provide more focus and attention to Medical device
regulation, it was in 1999 when the Bureau of Health Devices and
Technology (BHDT) was created to regulate medical devices upon
issuance of Executive Order No. 102. However, the order has not
fully given the BHDT the authority to accept and process registration
applications and issue administrative orders relating to medical
device registration.
When Republic Act No. 9711 was enacted into law in August
2009, the Philippine Food and Drug Administration (FDA) was
created. It introduced a new FDA structure within the Department
of Health (DOH) to strengthen the regulatory authority over food,
drug, cosmetics, medical devices and other health devices.
The FDA Act created four centers:
(i) Centers for Drug Regulation and Research (to include
Veterinary medicine, vaccines and biological)
(ii) Center for Food Regulation and Research
(iii) Center for Cosmetics Regulation and Research (to include
household hazardous/urban substances)
(iv) Center for Device Regulation, Radiation Health, and Research
Department of Health (DOH) Agencies
Bureau of Food and Drugs (BFAD) with regulatory Bureau of Health Devices and Technology (BHDT)
function over food, drugs, medical devices, with regulatory functions over radiation devices and
cosmetics, and household hazardous substances radiation facilities
Food and Drug Administration (FDA)

of the Republic of the Philippines
Figure 33.1 The FDA Act affects two existing DOH agencies.
Regulatory Overview
459
460 Philippines
In the Philippines, all foreign medical devices are required to

undergo the same registration procedure, regardless of whether
they have been previously registered in other countries. Medical
equipment does not require pre-registration with BFAD, except
for radiation-emitting equipment, which must first undergo local
testing and is regulated by the BHDT within DOH. The BHDT will
issue a pre-registration certification for radiation-emitting devices.
However, distributors that market sterile or invasive medical
devices are required to hold a license to operate in the Philippines
and a Certificate of Product Registration (CPR) for all registrable
products.
33.3 History of Medical Device Regulation

The original provision of Republic Act 3720 did not prohibit the
manufacture or distribution, among others, of devices that are not
registered in BFAD. With the promulgation, however, of Executive
Order 175 on May 22, 1987, the said RA 3720 was amended
making it unlawful to manufacture, import, export, sell, offer for
sale, distribute or transfer devices that are not registered with
the BFAD.
Because of the E.O. 1975 amendment, the registration of devices
has become mandatory. Using the standards and requirements
and requirements in the registration of drug produczts and in the
licensing of drug establishments/outlets, establishments engaged
in the manufacture, distribution, etc., of medical devices are issued
license to operate and medical devices are given certificates of
product registration.
The checklists of requirements for registration of medical
devices and in vitro diagnostic products appear on 33.6 easy
reference. The registration of devices or reagents is generally
made subject to the following conditions.
• The device/reagent shall be made available only at drugstores
and hospitals and in other medical devices to be used or sold
only upon the written order of a practitioner licensed by law
to use said device/reagent.
• The labeling of the immediate container of such device/
reagent shall state
 the date (month and year) within which the device or
reagent may be used,
Regional Medical Device Harmonization under Development through ASEAN 461
 the lot or batch number of the device or reagent,

 BFAD registration number, and
 name and address of local agent.
There was yet, however, no specific rules or regulations
governing medical devices. On January 3, 1991, the Bureau of Food
and Drugs issued Memorandum Circular No. 1 series of 1991 to
establish what devices should first be registered in BFAD before
manufacture or distribution and what devices may not be registered.
Any device that was not either in the list of registrable medical
devices or in the list of medical devices will be deliberated upon by
BFAD for inclusion in either of the two afore-stated lists on a case-
to-case basis.
Although there had been efforts to define the coverage, scope,
and extent of device regulation over medical devices, the formal
issuance of these rules had been put on hold until the mandate to
regulate medical devices had been fully transferred to the BHDT.
By virtue of the Implementing Rules and Regulations of RA 9711,
the definition of the medical device had been adopted based on the
ACCSQ definition. To date, the following draft guidelines are being
reviewed:
• Registration of Medical Devices
• Registration of IVDs
• Licensing of Distributor/Wholesaler/Importer/Exporter/
Retailer
• Licensing of Manufacturer/Repacker/Trader
• Labeling Guidelines
• Advertisement
• Post-market Reporting
• Import Permit
• List of Registrable Products
33.4 Regional Medical Device Harmonization

under Development through ASEAN
The Philippines is one of 10 members of the Association of Southeast
Asian Nations (ASEAN). The BHDT is representing the Philippine
medical device sector at meetings of the ASEAN Consultative
Committee on Standards and Quality-Medical Device Product
Working Group (ACCSQ-MDPWG — hereafter ACCSQ) (created
462 Philippines
in 2004), which has met 15 times over the past eight years, most
recently in Phuket in April 2012. The working group is focusing on
three main activities:
• a comparative study of medical device regulation across all
ASEAN countries
• developing an ASEAN Common Submission Dossier Template
(more on this initiative below)
• formulating a Post Market Alert System for unsafe and
defective devices
The objective of the ACCSQ is to facilitate efforts to remove
technical barriers to trade and implement the Common Effective
Preferred Tariff to create an ASEAN-wide FTA in the next few years.
The ACCSQ is making efforts for fast-track integration within 11
priority areas, including pharmaceutical products and medical
devices, over the next few years.
Both the ACCSQ and the Asian Harmonization Working Party
(AHWP — a subgroup of the Global Harmonization Task Force
[GHTF]) intend to introduce a Common Submission Technical
Dossier for application and approval of medical device products in
each member country in the next few years (ACCSQ has implemented
the CSDT format by calendar year 2008). The two groups have
also separately adopted the GHTF medical device definition and
classification system for regulating medical devices.
33.5 Definition of Medical Device in Philippines

The Philippines uses the GHTF Study Group 1 guidance document as
the basis for its definition of medical devices
A medical device means any instrument, apparatus, implement,
machine, appliance, implant, in vitro reagent or calibrator, software,
material, or other similar or related article
(i) Intended by the manufacturer to be used, alone or in
purpose(s) of
of disease
• diagnosis, monitoring, treatment, alleviation of or
Registration with BFAD 463
• investigation, replacement, modification or support of

the anatomy or of a physiological process, supporting or
sustaining life
• disinfection of medical devices
• providing information for medical or diagnostic purposes
from the human body; and which does not achieve its
primary intended action in or on the human body by
pharmacological, immunological or metabolic means, but
which may be assisted in its intended function by such
means.
To explain further, medical devices range from a simple tongue
depressor to a complicated MRI machine. Medical devices also
included condoms, cottons, and test tubes. In vitro diagnostic devices
or self-test tubes are also considered medical devices.
33.6 Registration with BFAD

33.6.1 License to Operate
Companies that are selling registrable medical devices should first
apply for the License to Operate (LTO). The requirements for the
application of the LTO can be downloaded from the DOH Web site
(http://www.doh.gov.ph/node/398).
Only complete documents will be accepted during the
application and will be scheduled for inspection.
If the company complies with the requirements and passed
the inspection, a LTO will be issued. The company is given 60 days
to comply with all the deficiencies. Non-compliance will result in
temporary stoppage of the selling of medical devices.
The timeline given for the processing of the LTO is 90 days. This
is considering that all the documents submitted are in compliance
with the requirements and that the company passed the inspection.
Only complete documents will be accepted during the
application. The application will be reviewed and evaluated if it is
in accordance with the requirements. All complying applications
will be issued a CPR. All non-complying applications will be issued
a notice of deficiency. Each company is given a non-extendable 90
464 Philippines
CompanytosecureLicenseto
day compliance period. All those who will not be
Operate(LTO)asMedicalDevice Inspection
able to comply
establishment
will be disapproved but will be given a period of 60 days to file
for re-application and comply with all the deficiencies. In case
after this period the application did not satisfactory comply all the
CompanytoapplyforProduct
requirements, the application will be disapproved and the company
Registration(CPR)
needs to file for initial application.
ForMarketDistribution
CompanytosecureLicenseto
Operate(LTO)asMedicalDevice Inspection
establishment
CompanytoapplyforProduct
Registration(CPR)
Figure 33.2 Process of registration for registrable products (mandatory).
Companytoapplyfor(LTO) Companytoapplyfor
exemption Productexemption

Figure 33.3 Process of registration for non-registrable products
(voluntary).
Companytoapplyfor(LTO) Companytoapplyfor
The LTO is exemption
valid for one year initially followed by a two-year
Productexemption
validity.
33.6.2 License to Operate: Requirements
• Accomplished notarized petition form/joint affidavit of

undertaking
• List of medical device products to be imported/distributed
• Copies of Pharmacist’s Board of Registration Certificate, PRC ID,
valid PTR, ID picture, duties and responsibilities, certificate of
attendance of the owner or pharmacist to a BFAD seminar on
licensing of establishments
• Location plan and floor plan with dimensions
Registration with BFAD 465
• For corporations, registration certificate with SEC and articles of

incorporation or partnership
• For single proprietor, certificate of Business Name Registration
with Bureau of Trade Regulation and Consumer Protection
• Contract of lease for the space of the office and storage to be
occupied or any proof of ownership
• FAA duly authenticated by the Philippine Consular Office
• ISO/GMP of manufacturer
• Valid contract with BFAD licensed supplier/manufacturer
• Certification that products to be sold are registered with BFAD
• LTO of local distributor/manufacturer
• Copies of applicable laws
• Batch distribution record, product recall procedure
33.6.3 Certificate of Product Registration

The BFAD has issued the checklist of requirements for medical
device registration. Only companies with valid LTO as medical
device distributor-importer/wholesaler are qualified to file for
product registration application.
The requirements for the application for CPR can be downloaded
from the DOH Web site (http://www.doh.gov.ph/node/398).
The timeline given for the processing of a CPR is 90 days. This
is considering that all the documents submitted are in compliance
with the requirements. In cases there are deficiencies issued to the
company, the counting of the timeline stops and will resume only
upon submission of the compliance documents.
A Good Manufacturing Practices (GMP) certificate is sufficient to
meet a requirement attesting to the status of a manufacturer selling
in the Philippines.
A certificate for a Non-Registrable Product may be obtained
if the medical device in question falls outside the scope of BHDT
regulations. However, companies must submit the product
description and brochure to BHDT in order to assess whether the
product can be registered at all.
The validity period for initial registration of a medical device
is one year. Under BFAD Circular #05, series of 1998, medical
device renewal registrations are valid for five years.
466 Philippines
33.6.4 Certificate of Product Registration: Technical

Requirements
• Specific use and directions for use
• Copy of latest CPR
• List of amount and technical specifications of all raw materials.
• Brief description of the methods used, the facilities and
control in the manufacture, processing and packaging of the
product; for sterile products, include sterilization procedure
• Technical specification and physical description of the
finished product
• Stability studies of the product and physical description of the
finished product
• Labeling materials to be used for the product: immediate
label, box label and package insert/brochures, if available.
• Representative sample in the market or commercial pre-
sentation (at least one of each size)
• Evidence of registration/payment (charge slip/official receipt)
33.6.5 Certificate of Product Registration: Legal

Requirements
• Notarized Letter of Application from the manufacturer/trader/
distributor
• Valid LTO of manufacturer/trader/importer/distributor/
wholesaler
• Government Certificate of Clearance and Free Sale/Registration
approval of the product from the country of origin issued by
the health authority and duly authenticated by the territorial
Philippine Consulate for the imported product
• Government Certificate attesting to the status of the manu-
facturer, competency and reliability of the personnel and
facilities and duly authenticated by the territorial Philippine
Consulate and/or valid ISO Certification for the imported
product
• Certificate of agreement between the manufacturer and
trader/distributor/importer regarding the product involved
Summary of Regulatory System 467
33.7 Import Labeling

In addition to the international labeling requirements for medical
devices, the BHDT requires that the labeling of the immediate
container of such device/reagent states the following:
 the date (month and year) within which the device or reagent
may be used
 the lot or batch number of the device or reagent
 BFAD registration number
 name and address of local agent
33.8 Import Documentation

Import documentation requirements are limited to registration
of medical device firms and radiation-emitting products; these
requirements have been already summarized in the text earlier.
33.9 Summary of Regulatory System
Medical
Medical Device Device Establishment
Establishment License as
License as
• Manufacture •Manufacturer
•Distributor/importer
• Distributor/importer
•Distributor/wholesaler
• Distributor/wholesaler •Retailer
• Retailer
•Timeline maximum 90 days including the on-site inspection
• Timeline maximum 90 days including the on-site inspection
Medical DeviceMedical
Establishment License
Device Product as
Registration
• 4 Classifications
• 4 Classifications (class
(class 1 (low
1 (low risk),
risk), 2,2,3,3,44(highest
(highest risk))
risk))
• Registration
• Registration is per
is per product,per
product, per brand,
brand, perpermodel
model(except
(exceptif if
difference is in the sizes, and shapes)
difference is in the size, and shapes)
•Timeline maximum 90 days (with complete documentary
• Timeline maximum 90 requirements)
(with complete documentary
requirements)
Mandatory Reporting of Product

Mandatory Reporting
Recall
of Product Recall
Post-market
Post-marketSurveillance: on-sitevisit
Surveillance: on-site visit
to to monitor
monitor the the
continuous
continuous compliance of
compliance of the
themedical
medicaldevice
device establishments
establishments
totothe
the regulatory requirements
regulatory requirements
468 Philippines
33.10 Contacts
The Republic of Philippines
San Lazaro Compound, Sta Cruz, Manila
Trunkline: +632 651 7800
Bureau of Health Devices and Technology
Building 24, San Lazaro Compound Rizal Avenue, Sta. Cruz,
Manila, The Philippines
Telephone: +632 743 8301; local: 3402, 3408
Fax: +632 711 6016; 711 6824
Bureau of Food and Drugs
Civic Drive, Filinvest Corporate City
Alabang, Muntinlupa City 1781, The Philippines
Telephone: +632 807 07 21
Fax: +632 842 56 06
References
1. Medical Device Regulatory Requirements for the Philippines, retrieved

May 28, 2012, from http://www.ita.doc.gov/td/health/Philippines%2
0Reg%20Profile%202006.pdf.
2. Republic of the Philippines, Department of Health, Bureau of Food
and Drugs, retrieved May 28, 2012, from http://www.doh.gov.ph/
node/1395.
3. Republic of the Philippines, Department of Health, retrieved May 28,
2012, from http://www.doh.gov.ph/faq/350#t350n1432.
4. The New Food and Drug Administration (FDA) of the Republic of
the Philippines, retrieved, May 28, 2012, from http://www.who.int/
medical_devices/02_agnette_peralta.pdf.
5. Drug-related administrative orders and Memorandum circulars
(with summaries and annotations), Republic of the Philippines,
Department of Health, Bureau of Food and Drugs DOH Compound,
Alabang, Muntinlupa, M.M. Memorandum Circular No. 14 s. from
August 19, 1991.
Chapter 34
Saudi Arabia: Medical Device Regulation

System
Ali M. Al Dalaana,b
aAsianHarmonization Working Party
bSaudiFood and Drug Authority, 3292 North Ring Road,
Riyadh 13312-6288, Kingdom of Saudi Arabia
amdalaan@sfda.gov.sa
Disclaimer
34.1 Introduction
The Kingdom of Saudi Arabia (KSA) is a leading country in the world
economy and an influential market among the Middle East, North
Africa, and the Gulf Cooperate Council. It is one of only a few fast-
growing countries in the world with a relatively high per capita
income of $24,200 (2010); therefore, the Saudi Arabian medical
devices market is the biggest market in the middle east, with
growth rate of higher than 9%. Saudi Arabia has a highly sophisti-

www.panstanford.com
470 Saudi Arabia
cated healthcare facilities system associated with 390 hospitals

occupying more than 54,000 beds, 2037 primary healthcare
centers, 175 artificial kidney centers and approximately 217
private medical centers. However, the Saudi Arabia medical device
market is expected to grow tremendously in the next few years
due to the heavy investment in health care. The Saudi Arabian
Government established medical devices regulation to comply with
revolution of medical Devices technology and to safe guard the
public health of Saudi Arabia.
The Saudi Food and Drug Authority (SFDA) law issued by the
royal decree (M/6) on February 13, 2007, gave the SFDA the res-
ponsibility to regulate medical devices in Saudi Arabia. The council
of ministers’ decision no. 181 issued on June 18, 2007, came to
stress the importance of regulating medical devices. It was issued
specifically for medical devices to address the need of the rapid
growth of the Saudi Arabia medical device market to ensure safety,
quality, and effectiveness of medical devices throughout their life
cycle (pre-market, on-market and post-market).
34.2 Legislative Responsibilities

1. Providing technical support to importers
2. Setting mandatory specifications for medical devices, in vitro
diagnostics (IVDs), and radiation-emitting electronic devices
that affect the human health
3. Setting health and good manufacture practice requirements
for all medical device establishments and manufacturers
4. Laying down policies and procedures for medical devices
testing
5. Setting requirements for medical devices marketing and
distribution and all related issues
6. Laying down regulation for medical devices advertising
34.3 Executive Responsibilities

1. Test medical devices, prescription eye glasses, contact lances,
radiation-emitting electronic devices that effect human
health to ascertain their quality, safety, effectiveness and
compliance with mandatory standard approved by the SFDA
Surveillance Responsibilities 471
2. Test IVDs medical devices to ascertain of their quality,

effectiveness and compliance with the manufacturers
standards
3. Register and test of medical devices and all related issues
4. Issue marketing authorization for imported medical devices
after doing the necessary validation and testing
5. Permit the marketing of local manufactured medical device,
IVDs, prescription eye glasses, contact lenses and their
solutions when they have meet the marketing authorization
requirements
6. Establishing a central reference laboratory for medical
devices in SFDA headquarter, and specialized branched
laboratories in the kingdom’s provinces
7. Accredit and license the private medical devices laboratories
that relate to medical devices work field
8. Establish a medical devices database, and exchange
information with local, regional and international bodies
9. Establish a main research center to conduct research and
applied study relating to medical devices field
10. Conduct researches, studies and provide consultancy
services related to medical devices and cooperate with
medical devices establishments, authorities, universities,
scientific research centers and other institutions conducting
similar activities
11. Conduct training programs that enhance the competency of
those working in the medical devices field
12. Promote consumer awareness of medical devices and
sector’s responsibilities
13. Represent the KSA in regional and international authorities
and organizations relating to the sector’s activities
14. Establish National Center for Medical Devices Reporting
(NCMDR)
15. Establish Medical Devices National Registry (MDNR)
34.4 Surveillance Responsibilities

1. Monitor the implementation of regulations, guidelines
and procedures relating to licensing of medical device’s
manufactures
472 Saudi Arabia
2. Monitor the market of medical devices, IVDs, prescription

eye glasses, contact lenses and their solutions to make sure
marketed product have SFDA marketing authorization.
3. Inspection of medical devices establishments to assure their
compliance with the SFDA requirements.
4. Monitor the market of medical devices, IVDs, prescription
eye glasses, contact lenses and their solutions to ensure the
establishment has the establishment license.
5. Follow up medical devices recalls with hospitals, healthcare
providers in the kingdom, manufacturers and imports and
take appropriate corrective and/ or preventive action.
34.5 Regulation Overview

The Saudi FDA issued medical device interim regulation on
December 27, 2008; the interim regulation will be replaced with
the medical device main regulation that is being developed.
The medical device interim regulation is based on the
GHTF founding member jurisdiction regulatory requirements.
Therefore, to obtain marketing authorization, medical devices
shall comply with the relevant regulatory requirements applicable
in one or more of the jurisdiction of Australia, Japan, the United
States and the EU/EFTA, and additionally with provision specific
to the KSA concerning labeling and conditions of supply and or use.
The main objectives of the medical devices interim
regulation are to protect and maintain public health within the
KSA by the implementation of provisions ensuring a high level of
safety and health protection of patients, users and third parties with
regard to the use of medical devices as it relates to their manu-
facture, supply and use during their lifecycle and to mandate
measures, and allocate responsibilities, to ensure that medical
devices placed on the market and/or put into service within
the KSA comply with all relevant requirements and provisions
of the interim regulation and its implementing rules. Nevertheless,
Saudi FDA is working forward the development of frame-
work Regulation to cover all Medical Devices Requirements.
Information to Be Provided to SFDA 473
34.6 Registration Requirements

