Generic / hybrid applications: questions 35 to 43

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This page lists questions 35 to 43 of the European Medicines Agency's questions and answers on generic and hybrid applications.

The page is updated regularly to reflect new developments, to include guidance on further pre-authorisation procedures and to reflect the implementation of new European legislation. Revised topics are marked 'New' or 'Rev.' on publication.

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35. Which tools are used by the Agency to facilitate the streamlining of the European Decision making process?

See EMA pre-submission guidance for users of the centralised procedure.

36. How is a Pre-Submission Meeting conducted at the Agency?

See EMA pre-submission guidance for users of the centralised procedure.

37. Do I need to perform user consultation for a generic/hybrid medicinal product? When and how to submit information on user consultation?

Articles 59(3) and 61(1) of Directive 2001/83/EC require that the package leaflet reflects the results of consultation with target patient groups (‘user consultation’) to ensure that it is legible, clear and easy to use and that the results of the assessment carried out in cooperation with target patient groups are provided to the competent authority. This legal requirement applies also to generic/hybrid medicinal products.

However, if the Package leaflet of the generic medicinal product has the same content and layout as that of the reference medicinal product or other generic medicinal product of the same active substance for which user consultation has been performed, reference to already approved package leaflets will generally be considered an acceptable justification for not performing user consultation. Such justification should be included in Module 1.3.4 of the dossier.

When changes have been made to the package leaflet of the generic medicinal product or in case of differences from the reference medicinal product for hybrid medicinal products (e.g. change in pharmaceutical form, change in route of administration, etc.), a bridging report might have to be submitted. The bridging report should be included in Module 1.3.4 of the dossier.

For further information on user consultation, including methods of user consultation and submission and assessment of information on user consultation, please refer to question 33 of the general pre-submission guidance for users of the centralised procedure.

References:

38. How and when to submit a summary of the pharmacovigilance system?

The requirements for submission of a summary of the pharmacovigilance system are the same as for any marketing authorization application, independent of the legal basis for the application – please refer to Q&A “Pharmacovigilance system” of the EMA pre-submission procedural advice for users of the centralised procedure for all products.

39. Should I submit an EU Risk Management Plan as part of my generic medicinal product application? Rev. June 2016
39.1. What are the requirements for an RMP for a new application of an established generic product?

Marketing authorisation applications for generic medicinal products under Article 10(1) of Directive 2011/83/ECshould include an RMP in the application dossier. However as outlined in the Good Pharmacovigilance Practice (GVP) module V on risk management systems some parts or modules of the RMP for a generic may be omitted (see GVP V section V.C.3.1).

39.2. If there is no RMP in place for a reference medicinal product, how should module SVIII ‘summary of the safety conserns’ be populated for a generic medicinal product?

The applicant of the generic medicinal product should use the (European) public assessment and the summary of product characteristics of the reference medicinal product to obtain the safety concerns to be included in module SVIII of the RMP. Applicants may also discuss during the pre-submission phase what safety concerns should be included.

40. Do hybrid medicinal products applications have special requirements regarding the submission of EU Risk Management Plans?

See: EMA pre-submission guidance for users of the centralised procedure - List of questions

41. What is a safety variation?

Safety variations are variations that refer to safety issues, including those related to quality problems, requiring a change of the Summary of Product Characteristics (SmPC), Package Leaflet (PL) and/or Labelling, which does not need to be implemented via an Urgent Safety Restriction (see below), but should be implemented as soon as possible.

41.1 When should a safety variation be submitted for a generic or hybrid medicinal product following changes to the innovator product? Rev. December 2015

For centrally authorised generics or hybrids of centrally authorised innovator products the EMA will provide the Marketing Authorisation Holder (MAH) of the generic/ hybrid product at the time of the CHMP Opinion on a safety variation for the reference medicinal product with the exact wording to be implemented and will request the MAH to submit a type IB variation as soon as possible or at the latest within 2 months to implement the changes in the Product Information (PI) as adopted for the innovator.

For centrally authorised generics or hybrids of nationally authorised innovator products the EMA will provide the MAH of the generic/ hybrid product, upon notification by the respective competent authority, with the exact wording to be implemented and will request the MAH to submit a variation as soon as possible or at the latest within 2 months to implement the changes in the PI as adopted for the innovator.

Once received, the assessment of the variation(s) for the generic(s) should follow a 30-day timetable. A similar procedure would apply when a safety concern is first identified for a generic/ hybrid medicinal product.

The EMA Secretariat shall handle and finalise such “administrative” harmonisation between the reference and the generic/hybrid medicinal product.

Simple reference to fees payable can be found in Question 18 of the general pre-submission guidance for all products.

41.2 How should the outcome of the safety variation be communicated to the outside world?

The EPAR, the SPC and the PL will be updated on the EMA website.

In certain situations, the Agency/CHMP may decide that healthcare professionals should be informed quickly about the safety concern and the revised SPC and therefore request the MAHs of the innovator and generics to disseminate a Direct Healthcare Professional Communication (DHPC), commonly called "Dear Doctor-Letter". MAHs are referred to the Guideline “Direct Healthcare Professional Communications” included in Part IV of Volume 9A of The Rules Governing Medicinal Products in the European Union for details on the situations when DHPCs are usually considered necessary and the procedures to follow. This Guideline also contains the advice that MAHs for products with the same active substance should try to co-operate and propose a common DHPC as this will allow for dissemination of a single DHPC to the healthcare professionals.

In this Guideline, MAHs are also asked to propose to the EMA/CHMP, at the time of preparation of a DHPC, a plan for communication to patients and the general public for subsequent implementation.

