This page lists questions that marketing-authorisation holders (MAHs) may have on post-authorisation efficacy studies (PAESs). It provides an overview of the European Medicines Agency's (EMA) 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:
- European Medicines Agency post-authorisation procedural advice for users of the centralised procedure
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.
Scientific guidance on PAES
EMA has developed, in cooperation with national competent authorities and other interested parties, a draft scientific guideline on PAES which outlines how companies should design these studies in order to support regulatory decision making in the European Union:
- 1. What is a PAES imposed in accordance with the Commission Delegated Regulation?
PAES imposed in accordance with the Commission Delegated Regulation (EU) No 357/2014 it is meant an efficacy study which is requested by a Competent Authority pursuant to at least one of the situations set out in this said regulation. The data resulting from such a PAES conducted within an authorised therapeutic indication are required to be submitted as they are considered important for complementing available efficacy data in the light of well-reasoned scientific uncertainties on aspects of the evidence of benefits that is to be, or can only be, addressed post-authorisation. The results of the PAES have the potential to impact on the benefit-risk of the medicinal product or product information.
Such efficacy study conducted post-authorisation can be imposed either:
- at the time of granting the initial marketing authorisation (MA) where concerns relating to some aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed; or
- after granting of a MA where the understanding of the disease or the clinical methodology or the use of the medicinal product under real-life conditions indicate that previous efficacy evaluations might have to be revised significantly.
It is also possible to impose the conduct of post-authorisation efficacy studies in the specific situations of a conditional MA, a MA granted in exceptional circumstances, a MA granted to an advanced therapy medicinal product, the paediatric use of a medicinal product, a referral procedure initiated under Article 31 or Article 107i of Directive 2001/83/EC or Article 20 of Regulation (EC) No 726/2004, however these fall outside the scope of the Delegated Regulation.
- 2. How and where the PAES imposed in accordance with the Commission Delegated Regulation will be reflected in the marketing authorisation? Rev. June 2016
For centrally authorised medicinal products (“CAPs”), a PAES imposed as a condition to the MA is reflected in Annex II under section D “Obligation to conduct post-authorisation measures”.
The study objective and the deadline for the submission of the final study results are specified in the Annex II. At the beginning of the description of the study, such efficacy study imposed in accordance with the Delegated Regulation is explicitly named ‘Post-Authorisation Efficacy Study (PAES)’.
The imposition of such PAES shall meet one of the criteria set out in the Delegated Regulation. A justification will be provided in the CHMP assessment report.
If the MAH has to submit the protocol for endorsement by the European Medicines Agency, this will be reflected in Annex II in the wording of the condition (e.g. “according to an agreed protocol”).
Any post-approval amendments to the conditions in Annex II (objective and/or due date) should be duly justified and submitted as a variation, type IB C.I.11.z) for change in the due date or type II C.I.11.b) for changes other than the due date.
As for any imposed post-authorisation efficacy studies, those imposed in accordance with the Delegated Regulation should also be reflected in the risk management plan (“RMP”), part IV ‘Plans for post-authorisation efficacy studies’ and if applicable under part III in case of important safety concerns addressed by this study as well.
- 3. Following which procedure will my imposed PAES protocol be assessed?
If the review of the imposed PAES protocol has been reflected in the Annex II, the MAH will have to submit a draft protocol to the European Medicines Agency as a post-authorisation measure (“PAM”). Otherwise, the review of the protocol is not deemed necessary.
The MAH is generally advised to consider seeking scientific advice on the study design irrespective of whether the submission of the protocol has been requested, in order to discuss the design of the study and ensure that it meets the intended objectives.
In case the PAES is a clinical trial, it falls under the scope of Directive 2001/20/EC (to be superseded by the Clinical Trial Regulation (EU) No 536/2014) and is subject to the national clinical trial authorisations.
- 4. When should I submit my imposed PAES protocol? Rev. June 2016
If the submission of the protocol has been requested in the Annex II, the MAH should submit the protocol in accordance with the timeframe specified in the RMP, part IV as timelines for protocol submission are not specified in the Annex II.
At time of imposition, the MAH is asked to propose appropriate dates for the submission of the protocol and the post-authorisation data that are proportionate to the uncertainty to be addressed. The proposed dates for submission are subject to agreement with the Agency’s Committee(s).
