Post-authorisation safety studies (PASS)

A post-authorisation safety study (PASS) is a study that is carried out after a medicine has been authorised to obtain further information on a medicine's safety, or to measure the effectiveness of risk-management measures. The European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for assessing the protocols of imposed PASSs and for assessing their results.

The purpose of the information in PASSs is to evaluate the safety and benefit-risk profile of a medicine and support regulatory decision-making. They aim to:

• identify, characterise or quantify a safety hazard;
• confirm the safety profile of a medicine, or;
• measure the effectiveness of risk-management measures.

PASSs can either be clinical trials or non-interventional studies.

Updated 25/03/2025:
Questions marked with "Rev. Mar 2025"

Also on this topic

• Outcomes of imposed non-interventional post-authorisation safety studies

Imposed or voluntary PASSs

PASSs are either imposed or voluntary.

Marketing-authorisation holders (MAHs) are obliged to carry out imposed PASSs. These include studies that are a specific obligation for a marketing authorisation granted under exceptional circumstances and other studies that the PRAC requests the company carry out.

Voluntary PASSs are sponsored or conducted by MAHs on their own initiative. They include non-imposed studies that are requested in risk management plans.

Using the IRIS platform

From January 2025, marketing authorisation holders should use the IRIS platform when managing post-authorisation safety studies after the original submission. 

Further guidance on the use of the IRIS platform and how to prepare submissions is available on the dedicated IRIS website:

• IRIS: A secure online platform for handling product-related scientific and regulatory procedures with EMA

IRIS does not replace the current submission gateway; they coexist serving different functions.

Assessment of imposed PASSs

For imposed PASSs, the PRAC assesses the study protocol and the outcomes of these studies as given in the final study report.

EMA has published guidance on the format and content of study protocols and final study reports for non-interventional studies, together with the PRAC assessment report templates.

Study protocols:

Guidance for the format and content of the protocol of non-interventional post-authorisation safety studies

Reference Number: EMA/623947/2012

PRAC rapporteur post-authorisation-safety-study-protocol assessment-report template

Final study reports:

Guidance for the format and content of the final study report of non-interventional post-authorisation safety studies

Reference Number: EMA/48663/2013

Template PRAC assessment report of an non-interventional imposed PASS final study report

Reference Number: EMA/699686/2015

The guidance is based on Commission Implementing Regulation No 520/2012 of 19 June 2012. MAHs have to follow the guidance since January 2013.

For clinical trials, MAHs should follow the instructions in volume 10 of the rules governing medicinal products in the European Union (EU).

The timetable for the submission and assessment of imposed non-interventional PASS protocols is available below:

Timetable: Post-authorisation safety study (PASS) protocols and final results

Reference Number: EMA/404060/2015 Rev. 7 Legal effective date: 02/07/2015 Summary:

Timetable: Post-authorisation safety study (PASS) protocols and final results

The Agency recommends that companies submit protocols and study reports in the same manner for voluntary PASSs, although this is not mandatory.

Further guidance on PASSs is available in:

Guideline on good pharmacovigilance practices (GVP) - Module VIII – Post-authorisation safety studies (Rev. 3)

Adopted Reference Number: EMA/813938/2011 Legal effective date: 13/10/2017

Publication of information on PASSs

EMA publishes the protocols, abstracts and final study reports of PASSs on the HMA-EMA catalogue of real-world data studies.

To enable this publication to take place, marketing authorisation holders should register their PASSs in the catalogue mentioned above.

