Post-authorisation safety studies (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 is non-interventional if:

• the medicine is prescribed in the usual way in accordance with the terms of the marketing authorisation;
• deciding how to treat the patient is based on current practice and not a trial protocol;
• the prescription of the medicine is clearly separated from the decision to include the patient in the study;
• patients do not undergo additional diagnostic or monitoring procedures;
• data analysis uses epidemiological methods¹

An EU competent authority may impose a non-interventional PASS, either as a condition of marketing authorisation (category 1) at the moment of granting the marketing authorisation or in the post-authorisation phase, or as a specific obligation in a conditional marketing authorisation or a marketing authorisation under exceptional circumstances (category 2). For more information, please refer to the good pharmacovigilance practices (GVP) Module VIII- Post-authorisation Safety Studies.

¹ Systematic reviews and meta-analyses of safety data should be considered as non-interventional PASS.

References

• Directive 2001/83/EC
• Regulation (EC) No 726/2004
• GVP Module VIII - Post-authorisation safety studies

The rules governing non-interventional imposed PASS are set in Articles 107n-q of Directive 2001/83/EC.

Non-interventional imposed PASS will be assessed by the Pharmacovigilance Risk Assessment Committee (PRAC), except for studies to be conducted in only one Member State requesting the study according to Article 22a of Directive 2001/83/EC. Such studies should be submitted to the National Competent Authority (NCA) of the Member State in which the study is conducted, who will perform the assessment nationally.

The requirements for submission and assessment of protocols and final study reports for non-interventional imposed PASS:

Draft Protocols – Article 107n procedure

Before a non-interventional imposed PASS is conducted, the marketing authorisation holder(s) (MAH(s)) have to submit a draft protocol for review and endorsement by PRAC.

Substantial amendments of an agreed protocol – Article 107o procedure

After a study has commenced, the MAH has to submit any substantial amendment to the protocol, before its implementation, for review and endorsement by PRAC.

Amendments are considered substantial when the changes proposed are likely to have an impact on the safety, physical or mental well-being of the study participants or that may affect the study results and their interpretation, such as changes to the primary or secondary objectives of the study, the study population, the sample size, the study design, the data sources, the method of data collection, the definitions of the main exposure, outcome and confounding variables or the statistical analytical plan as described in the study protocol.

Changes in the milestones affecting the timelines for the submission of the final study reports should be considered as substantial amendments to the protocol and should consequently be submitted for assessment to the PRAC as an Article 107o procedure. Following the assessment and conclusion of the procedure, outcomes endorsing changes to the timelines on the submission of such final study results will be made public on the dedicated EMA webpage on PASS outcomes.

For centrally authorised medicinal products (CAPs) the change of the due date of the corresponding condition to the marketing authorisation (MA) should be first submitted for assessment by the PRAC as an Article 107o procedure. If endorsed by the PRAC, the change of the due date in the RMP and in the Annex II of the MA should be subsequently submitted via a variation application.

Final study results – Article 107q procedure

Upon completion of the study, the MAH has to submit a final study report within 12 months of the end of data collection to the PRAC (Article 107p of Directive 2001/83/EC).

Based on the results of the study and after consultation with the MAH(s), the PRAC may make recommendations concerning the marketing authorisation.

Importantly, only study reports that are considered final by the MAH(s) should be submitted to the Agency. For this purpose, the definitions included in Article 37(2) of Commission Implementing Regulation (EC) No 520/2012 (“End of data collection means the date from which the analytical dataset is completely available”) and GVP Module VIII (“Analytical dataset: the minimum set of data required to perform the statistical analyses leading to the results for the primary objective(s) of the study” – Section VIII.A.1. Terminology) should be applied.

In cases where the analytical dataset is not complete and/or further data are still being collected by the MAH(s), the Agency should be contacted prior to submitting the final study report.

Interim results and/or feasibility studies of non-interventional imposed PASS do not fall under the provisions in Articles 107n-q of Directive 2001/83/EC. When those are requested to be submitted, appropriate procedures should be followed (i.e. submission to NCA for nationally authorised products or to EMA for centrally authorised products-refer to question on ‘When and how should study progress reports and interim results be submitted?’).