• Each importer and distributor requires an Establishment
National Registry Number issued by the SFDA before it is
permitted to apply for a license and import or distribute
medical devices within the KSA.
• The application for registration will be made electronically
through the Medical Device National Registry (MDNR),
which is found on the SFDA Web site and prescribes the
information that has to be provided before the SFDA
assigns a National Registration Number to the importer or
distributor
• The importer and distributor shall attest that the
information specified in the electronic application is accurate
and will be regularly updated
• The same Web site is used to update previously submitted
information. In this case the importer or distributor has
10 calendar days from the occurrence of the change to
provide the SFDA with revised information.
• Where an authorized representative has also a legal entity
involved in importation or distribution activities of medical
devices within the KSA, it is subject to all the additional
requirements and responsibilities of such an importer or
distributor.
• Local manufacturers or retail pharmacies are deemed
to be distributors if they place medical devices on the KSA
market.
• The SFDA/MDS may ask the registrant to confirm the
registration information it holds remains true and complete
34.7 Information to Be Provided to SFDA

• Each organization involved in the importation and/or the
distribution of medical devices within the KSA requires
an establishment license, issued by the SFDA, before it
undertakes such activities.
474 Saudi Arabia
• Such an organization is normally an “importer” or “distrib-

utor” but may be a local manufacturer distributing its own
or another manufacturer’s medical device, or an authorized
representative of an overseas manufacturer involved in the
importation or distribution of medical devices, or a retail
pharmacy distributing medical devices.
• Organizations involved in both importation and distribu-
tion will have both activities included on the establishment
license.
• Each organization intending to import and/or distribute
medical devices in the KSA shall have obtained an Establish-
ment National Registry Number from the SFDA, before it
applies for an establishment license.
• Each importer shall, in cooperation with the authorized
representative(s) of one or more manufacturers, decide
which category(ies) or group(s) of medical devices it intend
to import into the KSA and establish the contact details of the
manufacturer(s) concerned.
• Each distributor shall, in cooperation with either the local
manufacturer(s) or with the authorized representative(s)
of one or more manufacturers, as relevant, shall decide
which category(ies) or group(s) of medical devices it
distribute within the KSA and establish the contact details
of the manufacturer(s) and authorized representative(s)
concerned.
• The device category is selected from: active implantable
devices; anesthetic and respiratory devices; dental devices;
diagnostic electro mechanical medical devices; hospital
hardware; In vitro diagnostic medical devices; non-
active implantable devices; ophthalmic and optical devices;
reusable devices instruments; single-use devices; assistive
products for persons with disability; diagnostic and
therapeutic radiating devices; complementary therapy
devices; biologically derived devices; healthcare facility
products and adaptations; IVD laboratory equipment.
• The application for establishment licensing will be made
electronically through the Medical Device Establishment
Licensing (MDEL), which is found on the SFDA Web site and
must be completed by each importer and distributor.
Information to Be Provided to SFDA 475
• Once satisfied that the application meets the relevant

requirements, the SFDA shall issue the applicant with an
establishment license that is renewable annually.
• Licensed organizations shall revise the information provided
to the SFDA within 10 days of the change occurring when
 there is a change in its contact information,
 there is a change in the category or group of medical
device it imports or distributes, and

 it adds another manufacturer to those it already
represents.
• To ensure medical devices placed on the KSA market are
suitable and properly supported
 any organization intending to import medical devices into
the KSA or
 any organization intending to distribute medical
devices within the KSA (including retail pharmacies)
shall do so only with the knowledge of the authorized
representative(s) or local manufacturer(s) concerned, as
relevant.
• Information for importation and distribution activities will
include
 the name of the overseas manufacturer of the medical
devices that the applicant imports or intends to import,

together with the name of that manufacturer’s licensed
authorized representative and its establishment National
Registry Number,
 an attestation that the manufacturer has been informed,
through its authorized representative, of the applicant’s

intention to import its medical devices into the KSA,
 an attestation that the importer has used its best
endeavors to establish that the imported device(s) is/are

in compliance with the relevant provisions of the Medical
Devices Interim Regulation and its implementing rules,
 the medical device category and generic device group
the applicant intends to import from the manufacturer,

 the name of the manufacturer of the medical devices that
the applicant intends to distribute, together with the

Establishment National Registry Number of either the
476 Saudi Arabia
local manufacturer or, for medical devices manufactured

outside the KSA, the authorized representative,
 an attestation that either the local manufacturer or the
authorized representative together with the importer, as

applicable, has been informed of the applicant’s intention
to distribute its medical device(s) within the KSA, and
 the medical device category or generic device group the
applicant intends to distribute within the KSA.
34.8 Medical Device Marketing Authorization

(MDMA)
• To obtain marketing authorization, medical devices shall
comply with the relevant regulatory requirements applicable
in one or more of the jurisdictions of Australia, Canada,
Japan, the United States, and the EU/EFTA, and additionally
with provisions specific to the KSA concerning labeling and
conditions of supply and/or use.
• Marketing authorization is required for
 all medical devices whatever their classification,
 contact lenses for cosmetic as well as for medical purposes,
and
 laser surgical equipment intended for cosmetic as well as
medical purposes.
• It is not required for medical devices designed and constructed
by health facility staff for internal use within that health
facility, alone.
• Medical device marketing authorization (MDMA) applications
shall be made by either a local manufacturer or, where the
manufacturer is established outside the KSA, by its authorized
representative.
• Information is submitted to the SFDA using the electronic
application forms found on the MDMA section of its Web site.
After indicating which of the five GHTF Founding Member
jurisdictions will be used as the basis of the MDMA application,
the applicant (either a local manufacturer or, where the
manufacturer is established outside the KSA, by its authorized
representative) will be directed to the appropriate part of
Medical Device Marketing Authorization (MDMA) 477
the Web site. Implementing Rule Marketing Authorization

describes the application procedure and the documentary
evidence that has to be provided to support the applicant’s
claim that the device meets all relevant requirements of the
Medical Device Interim Regulation.
• Two categories of information must be provided. The first
requires general information (such as the applicant’s contact
details) and information specific to the KSA. The second
requires information specific to the particular GHTF Founding
Member jurisdiction the manufacturer has chosen as the
basis of the MDMA application. In addition, the manufacturer
will hold, and make available to the SFDA upon request,
additional documentary evidence to support its MDMA
application.
• The documentation provided shall relate to the medical device
that is the subject of the MDMA and be sufficient to
 identify the medical device that is the subject of the
application, its manufacturer and the legal entity making

the application,
 demonstrate the device complies with all relevant
provisions specific to the KSA, and

 demonstrate the manufacturer of the device has been
authorized to place the device on the market in one of the

five GHTF Founding Member jurisdictions.
• MDS-G5 Guidance on Marketing Authorization Procedures/
(H)/Comment #13 states, “The end date of the period of
validity will be the same as that of the marketing authoriza-
tion granted in the GHTF Founding Member jurisdiction
unless the GHTF Founding Member’s authorization is open
ended and does not indicate a validity end-date, or where the
device has been marketed through a self-declaration process
(e.g. Class I devices that are not sterile or having a measuring
function under EU regulations), where validity shall be
3 years.”
• MDS-G5 Guidance on Marketing Authorization Procedures
states, “MDMAs Incorporating More Than One Medical Device
Type:
 Where the applicant’s MDMA groups more than one
medical device type (referred to as “bundling” in some

478 Saudi Arabia
jurisdictions) within a single application procedure,

the grouped medical device types shall all have been
authorized for marketing within the GHTF Founding
Member jurisdiction, upon which the MDMA is based, on
the same basis.
 Where the MDMA procedure involves medical device
types having different purposes, technical performance

and classification, the applicant will have to access
the MDMA portion of the SFDA’s website on multiple
occasions to provide the required information. While
some of that information will be common, the KSA
national provisions will vary with the different medical
device types.
• When the SFDA is satisfied that the medical device meets
the provisions of the Medical Devices Interim Regulation, it
authorizes the manufacturer to place the device on the KSA
market by issuing a numbered Marketing Authorization
Certificate and assigning each device to which the certificate
applies with a Medical Device Listing National Registry
Number.
34.9 Medical Device Listing

To obtain an establishment license, the importer and the
distributor have to indicate the categories of medical device they
intend to supply to the KSA market but do not have to provide full
details of the devices. Before particular medical devices within
each category or group are placed on the KSA market for the first
time, these devices/must have been authorized by the SFDA and
when these devices are imported or distributed within the KSA
market, the importers and the distributors must provide listing
information to the Medical Device National Registry (MDNR) for
the devices concerned.
34.10 Registration Fees

Table 34.1 presents the fee structure for Medical Device Marketing
Authorization (MDMA).
Registration Fees 479
Table 34.1 Medical Device Marketing Authorization processing fees
Basis of application Three More than Lead time

Fee for sfda marketing years or three years (working
groups authorization less (sr) (sr) days)
FG(1) All class I/general IVD 15,000* N/A 35
(other)/exempt IVD (TGA)
FG(2) All class II/class IIa/self- 19,000 21,000 35
test IVD, listable IVD
FG(3) Class IIb/class III (CA, 21,000 23,000 35
PAL)/Annex II list B (IVD)
FG(4) All other class III/class 23,000 25,000 35
IV/AIMD/Annex II list A
(IVD)/registrable IVD
*For class I, the Medical Device Marketing Authorization issues by the SFDA will be
valid for three years.
Note: For all other classes, the Medical Device Marketing Authorization issues by the
SFDA will be valid for the remaining validity of the original license or for three years
for license with undefined validity.
Table 34.2 presents the fee structure for the Medical Device
Authorized Representative (AR) License.
Table 34.2 Medical Device Authorized Representative License processing

fees
Basis of the application

for SFDA Authorized Annual fee (SR) Lead time (working
representative days)
Per manufacturer mandate 5200 20
Table 34.3 presents the fee structure for Medical Device

Establishment Licensing (MDEL).
Table 34.3 Medical Device Establishment Licensing processing fees
Establishment class Annual fees (SR) Lead time (working days)

(A) 35,000 15
(B) 30,000 15
(C) 25,000 15
(D) 15,000 15
480 Saudi Arabia
34.11 General Information and Documentary

Evidence to Be Provided to SFDA
• Where the applicant is a local manufacturer, he shall
provide his company name and contact information, together
with the contact details of the person responsible for the
medical device MDMA application. Also, he shall provide
his Establishment National Registry Number.
• Where the applicant is an authorized representative, he
shall provide the same information as in the previous point,
together with the contact information of the overseas
manufacturer on whose behalf he is acting, and his Authorized
Representative License Number.
• The applicant shall provide information that will allow the
medical device that is the subject of the application to be
identified unambiguously. Where the MDMA application
procedure covers more than one medical device type, the
requirements in Section 34.6 must be met. If they are not,
the MDMA application will be rejected and the applicant
must resubmit multiple applications.
• In addition to providing documentary evidence that the
medical device that is the subject of the MDMA application
complies with the medical devices regulation that applies
to it within a selected GHTF Founding Member jurisdiction,
the applicant must provide evidence that the device complies
with requirements specific to the KSA. These concern labeling,
any a/c power supply, environmental factors, handling/
transportation/ storage, and advertising.
• In addition to providing documentary evidence that
the medical device that is the subject of the MDMA
application complies with requirements specific to the
KSA, the applicant must provide evidence that the device
complies with the medical devices regulation that applies to
it within the particular GHTF Founding Member jurisdiction
that has been chosen as the basis of the application. By
indicating which GHTF jurisdiction is being used, the
applicant will be directed to the relevant part of the
Web site.
Post-Market Surveillance Requirement 481
34.12 Labeling Requirement for Medical Device

• In addition to providing documentary evidence that the
medical device that is the subject of the MDMA application
complies with the medical devices regulation that
applies to it within a selected GHTF Founding Member
jurisdiction, the applicant must provide evidence that the
device complies with requirements specific to the KSA. These
concern labeling, any a/c power supply, environmental factors,
handling/ transportation/ storage, and advertising.
• The SFDA requires electronic copies of the labels affixed
to the device and its wrappers, as well as a copy of the
instructions for use, in the format that will be used when the
device is marketed within the KSA. The SFDA will confirm,
in particular, they satisfy requirements in respect of product
identification, language, and tracking of individual devices
through the supply chain.
• Where the device is intended for use by laypersons, the text
of labeling shall be written in terms readily understood by
such persons.
• All required documents are in English except that labeling has
the following requirements:
 Labeling in English is acceptable where the user(s) of the
medical device is likely to be professionally qualified.

 Where the device is intended to be used by laypersons,
the labeling shall be in both Arabic and English. Medical

personnel at healthcare facilities are not considered to
be laypersons.
 Instructions for the handling, storage, transportation,
installation, maintenance, and disposal of the medical

devices shall be in English and, where justified, in Arabic.
 Advertising and marketing information shall be in
English and, where justified, in Arabic.
34.13 Post-Market Surveillance Requirement

• The SFDA shall ensure the appropriate and efficient operation
of the necessary medical device vigilance procedures.
482 Saudi Arabia
It shall, in particular, advise users and persons involved

in the provision of healthcare in the KSA to inform without
delay the manufacturer concerned of any adverse event
and the SFDA of any reportable adverse event they become
aware of, involving a specific medical device.
• All parties concerned shall be made aware of the existence
and responsibilities of the SFDA being the medical device
vigilance authority. Furthermore, the SFDA shall indicate
how it may be contacted to notify medical device reportable
adverse events.
• Investigate any adverse event of which it becomes aware.
If the manufacturer confirms a malfunction or deterioration
in the characteristics and/or performance of the medical
device, as well as any inadequacy in the labeling or the
instructions for use, has led, or might have led, to the death
of a patient, user or third person, or to a serious deterioration
in the state of health of a patient, use or third person, it shall
submit an adverse event report to the SFDA and agree a
corrective action plan.
• An important aspect of effective post-market surveillance
is the need of the SFDA, health authority and/or overseas
manufacturer to identify an individual medical device so
that it may be traced, examined, or recalled after is has been
put into service. Therefore, the manufacturer is required
to label the medical devices it manufactures with an
unambiguous identification, such as batch code / lot number,
or serial number, preceded by the word LOT or SERIAL
NUMBER (or an equivalent symbol) as appropriate. In general,
consumable and single-use devices have a batch code, while
powered medical devices have individual serial numbers.
References
SFDA, National Provisions & Requirements for Medical Devices, http://www.

sfda.gov.sa/NR/rdonlyres/5105459F-B824-4C8A-99BF EE5E0C7519
CF/0/NationalProvisionsandRequirementsfor MedicalDevices.pdf.
SFDA, MDS-IR1, Designation and Oversight of Conformity Assessment Bodies,
http://www.sfda.gov.sa/NR/rdonlyres/AC5CA167-BDDB-4609-
BBE4-9844A0B133AB/0/IR12011.pdf.
References 483
SFDA, MDS-IR2, Establishment Registration, http://www.sfda.gov.sa/NR/

rdonlyres/B963B4B2-BCEB-4F7C-84D9-74358B4CDF90/0/
MDSIR22011.pdf.
SFDA, MDS-IR3, Medical Device Listing, http://www.sfda.gov.sa/NR/rdo-
nlyres/311CDE1B-D150-4483-82F4-6D3C4F211904/0/MDSIR
32011.pdf.
SFDA, MDS-IR4, Establishment Licensing, http://www.sfda.gov.sa/NR/rdo-
nlyres/2FAD6767-2C25-410C-A4C0-E06B60ABE64D/0/MDSIR
42011.pdf.
SFDA, MDS-IR5, Licensing of Authorized Representatives, http://www.sfda.
gov.sa/NR/rdonlyres/75275AAA-6903-431B-83DD-12D4E5B6
DEC5/0/MDSIR52011.pdf.
SFDA, MDS-IR6, The Validation of Document to Be Provided to the SFDA
by Manufactures for Marketing Authorization, http://www.sfda.gov.
sa/NR/rdonlyres/8FB37D1B-C4CD-4B56-BFA0-D9216CE81BEB/0/
MDSIR62011.pdf.
SFDA, MDS-IR7, Marketing Surveillance, http://www.sfda.gov.sa/NR/rdo-
nlyres/93ECAE2F-923E-443B-A83C-AFE2E22CE52C/0/MDSIR
72011.pdf.
SFDA, MDS-IR8, Safeguard Procedures, http://www.sfda.gov.sa/NR/rdo-
nlyres/51ED1E9D-5E60-42DC-8C5B-B7C332200F98/0/MDSIR
82011.pdf.
484 Saudi Arabia
Appendix: Definitions
KSA: The Kingdom of Saudi Arabia
SFDA: Saudi Food and Drug Authority
The Board: The SFDA board of directors
Party: Any natural or legal person
Medical device: Any instrument, apparatus, implement, machine,
appliance, implant, in vitro reagent or calibrator, software, material
or other similar or related article
purpose(s) of
of disease
compensation for an injury or handicap
the anatomy or of a physiological process,
• supporting or sustaining life
from the human body
(b) which does not achieve its primary intended action in or on the
means, but which may be assisted in its intended function by
such means.
Accessory: A product intended specifically by its manufacturer
to be used together with a medical device to enable that medical
device to achieve its intended purpose
Advertising of medical devices: Any form of information,
canvassing activity or inducement intended to promote the supply
or use of medical devices
Applicant: Any party established within the KSA required to
provide information for establishment licensing purposes
Authorized representative: Any natural or legal person
established within the KSA who has received a written mandate
from the manufacturer to act on his behalf for specified tasks
Appendix 485
including the obligation to represent the manufacturer in its

dealings with the SFDA
CAB: A conformity assessment body (third party), established
within the KSA, independent of both the manufacturer and user
of the medical device that is subject to assessment
Distributor: Any natural or legal person in the supply chain
who, on his own behalf, furthers the availability of a medical device
to the end user
Establishment: Any place of business within the KSA that
is involved in the manufacture, and/or placing on the market,
and/or distribution of medical devices; or acting on behalf of the
manufacturer
Fully refurbished medical device: A used device that has
been returned to a state that would allow it to be subject to the
same conformity assessment procedures as applied to the original
device.
Global Harmonization Task Force (GHTF): Countries working
to achieve harmonization in medical device regulation among
themselves; these countries are Australia, Canada, Japan, the United
States, and the EU/EFTA
Importer: Any natural or legal person in the supply chain
who is the first to make a medical device, manufactured in another
jurisdiction, available in the KSA
In vitro medical device: A medical device, whether used
alone or in combination, intended by the manufacturer for the
in vitro examination of specimens derived from the human body
solely or principally to provide information for diagnostic, monitoring
or compatibility purposes; this includes reagents, calibrators,
control materials, specimen receptacles, software and related
instruments or apparatus or other articles
Labeling: Written, printed or graphic matter
(a) Affixed to a medical device or any of its containers or
wrappers
(b) Information accompanying a medical device, related to
identification, technical description
(c) Information accompanying a medical device, related to its use,
but excluding shipping documents
Manufacturer: Any natural or legal person with responsibility
for design and manufacture of a medical device with the intention
486 Saudi Arabia
of making it available for use, under his name; whether or not such
a medical device is designed and/or manufactured by that person
himself or on his behalf by another person
Medical Devices National Registry (MDNR): The database of
registered establishments and the medical devices they manufacture
or import or distribute
National Center for Medical Device Reporting (NCMDR):
An organization managing a database of information on safety
and performance related aspects of medical devices and capable of
taking appropriate action on any confirmed problems.
Placing on the market: The first making available in return
for payment or free of charge of a medical device, with a view to
distribution and/or use within the KSA, regardless of whether it is
new or fully refurbished
Putting into service: The stage at which a device has been
made available to the final user as being ready for use for the first
time in the KSA for its intended purpose
Registrant: Any party established within the KSA required
to provide information for establishment registration or medical
device listing purposes
Chapter 35
Singapore: Medical Device Regulatory