Non-interventional imposed PASS: questions and answers

1. What is a non-interventional imposed 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.

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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

Guideline on good pharmacovigilance practices (GVP) - Module VIII – Post-authorisation safety studies (Rev. 3)

Adopted Reference Number: EMA/813938/2011 Legal effective date: 13/10/2017

2. Under which procedure should I submit my non-interventional imposed PASS? Rev. Mar 2024

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), change of due date of the corresponding condition to the marketing authorisation (MA) will require a change of due date in the RMP and in the Annex II of the MA. Therefore, a change of due date can be 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

Guideline on good pharmacovigilance practices (GVP) - Module VIII – Post-authorisation safety studies (Rev. 3)

Adopted Reference Number: EMA/813938/2011 Legal effective date: 13/10/2017

3. What if the results of a non-interventional imposed PASS make a variation necessary?

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

4. How shall I present my non-interventional imposed PASS and in which format?

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 document below:

Guidance for the format and content of the protocol of non-interventional post-authorisation safety studies

Reference Number: EMA/623947/2012

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

Guideline on good pharmacovigilance practices (GVP) - Module VIII Addendum I – Requirements and recommendations for the submission of information on non-interventional post-authorisation safety studies (Rev. 2)

Adopted Reference Number: EMA/395730/2012 Rev. 2 Legal effective date: 09/08/2016

Guidance for the format and content of the protocol of non-interventional post-authorisation safety studies

Reference Number: EMA/623947/2012

Guidance for the format and content of the final study report of non-interventional post-authorisation safety studies

Reference Number: EMA/48663/2013

5. To whom should I submit my imposed non-interventional PASS?

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

Reference Number: EMA/497021/2012 Rev. 26

Dossier requirements for nationally authorised products (referral, PASS107, workshare, signal detection procedures) and ancillary medicinal substances in a medical device

Reference Number: EMA/13015/2014 Rev. 10

• eSubmission website
• Harmonized guidance for eCTD submissions in the EU

6. How do I submit a joint PASS?

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

Guideline on good pharmacovigilance practices (GVP) - Module VIII – Post-authorisation safety studies (Rev. 3)

Adopted Reference Number: EMA/813938/2011 Legal effective date: 13/10/2017

7. How will my non-interventional imposed PASS protocol be handled?

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.

Timetable: Post-authorisation safety study (PASS) protocols and final results

Reference Number: EMA/404060/2015 Rev. 7 Legal effective date: 02/07/2015 Summary:

Timetable: Post-authorisation safety study (PASS) protocols and final results

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:

Day	Action
Day 0	Start of the procedure according to the published timetable
Day 30	PRAC Rapporteur's preliminary assessment report
Day 45	PRAC members' comments
Day 53	PRAC Rapporteur's updated assessment report (if necessary)
Day 60	PRAC Recommendation

 

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

Guideline on good pharmacovigilance practices (GVP) - Module VIII – Post-authorisation safety studies (Rev. 3)

Adopted Reference Number: EMA/813938/2011 Legal effective date: 13/10/2017

Timetable: Post-authorisation safety study (PASS) protocols and final results

Reference Number: EMA/404060/2015 Rev. 7 Legal effective date: 02/07/2015 Summary:

Timetable: Post-authorisation safety study (PASS) protocols and final results

8. How will my imposed non-interventional PASS final study report be handled? Rev. Mar 2025

Submission

Upon receipt of a technically valid application, the EMA Product Lead (PL) will perform the validation of the application content. Supplementary information may be requested by the PL 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 case number and procedural timetable.

Timetable: Post-authorisation safety study (PASS) protocols and final results

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 of 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).

Day	Action
Day 0	Start of the procedure according to the published timetable
Day 30	PRAC Rapporteur's preliminary assessment report
Day 45	PRAC members' comments
Day 53	PRAC Rapporteur's updated assessment report (if necessary)
Day 60	PRAC Recommendation [or Request for Supplementary Information]
Day 74	CHMP opinion / CMDh position (in case PRAC recommends a variation, suspension or revocation of the MA)

 

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 (Rev. 3)Timetable: Post-authorisation safety study (PASS) protocols and final results

9. How is the CHMP opinion / CMDh position structured and which annexes need to be translated?

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:

