Periodic safety update reports (PSURs)

Periodic safety update reports are pharmacovigilance documents intended to provide a safety update resulting in an evaluation of the impact of the reports on the risk-benefit balance of a medicinal product. They shall be submitted by marketing authorisation holders at defined time points during the post-authorisation phase.

The legal requirements for submission of PSURs are established in the Regulation (EC) No 726/2004 and the Directive 2001/83/EC.

The format of PSURs shall follow the structure described in the Commission implementing Regulation (EU) No 520/2012.

Further details and guidance for the submission of PSURs in the EU, including the list of Union references dates and frequency of submission are provided in Module VII “Periodic safety update report” of the guideline on good pharmacovigilance practices (GVP) and in the following questions and answers.

References

• Regulation (EC) 726/2004
• Directive 2001/83/EC
• Commission implementing Regulation (EU) No 520/2012 of 19 June 2012 on the performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 of the European Parliament and of the Council and Directive 2001/83/EC of the European Parliament and of the Council
• European Commission questions and answers on transitional arrangements concerning the entering into force of the new pharmacovigilance rules provided by Directive 2010/84/EU amending Directive 2001/83/EC and Regulation (EU) No 1235/2010 amending Regulation (EC) No 726/2004 (SANCO/D5/FS/(2012)1014848)
• Questions and answers on practical transitional measures for the implementation of the pharmacovigilance legislation
• Guideline on good pharmacovigilance practices (GVP) – Module VII – PSURs
• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guideline E2C (R2) on periodic benefit-risk evaluation report - Step 5
• Guideline on good pharmacovigilance practices: Annex I - Definitions (Rev. 4)

The Pharmacovigilance Risk Assessment Committee (PRAC) is in charge of issuing recommendation on the PSUR assessment for a single centrally authorised product and of the EU PSUR single assessment.

The EU PSUR single assessment, referred also as PSUSA, is the assessment of PSURs for medicinal products subject to different marketing authorisations containing the same active substance or the same combination of active substances and for which the frequency and dates of submission of PSURs have been harmonised in the list of EU reference dates (referred also as EURD list). These PSURs will be jointly assessed by the PRAC or a Member State appointed by the CMDh and result in one single assessment report, which will be shared amongst all the marketing authorisation holders (MAHs) whose medicinal product(s) are part of the PSUR single assessment procedure. It should be noted that the responsibility for the quality of the submitted documentation lies with the MAH(s) and is crucial to the overall assessment. The data presented in the submissions should be intended exclusively for the purposes of the concerned procedure. The information and data contained in the individual submissions will be assessed and reflected in the single assessment report. Such information and data will not be redacted from the single assessment report with respect to individual products prior to sharing them with all concerned MAHs. Indeed, PSUR related data presented in agreement with Guideline on good pharmacovigilance practices (GVP): Module VII – Periodic safety update report as such are not considered to be commercially confidential. Of note, MAHs cannot use the information and data contained in the submissions for any other purposes than those related to the concerned procedure.

Overall, the PRAC will issue a recommendation for the assessment of the following PSURs:

• PSURs of centrally authorised product(s);
• PSURs of any mix of centrally authorised products and nationally authorised products (including through the mutual recognition and decentralised procedures);
• PSURs of nationally authorised products.

Please note that, for nationally authorised medicinal products which are marketed in only one Member State and whose active substance or combination of active substances is included in the EURD list, the MAH should submit a PSUR as part of PSUSA procedure. Note that a PSUSA is foreseen for each active substance or combination of active substances registered in the EURD list.

For purely nationally authorised medicinal products, containing substances or combination of actives substances not included in the EURD list, for which no PSUSA procedure has been established, the assessment of the PSURs will remain at national level. For more information, see:

• CMDh best practic guide

Purely nationally authorised medicinal products are considered those which contain substances or a combination of actives substances which are only authorised in one Member State.

The format and content of the PSUR, is legally required according to Commission implementing Regulation (EU) No 520/2012 since January 2013 and is further described in the Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report.

In addition, the required format and content of PSURs in the EU are based on those for the Periodic Benefit Risk Evaluation Report (PBRER) described in the ICH-E2C(R2) guideline (see Annex IV ICH-E2C(R2)). To keep the terminology consistent with the one used in the EU legislation, the new PBRER continues to be described as PSUR.

Unless otherwise requested by competent authorities, the marketing authorisation holder shall prepare a single PSUR for all its medicinal products containing the same active substance with information covering all the authorised indications, route of administration, dosage forms and dosing regiments, irrespective of whether authorised under different names and through separate procedures. Of note, the PSUR section “Worldwide marketing authorisation status" applies irrespectively to centrally authorised products and nationally authorised products. Regarding centrally authorised products, the marketing status should also be provided as a stand-alone report through the relevant mailbox and using the dedicated template as indicated in the EMA Post-authorisation Guidance on ‘marketing and cessation notification’ – What is the reporting format to the agency and to whom to report.

