Post-authorisation safety studies: questions and answers

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This page lists questions that marketing-authorisation holders (MAHs) may have on post-authorisation safety studies (PASSs). 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 a PASS?

A post-authorisation safety study (PASS) is defined in Article 1(15) of Directive 2001/83/EC as any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk-management measures.

A PASS may be initiated, managed or financed by an MAH voluntarily, or pursuant to an obligation imposed by a competent authority.

For detailed guidance, refer to the guideline on good pharmacovigilance practices (GVP): Module VIII – PASSs.

2. Is a meta-analysis of safety data a non-interventional PASS?

Module VIII of GVP provides general guidance for the transparency, scientific standards and quality standards of non-interventional PASSs conducted by MAHs voluntarily or pursuant to an obligation imposed by a competent authority.

Systematic reviews and meta-analyses imposed as an obligation should be considered as non-interventional PASSs. In annex III of Commission Implementing Regulation (EU) No 512/2012, provisions are made in the format of the study protocol (e.g. research methods) and the final study report if the study is a systematic review of a meta-analysis. According to Article 36, this means that, de facto, these designs should be considered as non-interventional PASSs.

3. How will an imposed non-interventional PASS be handled?

According to Article 107(n-q) of Directive 2001/83/EC, any non-interventional PASS imposed as a condition to the marketing authorisation will be supervised and assessed by the Pharmacovigilance Risk Assessment Committee (PRAC). The Committee supervision relates to both the study protocol and the final study report.

References

4. How is an imposed non-interventional PASS protocol assessed?

Before an imposed non-interventional PASS is conducted, the MAH will have to submit a draft protocol to the PRAC, except for studies to be conducted only in the one Member State that requests the study according to Article 22a of Directive 2001/83/EC. For such studies, the MAH shall submit the protocol to the national competent authority of the Member State in which the study is conducted.

For studies with PRAC oversight, the draft study protocol will need endorsement by the PRAC before the study start. The PRAC will issue a letter either endorsing or objecting the proposed protocol or concluding that the proposed study falls within the definition of a clinical trial. In the latter case, the PRAC would no longer be supervising the study, as it would fall under the scope of Directive 2001/20/EC.

Once the PRAC has endorsed the protocol of a non-interventional PASS, any substantial amendments to the protocol will also need to be assessed and agreed by the PRAC.

How is an imposed non-interventional PASS protocol evaluated by the PRAC (timetable)?

The PRAC evaluation of the PASS protocol is a 60-day procedure, which follows this timetable.

What are the possible outcomes of the PRAC evaluation of an imposed non-interventional PASS protocol?

The PRAC outcome is a decision that takes the form of a directly legally binding PRAC letter to the MAH with the following options:

  • a letter notifying the MAH that the study is a clinical trial falling under the scope of Directive 2001/20/EC;
  • a letter of objection specifying the grounds of objection and the timelines for resubmission and reassessment of the protocol;
  • a letter of endorsement of the protocol.

The PRAC assessment report is annexed to the letter. In case of a letter of endorsement, the PRAC assessment report may include recommendations for minor amendments to the protocol. These recommendations are for consideration by the MAH and do not require resubmission of the protocol to the PRAC. However, if they result in an amendment to the protocol, these amendments should be listed in section 5, amendments and updates, of the protocol.

In the instances when PRAC adopts a letter of objection, submission of an amended protocol may be required within X month(s) or within 14 days. In the former case, submission of the amended protocol is requested within X months depending on the extent of the revisions; the revised protocol will then follow a 30- or 60-day PRAC review procedure. In the case of a re-submission within 14 days, the PRAC will review the amended protocol within 15 days. This 30-day timeframe for the PRAC decision is applied when the PRAC considers that the protocol needs to be resubmitted quickly to allow endorsement at the following PRAC meeting.

How strict are the 30 days between PRAC meetings to urgently update a non-interventional PASS protocol?

The main purpose of the request for a 14-day urgent re-submission is to ensure that PRAC can re-evaluate its decision in the following plenary meeting. Timelines may need to be adapted to the PRAC meeting dates, which may result in small variation in the timelines for PRAC assessment.

Urgent resubmission procedures are expected to be used for limited changes to the protocol.

Under circumstances of urgency the protocol submission via Eudralink may be acceptable. However, this must be agreed with the Agency and/or PRAC rapporteurs beforehand. The e-mail address should include the Procedure Manager's e-mail and the product-specific mailbox.

