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 Data Monitoring
Committees in Clinical Trials
 Statistics in Practice
Advisory Editor

Stephen Senn
Luxembourg Institute of Health

Founding Editor

Vic Barnett
Nottingham Trent University, UK

Statistics in Practice is an important international series of texts which

provide detailed coverage of statistical concepts, methods and worked
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With sound motivation and many worked practical examples,
the books show in down-to-earth terms how to select and use an
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ments. Subject areas covered include medicine and pharmaceutics;
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The books also provide support to students studying statistical
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It is our aim to present judiciously chosen and well-written work-
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A complete list of titles in this series appears at the end of the volume.
 Data Monitoring
Committees in Clinical
Trials
A Practical Perspective

SECOND EDITION

Susan S. Ellenberg
Department of Biostatistics, Epidemiology and Informatics
University of Pennsylvania Perelman School of Medicine
USA

Thomas R. Fleming
Department of Biostatistics
University of Washington
USA

David L. DeMets
Department of Biostatistics and Medical Informatics
University of Wisconsin–Madison
USA
This edition first published 2019
© 2019 John Wiley & Sons Ltd
Edition History
John Wiley & Sons (1e, 2002)
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted,
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by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley
.com/go/permissions.
The right of Susan S. Ellenberg, Thomas R. Fleming, and David L. DeMets to be identified as the authors of this
work has been asserted in accordance with law.
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Library of Congress Cataloging-in-Publication Data
Names: Ellenberg, Susan S., 1946 - author. | Fleming, Thomas R., 1950 - author. |
DeMets, David L., 1944 - author.
Title: Data monitoring committees in clinical trials : a practical perspective / Susan
S. Ellenberg, Thomas R. Fleming, David L. DeMets.
Other titles: Data monitoring committees in clinical trials
Description: Second edition. | Hoboken, NJ : Wiley, 2019. | Series:
Statistics in practice | Preceded by Data monitoring committees in
clinical trials : a practical perspective / Susan S. Ellenberg, Thomas R.
Fleming, David L. DeMets. 2002. | Includes bibliographical references and
index. |
Identifiers: LCCN 2018043881 (print) | LCCN 2018044429 (ebook) | ISBN
9781119512646 (Adobe PDF) | ISBN 9781119512677 (ePub) | ISBN 9781119512653
(hardcover)
Subjects: | MESH: Clinical Trials Data Monitoring Committees–organization &
administration | Clinical Trials as Topic | Data Collection–methods |
Clinical Trials Data Monitoring Committees–ethics
Classification: LCC R853.C55 (ebook) | LCC R853.C55 (print) | NLM W 20.55.C5
| DDC 610.72/4–dc23
LC record available at https://lccn.loc.gov/2018043881
Cover Design & Image: Wiley
Set in 13/15.5pt PhotinaMT by SPi Global, Chennai, India

10 9 8 7 6 5 4 3 2 1
 Contents

Preface to the Second Edition xiii

Preface to the First Edition xv

1 Introduction 1
1.1 Motivation 1
1.2 History of data monitoring committees in
government-sponsored trials 8
1.3 Data monitoring committees in trials sponsored by the
pharmaceutical industry 15
1.4 Statistical methods for interim monitoring 18
1.5 When are data monitoring committees needed? 21
1.6 Models for data monitoring committees 22
1.7 Where we are today 24
1.8 Fundamental principles of data monitoring 25
References 27

2 Responsibilities of the Data Monitoring

Committee and Motivating Illustrations 35
2.1 Fundamental charges 36
2.2 Specific tasks of the data monitoring committee 39
2.2.1 Initial review 40
2.2.1.1 Review of the study protocol 40
2.2.1.2 Review of procedures to ensure quality
of study conduct 45
2.2.2 Evaluating the quality of ongoing study
conduct 47

v
vi Contents

2.2.3 Assessing safety and efficacy data 56

2.2.3.1 Termination due to favorable
benefit-to-risk 58
2.2.3.2 Termination due to unfavorable
benefit-to-risk 63
2.2.3.3 Termination due to inability to answer
trial questions 65
2.2.3.4 Continuation of ongoing clinical
trials 68
2.2.3.5 Consideration of the overall picture:
primary and secondary analyses 72
2.2.3.6 Modifying sample sizes based on
ongoing assessment of event rates 76
2.2.4 Reviewing the final results 80
2.3 The data monitoring committee charter 83
References 84

3 Composition of a Data Monitoring

Committee 89
3.1 Introduction 89
3.2 Required areas of expertise 90
3.3 Other relevant characteristics of committee members 96
3.4 Committee size 98
3.5 Selecting the committee chair 102
3.6 Responsibility for appointing committee members 102
3.7 Representation of other study components on the
committee 104
3.8 Preparation for service on a committee 106
References 109

4 Independence of the Data Monitoring

Committee: Avoiding Conflicts of Interest 113
4.1 Introduction 113
4.2 Rationale for independence 114
4.3 Financial independence 116
4.3.1 Commercial sponsors 117
4.3.2 Government sponsors 118
4.3.3 Academic investigators 118
 Contents vii

4.4 Intellectual independence 125

4.5 Emotional conflicts 131
4.6 Best practices to address challenges to the DMC’s
independence 132
4.6.1 Adequate training/experience in the
DMC process 133
4.6.2 Indemnification of DMC members 135
4.6.3 Maintaining confidentiality of interim
data 136
4.6.4 Flexibility of procedures 138
4.6.5 DMC meeting format 139
4.6.6 Creating independent relationships and
reducing conflicts of interest 141
4.6.7 Adequately informative DMC reports 142
4.7 Summary 143
References 144