Even if a single PSUR is prepared for several products, please note that for medicinal products with documentation previously submitted in eCTD format, PSURs should be presented in a new eCTD sequence in the respective eCTD lifecycle of the concerned product. Where relevant, data relating to a particular indication, dosage form, and route of administration or dosing regimen, shall be presented in a separate section of the PSUR and any safety concerns shall be addressed accordingly.

Within the PSUR, the marketing authorisation holder is required to consider the impact of the data and evaluations presented within the report, on the marketing authorisation. Based on the evaluation of the cumulative safety data and the risk-benefit analysis, the marketing authorisation holder shall draw conclusions in the PSUR as to the need for changes to the product information of the products covered by the PSUR. For the purpose of analysing the impact of the PSUR data, the MAH can establish a so-called reference product information which should include “core safety” and “authorised indications” components, as explained in the GVP module VII on PSURs (section VII.B.4. ‘Reference information’). The changes proposed to the labelling can be based on the reference product information. However, as the reference product information might be different for the various EU product information, it is essential that the MAH considers the proposed changes for the reference product information in the context of the different EU product information for the products covered by the submitted PSUR. This should be clearly discussed in both the conclusions and actions section of the body of the PSUR as well as in the EU regional appendix.

In the EU regional appendix, sub-section “Proposed product information” of the PSUR, the marketing authorisation holder should provide their proposal for product information (SmPC and package leaflet) changes based on the above-mentioned evaluation. These should take into account all EU authorised indications for products containing that active substance or combination of active substances. For marketing authorisation holders of nationally authorised products with a large number of marketing authorisations with different product information, the Agency will also accept that the core message of the proposed changes to the product information be included in the EU regional appendix as described below (see question “How can I propose changes to the Product Information within the PSUR for NAPs which are part of an EU single assessment?”).

It is important that changes proposed to the product information which are based on the submitted PSUR data are not submitted in parallel via a separate variation procedure.

Additional clarification on the content of the PSUR can be found in the explanatory note to GVP Module VII and should be used by MAHs for the preparation of PSURs subject to single assessment. As it complements GVP Module VII, both documents should be consulted in conjunction. The explanatory note will form the basis of the upcoming revision of GPV VII; this update, once finalised, will therefore supersede this guidance document.

The explanatory note highlights and addresses challenges specific to the EU single assessment for nationally authorised products. Points highlighted in this document may nevertheless also apply to the assessment of centrally authorised products and hence it is recommended that all MAHs consult the document prior to finalisation of their PSUR.

In connection with the explanatory note to Guideline on good pharmacovigilance practices (GVP): Module VII – Periodic safety update report, an assessors question and answer guidance document has also been developed.

The submission should include a cover letter and in order to facilitate the registration of the submission, marketing authorisation holders are required to fill in all the submission attributes through the eSubmission delivery file UI. This delivery file should be completed in accordance with the published EURD list, where the procedure number is the combination of a unique ID and the applicable Data Lock Point (DLP) in YYYYMM format.

All the entries in the EURD list have been assigned a procedure number presented in the column “Procedure number of the PSUR single assessment”. 

In order to facilitate the identification of procedures containing centrally and/or nationally authorised substances, the extra columns “Centrally Authorised Product (CAP) and “Nationally authorised product (NAP)” have been added in the EURD list”.

In line with article 57(2) of Regulation (EU) No 1235/2010 all holders of marketing authorisations for medicines in the European Union and the European Economic Area must submit information to the European Medicines Agency on authorised medicines and keep this information up to date. This is a legally binding requirement from the EU pharmaceutical legislation. The Agency uses this information to support the analysis of data, regulatory activities and communication. In relation to the submission of PSURs, this facilitates the processing of the submissions in the PSUR Repository.

Please see question “To whom should I submit my PSUR?” for further details on submission requirements.

References

• Directive 2001/83/EC
• Guideline on good pharmacovigilance practices (GVP) – Module VII –Periodic safety update report
• Guideline on good pharmacovigilance practices (GVP) – Module VII –Periodic safety update report - Explanatory note
• Commission implementing Regulation (EU) No 520/2012 on the performance of pharmacovigilance activities
• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guideline E2C (R2) on periodic benefit-risk evaluation report - Step 5
• Guideline on good pharmacovigilance practices (GVP): Module VII – Periodic safety update report - Explanatory note
• Harmonised Guidance for eCTD Submissions in the EU

The list of Union reference dates and frequency of submission of PSURs” (so-called the “EURD list”) consists of active substances and combinations of active substances, for which PSURs shall be submitted in accordance with the EU reference dates and frequencies determined by the Committee for Medicinal Products for Human Use (CHMP) and the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) following consultation with the Pharmacovigilance and Risk Assessment Committee (PRAC).

