Post-authorisation measures: questions and answers

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This page lists questions that marketing-authorisation holders (MAHs) may have on post-authorisation measures. It provides an overview of the European Medicines Agency's (EMA'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 are post-authorisation measures?

At the time of finalising a procedure or in follow-up of a signal evaluation, the Agency’s Committee(s) may agree that the applicant/MAH should provide additional data post-authorisation, as it is necessary from a public health perspective to complement the available data with additional data about the safety and, in certain cases, the efficacy or quality of authorised medicinal products. Such post-authorisation measures (PAMs) may be aimed at collecting or providing data to enable the assessment of the safety or efficacy of medicinal products in the post-approval setting.

The existence of such a system of PAMs does not aim at promoting premature approvals of marketing authorisations or post-authorisation procedures. The background and rationale for requesting PAMs will be described in the relevant assessment, which will present the context and nature of the PAM. Based on the assessment of the committee(s), PAMs are classified into their appropriate legal framework under which they will be enforced.

The following diagram explains how PAMs are categorised; in addition, each PAM category is explained in the following sections:

Consequently, PAMs fall within one of the following categories [EMA codes1]:

  • specific obligation [SOB]
  • annex II condition [ANX]
  • additional pharmacovigilance activity in the risk-management plan (RMP) [MEA] (e.g. interim results of imposed/non-imposed interventional/non-interventional clinical or nonclinical studies)
  • legally binding measure [LEG] (e.g. cumulative review following a request originating from a PSUR or a signal evaluation [SDA],Corrective Action/Preventive Action (CAPA), paediatric [P46] submissions, MAH’s justification for not submitting a requested variation)
  • recommendation [REC] e.g. quality improvement

Only certain medicinal products can be subject to specific obligations (see also ‘What is a Specific Obligation?’). PAMs other than specific obligations can be required for any type of authorisation and will be included in the opinion of an initial marketing authorisation or further to the committees’ assessment during post-authorisation.

The wording of the PAM will describe the issue under investigation that has led to the request together with a clear outline of the studies or activities expected to address it and the deadline for its submission. Compliance with these measures is defined by both the submission of the requested data and adherence to the agreed timeframe.

References


1These codes relate to the Agency’s product and procedure tracking database called SIAMED and will be used, together with a numbering system, to identify each PAM of a medicinal product both in the database and in any correspondence of the Agency with the MAH.

2. What is a specific obligation [SOB]? Rev. June 2016

Specific obligations can only be imposed on marketing authorisations granted under exceptional circumstances or on conditional marketing authorisations (see also Q&A 38 ‘Is my medicinal product eligible for approval under exceptional circumstances?’ and Q&A 50 ‘Could my application qualify for a conditional marketing authorisation?’ of the Agency’s presubmission guidance). These are conditions to the marketing authorisation included in annex II.E of the Commission decision and form the basis of the annual re-assessment or the annual renewal. These may also be additional Pharmacovigilance activity and will be included as well in the RMP (category 2 studies). Specific obligations can only be imposed at the time of the granting of the initial marketing authorisation, i.e. not in the context of post-authorisation procedures such as extension applications or extension of indication variations.

Continuation of a marketing authorisation under exceptional circumstances or the renewal of a conditional marketing authorisation will be determined by the MAH’s compliance with the specific obligations, which are checked annually as part of either the annual reassessment or the annual renewal procedures.

As specific obligations are binding conditions to the marketing authorisation, any modification proposal by the MAH with regards to their description or due date (as described in Annex II of the product information) has to be submitted within an appropriate procedure, i.e. either within the annual re-assessment, the annual renewal or a variation application.

Interim results not impacting on the product information or on the description of the specific obligation can be submitted as a PAM as described below, if they are not part of the annual reassessment or annual renewal. (see: How and to whom shall I submit my PAM data?).

In case of interim results impacting on the product information, a variation should be submitted without waiting for the annual re-assessment or annual renewal.

Final results leading to the fulfilment of the specific obligation should be submitted within an appropriate procedure, i.e. either within the annual re-assessment, the annual renewal or a variation application.