References

• Directive 2001/83/EC
• Regulation (EC) No 726/2004
• Commission Implementing Regulation (EC) No 520/2012
• GVP Module VIII - Post-authorisation safety studies

The results of non-interventional imposed PASS should be evaluated by the MAH(s), who should consider whether the results have an impact on the marketing authorisation. If the MAH(s) concludes that this is indeed the case, the MAH(s) should submit the results directly as an application for variation to the relevant competent authority.

Independently of the MAH(s) evaluation of the need for a variation, and following the assessment of the final study report, the PRAC may issue a recommendation to the Committee for Medicinal Products for Human Use (CHMP) for any regulatory action that is deemed to be appropriate.

References

• Directive 2001/83/EC
• Regulation (EC) No 726/2004

The format of non-interventional imposed PASS protocols and final study reports (Articles 107n-q of Directive 2001/83/EC) is provided in Annex III of Commission Implementing Regulation (EC) No 520/2012.

Further guidance is provided in GVP Module VIII and in the EMA Guidance for the format and content of the protocols and the final study reports of non-interventional post-authorisation safety studies.

4.1. Protocols and protocol amendments (Articles 107n-o)

Draft protocols of non-interventional imposed PASS should be submitted as a separate document in module 1.8.2 of the common technical document (CTD). They should only be included as an annex to the risk management plan (RMP), once they are endorsed by PRAC, at the next regulatory opportunity.

In case national variants of a study protocol are necessary to ensure the appropriate implementation of the study requirements to the specificities of national law, they should be submitted in the form of a regional appendix to the main protocol.

4.2. Final study results (Article 107q)

Imposed non-interventional PASS final study reports should be submitted in module 5.3.6 of the CTD.

Proposed changes to the product information as a result of the data within the PASS final study report can be submitted as part of the Article 107q procedure. The revised product information of the product(s) concerned should be presented in English language in module 1.3.

Where the proposed changes are not based on the data submitted within the final study report, these will not be considered and a variation will have to be submitted as appropriate to the relevant national competent authority.

A RMP update can also be submitted with a final PASS study report for single centrally authorised medicinal product or a mixture of CAPs belonging to the same global marketing authorisation (GMA) when the changes to the RMP are a direct result of data presented in the study report. In this case no stand-alone RMP variation is necessary. If the above does not apply, the updated RMP should be submitted as a stand-alone variation.

The submission should include a cover letter and in order to facilitate the registration of the submission, the eSubmission delivery file should be duly completed as required for the procedure. For joint studies, the contact point of the marketing authorisation holders or consortium may be contacted for financial purposes.

References

• Directive 2001/83/EC
• Commission Implementing Regulation (EC) No 520/2012
• GVP Module VIII - Post-authorisation safety studies
• Guidance for the format and content of the protocol of non-interventional post-authorisation safety studies
• Guidance for the format and content of the final study result of non-interventional post-authorisation safety studies

The following requirements are related to the non-interventional imposed PASS protocols and final study report which are supervised by the PRAC.

• for CAPs and NAPs: to be submitted to EMA in eCTD format only via the eSubmission Gateway or eSubmission Web Client (as per Dossier requirements for centrally authorised products (CAPs) and Dossier requirements for NAPs (referral, PASS107, worksharing, signal detection procedures and ancillary medicinal substances in medical devices).

All submission for CAPs and NAPs sent to EMA via eSubmission Gateway/Web Client will be considered delivered to the PRAC Rapporteur and all members of the PRAC.

Any additional copies should not be submitted directly to the NCAs on CD/DVD or via CESP as this might lead to validation issues and cause delays. All centralised procedure submissions should be made via EMA eSubmission Gateway/Web Client only.

Any response to a request for supplementary information must be sent to EMA, the PRAC Rapporteur and all PRAC members as per above requirements.

All submissions should contain a cover letter and a duly completed eSubmission delivery file.

More information is available on ‘Submitting a post-authorisation application’.

