Guidance

Comparator products in bioequivalence/therapeutic equivalence studies

Information on comparator products used in studies supporting abridged marketing authorisation application.

• From: Medicines and Healthcare products Regulatory Agency
• Published: 31 December 2020
• Last updated: 20 December 2024 — See all updates

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 applicant’s 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. representativeness 

The non-UK CP used must be representative of the UK RMP, but it does not need to be identical to it. This means that certain minor differences between both products may be accepted provided this is supported by bridging data (see below) or otherwise justified. 

These differences could include but are not limited to: 

• colour of tablet coatings (assuming no difference in functionality of coat) or capsule shells 

• scorelines, embossing and imprinting on solid dosage forms 

• flavours in liquid dosage forms 

• container closures 

3.4 Demonstration of identicality of the non-UK CP to the UK RMP 

In cases where the applicant provides written confirmation from the MAH of the non-UK CP that the CP is identical to the UK RMP, no further analytical data are required. 

This written confirmation should confirm the following are identical in both products: 

• the drug substance specifications 

• the finished product quantitative composition 

• the finished product manufacturing process including in-process controls 

• the finished product specifications 

• the stability data 

In cases where identicality can be confirmed, the use of a non-UK CP is also acceptable for more complex formulations. 

For the drug substance and finished product specifications, non-significant differences in specifications may be acceptable, if fully justified. 

3.5 Demonstration of representativeness of the non-UK CP to the UK RMP 

If a CP authorised and sourced from outside UK is used, there is no letter of confirmation from the MAH of the CP stating it is identical to the UK RMP, or if the product does not fall within the scenarios in section 3.6, the applicant should provide adequate data or information to establish an acceptable bridge to the UK RMP. The relevance of these comparative data should be scientifically justified. 

As a scientific matter, the type of bridging data needed should always include data from analytical studies as indicated below: 

• between the UK RMP and the non-UK CP to establish suitability of the latter as CP in BE/TE studies 

• between the proposed medicinal product and the non-UK CP to support the BE/TE studies 

Any observed differences in the data must be justified with regard to their potential impact on the safety and efficacy of the proposed product. 

Only data requirements between the UK RMP and the non-UK CP are discussed here; for other data requirements please see current guidelines on the investigation of bioequivalence. 

The following information for both the UK RMP and non-UK CP should be provided in Module 1.5.2 of the common technical document: 

• name and address of the authorisation holder of the non-UK CP used, the product name, the country of authorisation, country of source and authorisation number

• proof of purchase (batch number, date and place of purchase, expiry date)

• confirmation that samples in their original container closure systems are available upon request

• product information (summary of product characteristics or equivalent)

• certificates of analysis (tested according to the proposed specification for the proposed medicinal product) 

• a comparison of the excipients in the formulation of the UK RMP, when compared to the non-UK CP (the excipients should be qualitatively the same; any differences in excipients would need to be shown, or otherwise justified, as having no effect on safety or efficacy 

• if available, a comparison of the quantitative formulations of the non-UK CP and the UK RMP (if this information is available, it should show the non-UK CP to be representative of the UK RMP) 

The experimental comparison should include the physico-chemical properties and all critical quality attributes of the medicinal product. These should include device attributes where appropriate. Where provided, dissolution data should cover the physiological pH range and take account of current guidance on the development and choice of test conditions. The method used should have been shown to be discriminatory. 

3.6 Number of batches to be tested 

The number of batches needed to demonstrate that the non-UK comparator product is representative of the UK RMP should be justified on the basis of the complexity of the dosage form and method of manufacture.   

To provide assurance of representativeness between the UK RMP and the non-UK CP, we would usually expect data on at least 3 batches of each product.   

In cases where the UK RMP and the non-UK CP have a recent shared regulatory history,   applicants may be able to justify representativeness without further batch testing.   

This utilises the principle that post-authorisation changes to products that have more than a minor impact on quality have been reviewed by the relevant regulatory authorities to ensure that they do not impact on the safety, efficacy or overall balance of benefit and risk. 

Justification based on shared regulatory history will be considered where the comparator product is: 

• a centrally authorised product that has, until 31 December 2024, been authorised for Northern Ireland 

• a product authorised through MRP/DCP (mutual recognition procedure decentralised procedures) where Northern Ireland is or was a concerned member state (CMS)  

This will not normally be acceptable for products that fall into any of the categories described in section 3.8.  

In cases of products that exhibit a higher inherent batch-to-batch variability or that are complex, further evidence from a larger number of batches may be required to establish representativeness. 

3.7 Analytical methods 

The validity of the analytical methods and the inter-batch variability are critical to deciding if the non-UK CP is representative of the UK RMP. The analytical methods and analytical method validation reports used to generate the comparative data should be provided. 

Test methods should be shown to be robust in line with current guidance on method development and validation.   

Dissolution tests for oral solid dosage forms should be shown to be discriminatory as set out in Reflection paper on the dissolution specification for generic solid oral immediate release products with systemic action (europa.eu).   

3.8 Acceptability of approach 

In cases without confirmation from the MAH that the UK RMP and the non-UK comparator product are identical, the overall acceptability of the approach to justify or demonstrate representativeness will be a case-by-case/product-type decision. We recommend that you discuss it with the MHRA before submission if one or more of the following applies.  

The product: 

• does not exhibit immediate release of the drug substance 

• is not for oral administration 

• is for parenteral administration but is not a simple solution 

• involves complex methods of manufacture 

• exhibits a narrow therapeutic range or safety margin (for example, careful dosage titration or patient monitoring is required) 

• has a steep dose-response relationship 

• has a risk of serious undesired effects 

• exhibits complicated or variable pharmacokinetics (such as nonlinear pharmacokinetics, variable or incomplete absorption) 

• has a physiological absorption window (that is, site-specific absorption) 

• has substantial (for example, greater than 40%) first-pass metabolism 

The final determination of the adequacy of the scientific justification and bridging will only be made during the assessment of the application. This will take the quality, safety and efficacy of the medicinal product into account. 

If representativeness between the non-UK CP and the UK RMP cannot be demonstrated, BE or TE studies should be performed against the UK RMP. Where this is not possible, for example because the UK RMP is no longer available, an alternative legal basis of submission, for example, Regulations 54 (well-established use) or 50 (full, mixed dossier) of the HMRs will need to be considered.  

4. Contact 

For further information, email [email protected].

Published 31 December 2020
Last updated 20 December 2024 + show all updates

1. 20 December 2024

   Added section numbers and document overview. Updated all sections for clarity and territorial changes – GB revised to UK. Updated references to applicable regulations. Updated section 3.2 list of acceptable regulator countries. Updated section 4 contact details

2. 31 December 2020

   First published.