Where a specific obligation falls within the definition of a non-interventional post-authorisation safety study (PASS) imposed after 2 July 2012, the MAH will have to follow the procedure for review of imposed PASS protocols and results as described in the Agency’s post-authorisation procedural advice on PASS and in the corresponding guideline on good pharmacovigilance practices (GVP): module VIII - PASS.

References

3. What is an annex-II condition [ANX]? Rev. June 2016

The European Commission can impose on the marketing authorisation holder (MAH) the obligation to conduct post-authorisation measures. These obligations can be imposed at the time of the granting of the marketing authorisation or later, as conditions to the marketing authorisation. These are conditions to the marketing authorisation included in Annex II.D of the marketing authorisation. These may also be additional Pharmacovigilance activity and will be included in the RMP (category 1 studies).

Annex-II conditions are post-authorisation measures which, whilst not precluding the approval of a marketing authorisation or other post-authorisation procedures, are considered to be key to the benefit / risk balance of the product. These can consist of post-authorisation safety or efficacy study.

As annex-II obligations are binding conditions to the marketing authorisation, any modification proposal by the MAH with regards to their description or due date has to be submitted as a variation application.

Interim results not impacting on the product information or on the condition as stated in the Annex II can be submitted as a PAM as described in question How and to whom shall I submit my PAM data?.

Final results leading to the fulfilment of the Annex II condition should be submitted as a variation application.

Where an annex-II condition falls within the definition of a non-interventional PASS imposed after 2 July 2012, the MAH will have to follow the procedure for review of imposed PASS protocol and results as described in the Agency’s post-authorisation procedural advice on PASS and in the corresponding guideline on good pharmacovigilance practice (GVP): module VIII - PASS

References

4. What is an additional pharmacovigilance activity in the risk-management plan [MEA]? Rev. June 2016

Additional pharmacovigilance activities in the RMP (category 3 studies) may be non-clinical studies, clinical trials or non-interventional studies which are required to investigate a safety concern of a medicinal product. These studies are listed in the pharmacovigilance plan of the risk-management plan (RMP) and are either aimed at identifying and characterising risks, or at assessing the effectiveness of risk-minimisation activities.

All relevant milestones, together with their due dates should be included in the summary table of additional PhV activities in the RMP. The MAH has the obligation to provide the requested data within the stated timeframes.

Once additional pharmacovigilance activities have been agreed within the RMP, changes to these measures (e.g. proposals for adjusting due dates of agreed milestones, proposals to change the scope of agreed study or its duration, etc.) should be submitted via the appropriate variation procedure to amend the RMP.

Information not impacting on the product information or description/due date of the measure itself, (e.g. interim results) , can be submitted as a self-standing PAM as described in question How and to whom shall I submit my PAM data?.

Submissions of final study reports leading to the fulfilment of a MEA should be addressed via the appropriate variation procedure. (see also: Should I submit a variation to fulfil a PAM?).

References

5. What is a legally binding measure [LEG]? Rev. June 2016

Some post-authorisation measures (PAMs) are already defined as statutory obligations in the pharmaceutical legislation. As such, they have to be fulfilled by the MAH upon request of the Agency and its committees. Examples for such directly binding legal measures evaluated as PAMs are:

  • Requests for provision of data as a stand-alone submission (e.g. cumulative review following a PSUR assessment).
  • Requests for supplementary information to evaluate a signal (see EMA’s Questions and answers on signal management)
  • Requests for update of the product information
  • Obligations to submit any data requested in relation to CAPA corrective action or preventive action (CAPA) in the context of inspections
  • Submission of final results of study involving paediatric patients submitted in fulfilment of Article 46 of the paediatric regulation.

Where requested, these are directly addressed to the MAH by the Agency, either within the assessment report of the committee(s) or within a letter informing about the Committee(s)’(s) conclusions, and have to be responded to within the stated time frame.

Requests for updates of the product information should be addressed via a variation; a scientific justification for not submitting a requested variation should be submitted as a PAM.

