Multisource (generic) products must satisfy the same standards as those applied to originator products. The manufacturer of a multisource (generic) product must demonstrate that its product:

• satisfies the same standards as those applicable to the innovator product
• provide assurance that it is clinically interchangeable with, i.e. therapeutically equivalent or bioequivalent to, the innovator product (or PQT/MED-identified comparator product).

The manufacturer may therefore need to carry out a bioequivalence (BE) study. The data generated should provide a bridge between the product for which clinical safety and efficacy data are available (the comparator product) and the generic product for which such data are not available.

The WHO Technical Report Series (TRS) contain a number of annexes that manufacturers can consult regarding registration requirements for establishing the interchangeability of a generic product with its comparator product. These requirements must be met by any generic product that is submitted for prequalification.

In some cases, it may be possible to request that the requirement to conduct an in vivo study to establish bioequivalence be waived. The topic of biowaivers is discussed below.

Design of BE studies

The WHO Prequalification Team - Medicines (PQT/MED) supports applicants in addressing specific scientific issues related to product development and design of BE studies that are intended to support an application for prequalification. It strongly recommends that applicants submit the final draft of their BE study protocol for review before embarking on the study. Questions on BE studies or final draft protocols can be sent to Dr Matthias Stahl at stahlm@who.int.

Support is also available in the form of PQT/MED-specific guidance on the design of BE studies for products that are invited to the programme in the PQT/MED Expressions of Interest. These product-specific guidance, known as Notes on the Design of Bioequivalence Study (NDBS), are available in the expandable box below.

The expandable box below also includes a detailed guidance document on BE studies for reproductive health medicines, a document highlighting frequent deficiencies the application of reference-scaled acceptance criteria for BE studies conducted for submission to PQT/MED.

Comparator products for bioequivalence studies

The quality, safety and efficacy of the innovator product, which was first authorized for marketing, were fully assessed and documented in pre-marketing studies and post-marketing monitoring schemes. The innovator product is therefore the most logical comparator product to use for establishing interchangeability. Indeed, a generic pharmaceutical product should not be used as a comparator if an innovator product is available for this purpose. The risk with using a generic pharmaceutical product as a comparator instead of the innovator is that for these future generic products it cannot be guaranteed that they are bioequivalent with the innovator leading to a lack of interchangeability with the innovator.

WHO has compiled lists of comparator products that are recommended for use in BE studies that aim to generate data for demonstrating bioequivalence of products invited for prequalification.

Questions relating to bioequivalence or choice of comparator products outside the recommended lists, can be submitted to Dr Matthias Stahl at stahlm@who.int before the start of any BE study.

Selection of a comparator

Comparator products should be purchased from a well-regulated market within the jurisdiction of a stringent regulatory authority (SRA). For WHO PQT/MED, an SRA is considered the regulatory authority of a country officially participating in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and:

a) a member of ICH prior to 23 October 2015, namely: the US Food and Drug Administration, the European Commission and the Ministry of Health, Labour and Welfare of Japan also represented by the Pharmaceuticals and Medical Devices Agency;

or

b) an ICH observer prior to 23 October 2015, namely: the European Free Trade Association, as represented by Swissmedic and Health Canada;

or

c) a regulatory authority associated with an ICH member through a legally-binding, mutual recognition agreement prior to 23 October 2015, namely: Australia, Iceland, Liechtenstein and Norway.

If no WHO-recommended comparator product can be identified, or if the selected WHO-recommended comparator product cannot be obtained from a well-regulated market falling within the jurisdiction of a stringent regulatory authority, the applicant should consult WHO regarding the choice of comparator, before initiating a study.

To be noted, the strength of the invited product may differ from that of the available recommended acceptable comparator product. It is not necessarily the case in such instances that a BE study at the same dose level will be required. Instead, if the active substance shows linear pharmacokinetics, extrapolation, applied by dose normalization, may generate sufficient data for submission to WHO. Consultation with PQT/MED is strongly encouraged.