The European Union reference date (EURD) corresponds to the date of the first or the earliest known date of the marketing authorisation in the EU of a medicinal product containing the active substance or combination of active substances.

In addition to the EU reference dates and frequencies of PSURs, the EURD list also provides the Data Lock Point (DLP) of the next PSUR submissions.

The EURD list facilitates the harmonisation of DLPs and frequency of submission of PSURs for medicinal products containing the same active substance or the same combination of active substances subject to different marketing authorisations, authorised in more than one Member State. This will, where appropriate, allow one single assessment of PSURs for products containing the same active substance.

The PSUR frequency as published on the EURD list for a given active substance or combination of active substances overrules the standard submission cycle (i.e. 6-monthly, yearly and thereafter 3-yearly) set out in the legislation and any condition related to the frequency of submission of PSURs included in the Marketing Authorisation. However, national competent authorities (NCAs) may still request the submission of a PSUR at any given time.

The EURD list is a living document, meaning that it can be amended whenever considered necessary by the PRAC, CHMP or CMDh in response to the emergence of relevant new safety information, newly authorised substances or requests from the marketing authorisation holders.

Full information on the EURD list is included in the GVP Module VII – Periodic safety update report and the introductory cover note to the EURD list.

For guidance on submission of requests for amendment of the EURD list, please refer to the question “How can I request to amend the list of EU reference dates”.

Reference

• Directive 2001/83/EC
• Guideline on good pharmacovigilance practices – Module VII –Periodic safety update report

The EURD list is updated on a monthly basis and any changes in the EURD list, such as the PSUR submission frequencies, the dates of submission and the PSUR submission requirement for medicinal products referred to in Articles 10(1), 10a, 14 or 16a of Directive 2001/83/EC come into force 6 months after its publication. This publication occurs after adoption of the EURD list by the CHMP and CMDh following consultation of the PRAC.

Whilst changes become binding 6 months after publication, there might exceptionally be situations where PSUR submissions are necessary prior to the new frequency taking effect and this will be indicated in the EURD list as well.

It is the responsibility of the marketing authorisation holder to check regularly the list of EU reference dates and frequency of submission published in the European medicines web-portal to ensure compliance with the PSUR reporting requirements for their medicinal products.

References

• Directive 2001/83/EC

Marketing authorisation holders can submit requests to the CHMP or the CMDh, as appropriate, to determine the Union reference dates or to change the frequency of submission of PSURs on one of the following grounds:

• for reasons relating to public health;
• in order to avoid a duplication of the assessment;
• in order to achieve international harmonisation.

The request and its grounds should be considered by the PRAC and the CHMP if it concerns at least one marketing authorisation granted in accordance with the centralised procedure or the CMDh otherwise, which will either approve or deny the request.

The list will then be amended accordingly when appropriate and published on the European medicines website.

For more details on how to submit amendments to the list, please refer to the Introductory cover note to the list of European Union reference dates and frequency of submission of periodic safety update reports.

Reference

• Directive 2001/83/EC
• Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report

If the active substance contained in the medicinal product is not included in the EURD list, the MAH should submit the PSUR directly to the PSUR repository, using the non-EU single assessment functionality, via the eSubmission Gateway. The PSUR will then be considered delivered to the relevant national competent authority (NCA) where the product is authorized. The frequency of submission shall be in accordance with the conditions specified in the marketing authorisation (MA), or otherwise according to the standard submission schedule of PSURs (i.e. 6 month intervals, yearly and thereafter 3 yearly). Marketing authorisation holders for certain medicinal products containing active substances not in the EURD list, such as medicinal products authorised under Article 10(1) or 10a of Directive 2001/83/EC, a homeopathic simplified registration or a traditional-use registration are not required to submit PSURs, unless there are specific requirements in the MA for the product. PSURs shall also be submitted upon request of NCA.

For more details on PSUR submissions for generics, products containing well-established substances, homeopathic or herbal medicinal products, please refer to the question Do I have to submit a PSUR my medicinal product if it is a generic, a product containing a well-established substance, a homeopathic or herbal medicinal product?

If the specific fixed dose combination is not listed in the EURD list, PSURs should not be submitted according to the EURD list entry of one or more individual components. However PSURs should be submitted as specified in the conditions of the marketing authorisation for the combination product (if any), or otherwise according to the standard submission cycle (i.e. 6-monthly, yearly and thereafter 3-yearly) unless the combination medicinal product falls within the categories of medicinal products exempted from the obligation to submit PSURs.

MAHs or national competent authorities can request the inclusion of the fixed combination in the EURD list for reasons related to public health, in order to avoid duplication of assessment or in order to achieve international harmonisation. Instructions on how to submit requests to amend the EURD list can be found on the EURD list webpage.

MAHs are required to submit PSURs once a medicinal product is authorised in the EU, regardless of its marketing status.