5 Confidentiality Issues Relating to the Data

Monitoring Committee 147
5.1 Rationale 147
5.2 Limits of confidentiality 159
5.2.1 Interim analysis reports 159
5.2.2 Access to aggregate data on efficacy and
safety outcomes 161
5.2.3 Providing access to interim data on a
“need-to-know” basis 164
5.2.4 Settings and procedures allowing broader
unblinding of safety data 166
5.2.5 Consequences of unblinding interim data for
regulatory review in ongoing trials 168
5.2.6 Some illustrations of broader unblinding 175
5.2.7 The steering committee and maintaining
confidentiality 187
5.2.8 Indirect challenges to confidentiality 189
5.3 The need for the DMC to review unblinded
data 190
5.4 Conclusions: consensus regarding confidentiality 195
References 198
viii Contents

6 Data Monitoring Committee Meetings 203

6.1 Introduction 203
6.2 Specific objectives and timing of meetings 204
6.2.1 Organizational meeting 205
6.2.2 Early safety/trial integrity reviews 208
6.2.3 Formal interim efficacy analyses 212
6.2.4 End-of-trial debriefing 213
6.3 Preparation of meeting reports 214
6.3.1 Currentness of data in the report 217
6.3.2 Inclusion of unadjudicated data 220
6.4 Format for meetings 221
6.4.1 The initial closed session 223
6.4.2 The open session 224
6.4.3 The final closed session 227
6.4.4 Various formats for holding the open and
closed sessions 227
6.4.5 Meeting duration and venue 229
6.5 DMC meeting minutes and the DMC
recommendations 230
6.5.1 The DMC recommendations, the open
minutes, and the closed minutes 230
6.5.2 The level of detail 232
6.5.3 The authorship of the minutes and the
sign-off by committee members 233
References 235

7 Data Monitoring Committee Interactions

with Other Trial Components or Related
Groups 237
7.1 Introduction 238
7.2 Study sponsors 238
7.2.1 Industry sponsors 239
7.2.2 Government sponsors 241
7.3 Study steering committee/principal investigator 243
7.4 Study investigators 247
7.5 Trial statisticians and statistical centers 247
7.5.1 The independent statistical center 248
7.5.2 Ensuring optimal data presentations 253
 Contents ix

7.6 Institutional review boards 253

7.7 Regulatory agencies 256
7.8 Study participants and/or advocacy groups 257
7.9 Other data monitoring committees 259
References 262

8 Statistical, Philosophical, and Ethical Issues

in Data Monitoring 265
8.1 The need for statistical approaches to monitoring
accumulating data 266
8.2 Overview of statistical methods 270
8.2.1 Group sequential methods 271
8.2.1.1 Some group sequential boundaries
for establishing benefit 273
8.2.1.2 Group sequential alpha spending
functions 277
8.2.1.3 Some group sequential boundaries
when early results are unfavorable 280
8.2.2 Triangular boundaries 284
8.2.3 Stochastic curtailment/conditional power 286
8.2.4 Bayesian monitoring 290
8.2.5 The general approach to sequential stopping
boundaries 293
8.2.6 Software packages for sequential clinical trial
designs 294
8.2.7 Adaptive clinical trial designs 294
8.3 Protocol specification of the monitoring plan 299
8.4 Other statistical considerations in monitoring trial
data 300
8.4.1 Primary versus secondary endpoints 300
8.4.2 Short-term versus long-term treatment
effects 302
8.4.3 Results in subgroups 303
8.4.4 Taking external information into account 307
8.4.5 Evaluating safety in the context of evidence
about efficacy: role of boundaries 309
8.4.6 Ensuring proper robustness when defining
boundaries for establishing benefit 311
x Contents

8.5 Ethical considerations 313

8.5.1 Early termination philosophies 313
8.5.1.1 Responding to early beneficial
trends 314
8.5.1.2 Responding to early unfavorable
trends 318
8.5.1.3 Responding to unexpected safety
concerns 324
8.5.2 Other ethical considerations 325
References 326

9 Determining When a Data Monitoring

Committee is Needed 335
9.1 Introduction 336
9.2 Typical settings for an independent data monitoring
committee 336
9.3 Other settings in which an independent data monitoring
committee may be valuable 339
9.3.1 Early trials of high-risk treatments 339
9.3.2 Trials in vulnerable populations 340
9.3.3 Trials with potentially large public health
impact 341
9.4 An alternative monitoring approach: the internal
monitoring committee 342
9.5 A decision model assessing need for an independent
DMC or an internal monitoring committee 346
9.6 Settings with little need for an independent or internal
monitoring committee 351
9.7 Summary 352
References 353

10 Regulatory Considerations for the Operation

of Data Monitoring Committees 355
10.1 Introduction 356
10.2 Data monitoring committees in government
regulations 356
10.3 Regulatory guidance 357
 Contents xi

10.3.1 US Food and Drug Administration 357

10.3.2 International regulatory guidance 360
10.3.2.1 European Union 360
10.3.2.2 International Conference on
Harmonization 361
10.3.2.3 The World Health Organization 363
10.4 Regulatory approaches relevant to data monitoring
committee operation: the US FDA 364
10.5 Policies of funding agencies regarding DMC
operations 367
10.5.1 National Institutes of Health 367
10.5.2 Other federal agencies 369
10.5.3 Funding agencies outside the US 369
10.6 Involvement of FDA staff in data monitoring committee
deliberations 370
10.7 Examples of regulatory authority interaction with data
monitoring committees 372
References 379