References

• Dossier requirements for centrally authorised products (CAPs)
• Dossier requirements for referral, ASMF and NAP submissions (PASS107, workshare, signal detection procedures) and ancillary medicinal substances in a medical device.
• eSubmission website
• Harmonized guidance for eCTD submissions in the EU

If the same safety concerns apply to more than one medicinal product, the  relevant competent authority shall, following consultation with the PRAC, encourage the MAHs concerned to conduct a joint PASS (Article 10a(1)(a) of Regulation (EC) No 726/2004, Article 22a(1)(a) of Directive 2001/83/EC).

At the time of imposition of the study by the PRAC, EMA will support interactions between the MAHs concerned by sharing contact details among those that wish to participate in a joint study. A dedicated meeting with the PRAC Rapporteurs may be organised to support interactions between the MAHs and to provide suggestions for the joint study proposal.

Submissions of joint PASS follow the same requirements as single studies. A single contact person for the submission should be appointed amongst all MAHs concerned and specified in the cover letter. This person will be the primary contact point on all interactions with EMA and will receive the documentation relevant for the procedure. The responsibility to communicate with the rest of the participants in the joint study lies with the appointed contact person as per the specific contractual arrangements among MAHs.

For joint studies it is of particular importance to accurately reflect in the cover letter the full list of medicinal products and MAHs concerned by the joint study (the eSubmission delivery file should list all the concerned medicinal products), as this will define the scope of the procedure, directly affecting the calculation of fees payable to EMA.

References

• Directive 2001/83/EC
• Regulation (EC) No 726/2004
• GVP Module VIII - Post-authorisation safety studies

Submission

Upon receipt of a technically valid application, the Risk Management Specialist (RMS) will perform the validation of the initial application (including format of the protocol). Supplementary information may be requested by the RMS in order to finalise the validation. The procedure will commence at the next available start date after all validation issues have been resolved. The Agency will inform the MAH of the outcome of the validation, the procedure number and procedural timetable .

For NAPs, a PRAC Rapporteur will be appointed upon receipt of a PASS protocol. The name of the appointed PRAC Rapporteur will be communicated to the marketing authorisation holder by EMA at the start of procedure. For CAPs, the PRAC Rapporteur will be the one already appointed for the product.

Assessment

The assessment under a 107n procedure is as follows, regardless whether it refers to one or more centrally authorised medicinal products, a mix of centrally authorised medicinal products and nationally authorised products, or nationally authorised products only.

The assessment of a non-interventional imposed PASS protocol is performed by the PRAC. The timelines for assessment are 60 days, the following timetable shall apply:

The outcome is a legally binding PRAC letter to the MAH(s) 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 draft protocol.

In the instances when PRAC adopts a letter of objection, submission of an amended protocol will be required usually within 60 days (which could be shortened or extended depending on the revisions). The revised protocol can then follow subsequent 60-day assessment procedures as per the timelines above until it is fully endorsed by the PRAC.

References

• Directive 2001/83/EC
• Regulation (EC) No 726/2004
• Commission Implementing Regulation (EC) No 520/2012
• GVP Module VIII - Post-authorisation safety studies
• Timetables for non-interventional imposed PASS protocols and results

Submission

Upon receipt of a technically valid application, the Risk Management Specialist (RMS) will perform the validation of the application content. Supplementary information may be requested by the RMS in order to finalise the validation. The procedure will commence at the next available start date after all validation issues have been resolved. The Agency will inform the MAH of the outcome of the validation and procedural timetable .

For NAPs, a PRAC Rapporteur will be appointed upon receipt of a PASS final study report. The name of the appointed PRAC Rapporteur will be communicated to the marketing authorisation holder by EMA at the start of procedure. For CAPs, the PRAC Rapporteur will be the one already appointed for the product.

Assessment

The assessment under a 107q procedure is as follows, regardless whether it refers to one or more centrally authorised medicinal products, a mix of centrally authorised medicinal products and nationally authorised products, or nationally authorised products only.

The assessment of a non-interventional imposed PASS final study report is performed by the PRAC. The timelines for assessment are for up to 74 days followed by 67 days of European Commission (EC) decision making process (if applicable).

If issues which prevent the adoption of a recommendation are identified, the PRAC will adopt a request for supplementary information together with a deadline for submission of the requested data by the MAH and a timetable for the assessment of the MAH's responses. The MAH will receive the adopted timetable together with the request for supplementary information. The clock will be stopped until the receipt of the requested supplementary information.

