Annual re-assessment: questions and answers

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This page lists questions that marketing-authorisation holders (MAHs) may have on annual re-assessments. It provides an overview of the European Medicines Agency's position on issues that are typically addressed in discussions or meetings with MAHs in the post-authorisation phase. Revised topics are marked 'New' or 'Rev.' upon publication.

A PDF version of the entire post-authorisation guidance is available:

These questions and answers have been produced for guidance only and should be read in conjunction with the rules governing medicinal products in the European Union, volume 2, notice to applicants.

MAHs must in all cases comply with the requirements of Community legislation. Provisions that extend to Iceland, Liechtenstein and Norway by virtue of the European Economic Area agreement are outlined in the relevant sections of the text.

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1. What is the annual re-assessment?

In exceptional circumstances and following consultation with the applicant, an authorisation may be granted subject to certain conditions, so called specific obligations (SOBs), in particular relating to the safety of the medicinal product, notification to the national competent authorities of any incident relating to its use, and action to be taken.

Such a marketing authorisation may only be granted when the applicant can show that they are unable to provide comprehensive data on the efficacy and safety of the medicinal product under normal conditions of use and must be based on one of the grounds set out in Annex I of Directive 2001/83/EC (rarity of the condition, state of scientific knowledge, ethical grounds).

Continuation of such a marketing authorisation shall be linked to the annual re-assessment of the conditions mentioned above. The SOB(s) may include an identified programme of studies to be conducted within a specified time period and aim at the provision of additional safety and efficacy data, e.g. a registry or an observational cohort study, where data is collected and reported annually based on an agreed protocol.

The outcome of the annual re-assessment will reflect the status of fulfilment of the SOB(s) and the impact of the SOB data on the benefit / risk profile of the medicinal product and will conclude on whether the marketing authorisation should be maintained, varied or suspended based on the review of these two elements.

References

2. Are the CHMP Co-Rapporteur and the PRAC involved in the assessment?

The CHMP Co-Rapporteur is not systematically involved in the evaluation of the annual re-assessment application. The PRAC is systematically involved in the assessment and will focus on the assessment of the SOB data and any methodological aspects of the generation of these data in case they are falling within the definition of a non-interventional post-authorisation safety study (PASS). In this case the PRAC provides its expertise to the CHMP in terms of the assessmentof the non-interventional PASSs and any potential changes to additional pharmacovigilance and risk minimisation activities proposed in the Risk Management Plan.

3. How shall I present my annual re-assessment application? Rev. August 2017

Annual re-assessment applications should be presented as indicated below, in accordance with the appropriate headings and numbering of the EU-eCTD format.

In order to ensure that annual re-assessment applications are complete and correct before submitting them to the Agency, it is strongly recommended to use the pre-submission checklist for annual re-assessment of a marketing authorisation under exceptional circumstances application.

Module 1:       1.0       Cover letter with the following documents attached:

A chronological tabulated summary table of the SOBs stating the following for each: description, reference number (preferably SIAMED number), due date indicated in Annex II of the Product Information, date of submission and procedure within which the SOB was submitted (if appropriate), and status.

  • Revised list of pending SOBs (where applicable).
  • A present/proposed table listing any changes introduced to the product information (incl. any minor linguistic amendment introduced for each language), if applicable.

The cover letter should indicate the time period covered by the Annual Re-assessment application.

The cover letter should also contain the template table to facilitate submission and registration.

Note: The Cover Letter should be signed by the person designated as MAH contact with the EMA. The Annual Re-Assessment application is not an opportunity to notify the Agency of changes in contact person, which should be notified separately (see dedicated question undersection ‘Other post-authorisation activities: questions and answers’ of the EMA published guidance:How do I notify the EMA of changes to my Contact Persons specified in the application form”).