11 Legal Considerations for DMCs 383

11.1 DMC indemnification 383
11.1.1 Motivating examples 385
11.1.2 Emergence of DMCs and heightened
awareness of their existence 388
11.1.3 Further motivation for indemnification
to protect the DMC 390
11.1.4 Some specific concerns from current experiences
with indemnification 392
11.1.5 Potential solutions to indemnification issues 394
11.1.6 Confidential disclosure agreement (CDA) 397
11.1.7 Summary of indemnification, liability, and
contracting issues 399
11.2 Balancing legal and ethical responsibilities: a need for a
mediator? 400
11.2.1 A case study: the setting of Actimmune
in patients with idiopathic pulmonary
fibrosis 402
11.2.2 IMMUNE response AIDS clinical trial 405
References 406
xii Contents

Appendix A The Data Monitoring Committee

Charter 411

Appendix B Performance Standards

Document 431

Statistics in Practice 451

Index 455
 Preface to the Second Edition

We were gratified by the positive reception given to the First

Edition of this book, and believe it remains a useful guide to
the principles and practices of clinical trial data monitoring
committees. Since the time of its publication, however, there
have been a number of new developments that impact on
the conduct of these committees. Some of these include
guidances issued by regulatory and funding agencies, new
types of trial designs that impose new demands as well as
limitations on DMC functioning, and many more journal
publications addressing DMC issues and illustrating the types
of difficult issues that DMCs may face. Thus, several years
ago it appeared that an update of the book was needed. In
this new edition, we have added material to each chapter to
provide the most current information about policies related
to DMC operations, to describe experiences of recently pub-
lished trials relevant to DMC decision-making, and to address
special issues in monitoring trials using newly emerging
designs. We have also added a chapter focusing on legal
issues affecting DMC members, motivated by increasing con-
cerns about litigation related to clinical research generally.
We are grateful to our many colleagues who have written,
and continue to write, about their experiences serving
on DMCs for trials that presented challenging situations.
xiii
xiv Preface to the Second Edition

These publications inform and enlighten the clinical trials

community, especially as they relate to emerging issues in
clinical trials, such as new types of clinical trial designs.
The oversight of clinical trials remains an extremely impor-
tant responsibility. We hope this book will be useful to those
engaged in DMC activities, whether as members, sponsors, or
investigators reporting to these committees.
 Preface to the First Edition

The randomized clinical trial has been recognized as the gold

standard for evaluation of medical interventions for only
half a century (Doll, 1998). Over the past several decades,
the increasingly central position of randomized clinical trials
in medical research has led to continual advances in the
development of methodology for the design, conduct, and
analysis of these studies. An enormous body of literature
relating to clinical trials methodology is now available,
a professional society focusing on clinical trials has been
established (Roth, 1980; www.sctweb.org), and a large
number of statisticians, clinicians, and epidemiologists
consider clinical trials as their primary area of research
and/or application.
One area of clinical trials that has received relatively little
attention but that can be critical to the ethics, efficiency,
integrity, and credibility of clinical trials and the conclusions
of such trials is the process of interim monitoring of the accu-
mulating data. To an increasing extent, interim monitoring
is becoming the province of formally established committees.
While a great deal has been written about statistical methods
for interim data monitoring, the practical aspects of who
should serve on data monitoring committees (DMCs) or
otherwise be involved in the monitoring process, what data

xv
 Motivation 5

the atmosphere surrounding early trials of AIDS treatments,

such as this one, was particularly “high pressure.” Trial 002
was monitored by the DMC that had been established by the
National Institute of Allergy and Infectious Diseases (NIAID)
to oversee all of its extramural trials of treatment for HIV
infection (DeMets et al. 1995). The CPCRA was a clinical
trials group funded by NIAID; therefore, access to interim
data was limited to DMC members – none of whom were
treating patients on this or any other NIAID-funded AIDS
trial, or had any financial stake in the trial outcome – and to
a limited number of NIAID staff.
The interim results from this trial, shown in Figures 1.1
and 1.2, illustrate how substantially relative risk estimates

ddC Better ddl Better

September 20, 1992 Confidence intervals:

157:152 (ddl:ddC) Repeated
95%
August 21, 1992
130:130 (ddl:ddC)

February 13, 1992

77:91 (ddl:ddC)

November 8, 1991
50:66 (ddl:ddC)

August 29, 1991 5.7

19:39 (ddl:ddC) 3.8

0.80 1.00 1.25

Relative Risk (log scale)

Figure 1.1 Relative risk of progression of disease (including

death) by date of DMC review. Numbers to the right of the arrows
are upper confidence limits. Source: From Fleming et al. (1995).
Reproduced by permission of Lippincott, Williams & Wilkins.
Another random document with
no related content on Scribd:
 CHAPTER VII
WHAT THE RED ENVELOPE HELD