System
Lee Ching Hwee

Johnson & Johnson Medical Singapore,
No. 2 International Business Park, #07-01,
Tower One, The Strategy, 609930 Singapore
Clee14@its.jnj.com
Disclaimer
35.1 Market Overview Introduction: An

Explanation of the Process and Approach
Singapore, as the region’s healthcare hub and center of healthcare
excellence, is striving to deliver first-class health care management
to its residents as well as serving patient’s needs internationally.

www.panstanford.com
488 Singapore
With improvements in sanitation, medical technology, and

public health awareness, life expectancy has risen significantly
over years. As of 2011, the resident population of Singapore was
5.18 million. By 2030, elderly people aged 65 and older are expected
to make up 19% of the population. This indirectly signifies the
importance of health care delivery and medical care to its nations.
In 2004, Singapore’s total market size for medical devices was
estimated to be US$ 535 million (Fig. 35.1) The market for medical
devices is in the growing trend as a result of Singapore’s position as
the regional medical and research hub.
Medical Device Market in Singapore

Total import 898
The above statistics are unofficial estimates in 2004

Source: IE Singapore, Singapore Trade Statistics Total export 1320
Data is in millions of USD (1USD = 1.7SGD)
Figure 35.1 Angelique Chan, Singapore’s Changing Structure and the

Policy Implications for Financial Security, Employment, Living
Arrangements and Health Care. ASIAN Metacentre Research
Paper Series No. 3.
35.1.2 Overview of Regulatory Environment and What

Laws/Regulations Govern Medical Devices
Singapore Health Sciences Authority (HSA), Medical Device Branch,
is entrusted with regulating medical devices in Singapore. HSA
has adopted the new regulatory system based on the principles
endorsed by the Global Harmonization Task Force (GHTF) with
modification to suit the Singapore context. HSA has also studied
the medical device regulatory system in developed country counter
parts, including the US Food and Drug Administration (FDA),
According to the Department of Statistics, Singapore.
Market Overview Introduction 489
European Union, Canada’s Medical Devices Bureau (MDB), Japan’s

Ministry of Health, Labour and Welfare (MHLW), and Australia’s
Therapeutic Goods Administration (TGA). In general, the regulatory
framework for medical devices in Singapore is mapped in order to
safeguard public health but without unduly restricting consumer
choices and their access to new technologies.
In 2002, HSA introduced the Voluntary Product Registration
Scheme and post-market monitoring and surveillance program for
medical devices in the Singapore market. With the passage of the
Health Products Act 2007 in February 2007, HSA implemented the
Health Products (Medical Devices) Regulations to further strengthen
the control of medical devices in local market. The regulatory
controls were implemented in three phases:
35.1.2.1 Phase I implementation

On November 1, 2007, duties and obligations were imposed on
medical device dealers to
• report adverse events to HSA within the stipulated time
frame
• notify HSA prior to the initiation of a product recall
• maintenance of product compliant and distribution records
In addition, false or misleading advertisements and promotions
of medical devices are prohibited.
35.1.2.2 Phase II implementation

On November 1, 2008, HSA rolled out medical device dealers and
registrant licensing, whereby companies dealing with medical
device manufacturing, importation, and exportation shall submit
application in order to be licensed.
35.1.2.3 Phase III implementation

Since August 10, 2010 (IIIa), unlicensed manufacturing, importation,
and wholesaling of medical device have been prohibited. Class C
and D medical devices that are imported and supplied must fulfill
one of the following criteria:
• listed on Singapore Medical Device register
• listed on the Transition List
• authorized via one of the Authorization Routes
490 Singapore
Medical devices licensed under the Radiation Protection Act by

the Centre for Radiation Protection and Nuclear Science (CRPNS)
of the National Environment Agency (NEA) are exempted from
product registration with HSA until August 1, 2011. Post August
1, 2011, the ionizing radiation irradiating medical devices must
be registered under HSA Medical Device Branch and separate
application should be made to the Centre for Radiation Protection
and Nuclear Science (CRPNS) under National Environmental
Agency (NEA).
From January 1, 2012 (IIIb), unless exempted from product
registration, all medical devices (Class A, B, C, and D) that are
imported and supplied must meet one of the criteria listed in
Table 35.1:
Table 35.1 Various implementation phases of the regulatory control
November
November 1, 1, 2008, May 1, August 10,
2007, onward onward 2010 2010 January 1, 2012
Phase 1 Phase 2 Phase 3A Phase 3B
Imposition Acceptance Transition Only licensed Unless

of duties and of license List is dealers shall authorized by
obligations on application finalized manufacture, HSA or listed on
dealers: of parties and import and the Transition
• Report product dealing with published supply MDs List, all classes
defects and AEs MD (last entry Unless of MDs are
• Recall product Acceptance of April 30, authorized prohibited from
upon HSA registration 2010 by HSA or supply (Class A,
instructions of Class listed on the B, C, D)
• Keep C, D MDs Transition MDs licensed
distribution (Transition list, all under Radiation
records list/ unregistered Protection Act,
registered) Class C, D MDs NEA — August 1,
are prohibited 2011
from supply
Advertisement and Acceptance of registration of Class A, B and

promotion control MDs currently licensed under CRP, NEA
Detail of Key Regulator(s) 491
35.2 Detail of Key Regulator(s)

The Health Products Regulation Group (HPRG) of HSA is the
national regulator for health products. HPRG ensures that drugs,
innovative therapeutics, medical devices and health-related
products in Singapore are controlled and meet appropriate
standards of safety, quality and efficacy.
Figure 35.2 The HSA organization chart.
The Medical Device Branch is entrusted with regulating medical

devices in Singapore.
HealthȱProductsȱRegulationȱGroup
Complementaryȱ Auditȱ&ȱ
PreȬmarketingȱDivision Vigilance,ȱComplianceȱ&ȱ
HealthȱProductsȱ Licensingȱ
EnforcementȱDivision
Division Division
Pharmaceuticalsȱ&ȱ
QualityȱAssuranceȱ
RegulationȱBranch
MedicalȱDeviceȱ
VigilanceȱBranch
BiologicȱBranch
Genericȱ&ȱBioȬ
similarȱBranch
ClinicalȱTrialȱ
AuditȱBranch
Enforcementȱ
Complianceȱ
Tobaccoȱ
Branch
Branch
Branch
Office
Branch
Figure 35.3 The Health Products Regulation Group organization chart.

492 Singapore
ontact information
C
Medical Device Branch — Therapeutic Products Division,
Health Products Regulation Group — Health Sciences Authority,
11 Biopolis Way #11-01 Helios, Singapore 138667
Telephone: +65 6866 3560
Fax: +65 6478 9028
Web site: www.hsa.gov.sg
Email: HSA_MD_Info@hsa.gov.sg

35.3.1 The Definition of Medical Device
“Medical device” means any instrument, apparatus, implement,
machine, appliance, implant, in vitro reagent or calibrator, software,
material or other similar or related article that is intended by its
manufacturer to be used, whether alone or in combination, for
humans for one or more of the specific purposes of
• diagnosis, prevention, monitoring, treatment or alleviation of
any disease,
compensation for an injury,
• investigation, replacement, modification, or support of the
anatomy or of a physiological process,
• supporting or sustaining life,
• control of conception,
• disinfection of medical devices, or
from the human body, which does not achieve its primary
intended action in or on the human body by pharmacological,
immunological or metabolic means, but which may be assisted
in its intended function by such means.
An in vitro diagnostic device includes any medical device that
is a reagent product, calibrator, control material kit, instrument,
apparatus, equipment, or system, whether used alone or in
combination, intended by the manufacturer to be used in vitro for
the examination of specimens, including blood and tissue donations,
derived from human body, solely or principally for the purpose of

providing information
• concerning a physiological or pathological state, state of health
or disease,
• concerning a congenital abnormality,
• to determine the safety and compatibility with the potential
recipients, or
• to monitor therapeutic measures.
Medical devices cover a wide range of products, ranging from
simple bandages, walking stick, contact lenses, and wheelchair,
through life-maintaining implantable device, equipment to screen
and diagnose diseases and health conditions, to the most sophisti-
cated diagnostic imaging and minimal invasive surgery equipment.
Products that are not intended for use in preventing, diagnosing,
curing, or alleviating diseases, ailment, defects, or injuries are
not medical devices. Examples of products that are not medical
devices are body-toning equipment and magnetic accessories.
35.3.2 Classification of Medical Devices (Classes A, B, C,

and D)
35.3.2.1 Principle
Regulatory control is proportional to the level of risk associated
with a medical device, which increases with higher degree of risk
involved. Therefore, medical devices are classified on the basis
of their risk to patients and users substantially on its intended
purpose and effectiveness of the risk management techniques
applied during design, manufacture and use.
35.3.2.2 Classification
Various factors contribute to the risk classification of medical
devices, which include
• duration of medical device contact with the body
• degree of invasiveness
• delivery of medicinal products or energy to the user
• intended to have biological effect on the user
Based on the product owner’s intended purpose, two or more
risk classification rules apply to the medical device, the highest
494 Singapore
level of risk classification indicated shall be allocated to the medical

device.
Table 35.2 The general risk classification system for medical devices
Risk class Risk level Medical device examples

A Low risk Surgical retractors/tongue depressors
B Low-moderate risk Hypodermic needles/suction equipment
C Moderate-high risk Lung ventilator/bone fixation plate
D High risk Heart valves/implantable defibrillator
35.3.2.3 Determination
The determination of medical device risk class in Singapore uses
the rules-based system depending on the claims made by the
product owner and on its design and intended purpose.
For more details, please read GN-13-R1 Guidance on the Risk
Classification of General Medical Devices and GN-14-R1 Guidance
on the Risk Classification of in vitro Diagnostic Medical Devices
available at the HSA Web site.
35.4 Product Grouping

Diversified medical devices require registration prior to supply
to the local market, from simple medical devices, such as syringe
and tongue depressor, to highly complex medical devices that
comprise myriad components, such as anesthesia monitoring
system. These various components can be sold separately, as
replacement, in different combinations as a convenient all-in-one
kit, or as an individually customized pack. Thus, medical devices
can be grouped into one of the following categories, to be submitted
as one product registration application — SINGLE, FAMILY,
SYSTEM, GROUP, and IVD CLUSTER — and eventually listed in the
Singapore Medical Device Register (SMDR).
35.4.1 Single
A SINGLE medical device is a medical device from a product owner
identified by a medical device proprietary name with a specific
intended purpose. It may be offered in a range of package sizes.
Product Grouping 495
Example: condoms that are sold in packages of 3, 12, and

24 can be registered as a SINGLE medical device.
35.4.2 Family
A medical device FAMILY is a collection of medical devices and each
medical device FAMILY member
• is from the same product owner,
• is of the same risk classification class,
• has the same medical device proprietary name,
• has a common intended purpose,
• has the same design and manufacturing process, and
• has variations that are within the scope of the permissible
variants, such as concentrations, flavor, color, and diameter.
Example: IV administrative sets that differ in features, such as
safety wings and length of tubing, but are manufactured from the
same material and manufacturing process and share a common
intended purpose.
35.4.3 System
A medical device SYSTEM comprises a number of constituent
components that are
• from the same product owner,
• intended to be used in combination to complete a common
intended purpose,
• compatible when used as a SYSTEM, and
• sold under single SYSTEM name or the labeling, IFU,
brochures, or catalogues for each constituent component
states that the constituent component is intended for use
with the SYSTEM.
Example: A hip replacement system comprising femoral
and acetabular components can be registered as a SYSTEM. The
components must be used in combination to achieve a common
intended purpose of total hip replacement. The size of the
components may vary.
496 Singapore
35.4.4 Group
A medical device GROUP is a collection of two or more medical
devices, supplied in a single package by a product owner. The
medical GROUP has the following:
• a single proprietary GROUP name
• a common intended purpose
Each medical device in the GROUP may have different medical
device proprietary name and intended purposes and may be
assigned and manufactured by different product owners. When
the GROUP is registered, the product owner is able to customize
the group for particular hospitals or physicians, while maintaining
the same GROUP name and intended purpose. When the GROUP is
registered, all other combinations in that GROUP can be supplied on
the market.
Example: A first-aid kit consisting of medical devices such as
bandages, gauzes, drapes, and thermometers, when assembled
together as one package by a product owner.
35.4.5 IVD Cluster

An IVD CLUSTER comprises a number of in vitro diagnostic reagents
or articles that are
• from the same product owner,
• within risk classification A or B,
• of a common test methodology, and
• of the same IVD CLUSTER category.
The IVD CLUSTER may include analyzers that are designed for
use with the reagent in the IVD CLUSTER.
35.5 Product Registration and Time Required

35.5.1 Application Process: Product Registration for
Higher Risk Medical Devices (Class B, C, and D)
All product registration applications are to be submitted via the
online Medical Device Information and Communication System
Product Registration and Time Required 497
(MEDICS). Upon successful submission, the application will be

screened before it can be accepted for evaluation to ensure that
there are no major deficiencies that would hinder the evaluation.
Along the screening and evaluation processes, the registrant
may be requested to provide additional information if any major
deficiencies are identified. The input request will be made to the
registrant and the registrant will be required to submit the requested
material and information within 14 calendar days from the date
of request.
The evaluation decision will be made on the basis of the
evaluation outcome of the submitted information, i.e., registrable,
rejection. For medical devices that receive a “Registrable” evaluation
decision, the registrant may submit an application to list the
medical device on the SMDR.
35.5.2 Product Registration for Lower Risk Medical

Devices (Class A)
Submission in Common Submission Dossier Template (CSDT) is

not required for Class A medical devices.
The data requirement for Class A medical devices
• Letter of Authorization
• Singapore Declaration of Conformity
• Copies of product labeling, i.e., instructions for use, brochure,
label, etc.
• Name, address, and contact information for all authorized
importers
• Quality management system certificate for the manufacturing
site and sterilization site (if applicable)
• Sterilization method and sterilization validation standard(s)
used (if applicable)
Additional requirement for Class A, in vitro Diagnostic
(IVD)
• List of all materials and source of animal, human, microbial,
and recombinant origin used in the IVD medical device.
498 Singapore
• Upon review of its intended purpose/indication and appro-

priateness in risk classification, the Class A medical devices
shall be listed on the SMDR.
35.5.3 Evaluation Routes

For Class B, C, and D medical devices, there are two evaluation
routes:
1. Abridged evaluation
The abridged evaluation route applies to medical device that
have been evaluated and approved in at least one of the GHTF
founding members (Australia, Canada, European Union, Japan,
and the United States).
All aspects of the medical device’s quality, including packaging,
labeling, and intended purpose/indication for use, intended for
supply in Singapore shall be the same as that approved by the
reference agency.
This route allows submission of summary data sets in certain
sections of the submission document.
2. Full evaluation
All other medical devices without prior approval from the
reference agencies are subjected to full evaluation.
Table 35.3 Turn-around-time (TAT) for product registration
TAT for abridged TAT for full

Risk classification evaluation evaluation
B 100 working days 160 working days
C 160 working days 220 working days
D 220 working days 310 working days
Combination product 310 working days
A 60 working days
The product license has a validity of one year.

Technical Material Requirement 499
35.6 Product Registration for Combined

Device–Drug Product
A combination product is defined as product that combines a
medicinal product and a medical device such that the distinctive
nature of the medicinal product component and device component
is integrated in a singular product, e.g., heparin-coated catheters,
drug-eluting stents.
Guidance on product registration of combination product
will be published in the near future. Registrant may consult the
Authority for registration requirements.
35.7 Application Fee

The application fee is payable at the time of submission in
MEDICS. Evaluation fees are payable upon the acceptance of the
application for evaluation.
Table 35.4 Fees for product registration of medical devices
Risk classification Abridged route (S$) Full evaluation (S$)
A 25
Application fee 500
Combination 10,000 75,000
D 5,700 11,400
C 3,500 5,700
B 1,800 3,500
35.8 Technical Material Requirement

Documents in support of applications submitted to the Authority
should be organized according to the ASEAN Common Submission
Dossier Template (CSDT) format. The submitted documents
500 Singapore
in support of product registration must be in English. CSDT

requirements are summarized Table 35.5:
General medical devices In vitro diagnostics

Executive summary
Essential Principles and Evidence of Conformity
Device Description
Summary of Design Verification and Summary of Design Verification and
Validation Validation
• Sterilization validation • Analytical sensitivity
• Shelf life data • Analytical specificity
• Projected useful life • Precision (Repeatability/
• Metrological requirement Reproducibility)
• Linearity/Assay’s Measuring
Pre-clinical studies
• Traceability
• Physical test
• Cut-off value
• Biocompatibility studies
• Trueness
• Animal studies
• Stability of reagent
• Software validation and
• Stability of specimen type
verification studies
• Devices containing instrument and
• Biological safety
articles
• Sterilization validation for any
sterile product
• Software verification and validation
• Devices containing biological
material
Clinical evidence Clinical evidence
• Clinical sensitivity
• Clinical specificity
• Comparison studies using clinical
specimens
• Clinical studies/performance
evaluation studies involving human
specimens
• Reference interval
• Performance evaluation studies
under simulated conditions of use
• Batch release
• Use of existing bibliography
Device labeling
Risk analysis
Manufacturer information
Labeling Requirement of Medical Devices 501
In addition to a dossier prepared in the CSDT format, the

following documents shall also be submitted in the application:
• Name, address and contact information for authorized
importers and wholesaler of the medical device
• Declaration of conformity
• Letter of authorization
35.9 Labeling Requirement of Medical Devices

Label, in relation to a medical device, refers to any written, printed
or graphic representation that appears on or is attached to
the medical device or any part of its packaging, and includes
any informational sheet or leaflet that accompanies the health
product or active ingredient when it is being supplied.
In general, the labeling for all medical devices should adhere
to the following guidelines:
• The information needed to identify and use the device safely
should be provided on the device itself, as far as it is practical
and appropriate.
• The medium, format, content, readability and location of
labeling should be appropriate to the particular device.
• The use of internationally recognized symbols is encouraged.
• The product labeling must be in English.
Content of labeling
Primary and secondary levels of packaging shall contain contact
information of the product owner on the labeling, which include the
name and contact details, i.e., address, phone number, fax number
or Web site. The labeling should bear sufficient information on
identification, batch code/lot number, expiry, warning, precautions,
side effects, storage and handling where relevant.
The Instructions for Use (IFU) for medical devices shall
include detail information informing the users on any contra-
indications, warning, and precautions to be taken. It is important
to keep the IFU up-to-date with date of issue or identification
number where appropriate.
502 Singapore
35.10 Post-Marketing Surveillance Requirement

HSA uses a number of post-marketing measures to ensure the
continued safe use of medical devices. These measures include
reporting from healthcare professionals, mandatory reporting
from device dealers, and exchange of regulatory information with
other medical device regulatory agencies.
(i) Adverse Events
As a general principle, Adverse Events (AEs), which meet the
three basic reporting criteria listed as follows, must be reported to
HSA:
• An AE has occurred.
• The medical device is associated with the AE.
• The AE led to one of the following outcomes:
o a serious threat to public health
o death of a patient, user or other person
o serious deterioration in state of health, user or other
person
o no death or serious injury occurred, but the event might
lead to death or serious injury of a patient, user or other
person if the event recurs
The Adverse Event Report Form can be downloaded from HSA
Web site and the completed form is submitted by mail or fax to
HSA.
All AEs should be reported immediately and not later than
48 hours for events that represents a serious threat to public
health; not later than 10 days for events that has led to the death,
of the medical device or any other person; not later than 30 days
for events where a recurrence of which might lead to the death, or
a serious deterioration in the state of health, of a patient, a user
of the medical device or any other person.
Upon submission, the Authority will acknowledge the receipt
of the AE report, review it, and enter it into the computer database
for tread analysis.
(ii) Field Safety Corrective Actions (FSCA)/Recalls
An FSCA is required when it becomes necessary for the product
owner of the medical device to take action (including recall of the
Manufacturing-, Importing-, and Wholesaling-Related Regulation 503
device) to eliminate or reduce the risk of, the hazards identified.