Day 5 (5 days after opinion/ position)	Translations of the adopted Annexes in EN and in all other EU languages (and in Icelandic and Norwegian) are to be provided electronically (in one Eudralink package if applicable) to the member states contact points for translations review and to the EMA procedure assistant. Member states contact points for translations review Reference Number: EMA/102302/2005 v. 6.9
Day 19 (19 days after opinion/ position)	Member States will send linguistic comments on the Annexes to the MAH by e-mail with a copy to the Mailbox.
Day 25 (25 days after opinion / position)	The MAH(s) will implement the required changes, compile the translations and send it back to the EMA. In case of disagreement between a Member State and the MAH, EMA will not interfere in the translation process. Disagreements should be solved directly with the concerned Member State. In order to facilitate and accelerate the check of the implementation of the comments, the MAH should indicate in the document below for each language if all comments have been implemented or not. In the latter case, a justification should be provided for the appropriate language(s) stating why certain comments are not reflected in the final texts. The referenced media source is missing and needs to be re-embedded.

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:

Day 1 – 14 (1 to 14 days after position):	MAH translates the adopted Annexes in all other EU languages based on the EN provided version. MAHs with marketing authorisations in Iceland and/or Norway will provide translations in these languages as well.
Day 15 (15 days after the position):	Translations of the adopted Annexes in EN and all other EU languages (and in Icelandic and Norwegian, if applicable) are to be provided electronically (in one Eudralink package if applicable) to the Member States (MS) contact Points for Translations and to the EMA procedure assistant for voluntary linguistic check.
Day 28-34 (28-34 days after position)	The MAH(s) will implement the required changes. Translation of the adopted Annexes in EN and in all other EU languages (and in Icelandic and Norwegian) are to be compiled and provided electronically (in one Eudralink package if applicable) to the EMA procedure assistant.
Day 35-45 (35-45 days after position)	EMA will send the package to the CMDh and prepare the translations for publication.

 

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 this document:

The referenced media source is missing and needs to be re-embedded.

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 below document (e.g. format, layout and margins).

EMEA implementation of electronic-only submissions and eCTD submissions in the centralised procedure: Statement of intent

Adopted Reference Number: EMEA/563366/2007

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

Quality Review of Documents (QRD) convention to be followed for the European Medicines Agency QRD templates

Adopted Reference Number: EMA/62470/2007 Legal effective date: 01/06/2007

• Product Information Templates
• Product Information: Reference documents and guidelines

Member states contact points for translations review

Reference Number: EMA/102302/2005 v. 6.9

The linguistic review process of product information in the centralised procedure - Human

Reference Number: EMEA/5542/02 Rev. 6

• 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

10. How shall I implement the outcome of a non-interventional imposed PASS final study report procedure?

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.

	CAP products		NAP products
Product involved in procedure	Yes	No	Yes	No
Implementing variation needed, type and classification	Not applicable; implemented through EC decision to MAH	Yes (if changes applicable) IB C.1.3.z	Yes - IAIN C.1.3.a (harmonised national translations available) - IB C.1.3.z (adaptation of wording needed) - II (new data submitted; classification dependent on proposed changes)	Yes (if changes applicable) - IAIN C.1.3.a (harmonised national translations available) - IB C.1.3.z (adaptation of wording needed) - II (new data submitted; classification dependent on proposed changes)
Timeframe for submission of variation	Not applicable	MAHs to submit variations within two months after receipt of the EMA communication encompassing the safety updates referred to in the relevant procedure	For CMDh position by consensus (no EC decision adopted): As per the date indicated in the translation timetable i.e. 1055calendar days after adoption of the CMDh position (see Question 10).
			For CMDh position by majority vote or CHMP opinion (EC decision adopted): 10 days after publication6 of EC decision on EC website.	For CMDh position by majority vote or CHMP opinion (EC decision adopted): 60 days after publication of EC decision on EC website.

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

11. When should I register my studies in the EU PAS Register? Rev. Mar 2025

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 Catalogue of real-world data studies (previously known as EU PAS Register).

MAH(s) should enter in the Catalogue of real-world data studies (see link above) 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 database 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 Catalogue of real-world data studies (previously known as 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 Catalogue of real-world data studies for PASS studies can be found at Support | HMA-EMA Catalogues of real-world data sources and studies (europa.eu). 