“My dear Angel,” wrote Jimmy, “I commend to you one Mr. Spedding,
an ingenious man. If by chance you ever wish to visit him, do so in
business hours. If you desire to examine his most secret possession,
effect an entrance into a dreary-looking house at the corner of Cley’s
Road, a stone’s-throw from ‘High Holly Lodge.’ It is marked in plain
characters ‘To Let.’ In the basement you will find a coal-cellar.
Searching the coal-cellar diligently, you will discover a flight of stone
steps leading to a subterranean passage, which burrows under the
ground until it arrives at friend Spedding’s particular private vault. If
this reads like a leaf torn from Dumas or dear Harrison Ainsworth it is
not my fault. I visited our legal adviser last night, and had quite a
thrilling evening. That I am alive this morning is a tribute to my
caution and foreseeing wisdom. The result of my visit is this: I have
the key of the ‘safe-word’ in my hands. Come and get it.”
Angel found the message awaiting him when he reached Scotland
Yard that morning. He too had spent sleepless hours in a futile
attempt to unravel the mystery of old Reale’s doggerel verse.
A telegram brought Kathleen Kent to town. Angel met her at a quiet
restaurant in Rupert Street, and was struck by the delicate beauty of
this slim girl with the calm, gray eyes.
She greeted him with a sad little smile.
“I was afraid you would never see me again after my outburst of the
other night,” she said. “This—this—person is a friend of yours?”
“Jimmy?” asked the detective cheerily. “Oh, yes, Jimmy’s by way of
being a friend; but he deserved all you said, and he knows it, Miss
Kent.”
The girl’s face darkened momentarily as she thought of Jimmy.
“I shall never understand,” she said slowly, “how a man of his gifts
allowed himself to become——”
“But,” protested the detective, “he told you he took no part in the
decoying of your father.”
The girl turned with open-eyed astonishment.
“Surely you do not expect me to believe his excuses,” she cried.
Angel Esquire looked grave.
“That is just what I should ask you to believe,” he said quietly.
“Jimmy makes no excuses, and he would certainly tell no lie in
extenuation of his faults.”
“But—but,” said Kathleen, bewildered, “he is a thief by his own
showing—a bad man.”
“A thief,” said Angel soberly, “but not a bad man. Jimmy is a puzzle
to most people. To me he is perfectly understandable; that is
because I have too much of the criminal in my own composition,
perhaps.”
“I wish, oh, how I wish I had your faith in him! Then I could absolve
him from suspicion of having helped ruin my poor father.”
“I think you can do that,” said the detective almost eagerly. “Believe
me, Jimmy is not to be judged by conventional standards. If you ask
me to describe him, I would say that he is a genius who works in an
eccentric circle that sometimes overlaps, sometimes underreaches
the rigid circle of the law. If you asked me as a policeman, and if I
was his bitterest enemy, what I could do with Jimmy, I should say,
‘Nothing.’ I know of no crime with which I could charge him, save at
times with associating with doubtful characters. As a matter of fact,
that equally applies to me. Listen, Miss Kent. The first big
international case I figured in was a gigantic fraud on the Egyptian
Bank. Some four hundred thousand pounds were involved, and
whilst from the outsider’s point of view Jimmy was beyond suspicion,
yet we who were working at the case suspected him, and pretty
strongly. The men who owned the bank were rich Egyptians, and the
head of all was a Somebody-or-other Pasha, as great a scoundrel as
ever drew breath. It is impossible to tell a lady exactly how big a
scoundrel he was, but you may guess. Well, the Pasha knew it was
Jimmy who had done the trick, and we knew, but we dare not say so.
The arrest of Jimmy would have automatically ruined the banker.
That was where I realized the kind of man I had to deal with, and I
am always prepared when Jimmy’s name is mentioned in connection
with a big crime to discover that his victim deserved all he got, and a
little more.”
The girl gave a little shiver.
“It sounds dreadful. Cannot such a man as that employ his talents to
a greater advantage?”
Angel shrugged his shoulders despairingly.
“I’ve given up worrying about misapplied talents; it is a subject that
touches me too closely,” he said. “But as to Jimmy, I’m rather glad
you started the conversation in that direction, because I’m going to
ask you to meet him to-day.”
“Oh, but I couldn’t,” she began.
“You are thinking of what happened on the night the will was read?
Well, you must forget that. Jimmy has the key to the verse, and it is
absolutely imperative that you should be present this afternoon.”
With some demur, she consented.

In the sitting-room of Jimmy’s flat the three sat round a table littered
with odds and ends of papers.
The girl had met him with some trepidation, and his distant bow had
done more to assure her than had he displayed a desire to
rehabilitate himself in her good opinion.
Without any preliminaries, Jimmy showed the contents of the packet.
He did not explain to the girl by what means he had come into
possession of them.
“Of all these papers,” began Jimmy, tapping the letter before him,
“only one is of any service, and even that makes confusion worse
confounded. Reale had evidently had this cursed cryptogram in his
mind for a long time. He had made many experiments, and rejected
many. Here is one.”
He pushed over a card, which bore a few words in Reale’s
characteristic hand.
Angel read:—

“The word of five letters I will use, namely:

1. White every 24 sec.
2. Fixed white and red.
3. White group two every 30 sec.
4. Group occ. white red sec. 30 sec.
5. Fixed white and red.”

Underneath was written: “No good; too easy.”

The detective’s brows were bent in perplexity.
“I’m blessed if I can see where the easiness comes in,” he said. “To
me it seems so much gibberish, and as difficult as the other.”
Jimmy noted the detective’s bewilderment with a quiet smile of
satisfaction. He did not look directly at the girl, but out of the corner
of his eyes he could see her eager young face bent over the card,
her pretty forehead wrinkled in a despairing attempt to decipher the
curious document.
“Yet it was easy,” he said, “and if Reale had stuck to that word, the
safe would have been opened by now.”
Angel pored over the mysterious clue.
“The word, as far as I can gather,” said Jimmy, “is ‘smock,’ but it may
be——”
“How on earth——” began Angel in amazement.
“Oh, it’s easy,” said Jimmy cheerfully, “and I am surprised that an old
traveler like yourself should have missed it.”
“Group occ. white red sec. 30 sec.,” read Angel.
Jimmy laughed.
It was the first time the girl had seen this strange man throw aside
his habitual restraint, and she noted with an unaccountable
satisfaction that he was decidedly handsome when amused.
“Let me translate it for you,” said Jimmy. “Let me expand it into,
‘Group occulting White with Red Sectors every Thirty Seconds.’ Now
do you understand?”
Angel shook his head.
“You may think I am shockingly dense,” he said frankly, “but even
with your lucid explanation I am still in the dark.”
Jimmy chuckled.
“Suppose you went to Dover to-night, and sat at the end of the
Admiralty Pier. It is a beautiful night, with stars in the sky, and you
are looking toward France, and you see——?”
“Nothing,” said Angel slowly; “a few ships’ lights, perhaps, and the
flash of the Calais Lighthouse——”
“The occulting flash?” suggested Jimmy.
“The occ.! By Jove!”
“Glad you see it,” said Jimmy briskly. “What old Reale did was to
take the names of five famous lights—any nautical almanac will give
you them:

Sanda.
Milford Haven.
Orkneys.
Caldy Island.
Kinnaird Head.
They form an acrostic, and the initial letters form the work ‘smock’;
but it was too easy—and too hard, because there are two or three
lights, particularly the fixed lights, that are exactly the same, so he
dropped that idea.”
Angel breathed an admiring sigh.
“Jimmy, you’re a wonder,” he said simply.
Jimmy, busying himself amongst the papers, stole a glance at the
girl.
“I am very human,” he thought, and was annoyed at the discovery.
“Now we come to the more important clue,” he said, and smoothed a
crumpled paper on the table.
“This, I believe, to have a direct bearing on the verse.”
Then three heads came close together over the scrawled sheet.
“A picture of a duck, which means T,” spelt Angel, “and that’s erased;
and then it is a snake that means T——”
Jimmy nodded.
“In Reale’s verse,” he said deliberately, “there are six words; outside
of those six words I am convinced the verse has no meaning. Six
words strung together, and each word in capitals. Listen.”
He took from his pocketbook the familiar slip on which the verse was
written:—
“Here’s a puzzle in language old,
Find my meaning and get my gold.
Take one BOLT—just one, no more—
Fix it on behind a DOOR.
Place it at a river’s MOUTH
East or west or north or south.
Take some LEAVES and put them whole
In some WATER in a BOWL.
I found this puzzle in a book
From which some mighty truths were took.”
“There are six words,” said Jimmy, and scribbled them down as he
spoke:—
“Bolt (or Bolts). Leave (or Leaves).
Door. Water.
Mouth. Bowl.
Each one stands for a letter—but what letter?”
“It’s rather hopeless if the old man has searched round for all sorts of
out-of-the-way objects, and allowed them to stand for letters of the
alphabet,” said Angel.
The girl murmured something, and met Jimmy’s inquiring eyes.
“I was only saying,” she said hesitatingly, “that there seems to be a
method in all this.”
“Except,” said Jimmy, “for this,” and he pointed to the crossed-out
duck. “By that it would seem that Reale chose his symbols
haphazard, and that the duck not pleasing him, he substituted the
snake.”
“But,” said Kathleen, addressing Angel, “doesn’t it seem strange that
an illiterate man like Mr. Reale should make even these rough
sketches unless he had a model to draw from?”
“Miss Kent is right,” said Jimmy quickly.
“And,” she went on, gaining confidence as she spoke, “is there not
something about these drawings that reminds you of something?”
“Of what?” asked Angel.
“I cannot tell,” she replied, shaking her head; “and yet they remind
me of something, and worry me, just as a bar of music that I cannot
play worries me. I feel sure that I have seen them before, that they
form a part of some system——” She stopped suddenly.
“I know,” she continued in a lower voice; “they are associated in my
mind—with—with the Bible.”
The two men stared at her in blank astonishment. Then Jimmy
sprang to his feet, alight with excitement.
“Yes, yes,” he cried. “Angel, don’t you see? The last two lines of
Reale’s doggerel—
“‘I found this puzzle in a book
From which some mighty truths were took.’”
“Go on, go on, Miss Kent,” cried Angel eagerly. “You are on the right
track. Try to think——”
Kathleen hesitated, then turned to Jimmy to address the first remark
she had directed to him personally that day.
“You haven’t got——?”
Jimmy’s smile was a little hard.
“I’m sorry to disappoint you, Miss Kent, but I have got a copy,” he
said, with a touch of bitterness in his tone. He walked to the
bookcase at one end of the room and reached down the book—a
well-worn volume—and placed it before her.
The rebuke in his voice was deserved, she felt that.
She turned the leaves over quickly, but inspiration seemed to have
died, for there was nothing in the sacred volume that marshaled her
struggling thoughts.
“Is it a text?” asked Angel.
She shook her head.
“It is—something,” she said. “That sounds vague, doesn’t it? I
thought if I had the book in my hand, it would recall everything.”
Angel was intently studying the rebus.
“Here’s one letter, anyway. You said that, Jimmy?”
“The door?” said Jimmy. “Yes, that’s fairly evident. Whatever the
word is, its second letter is ‘P.’ You see Reale’s scribbled notes? All
these are no good, the other letters are best, I suppose it means; so
we can cut out ‘T,’ ‘O,’ and ‘K.’”
“The best clue of all,” he went on, “is the notes about the ‘professor.’
You see them:
