Q&A 31-44: Similar biological product applications

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- Rev. March 2013

Upon receipt of the application, the Agency will start the validation on the next submission deadline stated on its website. Validation has to be completed by the corresponding starting date of the procedure; Applicants need to be ready to answer within few days to any issues raised at this stage. 

At the end of the validation process and provided the Rapporteur and (Co) Rapporteur have received the dossier, the EMA starts the procedure at the monthly starting date published on the EMA website. For Biosimilars of centrally authorised medicinal products, provided successful validation, the procedure starts the same month. Where the application concerns a Biosimilar of a medicinal product authorised through a National/MRP/DCP procedure, the EMA will request from the Member State where the reference medicinal product received a marketing authorisation to transmit within a period of one month, a confirmation that the reference medicinal product is or has been authorised together with the information on the full composition of the reference medicinal product and if necessary other relevant information. Therefore the evaluation process will only start once all relevant information has been received.

If, within a month from the start of the procedure, any other member of the CHMP has not received the requested parts of the dossier from the Applicant, the EMA will stop the clock until the problem is resolved. A timetable is prepared by the Agency and presented to the CHMP for information.

Applicants are advised to submit the MAA according to the published EMA calendar (See submission timelines).

The Agency shall ensure that the Opinion of the CHMP is given within 210 days (not counting clock-stops within the procedure) and in accordance with the standard timetable. 

DAY

ACTION

1*

Start of the procedure

80

Receipt of the Assessment Reports from CHMP Rapporteur and (Co) Rapporteur by CHMP members and EMA. EMA sends CHMP Rapporteur and (Co) Rapporteur Assessment Reports to the Applicant making it clear that it only sets out their preliminary conclusions. The so-called Day 80 Assessment Reports in no ways bind the CHMP and are sent to the Applicant for information only.

87

PRAC Rapporteur circulates the RMP assessment report and proposed RMP LoQ

90

Adoption of GxP Inspection Request

100

Rapporteur, (Co) Rapporteur, other CHMP members and EMA receive comments

101-104

PRAC adopts PRAC RMP Assessment Overview and Advice for D120 LOQ

115

Receipt of draft List of Questions (LoQ) from CHMP Rapporteur and (Co) Rapporteur, including the CHMP recommendation and scientific discussions together with the PRAC RMP Assessment Overview and Advice, by CHMP members and EMA (If applicable). Quality part of the dossier reviewed by BWP.

120

CHMP adopts the LoQ as well as the overall conclusions and review of the scientific data to be sent to the Applicant by the EMA.

Clock stop. At the latest by Day 120, adoption by CHMP of request for GMP/GLP/GCP inspection, if necessary (inspection procedure starts).

DAY

ACTION

121*

Submission of the responses, including revised SmPC, labelling and package leaflet texts in English.

 

Restart of the clock.

After receipt of responses, the CHMP will adopt a timetable for the evaluation of the responses. In general, the following timetable will apply:

150

PRAC Rapporteur circulates the RMP assessment report and proposed LoOI

157

Circulation of the CHMP Rapporteur (Joint) Response Assessment Report (so-called Day 150 Assessment Report). EMA sends this (joint) Assessment Report to the Applicant making clear that it is sent for information only and does not yet represent the position of the CHMP

167

PRAC adopts PRAC RMP Assessment Overview and Advice for D180 LoOI

170

Comments from CHMP members to Rapporteur and (Co) Rapporteur, the EMA and other CHMP members. Responses to quality questions reviewed by BWP.

180

CHMP discussion and decision on the need for adoption of a list of “Outstanding Issues” and/or an Oral Explanation by the Applicant. If an Oral Explanation is needed, the clock is stopped to allow the Applicant to prepare the Oral Explanation. Submission of final inspection report to the EMA, Rapporteur and Co-Rapporteur by the inspection team (at the latest by day 180).

181

Restart of the clock. Oral explanation (if needed) and circulation of the final GxP Inspection Report

183

PRAC Rapporteur circulates the RMP assessment report

197

PRAC adopts the final PRAC RMP Assessment Overview and Advice

By day 210

Adoption of CHMP Opinion + CHMP Assessment Report

Adoption of a timetable for the provision of translations

* According to the published EMA calendar (see Dates for CHMP meetings dates), after receipt of the responses, the EMA will prepare a timetable for the evaluation of the responses.

After adoption of a CHMP Opinion, the preparation of the Annexes to the Commission Decision is carried out in accordance with the following timetable:

DAY

ACTION

+ 5 Days after adoption of Opinion

Applicant provides the EMA with SmPC, Annex II, labelling, package leaflet and Annex A in all EU languages (including Icelandic and Norwegian). EMA circulates draft translations to Member States for review

+ 22 Days after adoption of Opinion

Applicant provides EMA with final translations of SmPC, Annex II, labelling and package leaflet in all EU languages (including Icelandic and Norwegian), taking account comments received from Member States by +19 Days after adoption of the Opinion

+ 27 Days after adoption of Opinion

Transmission of Opinion and Annexes in all EU languages to Applicant, Commission, and members of the Standing Committee, and Norway and Iceland

Further details on the post-Opinion review of translations and forms to be used, are available in the "New linguistic review process of product information in the centralised procedure" guideline as published on the EMA website.

Mock-ups and specimens of the outer and immediate packaging together with the package leaflet must be submitted by the Applicant to the EMA for review, before commercialisation of the medicinal product. Further details on the mock-ups and specimens requirements are available on the EMA website.