In case of major disagreement with the PRAC Rapporteur's proposed recommendation as stated in the updated assessment report, the MAH should contact the Risk Management Specialist no later than two working days following receipt of the report and indicate whether they would wish to make use of the opportunity of an oral explanation to defend their position before the PRAC. In the absence of a reply within two days, EMA will assume that no oral explanation is requested.

The MAH(s) should submit a clean and a tracked version of the agreed amended product information prior to the adoption of the PRAC recommendation.

In case the PRAC recommends any regulatory action, i.e. variation, suspension or revocation of the marketing authorisation, the PRAC recommendation will be transmitted to the CHMP if it includes at least one CAP or to the CMDh if it includes only NAPs. At its next meeting following the PRAC recommendation, the CHMP or the CMDh, as applicable, will adopt an opinion or a position, respectively. Subsequently, where the procedure includes at least one CAP, the EC will adopt a decision to the MAHs for the centrally authorised products and, as applicable, to the competent authorities of the Member States for nationally authorised products.

Where the procedure includes only NAPs, the procedure ends with the CMDh position in case of consensus and in case of a majority vote, the CMDh position will be followed by a EC decision to the Member States, which will have to be implemented according to the timetable indicated in the CMDh position or within 30 days of the CD receipt by the Member States.

Amendments to the summary of product characteristics (SmPC), labelling and package leaflet (PL) as a result of the PASS final study report assessment are directly implemented through the EC decision for centrally authorised products and through the appropriate variation at national level for nationally authorised products (including those authorised through the mutual recognition and decentralised procedures).

References

• Directive 2001/83/EC
• Regulation (EC) No 726/2004
• Commission Implementing Regulation (EC) No 520/2012
• Guideline on good pharmacovigilance practices (GVP) Module VIII - Post-authorisation safety studies
• Guidance to applicants /marketing authorisation holders (MAHs) on oral explanations at EMA
• Timetables for non-interventional imposed PASS protocols and results

The Annexes of both the CHMP opinion as well as the CMDh position will be translated into all EU languages following an agreed time table. In addition, a linguistic review by Member States of these Annexes in all EU languages is performed after adoption of the CHMP opinion and CMDh position.

Procedures that contain only centrally authorised products (CAP(s))

• Annex B: Annexes I, II, IIIA, IIIB, IV¹ (scientific conclusions and grounds for the variation of the marketing authorisation) and 127a (conditions addressed to Member States)

Procedures that contain a mix of centrally authorised products (CAP(s)) and nationally authorised products (NAP(s))

For the CAP(s):

• Annex B: Annexes I, II, IIIA, IIIB, IV¹(scientific conclusions and grounds for the variation of the marketing authorisation) and 127a (conditions addressed to Member States)

For the NAP(s):

• Annex C:
• Annex I (scientific conclusions and grounds for variation to the terms of the marketing authorisations);
• Annex II (amendments to the product information of the nationally authorised medicinal products);
• Annex III (conditions to the marketing authorisations), as applicable.

Procedures that only contain nationally authorised products (NAP(s))

• Annex C:
• Annex I (scientific conclusions and grounds for variation to the terms of the marketing authorisations);
• Annex II (amendments to the product information of the nationally authorised medicinal products);
• Annex III (conditions to the marketing authorisations), as applicable;
• Annex III or IV (timetable for implementation²), as applicable.

The preparation of the translation process

In view of the short timeframe for finalisation of the translations and in order to optimise the quality of the translations, the MAHs are strongly advised to prepare for the translation process well in advance in the pre-opinion / position stage, i.e. just following adoption of the PRAC recommendation for variation.

In case of a procedure where several MAHs are involved, EMA will coordinate the translation process by approaching the MAHs individually and provide the timelines accordingly. MAHs should translate for their products all relevant Annexes.