When responding to these requests, the MAH should select the “LEG” PAM type in point 12 of the template table of the cover letter except for:

  • Submission of final results of study involving paediatric patients submitted in fulfilment of Article 46 of the paediatric where the MAH should select the “P46” PAM type in point 12 of the cover letter.
  • Provision of supplementary information to evaluate a signal or a scientific justification for not submitting a requested variation following a signal assessment, where the MAH should select the “SDA” PAM type in point 12 of the cover letter.

In accordance with the Paediatric legislation, MAHs should submit paediatric studies within six months of their completion and irrespective of whether it is part of a PIP (completed or not yet completed) or not, or whether it is intended for submission later on as part of a variation, extension or new stand-alone marketing-authorisation application.

References

6. What is a recommendation [REC]?

During the assessment of an application, the committee(s) may issue recommendations for further development of the medicinal product, e.g. either in terms of optimising some quality aspects or considerations for extending the patient population. Although these recommendations for further development are not binding to the marketing authorisation, they should be seen as important considerations in view of the potential future use of a medicinal product by the MAH.

This information can be submitted as a PAM however if data obtained in the framework of a recommendation has an impact on the authorised medicinal product and its product information, the MAH has the obligation to submit a variation application as appropriate (see: How and to whom shall I submit my PAM data?).

As such, the committee(s) will keep an overview of all recommendations made to a marketing authorisation and monitor whether, how and when the MAH has addressed them. Therefore, MAHs are encouraged to use the template for the cumulative letter of recommendations to acknowledge these recommendations.

MAHs should specify the following in their letter of recommendations:

  • a clear and concise description of each post-approval recommendation;
  • the procedure number where the recommendation was given.

No deadline needs to be mentioned.

When data in relation to a recommendation is provided to the Agency, an updated Letter of Recommendation should be provided, in which the MAH should indicate the date of submission and its format (e.g. as self-standing data, within a variation, within a renewal etc.).

References

7. Can the classification of my PAM change during its lifecycle?

New data or information regarding the medicinal product becoming available can result in the committee(s) considering that a PAM should be reclassified. Such reclassification will be performed within the procedure discussing the impact of the new information that has become available and will be justified in the assessment report where the measure is, as a consequence, up- or downgraded.

8. When should I submit my PAM? Rev. June 2016

The MAH shall submit the PAM data according to the timeframe specified by the Agency’s committee(s) as specified either in the annex II, the RMP or the respective committee assessment. When requested, the MAHs should propose due dates for the submission of the post-authorisation data that are realistic and proportionate to the uncertainty to be addressed which are then subject to agreement with the Agency’s committees .

Data submitted as PAM should be submitted as per the deadline specified by the Committee(s), and will start in accordance with the published submission dates for PAMs (see also Human Medicines - Procedural timetables / Submission dates). Assessment of PAM data submitted after the recommended submission date will start in accordance with the start date of the following month.

If the MAH is unable to provide the required data by the specified deadline, he must inform the Agency and the rapporteur in writing as early as possible in advance of the due time of submission. The reason for the delay must be justified and a new submission date proposed and is subject to agreement by the Committee(s). These submissions should be done as follows:

  • Changes to the due date for a SOB, Annex II condition or category 3 study in the RMP should be submitted as type IB variation category C.I.11.z, include the updated RMP and/or product information as applicable (one variation per change of due date is required).
  • Changes to category 4 studies listed in the RMP can be updated in the context of any other RMP update.
  • Proposals for changes to directly legally binding measures (LEG including SDA) have to be notified in writing, together with an appropriate justification, and have to be agreed as well by the Agency’s Committee(s). Such requests should be sent to pamquery@ema.europa.eu.

In the case of a non-justifiable delay, the Agency’s committees will consider taking regulatory action (see also next question).