 “‘Mem.: To get the professor’s new book on it.
Mem.: To do what the professor thinks right.
Mem.: To write to professor about——’
Now the questions are: Who is the professor, what is his book, and
what did he advise? Reale was in correspondence with him, that is
certain; in his desire for accuracy, Reale sought his advice. In all
these papers there is no trace of a letter, and if any book exists it is
still in Sped—it is still in the place from whence this red envelope
came.”
The two men exchanged a swift glance.
“Yes,” said Angel, as if answering the other’s unspoken thought, “it
might be done.”
The girl looked from one to the other in doubt.
“Does this mean an extra risk?” she asked quietly. “I have not
questioned you as to how this red envelope came into your
possession, but I have a feeling that it was not obtained without
danger.”
Angel disregarded Jimmy’s warning frown. He was determined that
the better side of his strange friend’s character should be made
evident to the girl.
“Jimmy faced death in a particularly unpleasant form to secure the
packet, Miss Kent,” he said.
“Then I forbid any further risk,” she said spiritedly. “I thought I had
made it clear that I would not accept favors at your friend’s hands;
least of all do I want the favor of his life.”
Jimmy heard her unmoved. He had a bitter tongue when he so
willed, and he chose that moment.
“I do not think you can too strongly impress upon Miss Kent the fact
that I am an interested party in this matter,” he said acidly. “As she
refused my offer to forego my claim to a share of the fortune, she
might remember that my interest in the legacy is at least as great as
hers. I am risking what I risk, not so much from the beautifully
quixotic motives with which she doubtless credits me, as from a
natural desire to help myself.”
She winced a little at the bluntness of his speech; then recognizing
she was in the wrong, she grew angry with herself at her
indiscretion.
“If the book is—where these papers were, it can be secured,” Jimmy
continued, regaining his suavity. “If the professor is still alive he will
be found, and by to-morrow I shall have in my possession a list of
every book that has ever been written by a professor of anything.”
Some thought tickled him, and he laughed for the second time that
afternoon.
“There’s a fine course of reading for us all,” he said with a little
chuckle. “Heaven knows into what mysterious regions the literary
professor will lead us. I know one professor who has written a
treatise on Sociology that runs into ten volumes, and another who
has spoken his mind on Inductive Logic to the extent of twelve
hundred closely-printed pages. I have in my mind’s eye a vision of
three people sitting amidst a chaos of thoughtful literature, searching
ponderous tomes for esoteric references to bolts, door, mouth, et
cetera.”
The picture he drew was too much for the gravity of the girl, and her
friendship with the man who was professedly a thief, and by
inference something worse, began with a ripple of laughter that
greeted his sally.
Jimmy gathered up the papers, and carefully replaced them in the
envelope. This he handed to Angel.
“Place this amongst the archives,” he said flippantly.
“Why not keep it here?” asked Angel in surprise.
Jimmy walked to one of the three French windows that opened on to
a small balcony. He took a rapid survey of the street, then beckoned
to Angel.
“Do you see that man?” He pointed to a lounger sauntering along on
the opposite sidewalk.
“Yes.”
Jimmy walked back to the center of the room.
“That’s why,” he said simply. “There will be a burglary here to-night or
to-morrow night. People aren’t going to let a fortune slip through their
fingers without making some kind of effort to save it.”
“What people?” demanded the girl. “You mean those dreadful men
who took me away?”
“That is very possible,” said Jimmy, “although I was thinking of
somebody else.”
The girl had put on her wrap, and stood irresolutely near the door,
and Angel was waiting.
“Good-by,” she said hesitatingly. “I—I am afraid I have done you an
injustice, and—and I want to thank you for all you have undergone
for me. I know—I feel that I have been ungracious, and——”
“You have done me no injustice,” said Jimmy in a low voice. “I am all
that you thought I was—and worse.”
She held out her hand to him, and he raised it to his lips, which was
unlike Jimmy.
 CHAPTER VIII
OLD GEORGE

