Guidance

Comparator products in Bioequivalence/Therapeutic Equivalence studies after Brexit

This guidance provides further information on comparator products used in studies supporting abridged marketing authorisation applications in a no-deal Brexit.

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Introduction

Reference Medicinal Product

In January 2019, MHRA and the Department of Health and Social Care published further guidance on how medicines, medical devices and clinical trials will be regulated if the UK leaves the EU without a deal.

In a no-deal Brexit, reference medicinal products (RMP) for new generic medicines or other abridged marketing authorisation applications submitted after exit day will be required to comply with the relevant legislation.

This legislation is the Human Medicines Regulations 2012, as amended by the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019 (HMRs), in particular regulations 48 and 51 to 55.

Eligible products will also include:

  • Products that are or have been authorised for at least 8 years in the UK (including those authorised by conversion from EU marketing authorisations)
  • Products in relation to which an EU marketing authorisation was in force on exit day, but which did not convert into UK marketing authorisations as the holder opted out of that process
  • Products in relation to which an EU marketing authorisation had ceased to be in force before exit day for reasons not relating to safety, quality or efficacy

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 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 RMP. This guidance document provides further information on the data required to demonstrate this.

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 would still be required to refer to an eligible UK RMP.

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

In order to determine the acceptability of this evidence, the licensing authority must be satisfied that a non-UK CP is representative of the RMP in the UK and that any differences between these 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 51 HMRs), equivalent to Article 10(1) of EU Directive 2001/83
  • Applications relating to certain medicinal products that do not qualify as generics etc (regulation 52 HMRs), equivalent to Article 10(3) of EU Directive 2001/83

This guidance applies to BE, PK and TE studies provided in support of applications made under any of the above legal bases. In case of complex products, it is recommended that we are consulted for specific advice.

The principles may also be applicable to BE, PK or TE studies conducted in support of other applications that are out of the scope of this guidance such as:

  • Applications relating to products in well-established medicinal use (regulation 54 HMRs), equivalent to Article 10a of EU Directive 2001/83
  • Applications relating to new combinations of active substances (regulation 55 HMRs), equivalent to Article 10b of EU Directive 2001/83
  • Variations requiring demonstration of BE to the RMP (e.g. for modified release solid oral dosage forms) (regulation 65C HMRs)
  • Extension applications (regulation 65C HMRs)

These principles may be applicable to certain non-clinical studies, for example those provided in support of “hybrid” applications.

If the use of a non-UK CP is proposed for applications that are out of the scope of this guidance, early discussion with us is recommended to obtain the relevant advice.

Applications relating to similar biological medical products (regulation 53 HMRs) are out of scope of this guidance.

This guidance should always be read in conjunction with relevant scientific guidelines and legislative provisions in force in the UK.

General principles

The general principles that are applicable are described below. For more specific guidance, especially for more complex dosage forms, it is recommended that the applicant seeks scientific advice from us.

Responsibility

It will be the applicant’s responsibility to demonstrate that any CP authorised and sourced from outside the UK is representative of the RMP authorised in the UK.

Source country of non-UK CP

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

  • EU/EEA countries
  • Switzerland
  • USA
  • Canada
  • Australia
  • Japan

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

  • part of the same global marketing authorisation (GMA) as the 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 contains the initial authorisation and all variations and extensions. It includes any additional strengths, pharmaceutical form, administration routes or presentations authorised through separate procedures and under a different name, granted to the Marketing Authorisation Holder of the initial authorisation.

Identicality vs. representativeness

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

These differences could include:

  • Colour of tablet coatings (assuming no difference in functionality of coat) or capsule shells
  • Scorelines, embossings and imprintings on solid dosage forms
  • Flavours in liquid dosage forms
  • Container closures

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

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

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

  • the route of synthesis of the drug substance(s)
  • the drug substance specifications
  • the finished product quantitative composition
  • the 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 products specifications, non-significant differences in specifications may be acceptable if fully justified.

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

If a CP authorised and sourced from outside the UK is used, the applicant should provide adequate data or information to scientifically justify the relevance of these comparative data and establish an acceptable bridge to the UK RMP.

As a scientific matter, the type of bridging data needed should always include data from analytical studies that compare all 3 products:

  • Between the 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 RMP to demonstrate similarity to allow bridging of the RMP data
  • Between the proposed medicinal product and the non-UK CP to support the BE/TE studies

Any observed differences in the data have to be duly justified with regard to their potential impact on safety and efficacy.

Only data requirements between the RMP and the non-UK CP are discussed here; for other data requirements see current guidance.

The following information should be provided in Module 1.5.2 of the Common Technical Dossier structure for both the RMP and non-UK CP:

  • Name and address of the authorisation holder of the non-UK CP used, the product name, the country of authorisation, country of origin, and authorisation number
  • Proof of purchase (batch number, date and place of purchase, expiry date)
  • Samples in their original container closure systems should be 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)
  • The excipients in the formulation of the RMP, when compared to the non-UK CP, should be qualitatively the same. Any differences in excipients would need to be shown to have no effect on safety or efficacy
  • If quantitative formulation information is available for these two products it should also show the non-UK CP to be representative of the RMP

The experimental comparison should include the physico-chemical properties and all critical product attributes of the medicinal product; these should include device attributes where appropriate. Where provided, dissolution data should cover the physiological pH range. Reference is also made to existing current guidance.

Number of batches to be tested

For the comparison between the RMP and the non-UK CP, data on at least 3 batches of each product would usually be expected.

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

Analytical methods

The precision and accuracy of the analytical methods and the inter-batch variability are critical to deciding if the formulations of the RMP and non-UK CP are representative of each other. The analytical methods and analytical method validation reports used to generate the physicochemical data should be provided to satisfy this requirement.

If the RMP is unavailable

Should the RMP not be marketed in the UK and not be available for the relevant comparison, the applicant should contact us for advice.

Acceptability of approach

The overall acceptability of such an approach and the type of bridging data needed will be a case-by-case/product-type decision and is recommended to be discussed upfront with the us.

  • does not exhibit immediate release of the drug substance
  • is not for oral administration
  • is made by complex methods of manufacture
  • exhibits a narrow therapeutic range or safety margin (for example, careful dosage titration or patient monitoring)
  • has a steep dose-response relationship
  • a risk of serious undesired effects
  • complicated or variable pharmacokinetics (such as nonlinear pharmacokinetics, variable or incomplete absorption)
  • an absorption window (i.e. site-specific absorption)
  • substantial (e.g. greater than 40%) first-pass metabolism

However, 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 safety, efficacy and quality of the medicinal product into account.

If representativeness between the non-UK CP and the RMP cannot be demonstrated, BE and TE studies should be performed against the RMP in the UK.

Published 22 October 2019