References

9. Under which procedure should I submit my PAM? Rev. June 2016

The procedure under which the PAM should be submitted will depend on the content and type of information submitted as part of the PAM, as summarised in the table below:

PAMSubmissionProcedure/Type of application

Specific obligation

(category 2)

[SOB]

Non-interventional PASSSee Post Authorisation Safety Study
  • Protocol and substantial amendments
Article 107n-o
  • Interim results
See below as for other SOBs
  • Final results
Article 107p-q
Others SOB than non-interventional PASS 
  • Protocol (where requested to be submitted)

Stand-alone PAM

 

Where a protocol is not requested to be submitted by the Agency’s Committee, the MAH should consider to seek scientific advice

  • Interim results

Conditional renewal, annual re-assessment

 

(Note: if submission of interim results is requested outside of the timelines of the renewal or annual re-assessment, these can be submitted as stand-alone PAM, if no changes to the PI are proposed), alternatively a type II would be required.

  • Final results
Conditional renewal, annual re-assessment or type II variation, depending on the timelines.

Annex II condition (category 1, PAES)

[ANX]

Non-interventional PASS and resultsSee Post Authorisation Safety Study
  • Protocol and substantial amendments
Article 107n-o
  • Interim results
See below as for other studies
  • Final results
Article 107p-q
Others studies than non-interventional PASS (including PAES) 
  • Protocol (where requested to be submitted)

Stand-alone PAM

 

Where a protocol is not requested to be submitted by the Agency’s Committee, the MAH should consider to seek scientific advice

Interim results

  • No changes to PI
  • Changes to PI

 

Stand-alone PAM

Type II variation

Other studies: Final resultsType II variation

Additional Pharmacovigilance activity in the RMP

(category 3)

[MEA]

Protocol (as requested by Committee and reflected as a milestone in the RMP )

Stand-alone PAM

Where a protocol is not requested to be submitted by the Agency’s Committee, the MAH should consider to seek scientific advice

Interim results

  • No changes to PI
  • Changes to PI

 

Stand-alone PAM

Type II variation

Final resultsType II variation

Legally binding measure

[LEG]

(including [SDA] and [P46])

 

Provision of data requested by the Committee (e.g. cumulative review, CAPA, interim study results)

([SDA] when related to a signal assessment)

 
  • with no changes to the PI

Stand-alone PAM

 

  • with PI changes
Type II variation
Final study reportType II variation

Justification for not submitting a variation

([SDA] when related to a signal assessment, otherwise [LEG])

Stand-alone PAM

 

Submission of final results of study involving paediatric patients in accordance with Article 46 of the paediatric regulation [P46] 
  • No changes to PI
Stand-alone PAM [P46]
  • Changes to PI
Type II variation

Recommendation

[REC]

Interim results

  • No changes to PI
  • Changes to PI

 

Stand-alone PAM

Type II variation

 Final resultsType II variation
 ERA study results with no impact to PIType IB CI.z variation

 

Where the deliverable of a measure is submitted as part of another procedure, the structure of the submission package should follow the requirements of this procedure and the MAH should indicate in the template table of cover letter of the application which PAM is being addressed, including the EMA reference number and the full description of the relevant PAM. The MAH does not need to submit a separate ‘stand-alone’ submission of the PAM data.

References

10. How should I structure my PAM submission dossier? Rev. June 2016

The Agency will check PAM submissions with respect to the Guidelines on Variations to ensure that it does not fall within one of the classifications. In this regard, the Agency will reject any PAM submission that should be filed as a variation application. In such cases, the eCTD submission of the variation application should provide a reference to the PAM eCTD submission for this sequence to be closed. Where the MAH is requested to resubmit as a variation application, the start of the variation procedure will be upon receipt of the complete application according to the next upcoming starting date as per published time table for Type II.

’Stand-alone’ PAM submission should include:

  • a cover letter indicating the full description and - as available - the reference number(s) of the PAM(s) (The number(s) to be quoted are the number(s) attributed by the Agency at the time of adoption of the PAM including - for SDAs - the EPITT number). The letter should mention the due date, including any agreed extension of it. The cover letter should also contain the template table to facilitate submission and registration. In this table, the MAH should indicate whether the PAM relates to Quality, Pre-clinical, Clinical orPharmacovigilance, whether it fulfils Article 46 of the paediatric regulation or is a response to a signal, among others. The completed table should also indicate whether the submission relates to protocol/ interim results of interventional/ non-interventional studies or follow-up queries further to the review of data by the PRAC or the CHMP. The MAH should describe from which procedure this PAM originates (initial MA, type II variation, PSUR/PSUSA, etc) and whether it is a follow-up to a previous PAM (responses to questions raised during the assessment of a PAM). This information will allow the involvement of the appropriate Committee(s) and identification of the timetable to be applied.
  • All supportive documentation relevant to the fulfilment of the PAM should be presented in accordance with the appropriate headings and numbering of the European Common Technical Document (EU-eCTD) format.
  • Any scientific advice or protocol assistance obtained in relation to the fulfilment of PAMs concerned should be included.