FSCA may be triggered when information from the product owner’s
post-market surveillance (including complaints, adverse events
etc) indicates an unacceptable increase in risk. On occasions, the
Authority may advise product owners or their representative to
implement an FSCA in relation to a medical device due to risk of
serious injury or death to patients, users or others.
The Authority shall be notified when the product owner or
its representative decides to initiate an FSCA. The time frame
for notification of an FSCA is within 24 hours of having made the
decision to conduct an FSCA. A preliminary report containing full
information on the FSCA must be submitted within 24 hours from
the commencement of the FSCA. A final report is to be submitted
to the Authority within 21 days from the date of commencement
of the FSCA.
35.11 Manufacturing-, Importing-, and

Wholesaling-Related Regulation
Companies performing manufacturing, importing, and supplying
by wholesale medical devices in Singapore have to comply with the
licensing conditions and any application legislative requirements.
There are three types of licenses for dealing in medical devices:
• Manufacturer’s license
• Importer’s license
• Wholesaler’s license
The supporting documents for application of the licenses are as
follows:
• Manufacturer’s License — ISO 13485 certificate for finished
medical device manufacturing
• Importer’s License — GDPMDS of ISO 13485 certificate with
scope of storage and distribution
• Wholesaler’s License — GDPMDS or ISO 13485 certificate
with scope of storage and distribution
• The dealer’s license — valid for 12 months
The licensee is obliged to maintain the key regulatory
responsibilities, which include product labeling advertising,
furnishing information, maintenance of records, reporting of adverse
504 Singapore
events, conducting field safety corrective action, and verification of

quality, safety, and efficacy of health products.
35.12 Good Distribution Practice for Medical

Devices
Companies that are involved in wholesaling and/or importing
medical devices in Singapore are required to be GDPMDS certified
prior to applying for importer or wholesaler’s license. In order to
be certified by the certification bodies, companies are required
to have implemented a quality management system that adheres
to current good distribution practices. This ensures medical device
products are consistently stored, transported and handled under
appropriate condition. In order to demonstrate such assurance,
companies are required to set up quality manuals, site master
file, and comprehensive procedures as well as to include qualified
personnel, credible documentation, and well-maintained facilities
and equipment.
35.13 Clinical Trial-Related Regulation

A “Clinical trial” means an investigation in respect of a health
product, such as drugs, medical devices, cell, and tissue-based
therapeutic products, that involve human subjects and that is
intended to
• discover or verify its clinical, pharmacological or
pharmacodynamic effects,
• identify any adverse effect that may arise from its use,
• study its absorption, distribution, metabolism and excretion,
or
• ascertain its safety or efficacy.
Current regulatory framework for medical devices requires the
following:
• Approval from local ethic committee.
• Reporting of defects, adverse events, recalls to authority.
• Labeling requirements “Investigational Device — To be used
by Qualified Investigators Only”
Special Access 505
• Additional approval of the authority Clinical Trial Test

Material (CTM) Medical Devices is required for importation
of unregistered medical devices into Singapore for use in
clinical trials.
Moving forward to the implementation of the Health Products
(Clinical Trials) Regulations in 2012, further regulation will be
imposed on the medical devices use in clinical trials. This includes
procedures for regulatory submissions, import controls prior
to initiation of clinical trials, and safety reporting requirement
after the trials have started.
35.14 Special Access

Supply of unregistered medical devices is prohibited under the
Health Products Act. However, there exists a possibility where an
unregistered medical device is required for a specific treatment
modality for a specific patient/patient population, emergency or in
a case where all conventional therapies have failed; the special route
provides an option to qualify practitioners, licensed laboratories
and hospitals to meet special needs arising in the course of his
practice. Besides, HSA approval shall be sought for import and re-
export as well as supply of unregistered medical device for non-
clinical purpose, which includes any form of use other than use
or administration on humans, i.e., display of the medical device
at an exhibition, training equipment, use on animals or use of in
vitro diagnostic medical devices for research-use only. The special
routes are listed as follows:
• import of unregistered medical devices for supply on named-
patient basis
• import of unregistered medical devices for supply to a clinical
laboratory, medical clinic, or private hospital licensed under
the PHMC Act
• import of unregistered medical devices solely for re-export or
for the export of unregistered medical devices
• supply of imported or manufactured unregistered medical
devices for non-clinical purpose
• import of medical devices on consignment basis
506 Singapore
Companies are required to submit application along with

supporting documents to HSA for review. Upon approval, import
and supply of medical device may commence. At the end of
authorization, the importer shall be required to submit a declaration
on the number of devices that have been imported and supplied in
Singapore.

35.15.1 Any Price Control of Medical Device
No, at this moment.

Not allowed.

Device?
Advertisement, for medical devices, means the publication,
dissemination, or conveyance of any information for the purpose
of promoting, whether directly or indirectly, the sale or use of the
medical device. The advertisement may come in any form, including
publication in a newspaper, magazine, display of posters, circulars,
brochures, letters addressed to individuals, corporate, photographs,
sound/visual broadcasting, the Internet, public demonstration,
and offer of trials to the member of public. However, it is strictly
prohibited to advertise to the general public the medical devices
meant for research use only or medical devices intended for
professional use only.
The advertisement should truthfully state the nature, quality
and properties of the medical device. All claims must be made
accurately in moderate terms, substantiated with scientific studies,
and should not encourage indiscriminate unnecessary or excessive
use. Advertisement also should not contain reference to HSA
or language suggesting approval or endorsement of the medical
device by HAS.
Upcoming Regulatory Implementation 507
In addition, all advertisement must also comply with the

Singapore Code of Advertising Practice (SCAP) drawn up by the
Advertising Standards Authority of Singapore.
35.16 Upcoming Regulatory Implementation
35.16.1 Regulatory Framework for Cell- and Tissue-

Based Therapeutic Products
Cell- and tissue-based therapeutic (CTT) products are defined as
articles containing or consisting of autologous (the use of tissues
and cells removed and applied to the same person) or allogeneic
(the use of tissues and cells removed from one person applied
to another person) human cells or tissues that are used for or
administered to human beings for the diagnosis, treatment, or
prevention of human diseases or conditions. Examples of CTT
products are bone marrow transplant, embryonic stem cells, and
demineralized bone matrix.
The objective of the CTT Regulatory Framework in Singapore
is to better regulate the quality, safety and efficacy of CTT products
intended for therapeutic use.
CTT products are classified as follows:
• High risk
o CTT product had been subject to substantial
manipulation
o Intended for non-homologous use
o Combined with drug, biologic or device
• Low risk
o CTT product that is minimally processed and undergoes
simple preservation and/or storage steps prior to patient
transplantation
The regulatory approach in Singapore is CTT product being
jointly regulated by both the Ministry of Health (MOH) and HAS.
The MOH will regulate the clinical use of CTT products, while HSA
will regulate the quality, safety, and efficacy aspects of high-risk CTT
products. The proposed controls include
508 Singapore
• pre-market registration for high-risk CTT

• enhanced pharmacovigilance requirements
• patient registry
• good tissue practice
• good manufacturing practice
• clinical trial authorization
References
1. Chan Angelique, ASIAN Metacentre Research Paper Series, Singapore’s

Changing Structure and the Policy Implications for Financial Security,
Employment, Living Arrangements and Health Care, No. 3 (Institute for
Asian Research National University of Singapore), p. 3.
2. GN-01 Guidance on the Application of Good Distribution Practice for
Medical Devices (Online), Available (October 2011):
http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_
products_regulation/medical_devices/guidance_documents.
Par.33419.File.tmp/GN-01-R3%20Guidance%20on%20the%20
Application%20of%20Good%20Distribution%20Practice%20for%
20Medical%20Devices.pdf.
3. GN-02-R2 Guidance on Licensing for Manufacturers, Importers and
Wholesaler of Medical Devices (Online), Available (November 2011):
Par.99323.File.tmp/GN-02-R2_Guidance%20on%20Licensing%20for
%20Manufacturers%20Importers%20and%20Wholesalers%20of%
20Medical%20Devices.pdf.
4. GN-04 Guidance on Medical Device Recall (Online), Available (October
2008):
Par.11355.File.tmp/GN-04-R1%20Guidance%20on%20Medical%20
Device%20Recall.pdf.
5. GN-05-R1 Guidance on the Reporting of Adverse Events for Medical
Devices (Online), Available (October 2008):
Par.56812.File.tmp/GN-05-R1%20Guidance%20on%20the%20
References 509
Reporting%20of%20Adverse%20Events%20for%20Medical%20
Devices.pdf.
6. GN-08 Guidance on Medical Devices Advertisements and Sales
Promotions (Online), Available (December 2008):
products_regulation/medical_devices/guidance_documents.Par.
72207.File.tmp/GN-08%20Guidance%20on%20Medical%20Devices
%20Advertisements%20and%20Sales%20Promotions.pdf.
7. GN-10 Guidance on Medical Device Field Safety Corrective Action
(Online), Available (October 2008):
Par.81192.File.tmp/GN-10-R1%20Guidance%20on%20Medical%20
Device%20Field%20Safety%20Corrective%20Action.pdf.
8. GN-12-R1 Guidance on Grouping of Medical Devices for Product
Registration (Online), Available (January 2011):
https://www.hsa.gov.sg/publish/etc/medialib/hsa_library/
health_products_regulation/medical_devices/guidance_documents.
Par.33271.File.tmp/GN-12-R1_Guidance%20on%20Grouping%20of
%20Medical%20Devices%20for%20Product%20Registration.pdf.
9. GN-13-R1 Guidance on the Risk Classification of General Medical Devices,
Revision 1 (Online), Available (October 2008):
Par.83962.File.tmp/GN-13-R1%20Guidance%20on%20the%20Risk
%20Classification%20of%20General%20Medical%20Devices.pdf.
10. GN-14-R1 Guidance on the Risk Classification of In Vitro Diagnostic
Medical Devices (Online), Available (October 2008):
Par.55206.File.tmp/GN-14-R1%20Guidance%20on%20the%20Risk
%20Classification%20of%20In%20Vitro%20Diagnostic%20Medical
%20Devices.pdf.
11. GN-15-R4.1 Guidance on Medical Device Product Registration (Online),
Available (November 2011):
products_regulation/medical_devices/guidance_documents.Par.2810.
File.tmp/GN-15-R4.1_Guidance%20on%20Medical%20Device%20
Product%20Registration.pdf.
510 Singapore
12. GN-23 Guidance on Labeling for Medical Devices (Online), Available

(August 2011):
Par.12236.File.tmp/GN-23%20Guidance%20on%20Labelling%20for
%20Medical%20Devices.pdf.
13. GN-26-R1 Guidance on the Requirements for Exemption from Product
Registration for the Import of an Unregistered Medical Device for Supply
on Named-Patient Basis (Online), Available (June 2010):
Par.73969.File.tmp/GN-26_Guidance%20on%20Named%20Patient%
20Basis.pdf.
Registration for the Import of Unregistered Medical Devices for Supply to
a Clinical Laboratory, Medical Clinic or Private Hospital licensed under
the PHMC Act (Online), Available (June 2010):
Par.45595.File.tmp/GN-27_Guidance%20on%20Named%20PHMC%
20Licensed%20Clinical%20Diagnostic%20Laboratory%20and%20
Hospitals.pdf.
Registration to Import Unregistered Medical Devices solely for Re-
export or for the Export of Unregistered Medical Devices (Online),
Available (June 2010):
products_regulation/medical_devices/guidance_documents.Par.
27627.File.tmp/GN-28_Guidance%20on%20Authorisation%20Route
%20for%20Import%20for%20Re-Export.pdf.
Registration to Supply Imported or Manufactured Unregistered Medical
Devices for Non-Clinical Purpose (Online), Available (June 2010):
Par.81112.File.tmp/GN-29_Guidance%20on%20Authorisation%
20Route%20for%20Import%20and%20Supply%20for%20Non-
Clinical%20Purpose.pdf.
References 511
17. GN-30-R1 Guidance on the Requirements for Approval to Import Medical

Devices on Consignment Basis (Online), Available (June 2010):
Par.92544.File.tmp/GN-30-R1_Guidance%20on%20Authorisation%
20Route%20for%20Import%20on%20Consignment%20Basis.pdf.
18. Health Sciences Authority Online (Online), Available (07 December
2011): www.hsa.gov.sg.
Chapter 36
Taiwan: Medical Device Regulatory

System
Li-Ling Liu
Division of Medical Devices and Cosmetics,
Taiwan Food and Drug Administration, Taiwan
LLL@fda.gov.tw
Disclaimer

36.1.1 Overview of Structure and Funding of Local
Healthcare System
The population of Taiwan is about 23 million. The Taiwan medical
device industry had revenue of NTD 92.86 billion in 2010, which

www.panstanford.com
514 Taiwan
has a 12.5% growth rate compared with that in 2009. The annual
revenue of Taiwan is about 1% of the global market. The global
market was USD 236 billion in 2010, and the growth rate was 6%
per annum (Fig. 36.1). The export value was NTD 40.2 billion and
import value was NTD 53.5 billion. The importing dependency of the
Taiwan market is 67%. The United States is the largest importing
and exporting country (Fig. 36.2).
The monetary value in 2010: USD 236 billion

Growth rate: 6% per year
Unit: USD billion
Global Medical Device Market
2010 Global Medical

Device Market Share
Figure 36.1 Global medical device market (Sources: Espicom Business

Intelligence (2009); IEK Center (April 2010)).
Import Export
Ireland, 5% UK, 4%
China, 70% China, 5%
Germany, 8%
Germany,
11%
USA: Largest Import/Export Market Share

Taiwan Export value: steady growth
Figure 36.2 Import and export of medical devices in Taiwan (Sources:

Taiwan Customs (2010); IEK Center (April 2010)).
Market Overview 515
36.1.2 Overview of Regulatory Environment and Laws/

Regulations Governing Medical Devices
Regulation of medical devices in Taiwan dates back to 1970, when
the Pharmaceutical Affairs Act was promulgated. Enforcement
rules of the act were subsequently enacted in 1973.
Regulatory changes in the premarket approval process and
post-market surveillance have continued to take place over the
years in order to safeguard public health and harmonize with inter-
national regulations. The major ones are as follows:
(1) Pharmaceutical Affairs Act (1993)
(2) Good Manufacturing Practice (1998)
(3) Reclassification of medical devices (2000)
(4) Regulations Governing Management of Medical Devices
(2004)
(5) Guidelines for Registration of Medical Devices (2004)
(6) Good Laboratory Practice for Nonclinical Laboratory Studies
(2006)
(7) Medical Device Good Clinical Practice (2007)
(8) Guidance of preclinical testing (2009–2011)
(9) Application Guidelines for Registration of in vitro Diagnostic
Medical Devices (2010)
(10) Medical Device Good Vigilance Practice (2011)
TheTheregulation
regulationsofofmedical
medicaldevices
device along
along with
with product life cycle
product
is shown life cycle
in Fig. 36.3.are shown in Fig 36.3.
Figure 36.3 Administration of medical device life cycle. (Source: Taiwan

Administration
Food of medical device life cycle.
and Drug Administration.)
516
Taiwan
Figure 36.4 TFDA organization chart. (Source: Taiwan Food and Drug Administration.)

To assure the quality and safety of medical products and to promote
industry development, the Taiwan government has strived to
reform and renovate the organization of the Department of Health
(DOH). By integrating the original Bureau of Food Safety, Bureau
of Pharmaceutical Affairs, Bureau of Food and Drug Analysis,
and Bureau of Controlled Drugs under the DOH into the newly
established Food and Drug Administration (FDA), the Taiwan FDA
(TFDA) was inaugurated on January 1, 2010. The organization chart
of the TFDA is shown in Fig. 36.4.
The Division of Medical Devices and Cosmetics in the TFDA
handles the administration of Medical devices in the public life cycle.
All medical devices are required to be registered by TFDA before
they can be manufactured domestically or imported from abroad.

According to the definition by the law, the term “medical devices”
refers to instruments, machines, apparatus, and their accessories,
fittings and parts that are used in diagnosing, curing, alleviating, or
directly preventing the diseases of human beings, or that may affect
the body structure or functions of human beings. In vitro diagnostic
devices (IVDs) are regulated by Guidelines for registration of
medical devices, and include diagnostic reagents, instruments or
systems used to collect, prepare, and test specimens from human
body in order to diagnose disease or other conditions (such as
status of health). Veterinary products are not under the scope of
medical devices in Taiwan.

Medical devices are stratified by risk level and are divided into class
I (low risk), class II (medium risk), and class III (high risk). Another
parallel classification system emphasizes the intended use and mode
of action, listed as follows:
(A) clinical chemistry and clinical toxicology devices
(B) hematology and pathology devices
(C) immunology and microbiology devices
(D) anesthesiology devices
518 Taiwan
(E) cardiovascular devices

(F) dental devices
(G) ear, nose, and throat devices
(H) gastroenterology-urology devices
(I) general and plastic surgery devices
(J) general hospital and personal use devices
(K) neurological devices
(L) obstetrical and gynecological devices
(M) ophthalmic devices
(N) orthopedic devices
(O) physical medicine devices
(P) radiology devices
For example, a resorbable calcium bone void filler would be
under the scope of (N) and class II medical device.
For detailed and updated information, please refer to the
TFDA medical device databases Web site (http://www.fda.gov.tw/
licnquery/DO8180.asp).