A stranger making a call in that portion of North Kensington which

lies in the vicinity of Ladbroke Grove by some mischance lost his
way. He wandered through many prosperous crescents and quiet
squares redolent of the opulence of the upper middle classes,
through broad avenues where neat broughams stood waiting in
small carriage-drives, and once he blundered into a tidy mews,
where horsy men with great hissings made ready the chariots of the
Notting Hill plutocracy. It may be that he was in no particular hurry to
arrive at his destination, this stranger—who has nothing to do with
the story—but certainly he did not avail himself of opportunity in the
shape of a passing policeman, and continued his aimless
wanderings. He found Kensington Park Road, a broad thoroughfare
of huge gardens and walled forecourts, then turned into a side street.
He walked about twenty paces, and found himself in the heart of
slum-land.
It is no ordinary slum this little patch of property that lies between
Westbourne Grove and Kensington Park Road. There are no
tumbled-down hovels or noisome passages; there are streets of
houses dignified with flights of steps that rise to pretentious street
doors and areas where long dead menials served the need of the
lower middle classes of other days. The streets are given over to an
army of squalling children in varying styles of dirtiness, and the halls
of these houses are bare of carpet or covering, and in some the
responsibility of leasehold is shared by eight or nine families, all
pigging together.
They are streets of slatternly women, who live at their front doors,
arms rolled under discolored aprons, and on Saturday nights one
street at least deserves the pithy but profane appellation which the
police have given it—“Little Hell.”
In this particular thoroughfare it is held that of all sins the greatest is
that which is associated with “spying.” A “spy” is a fairly
comprehensive phrase in Cawdor Street. It may mean policeman,
detective, school-board official, rent collector, or the gentleman
appointed by the gas company to extract pennies from the slot-
meters.
To Cawdor Street came a man who rented one of the larger houses.
To the surprise of the agent, he offered his rent monthly in advance;
to the surprise of the street, he took no lodgers. It was the only
detached house in that salubrious road, and was No. 49. The
furniture came by night, which is customary amongst people who
concentrate their last fluttering rag of pride upon the respectability of
their household goods. Cawdor Street, on the qui vive for the lady of
the house, learns with genuine astonishment that there was none,
and that the newcomer was a bachelor.
Years ago No. 49 had been the abode of a jobbing builder, hence the
little yard gate that flanked one side; and it was with satisfaction that
the Cawdor Streeters discovered that the new occupant intended
reviving the ancient splendor of the establishment. At any rate, a
board was prominently displayed, bearing the inscription:
J. JONES, BUILDER AND CONTRACTOR.
and the inquisitive Mr. Lane (of 76), who caught a momentary vision
of the yard through the gate, observed “Office” printed in fairly large
letters over the side door.
At stated hours, mostly in the evening, roughly-dressed men called
at the “Office,” stayed awhile, and went away. Two dilapidated
ladders made their appearance in the yard, conspicuously lifting their
perished rungs above the gate level.
“I tried to buy an old builder’s cart and a wheelbarrow to-day,” said
“Mr. Jones” to a workman. “I’ll probably get it to-morrow at my own
price, and it wouldn’t be a bad idea to get a few sacks of lime and a
couple of cartloads of sand and bricks in, also a few road pitchers to
give it a finishing touch.”
The workman grinned.
“You’ve got this place ready in time, Connor,” he said.
Mr. Connor—for such “J. Jones, Builder and Contractor” was—
nodded and picked his teeth meditatively with a match stick.
“I’ve seen for a long time the other place was useless,” he said with
a curse.
“It was bad luck that Angel found us there last week. I’ve been fixing
up this house for a couple of months. It’s a nice neighborhood,
where people don’t go nosing around, and the boys can meet here
without anybody being the wiser.”
“And old George?”
“We’ll settle him to-night,” said the other with a frown. “Bat is bringing
him over, and I want to know how he came to let Angel get at us.”
Old George had always been a problem to the “Borough Lot.” He
held the position of trust that many contended no demented old man
should hold. Was it safe or sane to trust him with the plate that had
been so laboriously acquired from Roebury House, and the jewels of
Lady Ivy Task-Hender, for the purloining of which one “Hog” Stander
was at that very moment doing seven stretch? Was it wise to install
him as custodian of the empty house at Blackwall, through which
Angel Esquire gained admittance to the meeting-place of the
“Borough Lot”?
Some there were who said “Yes,” and these included the powerful
faction that numbered “Bat” Sands, “Curt” Goyle, and Connor
amongst them. They contended that suspicion would never rest on
this half-witted old gentleman, with his stuffed birds, his goldfish,
caged rabbits and mice, a view that was supported by the fact that
Lady Ivy’s priceless diamonds lay concealed for months in the false
bottom of a hutch devoted to guinea pigs in old George’s strange
menagerie, what time the police were turning London inside out in
their quest for the property.
But now old George was under a cloud. Notwithstanding the fact that
he had been found amongst his live stock securely bound to a chair,
with a handkerchief over his mouth, suspicion attached to him. How
had Angel worked away in the upper room without old George’s
knowledge?
Angel might have easily explained. Indeed, Angel might have
relieved their minds to a very large extent in regard to old George,
for in marking down the haunt of the “Borough Lot” he had been
entirely deceived as to the part played by the old man who acted as
“caretaker” to the “empty” house.
In a fourwheeled cab old George, smiling foolishly and passing his
hand from time to time over his tremulous mouth, listened to the
admonitions of Mr. Bat Sands.
“Connor wants to know all about it,” said Bat menacingly; “and if you
have been playing tricks, old man, the Lord help you.”
“The Lord help me,” smiled old George complacently.
He ran his dirty fingers through his few scanty white locks, and the
smile died out of his face, and his loose mouth dropped pathetically.
“Mr. Sands,” he said, then stopped; then he repeated the name to
himself a dozen times; then he rubbed his head again.
Bat, leaning forward to catch what might be a confession, sank back
again in his seat and swore softly.
In the house of “J. Jones, Builder and Contractor,” were gathered in
strength the men who composed the “Borough Lot.”
“Suppose he gave us away,” asked Goyle, “what shall we do with
him?”
There was little doubt as to the feeling of the meeting. A low animal
growl, startling in its ferocity, ran through the gathering.
“If he’s given us away”—it was Vinnis with his dull fishlike eyes
turned upon Connor who was talking—“why, we must ‘out’ him.”
“You’re talking like a fool,” said Connor contemptuously. “If he has
given us away, you may rest assured that he is no sooner in this
house than the whole place will be surrounded by police. If Angel
knows old George is one of us, he’ll be watched day and night, and
the cab that brings him will be followed by another bringing Angel.
No, I’ll stake my life on the old man. But I want to know how Mr.
Cursed Angel got into the house next door.”
