Annex 8

Guidance on the selection of comparator pharmaceutical

products for equivalence assessment of interchangeable
multisource (generic) products

1. Introduction 186
2. Background 186
3. General principles 188
References 189

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1. Introduction
In recent years the need for the regulation and assurance of quality of medicines
has continued to increase. Large numbers of multisource (generic) medicines are
being produced by many different companies and in different countries; this may
result in different products. On a global level there is thus a need to address not
only the quality, safety and efficacy of multisource products that are exported
and imported, but also their possible interchangeability.
In light of the various approaches in scientific and regulatory environments,
the feasibility of developing a system of international comparator products was
considered in the past. This initiative led to the recommendations published in
2002 entitled, Guidance on the selection of comparator pharmaceutical products for
equivalence assessment of interchangeable multisource (generic) products (1). Since
the guidance was published, the World Health Organization (WHO) Model List
of Essential Medicines (EML) has been revised several times and many of the
products originally listed are no longer marketed and/or available as indicated in
the list, which means that the list of international comparators recommended by
the WHO Expert Committee on Preparations for Pharmaceutical Specifications
needs updating.
In view of the complexity of the list of comparators it was decided
to prepare two new, separate, guidance documents: one on the selection of
comparator products, including the general guidance on how to select comparator
products, and the second one comprising the international list of comparator
products. The aim was to facilitate the updating and maintenance process.

2. Background
The Guidelines on registration requirements to establish interchangeability for
multisource (generic) pharmaceutical products (2) are designed to provide
WHO Technical Report Series No. 992, 2015

recommendations to national regulatory authorities and manufacturers on the

requirements for approval of multisource (generic) pharmaceutical products in
their respective countries. The guidance provides appropriate in vivo and in vitro
requirements to assure interchangeability of the multisource product.
Multisource pharmaceutical products need to conform to the same
appropriate standards of quality, efficacy and safety as those applicable to the
innovator’s product. In addition, reasonable assurance should be provided that
the multisource product is therapeutically equivalent and interchangeable with
the comparator product. For some classes of products including, for example,
parenteral formulations of highly water-soluble compounds, interchangeability
is adequately assured by implementation of good manufacturing practices
(GMP) and provision of evidence of conformity with relevant pharmacopoeial
specifications.
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This guidance document provides an update of the previously published

list (1) and the respective chapter on selection of comparator products (3, 4).
The information could also be used for medicine procurement purposes.
The historical development of comparator product criteria is summarized
in Table A8.1.

Table A8.1
Historical development of comparator product criteria

Year Development Description

Pre-1996 International Conference of Drug No agreement on the criteria for
Regulatory Authorities (ICDRA) selecting a list of international
(1991 and 1994) recommended comparator products or any
development of global list of such products exists. The
standards and requirements for comparator product chosen
interchangeability of multisource is either the most widely used
products; WHO initiated the (leading) product on the market
process or the product that was first
introduced in that market. For this
reason, among others, significant
differences could exist between
the comparator products used in
different countries
1996 The question of choice of Multisource (generic)
reference product was raised pharmaceutical products: guidelines
on registration requirements to
establish interchangeability (WHO
Technical Report Series, No. 863),
Annex 9, including Appendix 7 on
“Choice of reference product”
2002 WHO issued the first list of Guidance on the selection of
International comparator comparator pharmaceutical
products for equivalence products for equivalence assessment
assessment of interchangeable of interchangeable multisource
multisource (generic) products (generic) products (WHO Technical
Report Series, No. 902), Annex 11
2006 “In order of preference” principle Multisource (generic)
in comparator product selection pharmaceutical products: guidelines
was clarified on registration requirements to
establish interchangeability (WHO
Technical Report Series, No. 937),
Annex 7

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3. General principles
The comparator product is defined as a pharmaceutical product with which the
multisource product is intended to be interchangeable in clinical practice.
As a general principle, multisource products should comply with the same
standards of quality, safety and efficacy as are applicable to the corresponding
comparator product. In addition, quality attributes of a multisource product
should be tested against the comparator product with which it should be
interchangeable.
The selection of the comparator pharmaceutical product is usually made
at the national or regional level by the national or regional regulatory authority.
The innovator product is usually the most logical comparator product
because its quality, safety and efficacy should have been well assessed in pre-
and post-marketing studies and, in addition, the data on its safety and efficacy
are usually linked to a pharmaceutical product with defined specifications for
quality and performance. However, these products may not always be easy to
obtain or may no longer be available on the market. The comparator product
chosen is therefore often the most widely used product (market leader) or the
product that was first introduced in that market. For this reason, among others,
significant differences may exist between the comparator products used in
different countries.
In principle, a national regulatory authority has several options for
selection of a comparator product. These are listed below in order of preference:
1. the innovator product for which quality, safety and efficacy has been
established if this product has been granted a national marketing
authorization (nationally authorized innovator);
2. national market leader product for which a national marketing
authorization has been granted;
WHO Technical Report Series No. 992, 2015

3. the WHO-recommended comparator product included in the

International list of comparator products (1) or, if different and if it
exists for the active pharmaceutical ingredient in question, the one
suggested within the context of the Prequalification Team;
4. an innovator product approved by a stringent regulatory authority,
i.e. a country associated to The International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH);
5. a product that has been granted approval in an ICH-associated
country;
6. in the case that no innovator or comparator product can be
identified according to the above, the choice of the comparator
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should be made carefully and should be comprehensively justified

by the applicant. In this case, the most important selection criteria
in order of preference are:
–– prequalification by WHO,
–– extensive documented use in clinical trials reported in peer-
reviewed scientific journals,
–– a long and unproblematic period of post-market surveillance.
Additionally, these comparators should conform to all appropriate
compendial quality standards.
It is important to note that a product that has been approved based
on comparison with a comparator product that has no national marketing
authorization in the country which approved the multisource product, including
the study for interchangeability, may or may not be interchangeable with currently
marketed domestic products.
The choice of comparator product should be justified by the applicant.
The country of origin of the comparator product should be reported together
with the product’s lot number and expiry date. Consultation with the relevant
regulatory authority before purchase of the comparator product is strongly
recommended.
Information specifically related to the selection of comparator products
for use in studies to be conducted for submission to the WHO Prequalification
Team – Medicines is available on the WHO website (www.who.int/prequal) and
in the WHO comparator document (1).

References
1. Guidance on the selection of comparator pharmaceutical products for equivalence assessment
of interchangeable multisource (generic) products. In: WHO Expert Committee on Specifications
for Pharmaceutical Preparations: thirty-sixth report. Geneva: World Health Organization; 2002:
Annex 11 (WHO Technical Report Series, No. 902).
2. Guidelines on registration requirements to establish interchangeability for multisource (generic)
pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical
Preparations: forty-ninth report. Geneva: World Health Organization; 2014: Annex 7 (WHO
Technical Report Series, No. 992).
3. Multisource (generic) pharmaceutical products: guidelines on registration requirements to
establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical
Preparations: fortieth report. Geneva: World Health Organization; 2006: Annex 7 (WHO Technical
Report Series, No. 937).
4. Multisource (generic) pharmaceutical products: guidelines on registration requirements
to establish interchangeability. Revision. In: WHO Expert Committee on Specifications for
Pharmaceutical Preparations: forty-ninth report. Geneva: World Health Organization; 2014:
Annex 7 (WHO Technical Report Series, No. 992).
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