TFDA issues product licenses only to domestic firms, all foreign
companies must make submissions through authorized domestic
distributors or subsidiaries. These local firms must have licenses
for wholesaling, retailing, importing, or exporting medical devices.
Also, these local firms are responsible for adverse events reporting,
and recalls.
In the future, good distribution practice (GDP) will be
implemented for enhancing quality and management of local
distributors.
36.2.4 Products Registration, Technical Material

Requirement, and Time Required
Device evaluation is based on the risk management concept.
For class I products, submission requirements are (1) affidavit
(2) GMP/ QSD certificate for sterilized devices or devices with
metric function, and (3) medical device dealer license. For class II
and III products, technical documents are required for full review,
Quality System Regulation 519
including preclinical testing, quality control, performance testing,

sterilization, etc. However, these data can be waivered if the devices
belong to class II and have both US and EU free sale certificates.
For devices not having substantial equivalent products, clinical
evaluation reports are mandated.
Regarding time required, the class I products follow on-site
registration. The average review time for new medical devices
was around 130 days in 2011; for substantial equivalent products
of class II and class III, it was around 80 days in 2011. The
statistics does not include the supplemental time for companies.
Therequired
The requireddocuments
documentsfor forregistration
registrationare
areclearly
clearlydepicted
depictedinin
Fig.36.5.
Fig. 36.5
High Risk
Low Risk
Figure 36.5 Risk-based regulation.
Risk-based regulation.
36.3 Quality System Regulation
The quality system of medical device manufacturers is audited to
the requirements of GMP using conformity assessment standard
based on ISO 13485. Newly established manufacturers and new
applications for device registration must comply with GMP beginning
on February 10, 1999. Full compliance with GMP for all devices on
the market becomes mandatory effective February 10, 2004.
520 Taiwan
The GMP certificate is valid for three years, so the GMP

inspection is done every three years routinely. However, we may
go for cause inspection at any time if necessary. GMP Inspection
to foreign manufacturers is conducted through the Quality System
Documentation review. The foreign manufacturer or its initial
importer may apply for on-site inspection as well as domestic
manufacturers in Taiwan.
36.4 Combined Device–Drug Product

The registration pathway depends on the primary mode of action.
For example, drug-eluting stents are considered a device, because
the primary made of action is dilating the blood vessel though the
stent. The combination product is jointly reviewed by device and
drug experts.
36.5 Registration Fee

For new medical devices, the registration fee is NTD 30,000 (about
USD 1000); for medical devices with predicates, the fee is NTD
10,000 (about USD 330); for Class III IVDs without predicates, the
fee is NTD 50,000 (about USD 1660), and for those with predicates
the fee is NTD 35,000 (about USD 1160).
36.6 Labeling Requirements of Medical Devices

Detailed requirements are listed in the guidelines for the registration
of medical devices. For imported products, labeling in standard
Mandarin is necessary, including product names, license number,
manufacturer and distributor names and addresses, and shelf life.
The labeling, instructions, and packaging of domestically
manufactured medical devices shall be in Chinese principally, and
the font size for foreign characters shall be relatively smaller.
For imported medical device, in addition to the instruction in
Chinese, the labeling and packaging shall also include the product
name, license number, and the name and address of the importer
pharmaceutical entity in Chinese and shall clearly mark the date of
Clinical Trial-Related Regulation 521
manufacture, expiration date, and storage period in Chinese or in a

way easily recognizable. The font size for Chinese characters for the
product name shall not be smaller than that for foreign characters.
36.7 Any Post-Marketing Surveillance

Requirement
Medical facilities, device firms, and pharmacies are required to
report any serious adverse reactions caused by medical devices.
For certain devices, TFDA may designate a specific period of time
to survey their safety after they have been approved for marketing.
Periodic safety update reports (PSUR) from the license holders
shall be submitted accordingly in the designated period. Currently,
license holders of the devices that have been designated are to
submit a PSUR every six months for three years. Taiwan started
joining NCAR (National Competent Authority Reporting) program
under GHTF (Global Harmonization Task Force) for exchanging ADR
reports with other countries in 2010.
36.8 Manufacturing-Related Regulation

The manufacturing of medical devices shall comply with the
relevant parts of the Factory Establishment Standards (FES), which
is under article 57 of the Pharmaceutical Affairs Act. A manufacturer
in compliance with Part 2 of FES, i.e., basic requirements for the
establishment of factories, will be issued a factory registration
certificate. Such manufacturer may then apply for compliance
with FES, which is the requirement for medical device GMP
certification.
36.9 Clinical Trial-Related Regulation

Preapproval of clinical trials is required for new medical devices
claiming new design, new materials, new combination, etc. The
process of submitting clinical trials protocols is illustrated in
Fig. 36.6. Both approvals from TFDA and IRB (Institutional Review
Board) are required prior to conducting clinical trials.
522 Taiwan
Clinical Protocol Review Process

Clinical Trial Protocol for
Registration/Licensing
TFDA
Center for Drug Evaluation

IRB/JIRB
Advisory Committee
Protocol Approval
GCP Inspection Approval Basis for

(GCP Inspection Team)
Registration/
(TFDA) Clinical Report licensing ͵ͳ
Figure 36.6 Clinical protocol review process.
36.10 International Cooperation

The mutual recognition of marketing approval may be achieved by
establishing international agreements. An example is the exchange
of letters between the Swissmedic of Switzerland and the
Department of Health of Taiwan signed on July 4, 2007, in which
both sides recognized that medical devices manufactured in
Taiwan that legally bear the CE mark require no additional
conformity assessment procedure for the Swiss market. Other
exchanges of letters, for example, with the United States in 1998
and with the European Union in 2001, have also been signed to
expedite the Quality System Documentation (QSD) review process
for manufacturers. In an expedited review, QSD is simplified by
submitting the following three documents instead: inspection
report, Free Sale Certificate, and ISO 13485 certificate.
36.11 Commercial Aspects

36.11.1 Price Control of Medical Device
The national health insurance system is implemented in Taiwan
under the National Health Insurance Act. For some diseases, the
References 523
payment of medical devices is covered in DRG (Diagnosis Related

Groups). For those that are not under DRG programs, the insurer
should pay the same amount for devices with the same functional
type.
36.11.2 Parallel Imports

To ensure the quality of products, only the license holders or
consignors can import the devices. The authorization letter to
the importer from the foreign original manufacturer is one of the
required documents.

Devices?
Persons other than medical devices dealers are not allowed to
make advertisements. For publishing or broadcasting advertisement,
the dealers shall, before publishing or broadcasting, submit all the
written or spoken words and/or drawings or pictures constituting
the advertisement to the central or municipal competent health
authority for approval. Interviews, news reports, or propaganda-
containing information implying or suggesting medical efficacy
shall be regarded as advertisements of medicaments.
References
1. Pharmaceutical Affairs Act (1970) (amended 2012), available as

amended at http://law.moj.gov.tw/LawClass/LawAll. aspx?PCode=
L0030001.
2. Medical Care Act (1986) (amended 2012), available in unofficial
English translation at http://law.moj.gov.tw/Eng/LawClass/LawAll.
aspx?PCode=L0020021.
3. Regulations for Governing the Management of Medical Device (2004)
(amended 2012), available in unofficial English translation at http://
www.fda.gov.tw/EN/includes/GetFile.ashx?id=1437&chk=f6a22c5f-
0d38-4582-b17 b-40603c41eabb&mid=172&name=fdContent.
4. Regulations for Registration of Medical Device (2004) (amended
2010), available in unofficial English translation at http://www.fda.
gov.tw/EN/includes/GetFile.ashx?id=1440&chk=37de015b-86b2-
4fa7-ad16-0c133963bc47&mid=172&name=fdContent.
524 Taiwan
5. Standards for Medicament Factory Establishments (1973) (amended

2012), available in unofficial English translation at http://law.moj.gov.
tw/Eng/LawClass/LawAll.aspx?PCode=L0030008.
6. Regulations of Medicament Manufacturer Inspection (1973) (amended
2011), available in unofficial English translation at http://law.moj.gov.
tw/Eng/LawClass/LawAll.aspx?PCode=L0030009.
7. Regulations on Human Trials (2009), available in unofficial English
translation at http://law.moj.gov.tw/Eng/LawClass/LawAll.aspx?
PCode=L0020162.
8. Regulations for Governing the Monitoring of Safety of Pharmaceuticals
(2004), available in unofficial English translation at http://www.fda.
gov.tw/EN/includes/GetFile.ashx?id=1438&chk=44e02808-072a-
4cc3-9d6 d-d65ab39898a3&mid=172&name=fdContent.
9. Regulations for Governing the Reporting of Serious Adverse Event of
Pharmaceuticals (2004), available in unofficial English translation at
http://www.fda.gov.tw/EN/includes/GetFile.ashx?id=1439&chk=080
0b408-a750-4840-92 bf-8ce36951e156&mid=172&name=fdContent.
10. Recognition of Medical Device International Standards (2011),
available at http://www.fda.gov.tw/tc/includes/GetFile.ashx?mID=4
6&id=10960&chk=42484d5f-bf 5b-49d9-baa7-860ed4787740.
11. Guidance for Pre-clinical Testing of Medical Device.
12. Guidance for Medical Device Good Vigilance Practice (2011), available
at http://www.fda.gov.tw/tc/includes/GetFile.ashx?mID=19&id=116
10&chk=a6edca23-6f ce-4bac-a81d-4b719411e788.
13. Guideline for Medical Device Good Clinical Practice (2007), available at
http://www.fda.gov.tw/upload/133/Content/0960300979%e5%
85%ac%e5%91%8a%e9%99%84%e4%bb%b6.pdf.
14. Good Laboratory Practice for Nonclinical Laboratory Studies (2006),
available at http://www.fda.gov.tw/TC/includes/GetFile.ashx?mID=1
33&id=1104&chk=a83d8a0b-d6 c9-4502-9048-31b29ad61bf7.
15. Information for Registration of In Vitro Diagnostic Device (2010),
available in unofficial English translation at http://www.fda.gov.tw/
tc/includes/GetFile.ashx?mID=46&id=11474&chk=0999e953-2ed b-
406f-a4c5-d53dd8fdaae6.
Chapter 37
Thailand: Regulatory and Medical Device

Control
Patanawong Yuwadee
Thai Food and Drug Administration
Ministry of Public Health, Thailand
puyuwade@fda.moph.go.th
Disclaimer

The health care industry in Thailand continues to grow annually,
especially in the area of health care services and medical devices,
because of several factors, including the government’s universal
health care coverage (UC) scheme introduced in 2000, good
infrastructure of hospitals and health care personnel, and

www.panstanford.com
526 Thailand
Thailand’s endeavor to become the medical hub of Asia. Thailand’s

medical device market in 2010 and 2011 was worth US$ 795 million
and US$ 900 million, respectively, and it is expected to reach US$
15 billion in 2015. The majority of the supply of medical devices in
Thailand still depends on imports. As of July 5, 2012, 433 medical
device local manufacturers and 1911 importers applied for
establishment licenses. There are nearly 1400 public and private
hospitals serving citizens and foreign patients. The main users of
medical devices are public hospitals, while private hospitals play
a major role as a hub for medical tourism and medical services
for 2 million international visitors each year. It is widely accepted
that Thailand is one of the few countries in the world that can
provide the best health care for a reasonable cost. Thailand’s
hospital infrastructure and upgrading drive for the medical-imaging
market was US$ 70 million in 2011 and is expected to reach US$
100 million in 2015 (the year for emerging ASEAN Economic
Community: AEC 2015).
37.2 Medical Device Regulations and

Regulators
In Thailand, medical devices are regulated under the Medical
Device Act 2008 by the Thai Food and Drug Administration (Thai
FDA), Ministry of Public Health. The Medical Device Control
Division under the Thai FDA is the key body and has main duties
and responsibilities for control of manufacture, import, sale
and advertisement of medical devices with the goal to ensure
safety, effectiveness and quality of medical devices available to
consumers. The Medical Device Control Division has performed
activities including pre-marketing control, post-marketing control,
pre- and post-advertisement control, standard development, and
law and regulation development and has worked with the Bureau
of Import and Export Control of the Thai FDA to control the
import and export of medical devices in Thailand. The import and
export of medical devices must undergo an inspection by Thai
FDA staff at the port of checkpoint. The previous and first Medical
Device Act 1988 was repealed and replaced by the Medical Device
Act 2008, which came into force on March 6, 2008. Medical devices
regulated under the Medical Device Act 2008 include medical
Medical Device Regulations and Regulators 527
devices for both human and animal use, in vitro diagnostic devices
and computer software. Any person (natural or legal person) who
wishes to manufacture or import medical devices must register for
establishment license with the Thai FDA, and the establishment
licensee (manufacturer or importer) has to submit for product
registration or product approval with the Thai FDA. Once the
licensee gets product approval, that medical device can be freely
sold throughout the country. At present, sale license is not required
except for selling HIV test kits. Thai FDA Good Manufacturing
Practice (GMP), which was adapted from the ISO 13485 standard,
was introduced in 2005 on a voluntary basis. It is currently compul-
sory for HIV test kit manufacturers and will be made compulsory
for a wider range of devices in future. An establishment license has
validity of five years (until December 31 of the fifth year from the year
of issuance) and sale license has validity of one year (until December
31 of the year of license issuance). The act also provides some
scope for exemption from medical device premise establishment
and product registration requirements (with specific condition and
procedure), such as importing necessary amount of medical device
for personal use or for exhibition or educational purpose.
By law, certain important issues are decided by the Medical
Device Committee and Subcommittees. The Medical Device
Committee has following powers and duties:
• to give recommendations on policies and measures
concerning the control of medical devices so as to ensure
compliance with the act.
• to give recommendations on the issuance of Ministerial
Notifications,
• to give approvals for suspension and revocation of an
establishment license and product registration.
The subcommittees were appointed by the Medical Device
Committee, including subcommittee on policy and measure of
medical device control, subcommittee on establishment license and
sale license, subcommittee on product registration, subcommittee
on medical device advertisement, subcommittee on technical issues,
subcommittee on standards of manufacture, import and sale of
medical devices, and subcommittee on regulation development.
Other important rules highlighted from the Medical Device Act
2008 include product liability, technology assessment procedure
528 Thailand
for announced particular products, and enforcement of Good

Importation Practice (GIP), Good Distribution Practice (GDP), and
Good Clinical Practice (GCP).
37.3 Definition of a Medical Device

A “medical device” means
(1) any instrument, apparatus, implement, machine, appliance,
implant, in vitro reagent or calibrator, software, material, or
other similar or related article
combination, for human beings or animals for one or more of
the specific purpose(s) of
(i) using in medical and health professional practices
(ii) diagnosis, prevention, monitoring, treatment or alleviation
of disease
(iii) diagnosis, monitoring, treatment, or alleviation of an
injury
(iv) investigation, replacement, modification, or support of
(v) upporting or sustaining life
(vi) control of conception or fertility development
(vii) aids or compensation for disability or handicap of human
beings or animals
(viii) providing information for medical or diagnostic purposes
from a human or an animal body
(ix) disinfection of medical devices, and
(b) which does not achieve its primary intended action in or on
the human or animal body by pharmacological, immuno-
logical or metabolic means, but which may be assisted in its
intended function by such means.
(2) apparatus or spare part of instrument, machine, product, or
article under (1)
(3) instrument, apparatus, machine, product or any other article
as specified to be medical device by the Minister of Public
Health.
Product Registration 529

Currently, medical devices are divided into three classes depending
on the level of control as follows:
(1) Licensed Medical Devices
This is the most stringent controlled group consisting of condoms,
examination gloves, surgical gloves, HIV test kits for diagnostic
purpose, corrective, and cosmetic contact lens.
(2) Notified Medical Devices
The control of this group is less stringent than group (1). It
consists of physical therapy products, silicone breast prostheses
implants, alcohol detectors, and equipment or instruments topically
used for breast enhancement.
(3) General Medical Devices
All other medical devices not classified as group (1) and group (2)
are in this class. The control of this group is the least stringent.
This classification is likely to depend only on the risk to
public and has not yet followed the GHTF guidelines. However,
it is in the process of changing toward a risk-based classification
as stipulated in the GHTF and the draft of ASEAN Agreement
on Medical Device Directive as well as a concern of the health
situation in Thailand.
37.5 Product Registration

37.5.1 Licensed Medical Devices and Notified Medical
Devices
For licensed medical devices, the standard requirements of each
licensed medical device are normally both adopted and adapted
from international standards and announced in the Ministerial
Notification. The following details of medical devices are required
to be submitted to the Thai FDA by the manufacturer or importer:
product name, category and type, product description, packaging,
type and quantity of components, details of manufacturing process,
intended use or indication, warning, precaution, instruction for
530 Thailand
use, storage, shelf life (if any), product standard and test report,
inspection or analytical procedure, local testing results for most
product categories, Certificate of Free Sale and Certificate of Quality
System of Manufacture (for imported products), label and leaflet,
and the name and address of the manufacturer (manufacturing
site/premise) and the importer.
For a notified medical device, the manufacturer or the
importer is required to submit to the Thai FDA the same details
as required for licensed medical devices except the details of the
manufacturing process. Local testing results are required for some
products.
It is in the process of changing toward using the ASEAN Com-
mon Submission Dossier Template (CSDT) as technical document
requirements for submission for product approval of licensed and
notified medical devices. At present, the ASEAN CSDT is implemented
for contact lens submission.
37.5.2 General Medical Devices

The importer has to submit the Certificate of Free Sale for all
kinds of general medical devices and the Certificate of Quality
System of Manufacture (in some human use product categories)
to get the Thai FDA Letter of Import Approval for product release
from the Thai FDA checkpoint at port of customs as indicated
and detailed in the Ministerial Notification No. 34 B.E. 2549
(A.D. 2006) on Medical Device Prohibited for Import or Sale,
dated July 19, 2006, and Food and Drug Administration Regulation
B.E. 2550 on Principles relating to Certification required for
Import of Medical Devices and Import Approval under Certification
Exemption, dated February 28, 2007. When necessary, additional
documents to support the intended use or safety data of medical
devices may be required.
Following is the list of medical devices for human use that
require the importer to submit a Certificate of Quality System of
Manufacture:
(1) implant products
(2) devices derived from tissues or tissue by-product
(3) sterile products
(4) diagnostic or treatment radiation devices
(5) in vitro diagnostic products for

(a) blood group tests: ABO system, Rhesus (C,c,D,E,e) anti-
kell
(b) diagnostic tests: HIV infection (HIV I and II), hepatitis
infection (A,B,C, and D), HTLV infection (HTLV I and
II), antihumanglobolin (Coombs’ reagent), anti-CMV
(cytomegalovirus), HPV, HLA typing, biochemical test:
glucose, lipid profile, liver function test, uric acid, BUN,
creatinine, pregnancy test, drug abuse, hormones (thyroid,
fertile), tumor markers (AFP, CEA and PSA) and cardiac
markers (CK, CK-MB and troponin)
(6) disinfectant solution for medical devices
(7) restorative and crowning material
37.5.3 Review Period (as Promulgated in 2012)
Procedure of
site inspection
or experts/ Review
working group/ period
subcommitee (working
Type of issuance review days)
Medical device manufacturing/import No 25
license
Medical device manufacturing/import Yes 60
license
Medical device manufacturing/import No 15
Notification acceptance
Notification acceptance
Letter of Import Approval: 1 item of device No 1
Letter of Import Approval: 2–100 items of No 4
devices
Letter of Import Approval: >100 items of No 10
devices
license or notification acceptance for new
products
532 Thailand
37.5.4 Fees and Validity of Granting or Issued Document
Fees Validity
Type of granting document (baht) (Years) Remarks
Medical device manufacturing 10,000 5 until the December 31 of
license the fifth year from the year
of issuance
Medical device import license 20,000 5 until the December 31 of
the fifth year from the year
of issuance
Medical device manufacturing 5,000 5 until the December 31 of
notification acceptance the fifth year from the year
of issuance
Medical device import 10,000 5 until the December 31 of
Notification acceptance the fifth year from the year
of issuance
Letter of import approval: ≤ 1,000 Align with the validity of the CFS
10 items of devices (Certificate of Free Sale), if no
validity specified in CFS, Letter of
Letter of import approval: >10 2,000
Import Approval will be valid for 5
items of devices
years
37.6 Labeling
It is in the process of drafting label requirements under the
Medical Device Act 2008. Currently, label requirements follow
the Act 1988, which states that medical devices for sale or in
possession for sale in Thailand must be labeled in Thai. Other
additional languages are also allowed but must correspond with
Thai and appear in size not larger than the Thai language.
Labels must include the product name, category and type
of medical device, name and address of the manufacturer
(manufacturing site/premise) as well as the importer, content, lot
number, license number, intended use or indication, instruction
for use, storage condition, warning, precaution, expiration date (if
any), and the phrase “Single-use only” for single-use devices. The
label contents of intended use or indication, instruction for use, and
storage condition can be waived if these contents are already in the
package insert.
References 533
37.7 Advertisement Control

The Medical Device Act 2008 strictly provides the measures on
advertisement control for all medical devices, regardless of the
class to which they belong. No person is allowed to advertise a
medical device for commercial purpose to both the general public
and the medical or health professionals unless he/she submits
the application to the Thai FDA for advertising license. The
objective is to ensure correct and clear dissemination of medical
device information, especially to the general public. The act prohibits
the following types of advertisement:
(1) to provide false or exaggerated information regarding the
benefits, quality, quantity, standard, constituent, or origin of
medical devices
(2) to represent any person’s endorsement or commendation of
the medical device’s benefits
(3) to offer a prize conditional upon the taking of chance by any
means
(4) to represent benefits of prevention, treatment, relief, or cure
of a disease or symptom of a disease, which is prohibited
under Ministerial Notification
(5) to issue misleading statement on an essential substance of a
medical device
If violation is found, the Thai FDA has the power to issue any of
the following orders:
(1) to make changes to the content or means of advertisement
(2) to prohibit the use of certain statements or means of the
advertisement
(3) to advertise correct information
References
1. Medical Device Act B.E.2551 (A.D.2008).