The MAH is not obliged to submit a PSUR if the granting of the Marketing Authorisation (MA) was notified on or after the DLP. The first PSUR will either be due following the subsequent DLP in the EURD list or, depending on the newly approved MA, a first PSUR submission might be considered earlier than the next DLP. However, if the MA was granted before the DLP, the obligation to submit applies.

Only MAHs are required to submit PSURs as per the provisions of Article 107b of Directive 2001/83/EC and Article 28(2) of Regulation (EC) No 726/2004. Parallel importers do not qualify as MAHs, and therefore they are not subject to the obligation to submit PSURs.

If however a PSUR has been submitted by a company holding a parallel import authorisation, such PSUR might be taken into account by the Lead Member State/PRAC Rapporteur and assessed in terms of its impact on the risk-benefit balance of the medicinal product concerned. If the data contained in the PSUR contribute meaningfully to the scientific assessment, these data should be included in the scope of the PSUR procedure. However, the parallel importer will not become party to the PSUR procedure and will not receive a copy of the assessment report and outcome documentation as a MAH would.

If a parallel importer receives a notification of an adverse drug reaction from a patient, a doctor or any other source, the parallel importer should inform this person that the adverse drug reactions should be reported directly to the MAH of the medicinal product concerned. The parallel importer should also inform the MAH immediately.

Medicinal products authorised under Articles 10(1), 10a, 14 or 16a of Directive 2001/83/EC are exempted from routine submission of PSURs unless otherwise specified in the marketing authorisation or required through the EURD list (see dedicated column “Are PSURs required for products referred to in Articles 10(1), 10a, 14, 16a of Directive 2001/83/EC as amended? Yes/No”). National competent authorities can also request PSUR for generic medicinal products at any time on the grounds detailed in Article 107c (2) of the Directive.

The MAHs of such medicinal products should use alternative mechanisms such as signal management and emerging safety issues channels to communicate relevant new safety information to regulatory authorities(see GVP Module VI and Module IX).

Additionally,product information should be kept up-to-date by the MAH by submitting the appropriate variations taking account of the latest scientific knowledge or conclusions of assessments and recommendations made public by means of the EMA and national competent authority websites.

Medicinal products which have been authorised through the equivalent legal basis as the current Articles 10(1) and 10a legal basis before the re-codification of the Directive 2001/83/EC i.e. respectively Article 4.8 a(iii), first paragraph (essential similarity) of Directive 65/65/EEC / 10 a(iii), first paragraph of Directive 2001/83/EC and Art 4.8 a(ii) (well established use) of Directive 65/65/EEC / 10.1 a(ii) of Directive 2001/83/EC are, by analogy, not required to submit PSUR unless there is a specific condition in the authorisation or there is an indication in the EURD list that PSUR submission is required, or in response to a specific request.

Medicinal products authorised under Article 10(3) of Directive 2001/83/EC (hybrid application) are not exempted from the obligation to submit PSURs.

Only MAHs are required to submit PSURs as per the provisions of Article 107b of Directive 2001/83/EC and Article 28(2) of Regulation (EC) No 726/2004. Holders of authorisation under Art 126a of Directive 2001/83/EC are not subject to the obligation to submit PSURs with regards to such authorisation.

In case of withdrawal, non-renewal or revocation of a marketing authorisation (MA) while the EU single PSUR assessment (PSUSA) procedure is ongoing, the impact on the ongoing procedure can be either that:

• the procedure will continue,
  • If the PSUSA procedure includes MAs remaining valid, or
  • If there are other medicinal products which contain the same active substance or combination of active substances (e.g. generics) as the medicinal product covered by the withdrawn/non-renewed/revoked MA.

OR

• the procedure will be stopped, if the withdrawn/non-renewed/revoked MA is the only MA covered by the ongoing PSUR assessment procedure, unless there are important safety concerns to consider the recall of any remaining medicinal products available on the market or the assessment could inform on public health concerns on long-term safety effects of the concerned product or evaluation of other medicinal products (e.g. same class of products) on the market regarding scientific and technical progress or future risk management or for other public health reasons.

For centrally authorised medicinal products, where the EU single PSUR AR will be completed, the information will be reflected in the EPAR of the concerned medicinal product.

Where a marketing authorisation is withdrawn, revoked or not renewed, the former marketing authorisation holder is encouraged to continue to collect spontaneous reports of suspected adverse reactions occurring in the EU (see Draft guideline on good pharmacovigilance practices: Module VI - Management and reporting of adverse reactions to medicinal products) to, for example, facilitate review of delayed onset adverse reactions or of retrospectively notified cases of adverse reactions.

Depending on the date of the EC decision on the revocation or withdrawal, or the date of expiry of the marketing authorization in case of non-renewal, marketing authorisation holders may still be required to submit a PSUR:

• If the date is after the submission deadline specified in the EURD list, submission is mandatory irrespective of whether the date is before or after the start date of the procedure.
• If the date is prior to the submission date specified in the EURD list, submission is no longer required except for exceptional cases for centrally authorised medicinal products, whereby the former marketing authorisation holder may be requested to submit a final / ad-hoc periodic safety update report (PSUR). An agreement on the procedural details of the PSUR submission should be reached between the marketing authorisation holder and the Agency. Since such PSUR will not be subject to a single PSUR assessment, it should not be submitted to the PSUR repository.

