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1. Overview听听

Until and including 31 December 2024听

This guidance is limited to applications intended for the Great Britain (England, Wales and Scotland) market only.听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).听听听

Applications intended for Northern Ireland (including UK-wide applications) must comply with鈥�EU鈥痳equirements 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听

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.听听听

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听

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 (the HMRs) (as amended).听

See further guidance on reference medicinal products.

1.2 Comparator products used in bioequivalence and therapeutic equivalence studies听

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

Generally, the鈥�CP鈥痵hould be sourced from the UK. However, if the鈥�CP鈥痠s not sourced from the UK market, the applicant should provide evidence that it is representative of the鈥疷K RMP. This guidance document provides further information on the data required to demonstrate this.听

The MHRA-published is helpful in considering study design.听

2. Scope听

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

The purpose of demonstrating pharmaceutical equivalence and/or鈥�BE/TE鈥痑gainst the鈥�CP鈥痠s to provide evidence that the safety and efficacy profiles of the proposed product will be equivalent to that of the鈥疷K RMP鈥痜or which safety and efficacy has been demonstrated.听

In order to determine the acceptability of this evidence, the licensing authority must be satisfied that a non-UK鈥�CP鈥痠s representative of the鈥疷K RMP鈥痑nd that any differences between the two products would not be therapeutically significant.听

The following types of abridged applications are commonly supported by鈥�BE鈥痮谤鈥�TE鈥痵tudies and are within the scope of this guidance:听

• applications relating to generic medicinal products (regulation 51B¹鈥�HMRs)听听

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

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

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

• extension applications (regulation 65C鈥�HMRs)听听

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鈥痵tudies 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鈥�HMRs).听

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

If the use of a non-UK鈥�CP鈥痠s 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.听

You should always read this guidance in conjunction with relevant scientific guidelines and legislative provisions in force in the鈥疷K.听

3. General principles听

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.听

3.1 Responsibility听

It is the applicant鈥檚 responsibility to demonstrate that any鈥�CP鈥痑uthorised and sourced from outside the UK is representative of the鈥疷K RMP.听

3.2 Source country of non-UK鈥�CP听

The non-UK鈥�CP鈥痵hould be authorised by and sourced from a country with similar scientific and regulatory standards as the鈥疷K. Examples would be:听

• EU/EEA听

• Switzerland听

• USA听

• Canada听

• Australia听

• Japan听

• Singapore听

The non-UK CP鈥痺ould be expected to be:听

• part of the same global marketing authorisation (GMA) as the鈥疷K RMP, or听

• 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

罢丑别鈥�GMA鈥痠ncorporates 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.听

3.3 Identicality vs. representativeness听

The non-UK鈥�CP鈥痷sed must be representative of the鈥疷K 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.听

These differences could include but are not limited to:听

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

• scorelines, embossing and imprinting on solid dosage forms听

• flavours in liquid dosage forms听

• container closures听

3.4 Demonstration of identicality of the non-UK鈥�CP鈥痶o the鈥疷K RMP听

In cases where the applicant provides written confirmation from the鈥�MAH鈥痮f the non-UK鈥�CP鈥痶hat the鈥�CP鈥痠s identical to the鈥疷K RMP, no further analytical data are required.听

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

• the drug substance specifications听

• the finished product quantitative composition听

• the finished product manufacturing process including in-process controls听

• the finished product specifications听

• the stability data听

In cases where identicality can be confirmed, the use of a non-UK鈥�CP鈥痠s also acceptable for more complex formulations.听

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

3.5 Demonstration of representativeness of the non-UK鈥�CP鈥痶o the鈥疷K鈥�RMP听

If a鈥�CP鈥痑uthorised 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鈥疷K RMP. The relevance of these comparative data should be scientifically justified.听

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

• between the鈥疷K RMP鈥痑nd the non-UK鈥�CP鈥痶o establish suitability of the latter as鈥�CP鈥痠苍鈥�BE/TE鈥痵tudies听

• between the proposed medicinal product and the non-UK鈥�CP鈥痶o support the鈥�BE/TE鈥痵tudies听

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

Only data requirements between the鈥疷K RMP鈥痑nd the non-UK鈥�CP鈥痑re discussed here; for other data requirements please .听

The following information for both the鈥疷K RMP鈥痑nd non-UK鈥�CP should be provided in Module 1.5.2 of the common technical document:听

• name and address of the authorisation holder of the non-UK鈥�CP鈥痷sed, 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)听

• a comparison of the excipients in the formulation of the鈥疷K 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听

• 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鈥�CP鈥痶o be representative of the鈥疷K RMP)听

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.听

3.6 Number of batches to be tested听

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.听听听

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.听听听

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

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.听

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

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

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

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

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.听

3.7 Analytical methods听

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

Test methods should be shown to be robust in line with current .听听听

Dissolution tests for oral solid dosage forms should be shown to be discriminatory as set out in .听听听

3.8 Acceptability of approach听

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.听听

The product:听

• does not exhibit immediate release of the drug substance听

• is not for oral administration听

• is for parenteral administration but is not a simple solution听

• involves complex methods of manufacture听

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

• has a steep dose-response relationship听

• has a risk of serious undesired effects听

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

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

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

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.听

If representativeness between the non-UK鈥�CP鈥痑nd the鈥疷K RMP鈥痗annot be demonstrated,鈥�BE鈥痮谤鈥�TE鈥痵tudies should be performed against the鈥疷K RMP.鈥疻here 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.听听

4. Contact听

For further information, email鈥�RIS.NA@mhra.gov.uk.