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 (Rev. 3)

12. Are outcomes of non-interventional imposed PASS published?

Protocols and public abstracts of results of imposed non-interventional PASS are publicly available in the Catalogue of real-world data studies (previously known as EU PAS Register).

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

• HMA-EMA Catalogues of real-world data sources and studies (europa.eu)
• Outcomes of imposed non-interventional post-authorisation safety studies

13. What fee do I have to pay? Rev. Mar 2025

For information on fees to be paid, applicable fee reductions and payment process, please refer to the Fee Q&As in Annex I, Section 15, on Fees payable to the European Medicines Agency.

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

References

• Directive 2001/83/EC
• Regulation (EU) 2024/56
• The referenced media source is missing and needs to be re-embedded.

14. Who should I contact if I have questions regarding my submission? Rev. Mar 2025

For centrally authorised products, if you cannot find the answer to your question in this Q&A when preparing your application, please contact the EMA Product Lead (PL) assigned to your product.

PASS protocols and final study results for NAPs will be handled by the PL. You will be able to contact this PLthroughout 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

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

15. Scientific advice for safety studies Rev. Mar 2025

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) involvement.

Scientific advice on safety studies is a voluntary procedure for Marketing Authorisation Holders (MAHs) 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 preparatory meeting with Agency secretariat to consider suitability and validity of the dossier
• a discussion 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.

Which post-authorisation safety studies could benefit from scientific advice?

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. Based on experience gained, 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 voluntary 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 advice requests 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.

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 either appointed as the PRAC peer-reviewer or involved through the SAWP coordinators (i.e. assessment team from the same member state) 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 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 PASS protocols?

Scientific advice procedures for PASS will involve PRAC systematically in the procedure. All scientific advice documents will be available to the PRAC during the procedure. The questions will be referred for discussion to the PRAC, 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 as PRAC peer-reviewer or through the SAWP coordinatorship 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.

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?

An application for scientific advice should be submitted to the Agency via the IRIS platform together with a briefing document in accordance with published EMA scientific advice guidance and timelines. For more information, please see: scientific advice and protocol assistance.

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 document below:

CHMP protocol assistance scientific advice briefing document template

What kinds of annexes are required?

Protocols or synopses, SmPCs, Risk Management Plans (RMPs) 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 the appointment of PRAC peer-reviewer and involvement of PRAC.

The EMA Secretariat should be formally notified by submission of a scientific advice or protocol assistance request via the IRIS platform.

A preparatory meeting with Agency staff will be arranged, if requested, to consider the suitability and validity of the submission. Following the preparatory 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 request taking into account the timetable for evaluation of such requests. In addition to the SAWP coordinators, a PRAC peer-reviewer is appointed to follow the procedure and contribute to the reports, plenary meeting discussions and discussion meeting with the MAH/Applicant when applicable. The preliminary reports are discussed in the SAWP and PRAC plenary meetings and are made available to other involved Working Parties, Committees, and experts, as appropriate. If considered necessary, a list of issues for discussion at the discussion meeting is sent to the MAH/Applicant. A discussion meeting with the MAH/Applicant and members of the SAWP is held the following month.

Following the discussion meeting with the MAH/Applicant, and further to the SAWP and PRAC plenary discussions, 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 adopted by the CHMP before sending to the MAH/Applicant.

For further information please refer to the steps of the scientific advice process.

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

Requests for preparatory meeting are voluntary and, the 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 in this document:

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, when applicable (refer to the question on ‘Is a discussion meeting with the MAH/Applicant during the procedure always expected?’). 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 program 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.

Will fees be levied for scientific advice provided for PASS protocols?

Yes, in accordance with the Agency's Fee Regulation (EU) 2024/568 of the European Parliament and of the Council and its working arrangements, fees will be levied on MAH/Applicants seeking scientific advice on PASS protocols.

For further details on fees and fee incentives/reductions please see Fees payable to the European Medicines Agency.

Where can I find further information about scientific advice?

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

16. When and how should study progress reports and interim results be submitted? Rev. Apr 2021

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.