In the case when the marketing authorisation of a medicinal product is suspended, this would not affect the requirement to submit a PSUR, since this situation corresponds to a temporary marketing cessation which could be lifted. The usual requirements in terms of submission apply. If the product has not been marketed during the whole reporting interval this should be specified in the PSUR.

The PSUR should focus on summary information, scientific assessment and integrated benefit-risk evaluation.

Marketing authorisation holders are not required to systematically include listings of individual cases, including case narratives, in the PSUR. However, they shall provide case narratives in the relevant risk evaluation section of the PSUR where integral to the scientific analysis of a signal or safety concern in the relevant risk evaluation section.

In this context “case narrative” refers to clinical evaluations of individual cases rather than the CIOMS narratives included in the individual case safety report (ICSR).

During the assessment of the PSUR, line listings for adverse reactions of special interest may be requested by the PRAC.

Reference

• Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report

According to the guidance set out in the Guideline on good pharmacovigilance practices (GVP): Module VII – Periodic safety update report , proposed changes to the EU labels as a result of the PSUR data should be provided under Section VII.C.5.1. PSUR EU regional appendix, sub-section “Proposed product information” of the PSUR.

It should be presented as a tracked change version of each EU SmPCs and package leaflets of the products concerned and each product information should be translated into English language including the tracked changes proposed, in order to enable the EU single assessment.

This can result in having to submit a large number of sets of tracked change product information with the additional burden of providing translations. Hence MAHs can consider the option to focus on the proposed amendments to SmPC and package leaflet. In such case, only the amended parts of the SmPC and package leaflet should be provided in track changes and in English language under the EU regional appendix.

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

In case no changes to the product information are being proposed as part of the PSUR, the MAH should not include any product information within the EU regional appendix.

Reference

• Guideline on good pharmacovigilance practices (GVP) – Module VII –Periodic safety update report

A risk management plan (RMP) update can be submitted with a PSUR for single centrally authorised medicinal product (CAP) 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 PSUR. 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.

A stand-alone variation should also be submitted for transitions to RMP Template Rev. 2 when significant changes, not consequential to the PSUR data, are proposed in the RMP, i.e. safety specifications changes (reclassifications or removal of safety concerns) related to the implementation of GVP V “Risk Management Systems” Rev. 2 principles. For the cases where there are also changes to the RMP consequential to the PSUR data, the stand-alone variation should be submitted in parallel to the PSUR procedure, to facilitate the assessment of the RMP update including both the changes related to the PSUR data and the other significant changes in the RMP to the safety specifications.

As an interim measure, submission of RMP updates cannot be accepted with PSURs subject to a PSUSA of:

• a mixture of CAPs pertaining to different GMAs;
• a mixture of centrally and nationally authorised medicinal products;
• a mixture of NAPs.

In these cases, MAHs should submit the updated RMPs as part of another procedure affecting the RMP, if one such procedure is foreseen. Alternatively, MAHs should submit a separate variation to update their RMP.

The EMA will check at the beginning of the procedure whether the submission of an RMP has been correctly performed in accordance to the above criteria. In order to facilitate this check, the MAH should confirm in the cover letter that the RMP update is a direct result of data in the PSUR. To further facilitate the check and assessment, the MAH should present clean and tracked changes Word versions of the RMP in the submission.

If an RMP is incorrectly submitted with a PSUR, this will be identified at the start of the procedure and both the MAH and PRAC Rapporteur will be made aware that the RMP will not be assessed and should be submitted through another appropriate procedure. If the RMP was submitted as an eCTD the MAH will have to delete that version of the RMP in the next sequence to maintain the correct lifecycle of the product.

The assessment of a PSUR may result in a recommendation to update the content of the RMP through a subsequent variation.

For nationally authorised medicinal products (i.e. authorised through MRP, DCP or national procedures), any RMP update should be submitted via a variation procedure to the national competent authority for assessment, even if PSURs are part of a PSUSA.

The PSUR should provide comprehensive information on the findings of all PASS, both interventional and non-interventional, in PSUR sections 7 and 8 respectively as an integrated summary.

Information regarding completed clinical trials provided in the PSUR section “Summaries of significant findings from clinical trials during the reporting interval” can be presented in the PSUR in either a narrative format or as a synopsis.