If the MAH would be unable to provide the protocol by the specified deadline, the MAH must inform the Agency and the Rapporteur in writing as early as possible in advance of the submission due time. The delay must be duly justified and a new submission date should be proposed. Such request should be sent to your Procedure Manager and will be subject to agreement by the Committee(s).
If the submission date of the final study results mentioned in the Annex II is impacted, this requires the submission of a type IB variation C.I.11.z).
- 5. In which timeframe will my imposed PAES protocol be evaluated (timetable)?
The evaluation of the PAES protocol will be led by the CHMP with consultation of other committees where foreseen. The evaluation will be handled as a 60 day PAM procedure, which follows the timetables available on the Agency’s website.
The protocol assessment will start in accordance with the published timetable for PAMs.
- 6. What are the possible outcomes of the evaluation of an imposed PAES protocol?
The CHMP, taking into account advice of other committees where provided, will conclude the assessment of the protocol according to the following options:
- endorsement of the protocol;
- objection to the protocol;
In case of endorsement, the assessment report may still include recommendations for amendments to the protocol. These recommendations are for consideration by the MAH and do not require resubmission of the protocol.
In case of objection, resubmission of an amended protocol for reassessment will be required.
- 7. Do I have to submit interim results?
There is no obligation to submit interim results, unless it has been requested by the Committee(s).
However, when requested, interim results should be submitted as a PAM (see: Under which procedure should I submit my PAM?) unless there is an impact on the product information. In such case a variation should be submitted.
- 8. Do I have to submit the final results of my imposed PAES? Rev. June 2016
Upon completion of the study, a final study report shall be submitted by the deadline specified in Annex II via the appropriate variation procedure irrespective of changes to the product information.
The MAH should consider whether the final results have an impact on the marketing authorisation. If the MAH concludes that this is the case, the MAH should submit the results together with the proposed changes to the product information.
The classification of the variation will depend on whether there are proposed changes to the product information.
With the application submitted, the MAH should indicate in the table of the cover letter of the application which post-authorisation measure is being addressed and the full description of the relevant measure.
The CHMP will lead on the assessment of the study results and will conclude, taking into account advice of other Committees where provided.
In addition, it is reminded that the MAH should provide in the PSUR, as usual, a summary of the clinically important efficacy and safety findings obtained from the study during the reporting interval.
- 9. Do I have to pay fees for the protocol and final study results submission?
There is no fee payable for the protocol submission as a PAM procedure.
For the final study results submission, there are fees applicable to the related variation procedure.
- 10. How is a PAES enforced?
The Agency will keep a record of the post-authorisation measure and its due date in its database.
In case of overdue condition or a MAH being found non-compliant in satisfying such condition, the competent authorities will consider the need for appropriate actions to be taken.
In such situations, the Rapporteur (or a lead Rapporteur nominated by the Committee in case of more than one affected product) may draft an assessment report on the impact of the lack of data on the benefit/risk balance of the affected medicinal product(s). Based on the outcome of such assessment and/or discussion, one or more of the following actions may be taken:
- Letter to the MAH by the Chair of the Committee
- Oral Explanation by the MAH to the Committee
- Initiation of a referral procedure with a view to vary/suspend/revoke the MA
- Inspection to be performed upon request of the Committee(s)
Such regulatory action in regards to non-compliance of the MAH may be made public on the Agency website, e.g. in the EPAR(s) of the affected medicinal product(s).
- 11. Will there be any publication on the outcome of my PAES protocol and final study results assessment?
Outcome of protocol assessment are not published on the EMA Website. However, in case of a clinical trial the protocol and summary will be available in the clinical trials database, as per usual procedure.
Outcome of final study results will be published in the EPAR under ‘Procedural steps taken and scientific information after the authorisation’. Relevant results of the study will be included in the SmPC.
To support transparency on PAES that are outside the scope of Directive 2001/20/EC, study information (including for studies conducted outside the EU) should be made available in the EU electronic register of post-authorisation studies (EU PAS Register) maintained by the Agency.
- 12. 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 this Q&A when preparing your application or during the procedure, please contact the Procedure Manager responsible for your product.
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