During the translation process

Depending on the type of outcome and whether a EC Decision is required (CHMP opinion or CMDh position by majority), the timelines for the translation process vary depending on the need for a linguistic review as illustrated below:

1. In case of CHMP opinion or CMDh position by majority i.e. followed a EC Decision, the MAH has to provide the translations of the adopted Annexes in all EU languages (and in Icelandic and Norwegian – if applicable, as detailed below) according to the following timelines:

2. In a case of CMDh position by consensus, Member States may perform a voluntary linguistic review in the translation process, therefore the following timelines apply:

After the translation process

Once the translations are received from the MAH, the Agency will check if the comments received from Member States' have been implemented.

1. In case of a CHMP opinion or a CMDh majority position the Agency will compile the Annexes in all languages and send the final copies to the EC, members of the Standing Committee and the MAH(s) at Day 27 (27 days after opinion).
   Following receipt of the final compiled translations, the EC will start the 22-day Standing Committee consultation, addressing only legal and public health matters (which means in principle no further linguistic review).
2. In case of a CMDh position by consensus, the Agency will compile the Annexes in all languages, send the final copies to the Member States and, where applicable, the full set of Annexes will be published on the EMA website.

Standards of translation of Annexes

• The structure of the English Annexes has to be strictly followed and should be exactly translated as per the adopted English version (i.e. full product information or only amendments to the relevant sections of the product information).
• For translations of Annexes QRD templates for each language should be used
• The title pages should be adjusted and all brackets (i.e. >) are taken out in the title.
• Sections should not be left out and Annex III should not be updated, e.g. the sections [to be completed on a national level] simply to be translated as 'to be completed on a national level'.
• Good quality of the translations and compliance with the Member States' comments are required to facilitate the process.

If a translation is considered not to be of an acceptable quality, the Member State concerned will inform the MAH and the Agency within 3 days of receipt of the translation. The Agency will inform the MAH of the insufficient quality of the translations and the transmission to the EC will be delayed until receipt of the amended translation (which would be expected within 1 week). A revised timetable will then be prepared.

The MAHs are also strongly advised to liaise directly with the Member States in case of disagreement with any of the comments made or in case further clarification on some comments is required, and to reflect the outcome in “ QRD Form 2 ”.

In addition, the MAHs are reminded that in case the complete product information is part of Annex III, it should be presented in strict compliance with the QRD Convention (e.g. format, layout and margins).

The Agency will monitor the quality of the translations, the review by the Member States and MAHs' compliance with the Member States' comments as part of the Performance Indicators.

References

• QRD Convention
• Product Information Templates
• Product Information: Reference documents and guidelines
• List of Member States contact points for translations (with guidance on the sending of product information to Member States)
• User guide on the preparation of PDF versions of the product information
• EC Guideline on the operation of the procedures laid down in Chapters II, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008

Depending on the type of outcome and whether an EC Decision is required (i.e. CHMP opinion or CMDh position by majority/ consensus), the implementation of the outcome of a non-interventional imposed PASS results vary as illustrated in the table below. For NAPs, further guidance on implementing variation can also be found on the CMDh website (Question Answers, Pharmacovigilance legislation).

Of note, products that are not involved directly in the procedure (i.e. products not listed in the Annex to the CHMP opinion or CMDh position) might be affected by the outcome and should implement accordingly when the adopted changes are applicable to their MA.

¹ 45 calendar days for translation publication + 60 calendar days from publication of translations

² See also Q 3.3 of the Q/A-LIST FOR THE SUBMISSION OF VARIATIONS ACCORDING TO COMMISSION REGULATION (EC) 1234/2008

According to Article 26(1)(h) of Regulation (EC) No 726/2004, protocols and public abstracts of results of non-interventional PASS imposed in accordance with Article 10 or 10a of Regulation (EC) No 726/2004 or with Articles 21a or 22a of Directive 2001/83/EC shall be made public by the Agency. In addition, Annex III of Commission Implementing Regulation (EC) No 520/2012 specifies that the final study report of imposed non-interventional PASS must provide the date of registration in the EU PAS Register.

MAH(s) should enter in the European Union electronic Register of Post-Authorisation Studies (EU PAS Register) protocols (as soon as possible after their finalisation and prior to the start of data collection) and public abstracts of results of non-interventional imposed PASS conducted in accordance with Articles 107n-q of Directive 2001/83/EC (as soon as possible and preferably within two weeks after their finalisation).