5. How are an imposed non-interventional PASS results assesed?

Upon completion of the study, a final study report shall be submitted to PRAC within 12 months of the end of data collection unless a written waiver has been granted by PRAC, as appropriate.

The PRAC will assess the final study report and, based on the results of the study, make recommendations concerning the marketing authorisation, stating the reasons on which they are based. The PRAC may recommend the maintenance of the terms of the marketing authorisation. In such cases the PRAC recommendation will be the final step in the procedure and the MAH will be informed as such.

Should the PRAC however recommend the variation, suspension or revocation of the marketing authorisation, this recommendation will be forwarded to the Committee for Medicinal Products for Human Use (CHMP). The CHMP will then adopt an opinion taking the recommendation into account. Should the CHMP opinion uphold the PRAC recommendation, it will be forwarded to the European Commission, which will then adopt a decision in accordance with this opinion.

How is an imposed non-interventional PASS final study report evaluated (timetable)?

Time tables for the PRAC and CHMP evaluation of a PASS final-study-report procedure are currently under development and will shortly be available on this website.

6. What if I, as the MAH, am of the opinion that the imposed non-interventional PASS results make a variation necessary?

The results of the PASS should be evaluated by the MAH, who should consider whether the results have an impact on the marketing authorisation. If the MAH concludes that this is indeed the case, the MAH should submit the results directly as a variation to the Agency.

Independently from the MAH evaluation of the need for a variation, and following the assessment of the final study report, the PRAC may issue a recommendation to the CHMP for any regulatory action that is deemed to be appropriate.

7. To whom should I submit my PASS protocol or study report?

For non-interventional PASS imposed as a condition to the marketing authorisation, the study protocol should be submitted in 1.8.2 of eCTD. Study results should be submitted in (e)CTD in Module 5.

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

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

For CAPs, if you cannot find the answer to your question in the Q&A when preparing your application or during the procedure, please contact the Procedure Manager responsible for your product.

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.

Imposed Post-Authorisation Safety Studies for NAPs will be handled by a dedicated team of Procedure Managers (PM). A PM will be nominated upon receipt of the application. This allocated PM will be the contact point for this procedure.

9. Scientific advice for safety studies

What is this pilot on Scientific Advice for Safety studies about?

The Agency will run a 12 month pilot to encourage scientific advice on safety studies. This pilot will focus on protocols for non-imposed Post-Authorisation Safety Studies (PASS) i.e. Category III. Scientific advice is elaborated through the Scientific Advice Working Party (SAWP) with the Pharmacovigilance Risk Assessment Committee (PRAC) endorsing the scientific advice letters in the case of PASS protocols.

Scientific advice on safety studies is a voluntary option for Marketing Authorisation Holders (MAH) or Applicants, and complementary to existing procedures.

Why is this pilot of Scientific Advice for PASS being run?

This pilot aims to encourage scientific advice on safety studies, to further develop an integrated lifecycle approach to advice on medicines across safety, quality, efficacy pre- and post-authorisation, and to support proactive pharmacovigilance planning. Procedural enhancements have also been put in place to strengthen the PRAC–SAWP interaction in order to meet these goals, and to better deliver on the Agency’s mandate to provide advice on studies to determine the quality, safety and efficacy of medicinal products.

Why should I consider seeking scientific advice on PASS?

By engaging in scientific advice on PASS, Applicants or Marketing Authorisation Holders (MAH) can benefit from

  • a strengthened PRAC-SAWP interaction
  • a lifecycle approach to medicines advice with integrated advice on all aspects of medicines development from involved Committees
  • support for proactive pharmacovigilance planning
  • advice at an early or late stage of the protocol development
  • targeted advice on key issues
  • a well-defined procedural timetable
  • a pre-submission interaction with Agency secretariat to consider suitability and validity of the dossier
  • a face to face meeting with involved regulators during the procedure
  • engagement with patient representatives
  • options to include other stakeholders such as HTAs or FDA further supporting optimised evidence generation
  • the possibility of seeking follow-up advice

Which post-authorisation safety studies are in the focus of this PASS-SAWP pilot?

The pilot will focus on category III PASS protocols. Protocols of PASS imposed as conditions to the marketing authorisation (i.e category I and II) and protocols of joint imposed PASS conducted by a consortium of MAH will be assessed and endorsed by the PRAC under the provisions of article 107n of Directive 2001/83/EC; however, applicants/MAHs wishing to request scientific advice from the Agency on specific aspects of the protocol, in advance of its final submission under article 107n, can submit a SA request under this pilot.