1.3       Product Information

1.3.1 Summary of Product Characteristics, Labelling and Package Leaflet

  • If no changes to the PI (SmPC, Annex II, outer/inner labelling and Package Leaflet) are proposed by the MAH, clear reference to it should be made in the cover letter.
  • If changes to the PI are proposed as part of the Annual Re-Assessment, a version of the PI in English, highlighting the changes proposed by the MAH should be provided in the eCTD and Word format. In addition, a ‘clean’ version of the PI should be provided in the eCTD and in Word format.
  • Note: All other language versions are only to be submitted after adoption of the opinion (See also question - “When do I have to submit (revised) product information? In all languages?”)

The Annexes provided should only reflect the changes introduced by the Annual Re-Assessment. However, if the PI update is already warranted by the Annual Re-assessment data, the MAH can also take the opportunity to implement changes due to the revision of the SmPC guideline, other relevant guidelines impacting on the product information, or EMA/QRD Product Information Templates and minor linguistic amendments . This should be clearly mentioned in the cover letter and list of such changes provided as an attachment to the cover letter. Any changes not listed will not be considered as part of the application.

1.4       Information about the Expert

1.4.3    Information about the Expert – Clinical (incl. Signature + CV)

1.8.2 Risk Management Plan

If an update of the RMP is proposed by the MAH as a consequence of SOB data submitted with the annual re-assessment application, section 1.8.2 should contain the updated RMP (‘clean’ version). A version of the RMP, highlighting the changes proposed by the MAH should also be provided in Word format.

Module 2:       2.5       Addendum to Clinical overview

The Expert report addressing the data as well as the status of fulfilment of the SOBs and their impact on the overall benefit/risk balance of the medicinal product, in the form of a Clinical overview update or addendum, based on the following structure (headings):

  • Summary of information previously submitted to address ongoing SOBs
  • Data submitted with the annual re-assessment to address outstanding SOBs
  • Critical evaluation of status of fulfilment of each pending SOB

Clinical summaries and clinical study reports should not be included in section 2.5 but in the respective dedicated eCTD sections; see below.

2.7       Clinical summaries

Clinical summaries will generally need to be updated, as appropriate, when new clinical study reports are submitted.

Module 5:       5.3.5 Reports of efficacy and safety studies (as appropriate)(as appropriate) submitted to fulfil SOBs:

5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication

5.3.5.2 Study Reports of Uncontrolled Clinical Studies

5.3.5.3 Reports of Analyses of Data from More Than One Study

5.3.5.4 Other Clinical Study Reports

References

4. Can I submit a PSUR with my annual re-assessment application?

A PSUR cannot be submitted as part of an annual re-assessment procedure (see also Q&A ‘PSURs’).

5. Can I submit an RMP with my annual re-assessment application? Rev. August 2017

If SOB data submitted with the annual re-assessment warrant an RMP update, an updated RMP should be submitted. In such cases, it is recommended to liaise with the Agency in advance of the planned submission to agree on the details of such an update. When updates to the RMP are not warranted by newly submitted SOB data, an RMP should not be submitted within the annual re-assessment application.

If an updated RMP is already warranted as a consequence of the annual re-assessment data provided, some additional changes to the RMP may also be included in that RMP update (for further guidance please see question “Which changes can be included in an RMP update without the need for an additional variation?”).

6. When, how and to whom shall I submit my annual re-assessment application?

When: The annual re-assessment application should be submitted on the anniversary date of the Commission Decision granting the Marketing Authorisation. Flexibility in the submission date could however be envisaged, in order to synchronise the annual re-assessment submission with the submission of data from the SOBs. The annual re-assessment application submission could be adjusted within a maximum of +/- 2 months in such cases.

Marketing Authorisation Holders are therefore advised to discuss and agree the annual re-assessment submission date with the Agency and the Rapporteur well in advance of the submission.

The MAH shall submit the annual re-assessment application at the latest by the recommended submission dates published on the EMA website. See also Human Medicines – Procedural Timetables / Submission dates).

How and to whom: Please refer to Other post-authorisation activities: questions and answers - How and to whom shall I submit my application?

Identical annual re-assessment applications for multiple Marketing Authorisations must be submitted separately. Each Marketing Authorisation is considered to be a stand-alone dossier. For this reason no cross-references will be accepted and applications must be submitted for each concerned product as a complete and stand-alone document.