They had not long to wait, for Bat’s knock came almost as Connor
finished speaking.
Half led, half dragged into the room, old George stood, fumbling his
hat in his hand, smiling helplessly at the dark faces that met his. He
muttered something under his breath.
“What’s that?” asked Connor sharply.
“I said, a gentleman——” began old George, then lapsed into
silence.
“What gentleman?” asked Connor roughly.
“I am speaking of myself,” said the old man, and there came into his
face a curious expression of dignity. “I say, and I maintain, that a
gentleman is a gentleman whatever company he affects. At my old
college I once reproved an undergraduate.” He was speaking with
stately, almost pompous distinctness. “I said, ‘There is an axiom to
which I would refer you, De gustibus non est disputandum, and—and
——’”
His shaking fingers went up again to the tell-tale mouth, and the
vacant smile came back.
“Look here,” said Connor, shaking his arm, “we don’t want to know
anything about your damned college; we want to know how Angel
got into our crib.”
The old man looked puzzled.
“Yes, yes,” he muttered; “of course, Mr. Connor, you have been most
kind—the crib—ah!—the young man who wanted to rent or hire the
room upstairs.”
“Yes, yes,” said Connor eagerly.
“A most admirable young man,” old George rambled on, “but very
inquisitive. I remember once, when I was addressing a large
congregation of young men at Cheltenham—or it may have been
young ladies—I——”
“Curse the man!” cried Goyle in a fury. “Make him answer, or stop his
mouth.”
Connor warned him back.
“Let him talk in his own way,” he said.
“This admirable person,” the old man went on, happily striking on the
subject again, “desired information that I was not disposed to give,
Mr. Connor, remembering your many kindnesses, particularly in
respect to one Mr. Vinnis.”
“Yes, go on,” urged Connor, and the face of Vinnis was tense.
“I fear there are times when my usually active mind takes on a
sluggishness which is foreign to my character—my normal
character”—old George was again the pedant—“when the
unobservant stranger might be deceived into regarding me as a
negligible quantity. The admirable young man so far treated me as
such as to remark to his companion that there was a rope—yes,
distinctly a rope—for the said Mr. Vinnis.”
The face of Vinnis was livid.
“And,” asked Connor, “what happened next? There were two of
them, were there?”
The old man nodded gravely; he nodded a number of times, as
though the exercise pleased him.
“The other young man—not the amiable one, but another—upon
finding that I could not rent or hire the rooms—as indeed I could not,
Mr. Connor, without your permission—engaged me in conversation—
very loudly he spoke, too—on the relative values of cabbage and
carrot as food for herbaceous mammals. Where the amiable
gentleman was at that moment I cannot say——”
“I can guess,” thought Connor.
“I can remember the occasion well,” old George continued, “because
that night I was alarmed and startled by strange noises from the
empty rooms upstairs, which I very naturally and properly concluded
were caused——”
He stopped, and glancing fearfully about the room, went on in a
lower tone.
“By certain spirits,” he whispered mysteriously, and pointed and
leered first at one and then another of the occupants of the room.
There was something very eerie in the performance of the strange
old man with the queerly-working face, and more than one hardened
criminal present shivered a little.
Connor broke the silence that fell on the room.
“So that’s how it was done, eh? One held you in conversation while
the other got upstairs and hid himself? Well, boys, you’ve heard the
old man. What d’ye say?”
Vinnis shifted in his seat and turned his great unemotional face to
where the old man stood, still fumbling with his hat and muttering to
himself beneath his breath; in some strange region whither his poor
wandering mind had taken him he was holding a conversation with
an imaginary person. Connor could see his eyebrows working, and
caught scraps of sentences, now in some strange dead tongue, now
in the stilted English of the schoolmaster.
It was Vinnis who spoke for the assembled company.
“The old man knows a darned sight too much,” he said in his level
tone. “I’m for——”
He did not finish his sentence. Connor took a swift survey of the
men.
“If there is any man here,” he said slowly, “who wants to wake up at
seven o’clock in the morning and meet a gentleman who will strap
his hands behind him and a person who will pray over him—if there’s
any man here that wants a short walk after breakfast between two
lines of warders to a little shed where a brand new rope is hanging
from the roof, he’s at liberty to do what he likes with old George, but
not in this house.”
He fixed his eyes on Vinnis.
“And if there’s any man here,” he went on, “who’s already in the
shadow of the rope, so that one or two murders more won’t make
much difference one way or the other, he can do as he likes—
outside this house.”
Vinnis shrank back.
“There’s nothing against me,” he growled.
“The rope,” muttered the old man, “Vinnis for the rope,” he chuckled
to himself. “I fear they counted too implicitly upon the fact that I am
not always quite myself—Vinnis——”
The man he spoke of sprang to his feet with a snarl like a trapped
beast.
“Sit down—you.”
Bat Sands, with his red head close-cropped, thrust his chair in the
direction of the infuriated Vinnis.
“What Connor says is true—we’re not going to croak the old man,
and we’re not going to croak ourselves. If we hang, it will be
something worth hanging for. As to the old man, he’s soft, an’ that’s
all you can say. He’s got to be kept close——”
A rap at the door cut him short.
“Who’s that?” he whispered.
Connor tiptoed to the locked door.
“Who’s there?” he demanded.
A familiar voice reassured him, and he opened the door and held a
conversation in a low voice with somebody outside.
“There’s a man who wants to see me,” he said in explanation. “Lock
the door after I leave, Bat,” and he went out quickly.
Not a word was spoken, but each after his own fashion of reasoning
drew some conclusion from Connor’s hasty departure.
“A full meetin’,” croaked a voice from the back of the room. “We’re all
asked here by Connor. Is it a plant?”
That was Bat’s thought too.
“No,” he said; “there’s nothin’ against us. Why, Angel let us off only
last week because there wasn’t evidence, an’ Connor’s straight.”
“I don’t trust him, by God!” said Vinnis.
“I trust nobody,” said Bat doggedly, “but Connor’s straight——”
There was a rap on the door.
“Who’s there?”
“All right!” said the muffled voice.
Bat unlocked the door, and Connor came in. What he had seen or
what he had heard had brought about a marvelous change in his
appearance—his cheeks were a dull red, and his eyes blazed with
triumph.
“Boys,” he said, and they caught the infectious thrill in his voice, “I’ve
got the biggest thing for you—a million pounds, share and share
alike.”
He felt rather than heard the excitement his words caused. He stood
with his back to the half-opened door.
“I’m going to introduce a new pal,” he rattled on breathlessly. “I’ll
vouch for him.”
“Who is he?” asked Bat. “Do we know him?”
“No,” said Connor, “and you’re not expected to know him. But he’s
putting up the money, and that’s good enough for you, Bat—a
hundred pounds a man, and it will be paid to-night.”
Bat Sands spat on his hand.
“Bring him in. He’s good enough,” and there was a murmur of
approval.
Connor disappeared for a moment, and returned followed by a well-
dressed stranger, who met the questioning glances of his audience
with a quiet smile. His eyes swept over every face. They rested for a
moment on Vinnis, they looked doubtfully at old George, who, seated