Does EMA expect all PASS studies to go through scientific advice? If not, what advice can be given to sponsors on how to target studies for which a scientific advice should be sought?

Scientific advice is a voluntarily procedure and it is the choice of the MAHs or Applicant to submit or not the PASS protocol for scientific advice. Advice is frequently sought for complex or controversial issues, or for innovative approaches or methodologies. Scientific advice can also be valuable where MAHs or Applicants would value expert advice.

Are Post-Authorisation Efficacy Studies (PAES) part of this pilot?

Post-authorisation efficacy studies can already be submitted for EMA scientific advice. However, these are not the focus of this particular pilot.

Could requests for ‘mixed’ advice be submitted e.g. questions on pre-marketing and post-marketing phases, or questions on PASS and pivotal phase III studies, or questions on interventional and non-interventional studies?

Yes, such mixed advices are possible.

Can a draft PASS protocol be submitted for scientific advice although the marketing authorisation application is still under assessment?

Early submissions of PASS protocols for scientific advice are possible. However, Applicants should duly consider the best timing for their request for scientific advice, i.e. whether at the moment of the submission there are sufficient certainties about the status and the objectives of the study.

Can scientific advice be sought for nationally as well as centrally authorised products?

Yes, scientific advice can be sought for nationally as well as centrally authorised products.

Can a follow up advice be requested?

Yes. Follow up procedures are possible.

How long will the pilot last?

The pilot will run for a 12 month period and will start in Q3 2015.

When will the pilot start?

PASS protocols can be submitted for scientific advice from the date of this document in line with published scientific procedural timelines. Please see the published scientific advice timelines for subsequent procedures here.

Who will assess the non-imposed PASS protocols for SAWP?

As per existing scientific advice procedures, the assessment is led by SAWP delegates acting as SAWP coordinators. Two SAWP members/alternates are appointed as coordinators for each scientific advice procedure. A further PRAC expert is appointed to provide additional product specific PRAC input.

How will the PRAC Rapporteur for a product be involved in the scientific advice?

The PRAC Rapporteur for a specific product is involved through either the SAWP coordinators (i.e. assessment team from the same member state) or appointed as the PRAC expert for a specific scientific advice procedure.

Is the necessary expertise available in SAWP to evaluate non-imposed PASS protocols?

Expertise in pharmacoepidemiology, needed to evaluate the PASS protocol within this pilot, is available through the extension of the SAWP to at least 2 joint SAWP- PRAC delegates who can also act as SAWP coordinators for a specific scientific advice product procedure.

What is the role of the PRAC within the scientific advice procedure for non-imposed PASS protocols?

Scientific advice procedures for PASS will involve PRAC systematically at all the stages of the procedure. All scientific advice documents will be available to the PRAC during the procedure. The PRAC will endorse the advice relating to PASS, and a Final Advice Letter will be issued.

Each procedure will have a named PRAC expert appointed to provide product specific PRAC input. The PRAC Rapporteur for a product will be systematically involved either through the SAWP coordinatorship or as PRAC expert roles to ensure continuity across procedures through the lifecycle of the products.

For PASS within the focus of this pilot (category III), is it mandatory for companies to submit non-imposed PASS protocols to PRAC?

For category III studies, there is no legal obligation for companies to submit the protocol to the PRAC. However, the PRAC may request to review the protocol of some of these category III studies which are of interest for the committee and for which such submission of protocol is reflected as a milestone in the Risk Management Plan.

Please note that the advice provided within this pilot is without prejudice to any national requirement regarding the PASS protocols that might be in place is some Member states.

What about non-imposed PASS protocols required to be submitted by the PRAC that have not been through an EMA scientific advice procedure?

The final protocols for non-imposed PASS required by the PRAC can continue to be submitted to the PRAC as a Post-authorisation measure (PAM).

How do I apply for scientific advice on a PASS protocol?

A letter of intent for scientific advice should be submitted to the Agency at the mailbox scientificadvice@ema.europa.eu together with a briefing document in accordance with published EMA scientific advice guidance and timelines. See link here.

What is the format of the briefing document?

The MAH or Applicant provides questions and an accompanying justification of the approach taken with the relevant introduction, background, annexes and references. Please see the published scientific advice template.

What kinds of annexes are required?

Protocols or synopses, SmPCs, Risk Management Plans and assessment reports pertinent to the topic should be annexed as appropriate. Ready availability of relevant documents and references facilitates assessment.