2. Ministerial Regulation on the Rules, Procedures and Conditions of the
Establishment Registration of Manufacturing Medical Devices, dated
November 19, 2009.
534 Thailand
3. Ministerial Regulation on the Rules, Procedures and Conditions of

the Establishment Registration of Importing Medical devices, dated
November 19, 2009.
4. Ministerial Notification No. 34 B.E.2549 (A.D.2006) on Medical Device
Prohibited for Import or Sale, dated July 19, 2006.
5. Food and Drug Administration Regulation B.E.2550 on Principles
relating to Certification required for Import of Medical Devices and
Import Approval under Certification Exemption, dated February 28,
2007.
6. Sasithorn Ongdee. Wind of Change Sweeps Healthcare Industry
(Online) (May 4, 2012), available:
http://www.nationmultimedia.com/business/Wind (July 6, 2012).
7. Oliver Languepin. Medical Device Industry Overview in Thailand
(Online) (30 August 2010), available:
http://thailand-business-news.com/health/2528 (July 5, 2012).
Chapter 38
UAE: Overview of Medical Device/IVD

Regulatory System
Amin Al Amiri
Ministry of Health, UAE
Disclaimer
38.1 Ministry of Health

38.1.1 Registration and Drug Control Department
The executive Registration and Drug Control Department (RDCD) in
the Ministry of Health (MOH) safeguards public health by ensuring

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536 UAE
that all medicines and medical devices on the UAE market meet
appropriate standards of safety, quality and efficacy.
38.1.2 Mission Statement

The mission of the RDCD is to protect and promote high standards
of public health through the regulation of the quality, efficacy and
safety of medicinal products used for humans and animals, the
pharmacy profession and the pharmaceutical industry.
Additionally, the RDCD is required to advise His Excellency
the Minister on the pricing of pharmaceutical products and to advise
on policy relating to pharmaceuticals and regulatory systems and
assist His Excellency in achieving the strategic aims of the UAE
MOH.
38.1.3 Medical Device Registration

The regulation of medical devices in the UAE is aimed to
maintain a balance between ensuring product safety, quality, and
effectiveness and provide the public with timely access to medical
devices and prevent the entry of unsafe or ineffective devices
into the UAE market. Accordingly, this guideline is constructed to
provide safeguard measures for patients, appliers, users, and third
parties against possible health and safety hazards they may be
exposed to during the use of such devices and their accessories.
The essential requirements for medical devices and their
accessories and their implementation were laid down by the
guideline to ensure that these devices shall meet the internationally
established principles and requirements relating to their design,
classification, manufacture, placing on the market, putting into
service, and inspection.
Medical device control and regulation in the UAE is supervised
and directed by the RDCD, MOH.
Classification, requirements, and evaluation of medical devices
in UAE are supported by the UAE Pharmacy Law No. 4 for 1983
Introduction to MD/IVD Regulatory System in UAE 537
and conform to the global trends, rules, and regulations recognized

as above.
38.2 Introduction to Md/ivd Regulatory

System in Uae
The UAE regulatory system is mostly based on the recommenda-
tions of the Global Harmonization Task Force (GHTF) for medical
devices (for types of certification, approval, and clearance system
according to product class and rules of classification of these
systems considered and accepted), and adapting with
(a) EU Medical Device Directives 93/42/EEC, EU in vitro
Diagnostic Device Directive (IVDD) 98/79/EC and EU Active
Implantable Medical Device Directive (AIMDD) 90/385/EEC.
(b) United States Food and Drug Administration (US FDA)
(c) Australia Therapeutic Goods Administration (TGA)
(d) Singapore Health Sciences Authority (HSA)
The regulatory body of medical devices/IVD is the RDCD —
Medical Practice and License Sector.
Contact Information:
Key contact persons:
Dr. Amin Al Amiri
Assistant Undersecretary for Medical Practice and License,
Ministry of Health, Abu Dhabi, P.O. Box 848, UAE
Telephone: +971 26117434
Fax: +971 2636742
Dr. Fatima Albraiki
Director of Registration and Drug control Department,
Ministry of Health, Abu Dhabi, P.O. Box 848, UAE
Telephone: +971 26117421
Fax: +971 2636742
www.moh.gov.ae
538 UAE
38.3 Medical Devices Marketing Approval Flow

Chart
Registration and Drug Control Department

Local authorized representative (scientific office)

Distributor Registration file for medical device company + registration
Medical store
Licensed
file of product(s)/ category
Declaration of conformity of essential requirements of

medical devices

Submit certificate for each device or device category

Labeling and artworks
Technical Documentation for pharmaceuticals, non-listing

devices

Registration Listing of devices
(Generally for devices with pharmaceutical (Generally for products used in hospitals under

ingredients, for products with exaggerated medical professional supervision, classical
medical claims intended for patients, new products with no claims, blood bags, etc., in vitro
technologies, self testing kits) diagnostics excluding self-testing)

Assessment

Products exempted from
Approval registration or listing

Import permit

Post-market surveillance

Vigilance reporting
Figure 38.1 Medical device marketing approval flow chart.

Approval on Importation Level 539
MD/IVDȱ
Marketingȱapprovalȱroute
Registration/listing Approvalȱonȱimportationȱ
Registration/listing
pre-import approval level
Figure 38.2 Medical device marketing approval flow chart with pre-
importation approval for each consignment.
38.4 Approval on Importation Level

Medical devices those are not subject for listing or registration
(a) printing graphing papers
(b) accessories for listed or registered medical devices
(c) medical device instruments operating solvents or liquids that
do not contact patients
(d) woven and nonwoven clothing materials and their products
(gowns, masks, support bandages, clothes, mattresses, etc.)
(e) hospital and clinic furniture, wheelchairs, walking support
devices
(f) in vitro diagnostic reagents given that they are not self-testing
or high-risk (A or B classes).
(g) optical lenses, except contact lenses
(h) external prosthesis (artificial extension that replaces a missing
body part) not intended for implantation.
(i) disposables and their equivalent: not intended for treating
disease (tongue pressers, medical trash bins, gloves, diapers,
disposable bedsheets, etc.)
(j) casts, plastic casts, collars, or any external devices to support
the movement or stabilizing of joints or the body parts
(k) materials and accessories used in manufacturing dental parts,
dentures, dental braces, given that they are not intended for
implantation within oral cavity and jaws.
(l) hearing aids (nonimplantable)
540 UAE
38.5 Definition of a Medical Device

A medical device is any instrument, apparatus, implement, machine,
appliance, implant, in vitro reagent or calibrator, software, material
or other similar or related article:
(a) intended by the company and its manufacturing site to be used,
alone or in combination, for human beings for one or more of
the specific purpose(s) of
of disease
• supporting or sustaining life
• Indicate the sterilization process completion
from the human body, and
(b) which does not achieve its primary intended action in or on the
means, but which may be assisted in its intended function by
such means.
38.6 Classification of Medical Device/IVD

(a) The control of medical devices is based on risk assessment and
risk management. The level of regulatory control applied to the
medical device is proportional to the degree of perceived risk
associated with the device.
(b) Medical devices are classified into four classes, based on the
GHTF classification: Class l (low risk), II and III (medium risk),
and IV (high risk).
• Class I devices are those that need the lowest level of
regulation because of low risk to the patient, except sterile
products.
Authorized Representative Concept 541
• Class II devices are of medium-risk and require assessed

quality system according to the ISO 13485 standards. These
devices are invasive in their interaction with the human
body, but the methods of invasion are limited to natural body
orifices.
• Class III devices are of a medium risk. They are either partially
or totally implantable within the human body and may modify
the biological or chemical composition of body fluids.
• Class IV devices are of high risk and require design/clinical
trial reviews, product certification, and an assessed quality
system involving clinical trials. These devices affect the
functioning of vital organs and/or life-support systems. They
are usually invasive, life-sustaining, life-supporting, or are
used “in preventing impairment of human health or if the
device presents a potential unreasonable risk of illness or
injury.”
(c) Classification of in vitro diagnostic medical devices is based
on the potential risk involved in their use and interpretation
clinically:
• Class A (low individual risk and low public health risk), e.g.,
clinical chemistry analyzer, prepared selective culture media
• Class B (moderate individual risk and/or low public health
risk), e.g., pregnancy self-testing, anti-nuclear antibody, urine
test strips
• Class C (high individual risk and/or moderate public health
risk), e.g., blood glucose self-testing, human leukocyte antigen
(HLA) typing, prostate-specific antigen (PSA) screening,
rubella.
• Class D (high individual risk and high public health risk), e.g.,
HIV blood donor screening, HIV blood diagnostics.
38.7 Authorized Representative Concept

(a) Legal manufacturers based outside the UAE (authorized
representative in the country of origin) have to appoint local
representative/s to act on their behalf (MOH licensed medical
store or scientific office).
( b) A local representative is the legal entity licensed by the MOH
who has received a mandate from the mother company to act on
542 UAE
its behalf regarding matters pertaining to placing the product in

the UAE Market and all its registration requirements.
(c) A legalized agreement stating the appointment of the
local authorized representative by the company should be
submitted.
(d) Importation and distribution activities should be performed
by an appointed licensed medical Store (one importer for a
product).
Responsibilities of the Local Representative
(a) Monitor the device on the market and inform the MOH
immediately after the detection of any problem related to a
registered device.
(b) Handle device recalls.
(c) Provide technical support and services to the users of registered
device(s).
(d) Advise on effective implementation of all regulatory procedures,
including Adverse and Near Incident Reporting, Advisory
Notice Issue (including Product Recall), Post-Market Feedback,
Complaint Handling, and Significant Change Notifications.
38.8 Company Registration

38.8.1 Medical Devices Classified as Nonpharmaceutical
Dosage Form
For the registration of the authorized representative in country
of origin (a legal manufacturer) along with source, the file should
include the required documents and information relevant to the
main source (manufacturing facility: final releaser/assembly) to be
evaluated according to the set regulation.
A declaration from the legal manufacturer should declare
the list of their manufacturing sites related to the source/s, along
with contract manufacturers, and contract sterilizers, specification
developers, packagers or labelers, processors of single-use devices.,
and manufacturers of components or accessories that are sold or
released directly to the end user.
Note: The MOH has the right to ask for certificates for any of the
above sites.
38.8.2 Medical Devices Classified as Containing

Pharmaceutical Ingredients
For the registration of the manufacturer, the documentation and
information relevant to all sites involved in the manufacturing
process is required according to the set regulation in case of
pharmaceutical dosage forms.
Main Documents to be provided
1. An official application form, which is to be signed by the legal
manufacturer and its local authorized representative.
2. Legal manufacturer business license issued by the competent
authority in the country of origin, including those for the
source/main manufacturing site.
If the company has multiple manufacturing sites, a flow chart
or table should be submitted identifying each manufacturing
location with the manufacturing step carried out, as following:
design, production, sterilization (if applicable), packaging,
labeling, final release.
3. Site Master File for each manufacturing site (if applicable;
mainly required for pharmaceutical product manufacturers).
4. Notarized copies of certificates pertaining to quality
accreditations from recognized assessment bodies (ISO-
13485) or GMP certificate issued by the health authority.
5. Post-marketing surveillance general plan (Global SOP).
6. General profile
38.9 Product Registration

38.9.1 Medical Devices Subject for Listing
(Must not be of pharmaceutical dosage form)
o all class 1, medical devices
o dressings and blasters intended to be in contact with wounds
o classical (not new technology) invasive, transient or implan-
table medical devices used by medical professionals or within
hospital use, given that do not carry labels intended for
patients or retail sale
o Blood-collecting tubes and bags
given that all these devices should have no labeling directed for
patients with exaggerated medical claims.
544 UAE
38.9.2 Product Registration: Main Documents

Table 38.1 lists the documents required to be provided by the
company. The application forms are available in the guide line
(published on the MOH Web site) and available for local distributors
at the customer service center.
Table 38.1 Main documents needed for product registration
Attachment Documents required

A Application Form
The application to place a medical device on the UAE market
must be signed and stamped by the company and local
representative
B Regulatory Approval
(Free Sale certificate or documentation and letters of regulatory
approval) and (certification or FDA clearance, TPP clearance
approval clearance, etc.)
C Post-market requirement/vigilance system and risk
assessment
SOP is required for a specific device
D Status of device distribution
List of countries where it is marketed, details of the regulatory
status
E Device Information (enclose device description and list of
models/codes/ref. no. (if any)
intended use, indications, instructions of use, contraindications,
warnings, precautions, potential, adverse events, device labeling,*
alternative labeling, which include physicians manual, pack
labeling, and promotional material, a general description of the
device and detailed description of the device attributes
F Labeling
• Three copies (artwork) of the each product packaging,
labeling.
• Labeling and packaging must have: the product name, name
and address of the company printed in English and/or Arabic,
manufacturing date and/or expiration date (if applicable).
• For single use medical devices must be labeled on outer pack
label with “SINGLE USE.”
G Declaration of conformity/evidence of conformity to essential
principles + quality certificates issued by assessment bodies
H Safety and effectiveness data (Summary report)

H.1: Safety and effectiveness data
H.2: Risk assessment
H.3: Pre-clinical and clinical studies
H.4: Biocompatibility
H.5: Special requirements for devices containing biological
material
H.6: Literature studies
I Manufacturing process (for pharmaceutical forms)
J Special requirements for medical devices manufactured
from or incorporating viable or nonviable animal tissue or
their derivative(s).
* Labels are subject to assessment by evaluation committee, and understandable
Universal symbols/instructions for professionals and consumers are required on
the label such as sterile, single use, storage condition, etc.
38.9.3 Required Attachments per Device Class

Table 38.2 Required attachments per device class
Class I (sterile and/ Class III/

Class I/ or with measuring class
general IVD function)/general Class II/ C IVD/self- Class IV/
A IVD (class A) class B IVD testing IVD class D IVD
A A A A A
B B B B B
Not Applicable Not Applicable C C C
Not Applicable Not Applicable D D D
E E E E E
F F F F F
G G G G G
Self- F. Self-declaration
declaration G. All certificates and
documents certifying
conformity to the
aspects of
manufacture relating
to sterility and
metrology
Not Applicable Not Applicable Not H H
Applicable
Not Applicable Not Applicable Not I (if required) I (if required)
Applicable
546 UAE
38.10 Pricing
• Not applicable unless the device containing ingredient for long
term therapeutic use, (e.g., intra-articular hyaluronic acid).
• Registration committee decides for device subject to pricing.
38.11 Parallel Importation

Not allowed.
References
1. Australia TGA (Therapeutic Goods Administration), http://www.tga.

gov.au/industry/devices.htm.
2. EU Medical Device Directives 93/42/EEC, EU in vitro Diagnostic
Device Directive (IVDD) 98/79/EC and EU Active Implantable Medical
Device Directive (AIMDD) 90/385/EEC, http://ec.europa.eu/health/
medicaldevices/documents/guidelines/index_en.htm.
3. Global Harmonization Task Force (GHTF) for Medical Device
Classification, http://www.ghtf.org/documents/sg1/SG1-N15-2006-
Classification-FINAL.pdf.
4. Medical Device Registration Guideline/ Registration and Drug
Control Department, Ministry of Health, UAE, http://213.42.151.126/
admincp/assetsmanager/Files/Pharmacusts/MEDICALDEVICEguid
linesforUAE.pdf.
5. Singapore HSA, http://www.hsa.gov.sg/publish/hsaportal/en/health_
products_regulation/medical_devices.html.
6. US FDA, http://www.fda.gov/MedicalDevices/default.htm.
Chapter 39
Vietnam: Medical Device Regulatory

System
Thuy Nguyen Thi Thu

Johnson & Johnson Medical Vietnam
17 Ngo Quyen St., Hoan Kiem Dist., Hanoi, Vietnam
thuyntt@its.jnj.com
Disclaimer

(i) Vietnam is a fast-growing country. Its population is about
87 million and is receptive to the use of advanced medical
products.
(ii) The main high-technology medical devices are imported from
foreign manufacturers. The imported medical devices account
for 80% of total medical devices in Vietnam.
(iii) Local manufacture is highly encouraged by the Ministry of
Health.

www.panstanford.com
548 Vietnam
39.2 Overview of Regulatory Environment and

Laws/Regulations Governing Medical
Devices
Medical device regulation is developing in Vietnam. The new
regulatory system will be largely based on the ASEAN Medical
Device Directives (AMDD), which refer to the Asian Harmonization
Working Party (AHWP) and the Global Harmonization Task Force
(GHTF) directives. The GHTF is a voluntary consortium with
representatives from trade and regulatory authorities from United
States, Canada, Australia, Japan, and the European Union, formed
in 1992 to harmonize the standards and principles of regulating
medical devices.
Currently, Circular 24/2011/TT-BYT dated June, 21, 2011,
guides medical device importing, in which imported medical
devices belonging to 50 categories need to get import license before
importation; other medical devices (except “new medical device”)
are considered for exemption. However, the requirements for
the exempted and non-exempted ones are the same. The only
difference is that the documents for exempted ones need not be
submitted to the authority to get the import license; instead, the
required documents may be inspected by the authority.
All local medical devices need to be registered according to
Circular 07/2002/TT-BYT dated May 30, 2002.

The regulatory body in Vietnam is the Department of Medical
Equipment and Construction (DMEC), the Ministry of Health.
Figure 39.1 presents the organizational chart of the DMEC in the
Ministry of Health.
Ministry of Health
Ministry of Health
DMEC Drug
Drug Medical
Medical Food
Food Other
Other dept.
DMEC Administration
Administration of Environment
Environment Administration
Administration of of
of Vietnam
Vietnam Management Dept.
Management Dept. Vietnam
Vietnam Dept.
Figure 39.1 DMEC organizational chart.

Contact Information
Department of Medical Equipment and Construction,
Ministry of Health, 138A Giang Vo Street, Badinh District,
Hanoi, Vietnam
Telephone: +844 62732272
Fax: +844 62732279
Web site: http://www.moh.gov.vn

Medical devices are equipment, devices, materials, and chemicals,
including necessary software, used alone or in combination, for
human for the purpose of
(i) preventing, monitoring, diagnosing, treating, or alleviating
disease or compensating for an injury
(ii) investigation, replacement, modification, or support of the
anatomy or of a physiological process
(iii) supporting and sustaining life
(iv) controlling contraception
(v) disinfecting medical devices (excluding chemicals, insect- and
bacterium-killing products for family uses and health)
(vi) specialized transport for health activities
Note:
(i) Disinfection products are not in the scope.