41.3 How soon after the safety variation for a generic/ hybrid medicinal product should the revised Product Information be implemented for batch release purposes? Rev. December 2015

With the application for the safety variation, the MAH should indicate in the application form the time frame for implementation of the safety variation. The exact implementation date for batch release purposes is to be agreed with the EMA.

References

41.4 How can I apply for the update of the product information after the outcome of a single PSUR procedure? New March 15

See web-link: European Medicines Agency post-authorisation procedural advice for users of the centralised procedure – List of questions on PSURs

42. What is an Urgent Safety Restriction (USR)?

An USR is an urgent regulatory action, which is triggered by a MAH of a Centrally Authorised Product or the European Commission in the event of, or to prevent risk to public health associated with the use of this medicinal product.

The outcome of an USR is an interim change to the Product Information (PI), due to new non-clinical and/or clinical information having a bearing on the safe use of the medicinal product, concerning particularly one or more of the following items in the SPC: the indications, posology, contraindications and warnings. In rare cases the changes may also relate to quality problems requiring a change of the Product Information.

42.1. When should a USR be submitted for a generic or hybrid medicinal product following a USR to the innovator product? Rev. December 2015

A USR is an urgent regulatory action to prevent risk to public health associated with the use of a medicinal product. In the case of a Centrally Authorised Product (CAP), it is triggered by the Marketing Authorisation Holder (MAH) or the European Commission.

The outcome of a USR is an interim change to the Product Information (PI), due to new non-clinical and/or clinical information having an impact on the safe use of the medicinal product. It usually concerns one or more of the following sections in the SPC: the indications, posology, contraindications and warnings. In rare cases the changes may also relate to quality aspects requiring a change of the PI.

For centrally authorised generics or hybrids of centrally authorised innovator products the Agency will provide, once the USR has been finalised for the innovator product and the final wording of the PI has been agreed, the MAH of the generic/ hybrid with the exact wording to be implemented and request the MAH to submit a USR application to implement the exact PI wording of the innovator.

For centrally authorised generics or hybrids of nationally authorised innovator products the Agency will provide, upon notification by the respective competent authority, the MAH of the generic/ hybrid product with the exact wording to be implemented and request the MAH to submit a USR application to implement the exact PI wording of the innovator.

Once received, the CHMP assessment of the USR for the generic or hybrid medicinal product will be finalised within 24 hours.

Immediately following the finalisation of the USR for the generic or hybrid medicinal product, the Agency will inform the MAH that the changes may be introduced and that a subsequent type IB safety variation should be submitted without any delay (no later than 15 days after the finalisation of the USR).

A similar procedure would apply when a safety concern is first identified for a generic/ hybrid medicinal product.

42.2. How should the outcome of the USR be communicated to the outside world?

Changes to the marketing authorisation introduced by means of an USR usually require that healthcare professionals are informed quickly about the safety concern and the revised SPC. MAHs are therefore requested to prepare and disseminate a Direct Healthcare Professional Communication (DHPC), commonly called "Dear Doctor-Letter". MAHs are referred to the Guideline “Direct Healthcare Professional Communications” included in Part IV of Volume 9A of The Rules Governing Medicinal Products in the European Union for details on the procedures to follow. This Guideline also contains the advice that MAHs for products with the same active substance should try to co-operate and propose a common DHPC this will allow for dissemination of a single DHPC to the healthcare professionals.

In this Guideline, MAHs are also asked to propose, at the time of preparation of a DHPC, a plan for communication to patients and the general public.

42.3. How soon after the USR for a generic/ hybrid medicinal product should the revised Product Information be implemented for batch release purposes? Rev. December 2015

With the notification for a USR, the MAH should include a letter of undertaking proposing timeframes for distribution/recall if needed of the revised product information. This action plan, which should also include proposed timelines for the circulation of the DHPC, will need to be agreed by the CHMP.

The timelines will be determined on a case-by-case basis depending on the nature of the safety issue in question. The importance of the safety issue should always be considered in relation to the possible problem caused by a potential lack of supply to patients.

For safety issues, including those related to quality aspects, requiring only a change of the SPC and not the PL and/or labelling, the revised Product Information will be disseminated mainly by means of the DHPC. 

References

43. Do the provisions of the marketing /cessation notification and the sunset clause apply to my generic/hybrid application?

The general principles described in the EMA Questions and Answers documents regarding marketing and cessation notification  as well as the sunset clause monitoring apply similarly to generic and hybrid medicinal products.

For a generic or hybrid medicinal product, when the medicinal product is not placed on the market as of the granting of the marketing authorisation, the 3-year period without marketing will start counting, for the purpose of the sunset clause monitoring, from the date of notification of the marketing authorisation to the MAH. (i.e. after expiry of the data protection period of the reference medicinal according to the previous legislation (either 6 or 10 years)).

The new data protection rules (8+2+1) apply to those reference medicinal products for which the initial application for authorisation has been submitted after the entry into force of the revised Community Legislation, i.e. after 30 October 2005 for national, decentralised and mutual recognition procedures and as of 20 November 2005, for the centralised procedure.

However, the start of the three-year period should also take into account the date when the medicinal product can be placed on the market by the marketing authorisation holder, i.e. as of the end of the 10-(or 11-) year period of market exclusivity of the reference medicinal product and at the end of other protection rules which must be respected.

MAHs are advised to inform the EMA, within 60 days from the granting of the marketing authorisation, of the existence and if known, the expiry date of the other protection period(s) to be respected as appropriate The need for an exemption request will be decided based on this information.

References:

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