What type of question is expected to be raised for the concerned study protocols?

In general, any question pertaining to the draft protocol can be posed in the draft briefing document. Feedback on whether the MAH or Applicant’s draft questions can be validated as posed or reworded will be given at the validation stage.

Could questions be asked about the choice of the adverse reactions of interest?

In general, any question pertaining to the draft protocol can be posed in the draft briefing document. Feedback on whether questions can be validated as posed or reworded will be given at the validation stage. Specifically scientific advice can be sought for the selection of adverse reactions of interest.

How will scientific advice procedures for safety studies be run?

In summary, scientific advice will follow the same procedure as other scientific advice with the exception of involvement of PRAC, the appointment of PRAC expert, and endorsement of the letter by PRAC.

The EMA Secretariat should be formally notified of the intent to submit a scientific advice or protocol assistance request via a Letter of Intent. A Letter of Intent should be sent by email to scientificadvice@ema.europa.eu in advance of the anticipated start of the procedure. The latest PDF letter of Intent form provided on the EMA scientific advice website should be used.

The draft package should be presented in line with published template for scientific advice. A pre-submission meeting with Agency staff will be arranged to consider the suitability and validity of the submission. Following the pre-submission meeting and validation, an amended electronic final package is submitted and circulated to the appointed coordinators and experts in line with agreed timelines.

The SAWP Coordinators will then draft preliminary reports in response to the scientific advice or protocol assistance requests taking into account the timetable for evaluation of such requests.In addition to the SAWP coordinators and the joint PRAC SAWP delegate, a PRAC expert is appointed to follow the procedure. The preliminary reports are discussed in the scientific advice plenary meeting and are made available to the involved Working Parties, Committees, and experts as appropriate. A list of issues for discussion at the Discussion meeting is sent to the MAH/Applicant (See figure 1 below SAWP 2). A face to face discussion meeting with the MAH/Applicant and members of the SAWP is held the following month (See figure 1 below SAWP 3).

Following the discussion meeting with the MAH/Applicant, and further to the SAWP plenary discussion, the SAWP Coordinators issue a draft joint report for comments by the involved participants. The joint report and the draft final advice letter are adopted by the SAWP through a written procedure.

All submission documents and reports are available to all PRAC members throughout the procedure. The final advice letter is endorsed by the PRAC and sent to the MAH/Applicant. SAWP will report to PRAC at each phase of the procedure.


 

Figure 1: Overview of scientific advice procedure on PASS.

Further details on routine scientific advice procedure are available.

Is a pre-submission meeting always expected or can the MAH/Applicant choose not to have one?

It is proposed that during the pilot phase, all procedures would have pre-submission meetings; optional pre-submission meetings could be envisaged further to review of experience gained during the pilot.

Is a discussion meeting with the MAH/Applicant during the procedure always expected?

It is proposed that during the pilot phase, all procedures would have a discussion meeting with the MAH/Applicant during the procedure; more targeted discussion meetings could be envisaged depending on the need for such discussions further to review of experience.

What is the nature of the discussion meeting?

Information regarding the discussion meeting is provided in the FAQ 21 “How do I prepare for a Discussion meeting?” in the published scientific advice guidance.

Can additional data or amended protocols be submitted during the procedure?

Additional data or amended protocols can be submitted at a specific point during the scientific advice procedure further to the SAWP list of issues. The MAH/Applicant may also propose in writing to the Agency additional points for discussion that are not part of the adopted list of issues and submit these in writing ahead of the Discussion meeting. Any amendment/change to the development programme should be notified to the Agency /SAWP ahead of the discussion meeting.

Will the EMA support for these protocols be different from any other scientific advice?

Procedures for non-imposed PASS protocols will not be handled any differently than for existing scientific advice procedures except the extension to and inclusion of PRAC interactions and relevant Agency staff, such as the Risk Management Specialist.

Will fees be levied for scientific advice provided for non-imposed PASS protocols?

Yes, in accordance with the Agency's Fee Regulationand its corresponding Implementing Rules, fees will be levied on MAH/Applicants seeking scientific advice on PASS protocols.

In this context, two different types of scientific advice fees are applied depending on whether the request is an 'initial request' or a 'follow-up'. For further details on fees and fee incentives/reductions please consult the Explanatory Note on fees payable to the EMA and the section on fees on the Agency's website.

Where can I find further information about scientific advice? Rev. August 2016

Please see the published EMA scientific advice guidance for many FAQs.

Notes

 

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