After the relevant PRAC recommendation the Agency will contact MAH(s) to make sure the information is available in the register and, unless alternative timelines are agreed, will enter the information on its own initiative in order to fulfil its legal obligations under Article 26(1)(h) of Regulation (EC) No 726/2004.

In addition, EMA strongly encourages MAHs to upload the final study results in the EU PAS register in order to support transparency on non-interventional PASS and to facilitate exchange of pharmacovigilance information between the EMA, NCAs and MAHs.

More information on how to provide documents to the EU PAS Register for PASS studies can be found here: EU PAS Register

References

• Directive 2001/83/EC
• Regulation (EC) No 726/2004
• Commission Implementing Regulation (EC) No 520/2012
• Guideline on good pharmacovigilance practices (GVP) Module VIII - Post-authorisation safety studies

Protocols and public abstracts of results of imposed non-interventional PASS are publicly available in the EU PAS Register on the European Network of Centres in Pharmacoepidemiology and Pharmacovigilance (ENCePP) website.

The outcomes of imposed non-interventional PASS final study results assessments for active substances found only in centrally authorised medicines are published as part of each medicine's European public assessment report (EPAR).

The outcome for nationally authorised medicinal products included in 'mixed' procedures where centrally authorised products were also involved can be found on the Union register maintained by the EC.

EMA publishes the outcomes of final study results of non-interventional imposed post-authorisation safety studies (PASS) for NAPs on the EMA website.

References

• The European Union electronic Register of Post-Authorisation Studies (EU PAS Register)
• Union register
• Outcomes of imposed non-interventional post-authorisation safety studies

As per Part II of the Annex to the Regulation EC No 658/2014, the fee for the assessment of PASS shall be paid in two instalments:

• first instalment (40%) for the assessment of the draft protocol (Article 107n of Directive 2001/83/EC);
• second instalment (60%) for the assessment of the final study report by the PRAC (Article 107q of Directive 2001/83/EC).

The Agency does not levy a fee for the assessment of significant protocol amendments as defined in Article 107o of Directive 2001/83/EC.

In case of a joint PASS (i.e. several marketing authorisation holders working together to conduct the PASS), the total amount of the fee will be divided equally among all the marketing authorisation holders concerned.

EMA has published further guidance on how the fees are calculated and collected.

For any remaining question, the dedicated EMA fees query form can be completed and submitted.

References

• Regulation (EC) No 658/2014
• Pharmacovigilance fees payable to the European Medicines Agency
• Pharmacovigilance fees: questions and answers

For centrally authorised products, if you cannot find the answer to your question in this Q&A when preparing your application, please contact the Risk Management Specialist (RMS) assigned to your product.

PASS protocols and final study results for NAPs will be handled by the RMS. You will be able to contact this RMS throughout the procedure.

For pre-submission queries that are not covered by this guidance please submit your query using the following web form.

In the web form you will be asked to provide your name, the name of your employer or organisation, contact details and the subject of your enquiry. You should type the full details of your query in the appropriate space. The use of key words in the subject line will help the Agency allocate your query to the correct person.

Please give as much detail as possible when completing your request and be sure to include your correct and complete contact details. If the contact details you provide are incomplete or inaccurate this may prevent the Agency from communicating with you. In case of incomplete or incorrect data in the web form, the request may not be processed.

For questions related to fees, please use the dedicated EMA fees query form instead (refer to Q.14).

For technical queries related to the submission please contact us through the EMA Service Desk portal .

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 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 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 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 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 scientific advice guidance for many FAQs.

Reference

• Pharmacovigilance fees payable to the European Medicines Agency

The timelines of the progress reports for a given study should be pre-specified and indicated in the protocol. These progress reports may include available interim results, but there is in general no obligation or recommendation to include interim results in RMPs unless required as part of an agreed pharmacovigilance plan. This is without prejudice that a variation as appropriate should be submitted should these interim results lead to product information changes or RMP changes.

For centrally authorised products, progress reports and interim results, when requested, should be submitted as post-authorisation measure (PAM) and should follow the timetable of PAMs assessed by PRAC.