The PSUR is not the appropriate procedure for submitting final or interim study reports to the EU regulatory authorities. Final study reports should be submitted and assessed via the appropriate procedure in line with the guidelines on the details of the various categories of variations, on the operations of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008. For centrally authorised products interim study reports not impacting on the product information or on the condition as stated in the Annex II of the marketing authorisation can be submitted as a post-authorisation measure (PAM) as described in question How and to whom shall I submit my PAM data (see Post-authorisation measures: questions and answers)?. For nationally authorised products, interim study reports, if requested, need to be submitted to the relevant competent authority unless specified otherwise.

However, in case a study report is able to further support either the discussion by the MAH or the PRAC/LMS’ assessment of the PSUR sections dealing with data from clinical trials, findings from non-interventional studies, or other clinical trials and sources, the MAH may provide the study report (or relevant parts thereof) as an appendix to the PSUR. The inclusion as an appendix does not discharge the MAH from their obligation to submit procedure in line with the above-mentioned guidelines on the details of the various categories of variations.

Relevant interim and final study results should be included in the PSUR sections “Summaries of significant findings from clinical trials during the reporting interval” and “Findings from non-interventional studies”, as applicable, in line with GVP VII.

Marketing authorisation holders should submit to the Agency PSURs as established in GVP Module VII as follows:

• within 70 calendar days of the data lock point (day 0) for PSURs covering intervals up to 12 months (including intervals of exactly 12 months); or
• within 90 calendar days of the data lock point (day 0) for PSURs covering intervals in excess of 12 months;
• the timeline for the submission of ad hoc PSURs requested by competent authorities will be normally specified in the request, otherwise the ad hoc PSURs should be submitted within 90 days of the data lock point.

The deadline for the submission of PSURs (Day 70 or Day 90 following the DLP) is published in the EURD list. This deadline is legally binding and must be adhered to. However, the PSUR repository allows for a submission window between the DLP and the submission deadline, there is therefore no technical restriction preventing MAHs to submit their PSUR in advance of the deadline.

The procedural start dates is published in the PSUR assessment timetable. It should be noted that the PSUSA cut-off date continues to apply to procedures containing nationally authorised medicinal products, and indicates the next upcoming start date for relevant submission deadlines in the EURD list.

The are published on the EMA website. 

Reference

• Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report, Rev 1 (EMA/816292/2011, 09 December 2013)
• Timetable: Periodic safety update report (PSUR) and PSUR single assessment (PSUSA)

It is the responsibility of MAHs to ensure that they submit the necessary PSUR by the submission deadline as stated in the EURD list and that they are not in breach of their legal obligations with respect to the submission of PSURs.

If you have missed the submission deadline due to technical issues with the PSUR Repository, please contact EMA as soon as possible via the Service Desk portal in order to request a late submission ID. Please note that late submissions can no longer be accepted once the procedure has started.

References

• User Guidance for marketing authorisation holders (MAHs) for PSUR repository

The use of the PSUR Repository is mandatory for all PSUR submissions. MAHs are required to submit PSURs directly to the PSUR repository using the eSubmission Gateway; the submission of PSURs directly to national competent authorities is no longer accepted. This affects all PSURs irrespective whether they are for centrally or nationally authorised medicinal products and whether they follow the EU single assessment or purely national PSUR procedure.

The obligation to submit to the PSUR Repository does not apply to products that have been given a positive CHMP scientific opinion under Article 58 of Regulation (EC) No 726/2004. For further information on how to submit PSURs for Article 58 products please refer to the guidance on Dossier requirements for Centrally Authorised Products (CAPs).

The use of the xml delivery file for submissions to the PSUR Repository is mandatory for all PSURs and any related submissions via the eSubmission Gateway and/or the Web Client. PSURs and any related submissions using the existing file naming conventions are no longer possible. The mandatory use of the PSUR xml delivery file is introduced to harmonise the submission mechanism for all PSURs and it applies to all types of PSURs and any related submissions. For further instructions on creation of the xml delivery file, please refer to the MAH PSUR Repository User Guidance document.

Reference

• Dossier requirements for centrally authorised products
• CMDh PSUR submission guidance document
• PSUR repository MAH user guidance document
• eSubmission website
• eSubmission gateway / Web client website
• Common repository website
• PSUR repository website
• Harmonised guidance for eCTD submissions in the EU

The official contact person for the PSUR procedure is the one provided in the xml delivery file. This person will be the sole recipient of any communication from EMA throughout this procedure, including the PRAC Recommendation, CHMP/CMDh output, and Commission Decision, as applicable. The contact information provided in the xml delivery file will always override any information provided in the cover letter.

The EMA levies a fee for the assessment of PSUR(s) since 26 August 2014.

For the PSUR assessment involving only one marketing authorisation holder (MAH) the total amount of the fee will be levied on that MAH.

For the PSUR assessment under a PSUSA procedure involving more than one MAH, the total amount of the fee will be divided among all the MAHs concerned proportionately to the number of chargeable units.

The MAHs concerned will be established on the basis of the obligation to submit the PSUR(s) and not on the basis of the actual PSUR submission(s) received by the EMA.