7. How shall my annual re-assessment be handled (timetable)?

The EMA will acknowledge receipt of a valid application of an annual re-assessment and shall start the procedure in accordance with the recommended starting dates published on the EMA website.

The submission deadlines and full procedural detailed timetables are published as a generic calendar on the EMA website (see: submission deadlines and full procedural timetables).

The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.

The annual re-assessment procedure will involve the CHMP and the PRAC.

The following 90-day timetable shall normally apply:

DAYACTION
Day 1Start of procedure (see published dates on EMA website)
Day 60

Receipt of CHMP RApporteur and PRAC Rapporteur Joint Assessment Report

Circulation CHMP and PRAC members

Day 66Comments from CHMP and PRAC members on the Joint Assessment Report
Day 73-76Discussion at PRAC Meeting (if required)
Day 90At CHMP:
- If no outstanding issues: adoption of opinion.
- If outstanding issues: adoption of List of Outstanding Issues + decision on possible oral explanation by MAH
Day 91MAH provides answers to list of outstanding issues to CHMP /PRAC Rapporteurs, CHMP/ PRAC members and EMA
Day 96

CHMP Rapporteur and PRAC RApporteur Joint Assessment Report

Circulation CHMP and PRAC members

Day 98Comments from CHMP and PRAC members on the Joint Assessment Report
Day 103-106Discussion at PRAC (if required)
Day 120Adoption of CHMP opinion / possible oral explanation by MAH

 

8. What could be the outcome of my annual re-assessment?

Depending on the assessment, one of the following outcomes can be envisaged:

  • Maintenance of the MA considering that:
    • SOBs remain in place unchanged
    • Data from the SOBs do not require changes to the MA (e.g. changes to benefit risk profile of medicinal product and product information)

All SOBs will be reviewed again at the time of the following annual re-assessment together with their impact on the benefit/risk profile of the medicinal product.

  • Variation of the MA considering that:
    • SOBs need to be modified; and/or
    • Data from the SOBs warrant changes to the MA (e.g. changes to benefit risk profile of medicinal product and/or product information)

All SOBs will be reviewed again at the time of the following annual re-assessment together with their impact on the benefit/risk profile of the medicinal product.

  • Suspension/revocation of the MA considering that:
    • Data from the SOBs affect the benefit/risk profile of the medicinal product to the extent it warrants the suspension/revocation of the MA for the medicinal product

or

    • The status of compliance with the SOBs is unsatisfactory and it is therefore considered that conditions to the marketing authorisation have not been fulfilled.
  • Exceptionally, the CHMP may consider that all specific obligations have been fulfilled and comprehensive data on the efficacy and safety of the product is available. In such cases the CHMP may recommend granting a Marketing Authorisation not subject to specific obligations.

The Agency will subsequently forward the opinion to the European Commission, the Member States, Norway and Iceland and the Marketing Authorisation Holder together with the CHMP assessment report. The Decision-Making Process of the European Commission starts once the opinion with annexes in all official EU languages has been received.

When the annexes to the Marketing Authorisation have not been affected by the annual re-assessment, no Commission Decision will be issued.

References

9. Can I submit my annual re-assessment within the renewal?

The annual re-assessment of medicinal products authorised under exceptional circumstances cannot be part of the 5-year renewal procedure, as their scope isdifferent.

References

10. Do I have to pay fees for an annual re-assessment?

There is no fee payable for the annual re-assessment.

References

11. What impact do ongoing Variation(s) ( Type IA/IB or Type II) have on the annual re-assessment?

In case that an ongoing variation(Type IA/IB or Type II) affects the product information and is not yet finalised at the time of the submission of the annual re-assessment application, the last product information adopted/accepted by the EC/CHMP/EMA should be used in the submission of the annual re-assessment application by the MAH.

If the variation procedure is finalised (notification of a Type IA/IB or opinion of the Type II) before or upon finalisation of the annual re-assessment procedure, the accepted/adopted variation changes should be used in the product information adopted with the annual re-assessment.

MAHs are advised to contact the Agency in order to discuss how to optimally handle the above situations.