References

32. How is an EMA Application Number attributed?

See web-link: EMA Pre-submission guidance for users of the centralised procedure - List of questions

33. Which information do I need to provide in my marketing authorisation application regarding GCP Inspections and GLP Compliance? Rev. September 2015

For the non-clinical studies and clinical studies submitted as part of the application, applicants are requested to provide the following information as annexes to the Cover Letter in their marketing authorisation applications:

Regarding GCP Inspections

A list of GCP inspection(s) conducted or planned by any regulatory authority at clinical trial sites for all clinical trials included in the dossier. In case of BE trials a list of the inspections conducted at the clinical and analytical facility were the study was conducted. 

Alternatively, a confirmation that no inspections had been requested nor taken place and that no inspections are planned.

Please also refer to Question “When can I expect a pre-approval GCP inspection and how are they conducted?” for more information on GCP Inspections and the information to include in the application regarding GCP compliance.

Regarding GLP Compliance

A summary table, listing the non-clinical studies claimed to be GLP compliant and indicating for each study:

  • study title
  • study code (Unique identifier assigned to the study)
  • date of completion of the Final Report
  • test facility and test sites in which the study was conducted
  • complete address of the test facility (and test sites were applicable)
  • period in which the test facility(ies) and/or test site(s) was(were) used indicating if in that period they were part of an European Union (EU) or an Organisation for Economic Co-operation and Development (OECD) Mutual Acceptance of Data (MAD) accepted GLP monitoring programme.

Regarding GLP compliance, as per Notice to Applicant, Volume 2B, there should be a comment in Module 2.4 Nonclinical Overview and Module 2.6 Nonclinical Summary on the GLP status of the studies submitted in the application.

References

34. When can I expect a pre-authorisation GCP inspection and how are they conducted?

The GCP standards applied to clinical trials carried out for similar biological medicinal products are the same as those applied to any other medicinal product.

This means that all the information published on the EMA website as part of the pre-submission guidance document is applicable.

35. When can I expect a pre-authorisation GMP inspection and how are they conducted?

The level of GMP supervision and the GMP standards applied to similar biological medicinal products are the same as for any other medicinal product.

This means that all the information included in the document: GMP inspections during the assessment of the application, published on the EMA website as part of the pre-submission guidance document, is applicable.

As for any other centralised application, two types of pre-authorisation GMP inspections are possible: to verify compliance with European Community Good Manufacturing Practice Principles and Guidelines and/or to verify specific manufacturing and control activities related to the assessment of an application.

The first type of inspection is normally carried out when a manufacturing site located outside the European Economic Area (EEA) and in a country where no operational Mutual Recognition Agreement with the EU is in place, has not been inspected for GMP compliance in the last 3 years by an EEA competent authority.

The need for this type of inspection is identified in the early stages of the procedure and an early inspection request can be adopted by the committee (e.g. at day 30), so that unnecessary delays are avoided.

As assessment-related inspections can not be foreseen until the Assessment Report is available, inspections are usually requested at day 90 of the Centralised Procedure. In this case a clock-stop might be necessary. The inspection is organised without delay by the EMA Secretariat and is usually carried out by the responsible inspectorate within 3 months of the adoption of the inspection request by the Committee.

References

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

See web-link: EMA Pre-submission guidance for users of the centralised procedure - List of questions

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

See web-link: EMA Pre-submission guidance for users of the centralised procedure - List of questions

38. Do I need to perform user consultation for a similar biological 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 similar biological medicinal products.

However, if the package leaflet of the similar biological medicinal product has the same content and layout as that of the reference medicinal product or other similar biological 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 similar biological medicinal product or in case of differences from the reference medicinal product, 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 the pre-submission guidance for users of the centralised procedure.

References:

39. How and when to submit a summary of the pharmacovigilance system description? - Rev. March 2013

The requirements for submission of a summary of the pharmacovigilance system are the same as for any marketing authorisation application, independent of the legal basis for the application. For further information please refer to the pre-submission guidance for users of the centralised procedure.

40. Should I submit an EU Risk Management Plan as part of my similar biological medicinal product application? - Rev. March 2013

See: Pre-authorisation guidance - section 3.5 Risk management plan (RMP).

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 similar biological medicinal product following changes to the innovator product? Rev. December 2015

If a centrally authorised similar biological medicinal product refers to a centrally authorised innovator product, the EMA will provide the Marketing Authorisation Holder (MAH) of the similar biological medicinal 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.

In the case, the implementation of the change requires to be further substantiated by new additional data to be submitted by the MAH of the similar biological medicinal product (e.g. comparability); a type II variation will be requested.

For centrally authorised similar biological medicinal products of nationally authorised innovator products the EMA will provide the MAH of the similar biological medicinal 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.

The EMA Secretariat shall handle and finalise such “administrative” harmonisation between the reference and the similar biological medicinal product.

Simple reference to fees payable can be found in 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 SmPC 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 SmPC and therefore request the MAHs of the innovator and Biosimilars 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 similar biological 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 timeframe for implementation of the safety variation. The exact implementation date for batch release purposes is to be agreed with the EMA.

References:

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 SmPC: 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 similar biological medicinal product following a USR to the innovator product? Rev. December 2015

If the centrally authorised similar biological medicinal product refers to a centrally authorised innovator product, 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 similar biological medicinal 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.

For centrally authorised similar biological products of nationally authorised innovator products the Agency will provide, upon notification by the respective competent authority, the MAH of the similar biological 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 similar biological medicinal product will be finalised within 24 hours.

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

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 SmPC. 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 as 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 similar biological 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 SmPC 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 similar biological 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 similar biological medicinal products.

For a similar biological 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 product 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 European Union 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 dates 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:

44. Will my similar biological medicinal product be considered interchangeable with the reference medicinal product?

The decisions on interchangeability and/or substitution rely on national competent authorities and are outside the remit of EMA/CHMP. Member States have access to the scientific evaluation performed by the CHMP and all submitted data in order to substantiate their decisions.

Reference:

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