(ii) Accessories/spare parts are listed together with their
equipment, if any.
(iii) Combination products will be decided on a case-by-case basis,
according to its primary action and reference regulations
from the EU and the United States.
Devices designed for the treatment or diagnosis of diseases
and injuries in animals are outside the scope of the proposed
regulatory framework.
550 Vietnam

(Class A, B, C, D )
The classification of medical devices based on the risk level is
being developed in Vietnam. It mainly follows the ASEAN Medical
Device Directive (AMDD)/GHTF recommendation.
39.5 Role of Distributors or Local Subsidiaries

The importer is the person who applies and holds the license for the
import of a medical device.
They have the following roles under Circular 24/2011/TT-BYT:
(i) effective communication with the manufacturer, distributor,
user, and DMEC
(ii) responsible for local labeling activity, if any
(iii) responsible for maintenance and services
(iv) notification and management of safety information to the user
and the authority
(v) annual report to the authority about business activity
Details can be found in Circular 24/2011/TT-BYT.
39.6 Product Registration or Conformity

Assessment Route and Time Required
The Medical Device Administration Control System is basically
divided into two parts: pre-market approval and exemption.
The DMEC is the competent authority and also responsible
for conformity assessment. Conformity assessment committee
includes DMEC, Medical Service Department, and other experts
working within the Ministry of Health.
Pre-market approval is in the form of import license application.
The medical device categories are subjects of pre-market approval,
including high risk one (e.g., implants) and high-value ones (e.g.,
MRI, PET). Other medical devices (except new medical device) are
exempted. The importer will work directly with the customs for
Product Registration or Conformity Assessment Route 551
clearance without import license. The documents required for pre-

market approval and exemption products are the same.
Suggested license Routes/Steps

The importer collects necessary documents and submits them to
the DMEC. Following are the documents required:
(i) CFG/CFS or CE marked
(ii) ISO 9001 or ISO 13485
(iii) Catalogue
(iv) Letter of authorization
(v) Executive summary in Vietnamese
• The DMEC receives the document and carries out assessment
(deficiency document will be requested from the importer,
if any).
• The conformity assessment committee meeting will be held
to approve the document.
• The Ministry of Health issues the import license, which is valid
for one year from the date of issue.
The importer pays the fee and receives the license.
According to the regulation, the timeline for evaluation is 15
working days.
39.6.1 Quality System Regulation

Vietnam follows ISO 9001, ISO 13485:2003, and Vietnam’s standards
(TCVN). It is voluntary to follow them.

Regulation for Combined Device–Drug Product
There is no specific rule for a combination product. Such a product
will follow either the medical device or the pharmaceutical regu-
lation.
39.6.3 Registration Fee

The fee for the import license is about USD 10–150 / product family,
depending on the value of the product.
552 Vietnam
39.6.4 Technical Material Requirement

See Section 39.6 for imported medical devices and Circular
07/2002/TT-BYT dated, May 30, 2002, for local ones.
39.6.5 Labeling Requirements for Medical Devices

The label on a medical device follows Decree No. 89/2006/ND-CP,
dated August 30, 2006, of the Prime Minister and Circular 09/2007/
TT-BKHCN, dated April 6, 2007, of the Ministry of Science and
Technology. The requirements regarding local manufacturing are
being developed on the basis of ISO 13485. They are expected to
be issued by 2014.
39.6.6 Post-Marketing Surveillance Requirement

The notification and management of safety information to user
and the authority must be done by the importer, but there is no
specific guideline on this requirement.
39.6.7 Manufacturing-Related Regulation

The requirements regarding local manufacturing are being deve-
loped on the basis of ISO 9001 and ISO 13485. They are expected to
be issued by 2014.
39.6.8 Clinical Trial-Related Regulation

Clinical trials of medical devices are regulated. They follow Decision
36/2006/QD-BYT, dated November 14, 2006. Clinical trials required
in the following cases:
1. Some local products: The Ministry of Health will decide which
case requires a clinical trial.
2. Imported products: This applies to medical devices
considered “new” products that are used for the application
of new diagnosis and therapeutic methods and imported into
Vietnam for the first time.
Upcoming Events 553
39.6.9 Is There a Procedure for Mutual Recognition of

Foreign Marketing Approval or International
Standards?
No.
39.7 Commercial Aspects
39.7.1 Any Control over Prices of Medical Devices?

No, at this moment.

Under the current regulation, medical devices are imported via
an authorized importer. However, the authority does not always
check the authorization letter for exempted products.
39.7.3 Any Regulation Regarding Advertisement of

Medical Devices?
The advertisement of medical devices follows the joint-circular
01/2004/TTLT-BVHTT-BYT, dated January 12, 2004.
39.8 Upcoming Events

Revision of the regulation on local clinical trial requirement is
being developed and is expected to be issued by 2013.
References
1. Ministry of Health, Vietnam Retrieved (March 2012) from

http://www.moh.gov.vn/wps/portal/boyte/trangchu/!ut/p/
c5/04_SB8K8xLLM9MSSzPy8xBz9CP0os3hnd0cPE3MfAwMLd3
NDA0_XUKdQDy8nQ4NgU_wkA5kFS5uFgZGTqZmnoEGLgYGn-
qYQeQMcwNFA388jPzdVvyA7O83RUVERAHJEoy0!/dl3/d3/
L2dBISEvZ0FBIS9nQSEh/.
554 Vietnam
2. Nguyen Minh Tuan, Director of Department of Medical Equipment and

Construction, March 2012 (email: ngmtuan@ymail.com; address: 38A
Giang Vo, Ba Dinh Dist., Hanoi, Vietnam; phone: + 84 4 62732277).
3. Nguyen Tu Hieu, Expert of Department of Medical Equipment and
Construction, March 2012 (email: hieuboyte@yahoo.com; address: 38A
Giang Vo, Ba Dinh Dist., Hanoi, Vietnam; phone: + 84 4 62732272).
Devices
Authority/ class & Roles Documen-
regulator particu- Product & Registration tation Post- Combination
Key dates name larities labeling licenses process & language market products
ASEAN
First Draft Each A-Low Risk Member Manufacturer/ Member Demonstration Member States to take AMDD covers the
Appendix:
of the Asian Authority in B-Low- States may Authorized States must of compliance appropriate measures device component
Medical each ASEAN moderate require local Representative put a system to the Essential and immediately of a combination
Device Member C-Moderate- languages shall register in place to Requirements inform other Member product
Directive high or notify the assess Medical CSDT (Common States
(AMDD) D-High Regulatory Devices Submission
issued in Authority of the MD shall be Dossier
January 2008 Member State assessed by Template)
Official the regulatory
Deadline for authority of Application to
all ASEAN a Member be submitted in:
Member State, or any English
States to appointed
comply with bodies
AMDD: 2015 recognized
ASEAN by a Member
Regulatory Summary Table
Consultative State and

Committee should be in
on Standards conformity
and Quality and in
(ACCSQ) compliance
Medical with the
Device requirements
Product laid down in
Working the AMDD and
Group other relevant
(MDPWG) statutes of
a Member
(Continued)
State.
556
Authority/ Devices Roles

regulator class & Product & Registration Documentation Post- Combination
Key dates name particularities labeling licenses process & language market products
Appendix
AUSTRALIA
TGA: MDD Class: Adverse

Events:
Therapeutic Grouping of MD Manufacturer Regulatory System follows EU MD Already CE marked MD: reduced TGA considers:
Goods Act Therapeutic I- Low Risk under one ARTG to designate Directive 93/42/EEC requirements • the primary
1989 Goods Is, Im, IIa -Low inclusion if same an Australian • Serious intended pur-
4 processes:
Therapeutic Adminis- - moderate manufacturer- Sponsor Not CE marked MD: full Conformity threat to pose
1. For class I(non-sterile, non-measuring)
Goods tration IIb-Moderate- sponsor- Assessment by TGA: public • the mode of
2. For MD manufactured in AUS (other
Regulations high classification- Once MD • Copy of current conformity health: to be action of the
than Class I)
1990 Office of III-High GMDN code included in assessment evidence reported or product
3. For MD manufactured overseas (other
Therapeutic Devices the ARTG • Risk Management File <48h to define if
than Class I)
Goods Authorizat AIMD: For Class III and (Australian • Clinical evidence • Led to death: they will be
4. For MD containing a medicine or
(Medical ion<TGA< All-High Risk AIMD: same as Register of • Essential Principles Checklist immediately regulated as a
materials of animal, microbial
Process 3: Application Audit:

Devices) Australian above + same Therapeutic STED format as reference or <10 days medicine or a
recombinant or human origin
Regulations Government Unique Product Goods), no • Other events: medical device.
2002 Department Identifier (UPI) expiry date immediately
2010: IVDs of Health – maintain • Device Classification by Manufacturer Level 1: documentation required: or <30 days
• Conformity Assessment Procedure by • Australian Declaration of
regulated and Ageing Product labeling: compliance
Manufacturer – validated by TGA or Conformity
as subset in English, use to Essential
EU Notified Body • Copy of current conformity as-
of Medical of recognized Principles
• Australian Declaration of Conformity sessment evidence
Devices symbols (e.g. ISO and submit
by Manufacturer • Information on device (labeling/
Level 2:
15223-1) changes
to TGA for • Manufacturer’s evidence submitted to IFUs/advertising materials)
evaluation as TGA by Sponsor
required • Application lodged on-line by Sponsor • Same as Level 1
Process 4:
to include MD in ARTG • Risk Management Report
MD supported
• Clinical Evaluation Report
by a TGA CA
(Conformity • Device Classification by Manufacturer • Efficacy and performance data
Assessment) • TGA Conformity Assessment
application by Manufacturer Australian-EC Mutual Recognition
Certificate:
validity 5 • Australian Declaration of Conformity Agreement (MRA) applicable
by Manufacturer to all classes and Class III (not
years
• Manufacturer’s evidence submitted to containing medicine or material of
TGA by Sponsor animal, human, microbial origin):
• Application lodged on-line by Sponsor abbreviated approval route
to include MD in ARTG
CHINA
1 April 2000: SFDA = I-Low Risk Chinese ISO 13485 Write product standard following China Application to be submitted in: Adverse Events: Regulation
Regulations State Food II-Moderate language recognized National Standard (ISO/IEC standard as Chinese • Class III changing
for the and Drug III-High required on Manufac- ref, but to be translated in Chinese) MD: severe
Supervision Adminis- primary, turing site: Product testing at National Testing centre AE must be
and Adminis- tration secondary • complies as per China National Standard reported
tration and IFU with Clinical Trial if required: within 15 days
of MD CCC Mark : Chinese • Class III, long-term implantable; CT independent
issued by GMPs mandatory in China of its
China Quality • Class III • Class II domestically produced: exempt location in the
Certification and from CT (21 MD group qualified for world
Centre; sterile exemption): demonstrate similarity
applies to 8 Class with approved product
categories II MD: • Class I: exempt from CT
of MD: inspected Director
• rubber by SFDA Application reviewed by :
condoms • SFDA Med Device Technical Evaluation
• diagnostic Centre
x-ray • SFDA Medical Device Registration
• hemodialysis Department
equipment • Director of SFDA Medical devices dept
• hollow fiber • Director General of SFDA
dialyzers MD Registration Certificate: valid 4 years
• extra-
corporeal Recognition of GHTF country approval
blood circuit
• electrocardi-
ographs
• pacemakers
• artificial
heart-lung
Appendix
machines
(Continued)
557
558

Regulator class & Product & Registration Documentation Post- Combination
Appendix
EUROPE
Competent MDD Class: Low-moderate risk devices Adverse Events:

Authority
1985: New National Manufacturer: Low risk devices (MDD: Class I; IVD: Based on
Approach: I, Is, Im-Low language (23 must inform Self-tests, Self-certifiable): (Class I, Is, Im, IIa and IIb from • Serious PMOA: Primary
set up the in each Risk languages) the CA of the • Self-Certification by the Legal MDD; List B, Self-test from IVD): threat to Mode of Action
legislative European IIa-Low- Use of symbols Member State in Manufacturer Technical File: public EU Directives
and technical Member moderate (EN 980) which he has his • CE Declaration of Conformity • Essential Requirements health: to do not apply
frame in the State (27) IIb-Moderate- registered place Checklist be reported cumulatively
Foreign
European high Add suitable of business Moderate- High risk devices (MDD: • Risk Management File immediately
Manufacturer
Community NB: Notified III-High specific label Class Is, Im, IIa, IIb, III; AIMD: High • Clinical Evaluation Report or <48h Drug/Device
CAB: AIMD:
(EC) Body for phthalate- Risk; IVD: list A and B): • Led to death: combination
1989: Global containing must appoint • NB Selection High risk devices (Class III from immediately product:
Representative
Approach Conformity All-High Risk devices an Authorized • Conformity Assessment Procedure MDD; List A from IVD; AIMD): or <10 days When PMOA
IVD:
(Conformity Assessment • Batch Verification by NB for IVD List Design File • Other events: physical,
Assessment Body located in A immediately classified as MD:
Modules, List A-High Europe: • Technical Documentation review by Application to be submitted or <30 days • Technical/
quality List B- Authorized NB in: English accepted, unless Design File
Assurance, Moderate Representative • Quality Management System audit specified by Member State to Periodic submitted to
Notified Self-test- to inform the CA by NB submit in local language Summary Report NB
Bodies) Moderate of the Member • CE Mark Certificate FSCA: Field • NB assess
1990: AIMD Self-Certifiable- State in which • Continued Batch Verification by NB Safety Corrective performance
90/385/EEC Low he has his for IVD List A Action of the
Directive registered place • CE Declaration of Conformity FSN: Field Safety device and
on Active Systems and of business Notice (= form usefulness
Implantable Procedure to be used to of the
Medical Packs Manufacturer notify a FSCA to substance
Devices to be ISO 13485 customers) • CA assess
1993: MDD certified Guideline the quality,
93/42/EEC MEDDEV 2.12: safety,
Medical Validity of forms for: clinical
Device product license • Incident benefit/
Directive (CE Mark): Report to CA risks of the
1998: IVD maximum 5 • FSCA Report substance
98/79/EC years to CA • Need the
Directive • Template for favorable
on In Vitro FSN opinion of
Diagnostics the CA for
Medical NB to deliver
Devices CE Mark
Regulator class & Product & Registration Documentation Post- Combination
HONG KONG
MDCO: Class II, III, IV: Adverse Events:

Class II, III, IV:
MD do not I-Low Risk English & Local Regulatory System: follows GHTF Drug-Device
require Medical II-Low- Chinese responsible • STED • Serious threat product:
registration, Device moderate Person LRP • Registration of Product, local to public registration
unless containing Control III-Moderate- to be assigned manufacturer, overseas manufacturer Application to be submitted in: health, led to and quality
pharmaceutical Office high (more than one death, serious system to
CAB:
(or its local representative), importer English
Class I:
products or IV-High allowed) • QMS Certification (ISO 13485) injury: to be follow MD
emitting ionizing reported <10 requirements
radiation Conformity Validity of Registration of local manufacturer and days
2004: MDCO Assessment product license: importer • Other events:
established Body 5 years <30 days
Nov 26th, 2004:
Medical Device
Administrative
Control System
MDACS:
Voluntary listing
of Class IV
Nov 14th, 2005:
Voluntary listing
of Class II and
INDIA
Class III
Drugs and DCGI: Drugs Notified MD Add the Foreign “Me Too” Route (prior approval): “Me Too” Route (prior approval): Complaints & No definition
Cosmetic Act Controller classified as approval Manufacturer/ • Abridged Evaluation when already • Application Form 40  DCGI Adverse Reactions of combination
1. Disposable
1940 General of Drugs: number Importer: local approved in at least one of the GHTF delivers approval Registration for Drugs and products as
Central Hypodermic
Drugs and India under (Import agent, License founding members Certificate (Form 41) New Drugs MD regulated
Government Syringes
Cosmetic Rules License No.) for sale and • Application in Form 8  DCGI Clinical Trials as Drugs
CDSCO: 2. Disposable
(1945) distribution delivers Import License (Form No specific
Hypodermic
October 2005 Language: 10) requirements for
Needles
Site inspection
Gazette Central Drugs English MDs
3. Disposable
by CDSCO and
notification Standards
Perfusion Sets
FDA; Conformity
for 10 categories Control
Assessment
of Organization
Procedures
Appendix
MD notified as
(Continued)
Drugs
559
560

Appendix
INDIA
3. Disposable
Perfusion
Food and performed New product: New product:
Sets
Drug by Notified • Complete evaluation, • Form 44 application
4. In-vitro
Adminis- Bodies are clinical trials (clinical Data)  Form 45
Diagnostic
tration acceptable Cert
Devices for
Drugs (ISO 13485, • Form 40  Form 41
HIV, HBsAg
Control USFDA QSRs) • Form 8  Form 10 License
and HCV
Depart-
5. Cardiac
Application to be submitted in
ment Local
Stents
English at the DCGI office.
under manufacturer:
6. Drug Eluting
State FDAs some time may
State to comply
Stents
have local language formats
Gover- with GMP;
7. Catheters
along with English as an
nment inspection by
8. Intra Ocular
alternate.
CDSCO and
Lenses
State FDA;
9. I V Cannulae
license valid
10. Bone
for 5 years
Cements
11. Heart Valves
Validity of
12. Scalp Vein

product license
Sets
(Registration
13. Orthopedic
Certificate): 3
Implants
years
14. Internal
Prosthetic
Validity of
Replacements
Form 10 is
1. Blood Group-
same as Form
ing Sera
41
2. Ligatures,
Sutures and
Staplers
3. Intra-Uterine
devices (Cu-T)
4. Condoms
5. Tubal Rings
6. Surgical
Dressings
7. Umbilical
tapes
8. Blood/Blood
Components
Bags
INDONESIA
Health
Mandatory Ministry of I-Low Risk English is Applicant: All manual with hard copies CSDT Voluntary Currently no
registration IIa-Low- acceptable must hold a • Pre-registration reporting guideline
will be moderate To be provided distribution • Submission Application to be submitted in: Serious
enforced IIb-Moderate- in Indonesian: license • Payment English or Indonesian adverse health
in 2014 high • Intended “IPAK”, must • License or death:
based on III-High use be officially mandatory to
the ASEAN • Direction appointed report, 24h
Medical for use by source with corrective
Device • Precautions company action plan
Directive • Warning or legal
(AMDD) • Adverse manufacturer
event as sole agent
(can be put in – validity of 2
IFU) years
Validity of
product
Appendix
license: 4 years
(Continued)
561
562