12. Do I have to submit mock-ups and specimens?

No mock-ups or specimens are required for the annual re-assessment of a marketing authorisation under exceptional circumstances.

13. When do I have to submit (revised) product information? In all languages?

Proposals for changes to the Annexes prompted by data submitted with the annual re-assessment application may be submitted as part of the annual re-assessment procedure. In such cases, the revised product information will be considered in the annual re-assessment opinion and implementation of changes will not initiate a separate variation procedure (see also Question “How shall I present my annual re-assessment application?”, Section 1.3.1).

At submission

In case the annual re-assessment affects the SmPC, Annex II, labelling and/or package leaflet, the revised product information Annexes must be submitted as follows:

LanguageFormat
EN only

- As part of the eCTD

- Word format (highlighted and clean)

English language (only): complete set of Annexes within the eCTD sequence and in Word format (clean and highlighted showing the changes proposed as part of the Annual Re-Assessment).

In case the annual re-assessment results in changes to the SmPC, Annex II, labelling and/or package leaflet, the revised complete set of Annexes must be submitted as follows:

After CHMP Opinion (Day +5)

LanguageFormat
EN only

- As part of the eCTD

- Word format (highlighted and clean)

All EU languages (incl. EN, NO and IS): complete set of Annexes in Word format (highlighted) and in PDF (clean).

After Linguistic check (Day +25)

LanguageFormat
EN only

- As part of the eCTD

- Word format (highlighted and clean)

All EU languages (incl. EN, NO and IS)

 -Via Eudralink

- Word format (highlighted)

- PDF format (clean)

All EU languages (incl. EN, NO and IS): complete set of Annexes in Word format (highlighted) and in PDF (clean)

Translations of the adopted product information in all EU languages (incl. EN, NO and IS) are to be provided electronically (in one Eudralink package) to the Member States Contact Points for Translations by Day +5 and copied to the EMA procedure assistant.

The ‘complete set of Annexes’ consists of Annex, I, II, IIIA and IIIB i.e. all SmPC, labelling and PL texts for all strengths and pharmaceutical forms of the product concerned and Annex related to the Art. 127a if appropriate.

Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB, and if applicable, Annex related to the Art, 127a) as one Word document for each official EU language. Annex related to the 127a (when applicable) must be presented as a separate PDF document with “127a” removed from the title page together with the Word files highlighted with tracked changes. All translations should be numbered as one document, starting with "1" (bottom, centre) on the title page of Annex I and Annex (127a) when applicable. The ‘QRD convention’ published on the EMA website defines format and layout of the PI. The PDF user guide should also be followed as it provides guidance on how to correctly prepare the PDF versions.. When submitting the full set of Annexes in PDF format, this should be accompanied by the completed Day +25 checklist. Highlighted changes should be indicated via ‘Tools – Track changes’. Clean versions should have all changes ‘accepted’.

The revised Annex A, where applicable, is to be provided to the Agency as a separate Word document in all EU languages. See point 1.12 below.

The Decision-Making Process of the European Commission starts once the opinion with Annexes in all official EU languages, as appropriate, has been received. When the Annexes to the Marketing Authorisation have not been affected by the annual re-assessment, no European Commission Decision will be issued.

Reference

14. Will there be any publication on the outcome of my annual re-assessment?

The EPAR (published on the EMA website) will be revised to reflect the CHMP conclusions in relation to the annual re-assessment procedure.

The CHMP meeting highlights published following each CHMP meeting gives information in its Annex on opinions in relation to annual re-assessment applications. This information includes the invented name of the product, its INN, the name of the MAH and the procedure outcome.

In case of an unfavourable opinion, recommending suspension or revocation of the MA, a Question and Answer (Q&A) document will be published by the Agency. This will include information and reasons for such an opinion. The information will be provided in lay language, so that it can be understandable for the general public.

References

15. Who should I contact if I have a question when preparing my application and during the procedure? Rev. June 2016

If you cannot find the answer to your question in the Question and Answer (Q&A) when preparing your application or during the procedure, please contact the Procedure Manager responsible for your product.

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