The Agency encourages scientific advice on safety studies to further develop an integrated lifecycle approach in the advice on medicines across safety, quality, efficacy pre- and post-authorisation, and to support proactive pharmacovigilance planning, which 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 procedure for Marketing Authorisation Holders (MAH) or Applicants, and complementary to existing ones.

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 could benefit from scientific advice? NEW May 2017

Applicants/MAHs are encouraged to request scientific advice (SA) from the Agency on specific aspects of PASS protocols, especially for complex or controversial issues or for innovative approaches or methodologies. Following experience gained from the scientific advice PASS pilot phase, scientific advice is encouraged to be sought for non–imposed PASS i.e. the category III PASS.

Applicants/MAHs wishing to request scientific advice on specific aspects of PASS protocols /or joint protocols by a consortium of MAHs for PASS imposed as conditions to the marketing authorisation (i.e category I and II PASS), can also submit a SA request. This is without prejudice to the provisions laid down in Article 107n of Directive 2001/83/EC for protocols of non-interventional imposed PASS to be assessed and endorsed by the PRAC.

Does EMA expect all PASS studies to go through scientific advice?

Scientific advice is a voluntarily procedure and it is the choice of the MAHs or Applicants to submit scientific questions related to PASS / PASS draft protocol for scientific advice.

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.

Who will assess the 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 peer-reviewer 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 peer-reviewer for a specific scientific advice procedure.

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

Expertise in pharmacoepidemiology needed to evaluate PASS protocols, is available through the extension of the SAWP currently to 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 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 peer-reviewer 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 peer-reviewer roles to ensure continuity across procedures through the lifecycle of the products.

For non-imposed PASS (category III), is it mandatory for companies to submit the study 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 CHMP protocol assistance scientific advice briefing document 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 theselection 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 peer-reviewer, 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 peer-reviewer 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.

All submission documents and reports are available to all PRAC members throughout the procedure. The final advice letter is endorsed by the PRAC and adopted by the CHMP through a written procedure before sending 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

are available.

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

The experience from the pilot phase showed an added value of pre-submission meetings and therefore it is proposed that all procedures would have such meetings to discuss the briefing document. However, some MAH/Applicant can choose not to request one.

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

The need for a discussion meeting is decided following the discussion of preliminary reports at SAWP plenary and it might not be considered necessary in some cases.

What is the nature of the discussion meeting?

Information regarding the discussion meeting is provided in the FAQ 21 in the published European Medicines Agency guidance for applicants seeking scientific advice and protocol assistance with track-changes.

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 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 PASS protocols?

Yes, in accordance with the Agency's Fee Regulation¹ and its corresponding Implementing Rules², 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.

¹ Council Regulation (EC) No 297/95 on fees payable to the European Medicines Agency

²Rules for the implementation of Council Regulation (EC) No 297/95 on fees payable to the European Medicines Agency and other measures EMA/MB/530034/2014

Where can I find further information about scientific advice?

Please see the published European Medicines Agency guidance for applicants seeking scientific advice and protocol assistance with track-changesfor many FAQs.

Reference