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Guidance: Comparator products in bioequivalence/therapeutic equivalence studies

Medicines Healthcare Products Regulatory Agency

December 20
12:47 2024

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1. Overview

Until and including 31 December 2024

This guidance is limited to applications intended for the Great Britain (England, Wales and Scotland) market only.Comparator products should be sourced from the Great Britain market and references to UK in this guidance should be read as applying to an application for a Great Britain only marketing authorisation (MA).

Applications intended for Northern Ireland (including UK-wide applications) must comply with?EU?requirements for comparator products to be used in bioequivalence and therapeutic equivalence studies and must be sourced from the EU/EEA market.

From 1 January 2025

Following the implementation of new arrangements for human medicines as part of the Windsor Framework, this guidance will be applicable to UK-wide applications submitted on or after 1 January 2025.

Applications for Northern Ireland-only marketing authorisations will need to continue to comply with EU guidelines as they will be submitted through EU mutual recognition or decentralised procedures.

1.1 Reference medicinal products

Reference medicinal products (RMPs) for new generic medicines or other abridged marketing authorisation applications must comply with the requirements in Regulation 48(2) of the Human Medicines Regulation 2012 (the HMRs) (as amended).

See further guidance on reference medicinal products.

1.2 Comparator products used in bioequivalence and therapeutic equivalence studies

Comparator products (CPs) used in bioequivalence (BE), pharmacokinetic (PK) and therapeutic equivalence (TE) studies supporting abridged applications should be representative of the?UK RMP?supporting the application.

Generally, the?CP?should be sourced from the UK. However, if the?CP?is not sourced from the UK market, the applicant should provide evidence that it is representative of the?UK RMP. This guidance document provides further information on the data required to demonstrate this.

The MHRA-published checklist for bioequivalence studies is helpful in considering study design.

2. Scope

With the aim of facilitating the global development of medicinal products and to avoid unnecessary repetition of clinical? BE/TE?studies, it may be possible for an applicant to compare the proposed medicinal product with a non-UK sourced?CP. The application for the new medicinal product would still be required to refer to an eligible?UK RMP.

The purpose of demonstrating pharmaceutical equivalence and/or?BE/TE?against the?CP?is to provide evidence that the safety and efficacy profiles of the proposed product will be equivalent to that of the?UK RMP?for which safety and efficacy has been demonstrated.

In order to determine the acceptability of this evidence, the licensing authority must be satisfied that a non-UK?CP?is representative of the?UK RMP?and that any differences between the two products would not be therapeutically significant.

The following types of abridged applications are commonly supported by?BE?or?TE?studies and are within the scope of this guidance:

  • applications relating to generic medicinal products (regulation 51B1?HMRs)

  • applications relating to hybrid medicinal products (that do not qualify as generics; submitted under regulation 52B2 HMRs)

  • applications relating to new combinations of active substances (regulation 55(iii)(b)?HMRs)

  • variations requiring demonstration of?BE to the?RMP?(for example, for modified release solid oral dosage forms) (regulation 65C?HMRs)

  • extension applications (regulation 65C?HMRs)

1Also applies to Regulation 51A until 1 January 2025.2Also applies to Regulation 52A until 1 January 2025.

The principles may also be applicable to BE, pharmacokinetic or TE?studies conducted in support of other applications that are out of the scope of this guidance or certain non-clinical studies, for example those provided in support of hybrid applications (regulation 52B?HMRs).

Note that for applications for similar biological medical products (regulation 53?HMRs) applicants should refer to specific guidance on the licensing of biosimilar products.

If the use of a non-UK?CP?is proposed for applications that are out of the scope of this guidance, we recommend early discussion with the MHRA to obtain the relevant regulatory and/or scientific advice.

You should always read this guidance in conjunction with relevant scientific guidelines and legislative provisions in force in the?UK.

3. General principles

The general principles that are applicable are described below. For more specific guidance, especially for more complex dosage forms, we recommended that you seek scientific advice from the MHRA.

3.1 Responsibility

It is the applicants responsibility to demonstrate that any?CP?authorised and sourced from outside the UK is representative of the?UK RMP.

3.2 Source country of non-UK?CP

The non-UK?CP?should be authorised by and sourced from a country with similar scientific and regulatory standards as the?UK. Examples would be:

  • EU/EEA

  • Switzerland

  • USA

  • Canada

  • Australia

  • Japan

  • Singapore

The non-UK CP?would be expected to be:

  • part of the same global marketing authorisation (GMA) as the?UK RMP, or

  • marketed in the country of origin through a licensing arrangement with the innovator company or corporate entity that currently markets the medicine in the UK

The?GMA?incorporates the initial authorisation and all variations and extensions. It includes any additional strengths, pharmaceutical forms, administration routes or presentations authorised through separate procedures and under different names, granted to the marketing authorisation holder (MAH) of the initial authorisation.

3.3 Identicality vs. r

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