The total of chargeable units in the procedure will be identified from the Art. 57 database. The share payable by each marketing authorisation will be calculated by the EMA. An advice note will be generated at the data lock point (DLP) date and sent accordingly to the relevant QPPVs in order to ensure the accurate identification of the chargeable units for the products involved in the procedure. At start of the procedure, the invoice will be sent to each MAH with the relevant chargeable units calculation. The fee will be due to the EMA within 30 calendar days from the date of the invoice.

Applicants requiring a purchase order number or similar references on their invoice are encouraged to issue a standing (blanket) purchase order covering pharmacovigilance fees levied by the Agency for a given period and to provide such reference to the Agency’s accounts receivable service at accountsreceivable@ema.europa.eu. The Agency does not accept stand-alone notifications of purchase order numbers or purchase order numbers associated with a dossier for this type of procedure only.

For MAHs already qualified as an SME (i.e. micro-, small- or medium-sized enterprise) by the EMA or for those that will send a SME declaration in advance of the start date or by the latest after 30 days of the invoice date, the fee will be reduced (small- or medium-sized enterprise) or waived (micro-sized enterprise).

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

Reference

• SME declaration
• Data submission for authorised medicines

The PSUR assessment under a PSUSA 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 PSUR or several PSURs for the same active substance(s) is done by the PRAC or in case of nationally authorised products only by the appointed Lead Member State, respectively. The timelines for assessment are for up to 134 days followed by 67 days of Commission decision making process (if applicable). Upon technical* validation by the EMA of the submitted PSUR(s), the following timetable shall apply:

*There is no validation of the content of the PSUR.

The MAH is expected to provide, as applicable, by Day 90:

• responses to the “request for supplementary information” as outlined in the relevant section of the PRAC Rapporteur / Lead Member State PSUR preliminary assessment report,
• comment on the proposed wording (in case the recommendation is a variation),
• propose a wording in case the recommendation is a variation but no exact wording is proposed by the PRAC Rapporteur / Lead Member State,
• provide a justification in case the MAH does not agree with the PRAC Rapporteur / Member State recommendation to vary, suspend or revoke the MA; and/or
• include additional comments or clarification deemed necessary by the MAH

The MAH's comments should be submitted as per the PSUR dossier submission requirements detailed in the question “How shall I submit the response to a request for supplementary information during a PSUSA procedure?”.

In case of major disagreement with the PRAC Rapporteur’s/Lead Member State’s proposed Recommendation as stated in the updated assessment report, the MAH should contact the Product Lead (for CAPs) or Risk Management Specialist (for NAPs only) no later than two working days following receipt of the report. In this communication the MAH should 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, the EMA will assume that no oral explanation is requested

The MAH of centrally authorised medicinal products 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 adopts a recommendation on the maintenance of the marketing authorisation, such recommendation is not transmitted to the CHMP or CMDh and the procedure ends with 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 Commission 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 Commission decision (CD) to the Member States, which respectively 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. For further details on the procedural aspects of the EU PSUSA for NAPs only, please refer to the relevant CMDh SOP.

The outcome of the PSUR assessment results in a legally binding decision or CMDh position and any action to vary, suspend or revoke the marketing authorisations must be implemented in a harmonised and timely manner for all products within the scope of the procedure across the EU.

There may be times when MAHs are requested to take action on the basis of aspects which was not necessarily part of the PSUSA procedural scope e.g. product information of some generics not in line with that of the originator, or products which have not implemented the outcome of a previous regulatory procedure. In such cases this information will be included in the “Other considerations” section of the PRAC assessment report. Any information included in this section, will be discussed by the CMDh (for nationally authorised products) with the aim of agreeing on any necessary action, which will then be transmitted to MAHs either in the CMDh minutes or as a press release (dependent on the issue). Guidance on the content of the “Other considerations” section may be found in the published PRAC PSUR assessment report templates (Templates for assessors).

For more information, see:

• CMDh Guidance on the Informal Work-Sharing procedure for follow-up for PSUSA for NAPs

Amendments to the SmPC, labelling and package leaflet as a result of the PSUR assessment are implemented without subsequent variation submission 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).

Reference

• Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report
• CMDh SOP

No specific template needs to be followed for the responses to the request for supplementary information (RSI).

The submission requirements for responses to requests for supplementary information are the same as those for the submission of the PSURs. For the submission of responses to the PSUR Repository, the xml delivery file is filled in the same way as the original PSUR submission apart from the selection of 'response' as a regulatory activity (submission unit). This xml delivery file should be attached to the relevant eCTD/NeeS sequence submitted via the eSubmission Gateway/Web Client. The regulatory activity 'PSUR' can only be used for the 'initial' PSUR submission due to the built-in business rules linking to the submission deadline.

Please refer to the e-submission webpage and the PSUR Repository MAH user guide for more information on the creation of the delivery file.