Demonstrating bioequivalence of fixed-dose combination products

The BE of fixed-dose combination (FDC) products should be established following the same general principles as those described above. The submitted FDC (comparator) product should be compared with the respective innovator FDC product. If no innovator FDC product is available on the market, individual component products administered in loose combination should be used as comparators.

Information on comparator product to be included in the product dossier

The generic finished pharmaceutical product (FPP) dossier submitted for full assessment should include the following information on the comparator product:

• country of origin
• lot number and expiry date
• results of pharmaceutical analysis to prove pharmaceutical equivalence.

Additionally, to prove the origin of the comparator product, the applicant must include the following documents in the product dossier submitted for evaluation:

• copy of the comparator product labelling which should include: the name of the product; name and address of the manufacturer; batch number; and expiry date (clearly visible on the labelling)
• copy of the invoice from the distributor or company from which the comparator product was purchased; the address of the distributor must be clearly visible on the invoice
• documentation verifying the method of shipment and storage conditions of the comparator product from the time of purchase to the time of study initiation
• a signed statement certifying the authenticity of the above documents and that the comparator product was purchased from the specified national market. The certification should be signed by the company executive or equivalent responsible for the application to PQT/MED.

Information on bioequivalence study to be included in product dossier

A BE study report that is submitted as a product dossier must comply with WHO guidance for bioequivalence studies and WHO Guidelines for Good Clinical Practice. Furthermore, a Bioequivalence trial information form (BTIF) should be completed in MS Word format for each BE study submitted within a dossier.

Product applications should include the following information in Module 2.7 of the dossier:

1. A list of all BE studies, including pilot studies, conducted with the proposed product i.e., same formulation and manufacturing process as that submitted for prequalification, regardless of the comparator (reference) product employed and regardless of the study outcome. Complete study synopses should be provided for all listed studies, in accordance with Annex I of ICH Guideline E3: Structure and Content of Clinical Study Reports.
2. A list of all bioequivalence or comparative bioavailability studies, including pilot studies, conducted during pharmaceutical development (development of formulation and/or manufacturing processes) of the product, regardless of the comparator (reference) product employed and regardless of the study outcome. Complete study synopses should be provided for all listed studies, in accordance with Annex I of ICH Guideline E3: Structure and Content of Clinical Study Reports.

Full study reports for all listed studies should be available upon request.

Waiver request for a bioequivalence study

A manufacturer may request a waiver of the requirement for submission of an in vivo bioequivalence study for an immediate-release oral dosage form.

A biowaiver is the term used to describe a regulatory drug approval process whereby the efficacy and safety part of a dossier (application) is approved based on evidence of equivalence other than through in vivo equivalence testing.

For solid oral dosage forms, biowaivers may be possible based on the Biopharmaceutics Classification System (BCS) or on the proportionality of the formulation of a product to the formulation of another strength of that product (an additional strengths biowaiver).

BCS-based biowaivers

For PQT/MED, the relevant guideline to be considered for BCS-based biowaivers is the WHO guideline ‘Biopharmaceutics Classification System-Based Biowaivers’ M9 (2019). In addition to the WHO guideline, applicants should refer to the PQT/MED guidance ‘PQT/MED-specific Annotations for the line for the WHO guideline Biopharmaceutics Classification System (BCS)-based Biowaiver Applications’ (2024) for more information on PQT/MED recommendations and recommendations. 

All BCS-based biowaiver applications should include a completed Biowaiver application form: Biopharmaceutics Classification System in MS Word format.

Additional strength biowaivers

Any application for a biowaiver for an additional strength of a submitted (test) product, based on the proportionality of its formulation to the strength of the product with which an in vivo BE study was conducted (biobatch strength) and comparative in vitro dissolution data, must include data on comparative dissolution between the additional strength and the biobatch strength of the test product in the three physiological pH media and the release medium, if different.

All additional strength biowaiver applications should include a completed Biowaiver application form: Additional strengths in MS Word format.