References

11. How and to whom should I submit my PAM data?

Please refer to Question 22. 5 Other - "How and to whom shall I submit my application?".

12. How shall my submission of PAM be handled (timetable), and what could be the outcome of the evaluation?

This section only applies to submissions of PAM data as a ‘stand-alone’ submission.

Most PAMs will be evaluated by CHMP (and CAT if an advanced therapy medicinal product).

However, PRAC will lead the review of protocols or interim results of non-interventional safety studies and in any follow-up PAM to a procedure primarily assessed by PRAC (e.g: cumulative safety review requested further to the assessment of PSUR [LEG] or a signal [SDA]).

PAMs will be handled using one of the three timetables:

  • CHMP led PAM assessment timetable
  • PRAC led PAM assessment timetable
  • Urgent PRAC led PAM assessment timetable, e.g. for urgent signal PAMs [SDA]

The submission deadlines and full procedural detailed timetables are published as a standard calendar on the EMA website (see: Human Medicines – Procedural Timetables / Submission dates).

The Agency will inform the MAH of the outcome of the committee’s evaluation in writing. The following may be envisaged depending on the committee’s conclusion:

  • the PAM is fulfilled and no further action is required;
  • the PAM is not yet fulfilled, as further clarifications or additional data are required. A request for supplementary information to be addressed by the MAH within a given timeframe will be issued and a follow-on PAM (such as MEA 00X.01) created. The PAM will only be considered as fulfilled, once all requests for supplementary information have been addressed by the MAH to the Agency’s committees’ satisfaction;
  • PAM is fulfilled but follow-up regulatory action is required, e.g. a request for variation and this will result in a new PAM being issued.

References

13. Do I have to pay fees for the PAM data submission?

There is no fee payable for a PAM stand-alone submission.

14. How are PAMs enforced?

The Agency will keep a record of the post-authorisation measure and its due date in its database.

In case of overdue measures or a MAH being found non-compliant in satisfying a post-authorisation measure, the responsible committee will consider the need for appropriate actions to be taken including involvement of the relevant committee(s). 

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 product or other analysis to support a discussion on the next steps by the Agency’s committee(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 MAH to the committee
  • initiation of a referral procedure with a view to vary/suspend/revoke the MA in light of art. 116 of Directive 2001/83/EC
  • inspection to be performed upon request of the committee(s).

Such regulatory action in regards to non-compliance of a MAH may be made public by the Agency on the Agency website e.g. in the EPAR(s) of the affected product(s).

Irrespective of the above regulatory actions, the Agency may take at any point in time a decision to take another enforcement action beyond those described here.

References

15. Will there be any publication on the outcome of my PAM?

Outcome of PAMs are not published in the EPAR ‘Procedural steps taken and scientific information after the authorisation’. However, assessment reports for data submitted in accordance with Article 46 of the paediatric regulation and PRAC recommendations on signals are published on the Agency’s website.

Reference

16. Who should I contact if I have a question when preparing my application?

If you cannot find the answer to your question in the Q&A when preparing your application, please contact us using the following email address: PAMquery@ema.europa.eu

The Agency aims to respond to your query within 5 working days. To help us deal with your enquiry, please provide as much information as possible including the name of the product in your correspondence.

The above email address is only applicable when you have a pre-submission query. A dedicated Procedure Manager (PM) will be assigned to the procedure once your application has been received. You will be able to contact this PM throughout the procedure.

17. Who is my contact at the European Medicines Agency during post-authorisation procedures?

Please refer to question 22.8 Other - "Who is my contact at the European Medicines Agency during post-authorisation procedures?".

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