Appendix
JAPAN
Pharma- MHLW: I-Low Risk (= To be in Regulatory MD: Minister’s approval, or STED Adverse Events: No clear
|ceutical Ministry of General MD) Japanese: System: follows 3rd party Certification or Marketing • Serious definition at this
Company: Class I:
Affairs Law Health, II-Low-moderate • brand name, GHTF Notification Application to be submitted in: threat to moment
(PAL) from generic name, Japanese public
PMDA:
Labour and (=Controlled MD)
1960 Welfare III-Moderate- • device • License for Self-Declaration health: to be
Class II:
high (=Highly category on Marketing by MAH reported <15
Pharma- Controlled MD) device itself, Authorization days
ceuticals and IV-High (=Highly wrappers or Holder (MAH) • Led to death:
Medical Controlled MD) containers • Pre-market certification application <150 days
(Types 1, 2 and reviewed by a Registered
Devices 3) - Validity: 5 • Other serious
Certification events: <30
RCB:
Agency JMDN (Japanese years
Medical Device Body days
• MAH located • QMS inspection (certification valid
Nomenclature) : in Japan: • Non-serious:
Registered generic name for for annual
must comply 5 years) –
Class III
Certifi-cation single MD and with GQP report
similar to ISO 13485
and IV:
Body grouping of MD (Good Quality
Practices) –
• Comply with
GVP (Good • Application reviewed
Vigilance by the PMDA and MHLW
Manufacturing
Practices) • QMS
Site/
Manufacturer:
license for
Manufacturer
or Foreign
Manufacturer
Accreditation
4 types of
License:
Biological,
Sterilization,
General,
Packaging
Validity: 5 years
Product License:
no expiry date
Key dates name particularities labeling licenses process & Language market products
JORDAN
Regulations JFDA: I-Low Risk Country of Distributors Evaluation of the importation requests • Notarized FDA Certificate to Incidents Combination
implemented Jordan Food IIa-Low- Origin & importers by the Medical Device Committee Foreign Government (CFG) or reporting system products such as
since 2005 and moderate No specific should be Analysis test at JFDA Drug Laboratory CE Certificates or Free Sales to JFDA drug containing
Drug IIb-Moderate- symbol to be put registered in Control Department certificates No timelines medical devices
Adminis- high on the product ministry of trade Class I follows the same registration • Finished product specifications should be
tration III-High after approval. and industry process such as II & III and methods of analysis registered
Language: • For MD containing ingredients
English language Validity of of animal origin; TSE/BSE
and/or Arabic. product license: Certificate (Transmissible
5 years Spongiform Encephalopathy/
Bovine Spongiform
Encephalopathy)
Application to be submitted in
English
MALAYSIA
Dec 2011: Medical A-Low Risk No labeling Manufacturer/ Class B, C, D: Class B, C & D: Voluntary Evaluated by
Adverse Events:
Medical Device B-Low- requirements at Importers/ Evaluation routes: • Abridged Evaluation: CSDT + reporting both National
Device Bill and Authority moderate that time Distributors • Abridged Evaluation when already Doc + Technical File (TF for Pharmaceutical
Medical Device C-Moderate- would need approved in at least one of the GHTF Class D only) • Serious threat Control Bureau
Authority Bill high to apply for founding members • Full Evaluation: CAB to public and Medical
passed by D-High establishment • Full Evaluation Assessment of CSDT + DoC + health: to Device Authority
Parliament licenses: it will Technical File (TF for Class D be reported
Class A:
MD are Product be defined in only) <48h
registered on grouping: the upcoming • Led to death:
a voluntary • Single regulation • Simplified CSDT + DoC <10 days
basis • System • Other events:
Validity of Application to be submitted in:
Mandatory • Kits <30 days
product license English acceptable
registration • Group
not defined yet
will be
enforced in
2014 based
on the ASEAN
Medical Device
Appendix
Directive
(Continued)
(AMDD)
563
564

Appendix
Philippines
BFAD Circular BFAD: I-Low No labeling Regulatory Sterile and invasive • GMP Certificate Voluntary No
#05-1998 Bureau Risk requirements at System: follows MD must be registered • Government Certificate of Reporting of Combination
of Food II-Low-mod- that time GHTF clearance and Free Sale from Adverse Events Product
and Drug erate Manufacturer/ country of origin Mandatory regulation
Adminis- III- Importers/ • ISO Certification for imported Reporting of – drug/biologic
tration Mode-rate- Distributors: product Product Recall part registered
high local • Certificate of agreement separately from
IV-High representative between manufacturer and Device part
to hold a License trader/distributor/importer
to Operate • Technical specifications of the
(LTO) product/stabilities/labeling
Validity of Application to be submitted in:
product license English
(Certificate
of Product
Registration
CPR):
• initial
registration: 1
year
• subsequent
renewal: 5
Republic of korea (south korea)

years
1997: MD KFDA: Korea I-Low For plastic made Manufacturer Class I: notification to one of the 6 Class II, III & IV: Adverse Events: Combination
Class II, III & IV:

regulated by Food and Risk MD: label to or Importer: Regional KFDA • Technical File (requirements • Serious threat products
the KFDA Drug II-Low-mod- specify if DEHP Device Business similar to CSDT or STED) to public covered by
2003: New Adminis- erate was added or License: Technical File review: health: to articles for MD
tration used in the license,
Republic of korea (south korea)
4 Quality
System
Medical III- manu-facturing Health • Technical File when device basically • Type Testing: reports to be reported <7 notification and
Audit
Device Act, Mode-rate-high process certificate of the same as previously approved be provided about bio- days technical file
Agencies:
fully enforced IV-High the company ones compatibility, electrical • Led to death: review
Int. recognized
since May30th, representative, • Safety and Efficacy review (SER) & mechanical safety, details shall be
symbols
2004 KTL, KCL, 25 product registered legal when significantly different: new- electromagnetic compatibility, additionally
accepted
6 Technical
From April 8th, KTC, KTR groups entity, list of to-market features (new materials, performance tests reported within
Files review
2012, foreign Korean language facilities mechanisms of action, usage or • Safety and Efficacy review 8 days from the
Agencies
manufacturers required on effectiveness) (SER): requires stability data, date of initial
Korea Good
“Regional
of Class II, both the outer Type Testing clinical study report reporting
Manufacturing
III and IV package & IFU KGMP Certification (identical to ISO Local clinical study report not • Recall of
Practice
MD should KFDA”: KTL, certification 13485) necessary if foreign clinical data harmful
be audited KTC, KCL, (KGMP) (validity strong enough and approved by medical devices
by Korean KTR, TUV- of 3 years) foreign regulator, if published in required recall
auditors for Science Citation Index (SCI) may submit a
13
SUD, SGS Product License:
their quality recall plan to
Domestic
no expiry date Application to be submitted in:
system at the KFDA within 5
Labora-
Korean preferably
on-site (re- to 15 days.
tories to
certification • The expected
perform
every 3 years) end date of
Type
recall shall be
Testing,
within 30 days
from the start
including of recall
KTL
(Continued)
Appendix
565
566

Appendix
Saudi arabia
Importer, Adverse Events:

Distributor
Royal Decree SFDA: Food Product group: When device Regulatory System: follows GHTF Since the
& Authorized
(M/6) issued and Drug guidance intended to Medical Device Marketing • Serious MDMA require
Represen-
on Feb 2007 Authority on MDMA be used by lay Marketing Authorization Certificate Authorization (MDMA) injury: to that the device
tative:
gave the incorporating person (i.e. and Medical Device Listing national applications: be reported complies with
SFDA the more than one not medical registry Number delivered if: • Electronic form imme-diately, the regulation
responsibility MD type personnel): • Register • MD to be already registered in one • Electronic copies of labels i.d. <10 days of one of the
to regulate MD, Arabic & English (electro- or more of the 5 GHTF founding • Copy of IFUs • Other events: GHTF founding
reinforced by nically) countries • Evidence that MD authorized <30 days member, the
the Council through the • MD labeling and conditions of in one of the 5 GHTF founding product was
of Ministers Medical supply to be compliant with Member National fully assessed
decision No. Device provisions from KSA (Kingdom of centre of Medical and the
181 issued on national Saudi Arabia) Same registration path for all Devices decision was
June 2007 registry classes – fees different reporting already made
MD interim (MDNR): STED format not applicable (NCMDR): to to regulate it as
regulation National report FSCA medical device
issued by Saudi Registration Application to be submitted in: or not.
FDA on Dec Number English
27th, 2008 issued by
|SFDA
• Apply
through
Medical
Device
Establish-
ment
Licensing
(MDEL)
to get an
establish-
ment License
Saudi arabia
Validity of
license: 1 year
Validity of
|product license:
• same as
MA granted
in GHTF
jurisdiction
• except when
open ended
or self-
declaration
process: 3
Singapore
years
HSA: Manufac- Class B, C, D: Adverse Events:

turers:
2002 A-Low Risk English Regulatory System: follows GHTF Guidance to be
Class B, C, D:
• Voluntary Singapore B-Low- International Common Submission Dossier • Serious threat published for
Importer and
Product Health moderate Recognized ISO 13485 template CSDT to public Drug-Device
Wholesaler:
registration Sciences C-Moderate- symbols Online Medical Device Information and Class A: health: to product
Scheme Authority high Communication System (MEDICS) for CSDT not required: be reported
• Post-Market - Health D-High GDPMDS (Good screening: registrable or rejection • Letter of Authorization immediately
monitoring Products Distribution Evaluation routes: • Singapore Declaration of and <48h
• Surveillance Regulation Product Practice for MD) • Abridged Evaluation when already Conformity • Led to death:
program Group grouping: of ISO 13485 approved in at least one of the GHTF • Product labeling, IFUs etc <10 days
for Medical • Single with founding members • Name, address, contact • Other events:
Class B: Expedited Registration

Devices on • Family scope of storage • Full Evaluation information of importer <30 days
FSCA:
route:
market • System and distribution • QMS Certificate for
2007 Health • Group Validity of manufacturing and
Products act: • IVD Cluster licenses: sterilization sites • Initiation of
• when approval by at least 2
From Nov 1st, 12 months Sterilization method and FSCA and
reference regulatory agencies, or
Appendix
2007 validation standard used
(Continued)
567
568

Appendix
Singapore
• Report Validity of • Approval by one of independent Application to be submitted in: preliminary

adverse product reference regulatory agency and English report to
events license: 1 year marketed for at least 3 years without be notified
to HAS
Class B: Immediate Registration

safety concerns. within 24h
within the
(IBR) Evaluation Route:

stipulated • Final
time frame report to be
• Notify HSA submitted
• when approved by at least 2
prior to within 21
initiation of independent reference regulatory
days
a product agencies (i.e. US FDA, EU/TGA,
recall Health Canada, Japan MHLW) and
• Maintenance marketed for at least 3 years without
of product safety concerns.
compliant
and
distribution
records
From Nov
st
1 , 2008: MD
dealers and
registrants
licensing
MD licensed
under
Radiation
Protection Act
exempted from
registration
with HSA until
Aug 1st, 2011
From Aug 10th,
2010 : Class C
and D MD must
be licensed
From Jan 1st,
2012 : Class A
and B MD must
be licensed
Taiwan
1970: TFDA: I-Low Risk Mandarin Authorized Class II: Class I: Periodic safety Drug-Device
Pharmaceutical Taiwan Food II-Moderate domestic Evaluation routes: Affidavit + GMP certificate + MD update reports product:
Class II:
Affairs Act and Drug III-High &foreign • Abridged Evaluation (Mutual dealer license (PSUR) to be registration
promulgated, Adminis- distributors or recognition) when already submitted for and quality
enacted in tration subsidiaries: approved certain devices system to
Abridged Evaluation:
1973 must have in US and/or EU every 6 months follow MD
• Technical Documentation
1998: Good licensing for • Full Evaluation for 3 years requirements
without pre-clinical testing
Manufacturing wholesaling, with additional
• QSD (Quality System
Practices retailing, summary report
Documentation) limited to
2000: importing or of total of 3 year
inspection report, Free Sale
reclassification exporting MD PSUR.
Certificate and ISO 13485
of MD No expiration
Certificate
2004: date on the
Full Evaluation: full Technical
Regulations company license
Documentation including pre-
governing
Class III:
clinical testing
Management Foreign
of MD manufacturer:
2004: TFDA issue QSD Full Evaluation: full Technical
Guidelines for (Quality System Documentation including pre-
Registration Documentation) clinical testing (+Clinical Reports
of MD Certificate when New MD)
2006: Good (validity: 3 STED format accepted for
Laboratory years) Class III
Practice for
Nonclinical Validity of Application to be submitted in:
Laboratory product license: English or Mandarin
Studies 5 years
2007 Medical
Device Good
Clinical
Practice
Appendix
(Continued)
569
570

Appendix
Taiwan
2010 Applica-
tion Guidelines
for Registration
of In Vitro Di-
agnostic Medi-
cal Devices
2011 Medical
Device Good
Vigilance
Thailand
Practice
Medical Device ThaiFDA I-Low Risk In Thai language, Manufacturer Manual submission by the importer to • Original CFS/CFG Mandatory No Guidance
Act (“the Act”) (“General”) product label to or its the regulator • Letter of authorization Reporting of Classification
in 1988 II-Moderate contain: representative • Product catalogue Adverse Events based on
Medical Device (‘Higher Risk’) • product must register in • Copy of the establishment for and Product intended
Act (2008) III-High name, person, through importation license Recall use: either
2551 B.E. (Highest Risk”) • class, type; a locally-based classified
• name, legal entity and
address and evaluated
Validity of
country of only as a
product license
origin of the Device, or
(“letter of
manufacturer as a Drug
importation”):
and importer; aligned with
• license the validity of
number CFS/CFG
• lot number;
summarized
usage
instructions
• expiration
date
United arab emirates
MOH: MD classified as non- Class I:
pharmaceutical dosage form:
UAE Pharmacy I-Low Risk English and/or Regulatory Timeline for MD classified
Law No 4 from Ministry of II-Low- Arabic System: follows • Application form, Free Sale Incidents report- containing
RDCR:
1983 Health moderate understandable GHTF Register the Authorized Representative certificate ing: 15 calendar pharma-
MD Regula- III-Moderate- Universal in Country Of Origin (COO) (supported • Device information days. ceutical
tory system is Registration high symbols/ Appoint Local by declaration/certificates from • Labeling Prior ingredients
MD classified containing
already applied and Drug IV-High instructions for Representative: source/manufacturing site) • DoC, evidence of conformity notification
pharmaceutical ingredients:
and a grace Control Follows professionals licensed by to to MOH Classification
period for department the GHTF and consumers MOH Essential Principles, Quality before FSCA according to
Class II:
importation rule-based are required on Local certificates is required. other
Register the manufacturer (supported
is granted for classification the label such Representative international
by documentation from source/
non-registered as Sterile, single subject to reference bod-
manufacturing site) Same as Class I + Post-market
professional use, storage annual renewal ies is accepted.
requirements, risk assessment
use items condition, and
through a Validity of
Class III & IV:

Status of device distribution
local licensed product license:
distributor. 5 years
Same as Class II + Safety
and effectiveness data and
Manufacturing process
Application to be submitted in:
Usa
English
USFDA: Class I&II: Class I:

(domestic &
1968 Radiation I-Low Risk English required Manufacturers MDR (medical OCP: FDA’s
foreign) &
control of United II-Moderate • Premarket Notification (510k) • Unless exempt, require a Device Office of
Health and States Food III-High Labeling clearance (21 CFR Part 807 Subpart 510k application Reporting) Combination
Safety Act and Drug requirements in distributors E) • Subject to General Controls (21CFR Part Products
(RCHSA) Adminis- 21 CFR Part 801 (importers): • Demonstration of “substantial (Registration and Listing, 803): electronic
1976: Medical tration Convenience Additional • Register equivalence”: device as safe and labeling, GMP) MD reporting 21 CFR 3.2:
Device kits requirements establish- effective as a predicate device program: eMDR physically or
Appendix
for: ment (=legally marketed device) (voluntary)
(Continued)
571
572

Appendix
Usa
Amendments HHS: US • In-vitro • Designate Class III: Class I & II: Adverse Events: chemically
to the US Department diagnostic a US Agent • Premarket approval (PMA) process • Unless exempt, require a • Serious threat combined
Federal Food, of Health device (if foreign (21 CFR Part 814) 510k application to public products;
Drug and and Human • IDE (Investi- manufac- • For innovative, non-substantially • Subject to General Controls health: to be co-packaged
Cosmetic Act Services gational turer) equivalent MD • Subject to Special reported <5 products;
(FD&C Act) (HHS) device Establishment Controls (special labeling days separately
CDRH:
(=Law) Exemption) registration requirements, patient • Led to deaths, marketed but
Regulations device valid for 1 year registries, mandatory serious “cross-labeled”
(=Federal Center for • Radiation- performance standards, post- injuries and products:
Class III:
Manufacturers
Laws) : Title 21 Devices emitting market surveillance studies) malfunctions: • Combina-
to comply
Code of Federal and products <30 days tion of drug
with FDA
Regulations Radiological • Natural • Require a PMA application • Other events: & device
CBER:
Quality System
(CFR) – 9 Health; rubber (includes submission of <30 days • Device &
Regulation (21
Volumes: the (latex) clinical data) • Interim biological
CFR Part 820)
one containing Center for • Subject to General Controls and annual product
(=GMP Good
the MD and Biologics • Subject to Special Controls updates • Biological
Manu-
electronic Evaluation Application to be submitted in: required if product &
facturing
product and any baseline drug
CDER:
Practices) English
regulations is Research; information • Drug, a
(few substantive
Part 800-1299 changes device, and
differences to
Center after initial a biological
ISO 13485, but
PMOA:
for Drugs submission product.
no conflicting
Evaluation requirements)
and
Product License: Primary Mode
Research
no expiry date of Action
RFD : Request
for Designation
submitted to
OCP Reviewed
CBER, CDRH,
by either/or:
CDER
Vietnam
DMEC: Importer: a-b; Same documentation

needed:
Circulate Will follow Vietnamese a-Pre-market Approval = import Notification and Based on
24/2011/TT- Depart- AMDD-GHTF labeling for the applies and license application Management primary mode
BYT dated ment of A-Low Risk outer packaging holds the import • For high risk MD • CFG/CFS or CE mark of safety of action, with
21st June 2011 Medical B-Low- only (not license • Submission to DMEC • ISO 9001 or ISO 13485 information reference
guiding MD Equipment moderate required for • Validity of Import License: 1 year • Catalogue to user and to EU, US
importing: 50 & Cons- C-Moderate- IFU )
b-Exemption: importer to work • Letter of Authorization Authority must regulations
categories need truction high
directly with custom for clearance
be done by
Executive summary in
submission D-High
without import license
importer
Vietnamese
to get import No specific
license; others, guideline on
no need to timeline
submit, but
documentation
may be
inspected
Local MD need
to be registered
according
to Circular
07/2002/TT-
BYT dated 30th
may 2002
Appendix
573

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What are the main regulatory requirements for medical devices in Vietnam?

What are the main regulatory requirements for medical devices in Vietnam?

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No claim to original U.S. Government works

International Standard Book Number-13: 978-981-4411-22-6 (eBook - PDF)

1. How to Train University Students in Regulatory Affairs 1

3. Ensuring Smooth Product Launch: Regulatory Interfaces

8.6 e-Labelling, Web Sites, Internet, and Social Media:

12.10 Scope, Exclusions and Non-Applicability 134

13.3.3 Control Risk 151

15. Asian Harmonization Working Party 169

17.2.1 Provisions of the AMDD 185

20.4 Legislation and Device Laws 214

21.7 Guidelines 244

22.4 The Standards for Determining Which FDA

23.4.1 Examples of Devices Incorporating an

Part 5 Medical Device Regulatory System

24.5.2 Process for Including Class 1 IVD Medical

25. China: Medical Device Regulatory System 317

25.5.3.7 The CCC mark 327

26.5 Commercial Aspect 339

28. Indonesia: Medical Device Regulatory System 365

29.2.1 The Ministry of Health, Labour and

30.1.1 Vision 403

31.2.12 Applying for a Product License 437

33.3 History of Medical Device Regulation 460

34.1 Introduction 469

35. Singapore: Medical Device Regulatory System 487

35.8 Technical Material Requirement 499

36.1 Market Overview 513

36.6 Labeling Requirements of Medical Devices 520

37.1 Market Overview 525

38.1 Ministry of Health 535

38.3 Medical Devices Marketing Approval Flow Chart 538

39.1 Market Overview 547

39.6.4 Technical Material Requirement 552

Medical device regulation in Asian markets has become important.

Asia Regulatory Professional Association

The Asia Regulatory Professional Association (ARPA) is an

How to Train University Students in

This chapter focuses on how to design a regulatory course to train

Handbook of Medical Device Regulatory Affairs in Asia

On completion of the course, students will be able to demonstrate

1.2 A Sample of Regulatory Affairs Exercises

Figure 1.1 Various sizes of hypodermic syringes.

To begin with, your client has suggested designing and

Task 1: Classification

Task 2: Risk Analysis

Task 3: Risk Evaluation and Risk Control

Task 4: Medical Device Registration Submission

1. ISO 13485 (Medical devices — Quality management systems —

The Evolution of the Regulatory

David Martin and Neil Lesser

Handbook of Medical Device Regulatory Affairs in Asia

In response, manufacturers are seeking a new type of regulatory

2.2 Drivers of Change

pharmaceutical and device manufacturers, and released a new Five