This section presents the translation process of procedures of the below Annexes to the CHMP opinion / CMDh position. The Annexes of both the CHMP opinion as well as the CMDh position will be translated into all EU languages following an agreed timetable.

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.

Please be reminded that in accordance with Union data protection requirements, no personal data should be included in the annotated PIs. This applies to the English version submitted at the time of opinion, the draft translations submitted at D+5 and the final translations submitted at D+25. Please submit annotated PIs in an anonymised format (i.e. names of the reviewers removed from the track-changes). If you do not wish to do so, please ensure that the individuals whose data is included consented to its sharing with EMA and its further sharing by EMA with third parties such as other marketing authorisation applicants, marketing authorisation holders and National Competent Authorities, as relevant. EMA expressly disclaims any liability or accountability for the presence of unnecessary personal data in the annotated PI submitted by the marketing authorisation holder.

Procedures that contain 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 (risk minimisation measures 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 (risk minimisation measures 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 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 implementation)², 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 PSUSA procedure where several MAHs are involved, the EMA will coordinate the translation process by approaching the MAHs individually and provide the timelines accordingly. MAHs should translate all relevant Annexes for each procedure.

During the translation process

Depending on the type of outcome and whether a Commission Decision is required irrespective whether the procedure includes CAPs and/or NAPs, the timelines for the translation process vary depending on the need for a linguistic review as illustrated below:

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

b. In 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 all Member States' comments 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 Commission, members of the Standing Committee and the MAH(s) at Day 27 (27 days after opinion).
   Following receipt of the final compiled translations, the Commission 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
• Make sure that the title pages are adjusted and all brackets (i.e. >) are taken out in the title.
• Do not leave sections out, do not update the Annex III, 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 is 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 Commission 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 “Submission of day +25 /235 final product information annexes (human and veterinary) - QRD Form 2 and checklist”.

In addition, the MAHs are reminded that in case the complete product information is part of the Annex III, it should be presented in strict compliance with the Quality Review of Documents (QRD) convention to be followed for the European Medicines Agency QRD templates (e.g. format, layout and margins).

The Agency will monitor the quality of the translations, the review by the Member States and industry's 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
• Product-information templates
• Product information: Reference documents and guidelines
• The linguistic review process of product information in the centralised procedure - Human
• Member states contact points for translations review
• 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

¹Annex IV are part of the next EPAR publication. However, they will not remain part of the EPAR and will become obsolete with the next following EPAR revision. They, however, remain part of the Commission Decision in the Union Registry on the Commission's webpage.

²This time table is adopted in case a CMDh position reached by consensus and therefore not followed by a Commission Decision; in case of a majority position, the deadlines foreseen in the legislation for implementation after the Commission Decision apply.

The submission of post-authorisation measures (PAMs) for CAPs to address follow-up data request to a PSUSA must be done in eCTD format via the eSubmission Gateway/Web Client, and will be considered delivered to all national competent authorities’ representatives, alternates and scientific experts. PAMs must not be submitted to the PSUR Repository.

As a general principle no follow-up measures for NAPs should be submitted to the Agency outside a formal procedure as there is no regulatory/legal framework to conduct the assessment. Should there be exceptionally follow up data for NAPs to be submitted further to a PSUSA procedure, these must not be submitted to the PSUR Repository. Submission and assessment is expected to take place at national level and, as necessary, be coordinated across the Member States. See also Question ‘How will my PSUR be handled’ about section ‘Other considerations’ of the PSUSA assessment report. MAHs should contact the relevant Risk Management Specialist in case of such requests if there is a need for initial clarification on the process.

Information on the outcome of centrally authorised medicinal products is made available in the European Public Assessment Report (EPAR) page of the relevant medicine.

Information regarding the variation of NAPs that are part of a CAP/NAP procedure is available in the Community Register for nationally authorised products.

Information on the outcome of the EU single assessment of PSURs involving nationally authorised medicinal products only is made available on the EMA website, on the 'Download medicine data' page.

For PSUSA of CAPs the product information is varied as part of the Commission Decision issued to the MAHs, without the need for a variation. For CAPs outside the procedure (e.g. generics), the changes should be introduced through a variation IB C.I.3z.

For the NAPs included in the PSUSA procedure regardless whether NAP only, or mixed CAP and NAP products, the Commission decision is addressed to the Member States and therefore, it should be implemented by the NCAs within 30 days following its notification for all NAP products involved in the procedure (as listed in the Annex to the EC decision). By analogy to the implementation of referral procedures, the respective variations for the NAPs have to be submitted to the relevant NCA within 10 days after publication of the Commission Decision on the EC website.

For PSUSAs of NAPs, for which a CMDh position was adopted by consensus or majority (EC Commission Decision), a timetable for submission of the variations which is applicable for all affected products, including those that are not listed in the annex to the decision, is published on the EMA website. Changes to the product information after finalisation of a single PSUR assessment (with PRAC recommendation) may be implemented through the submission of a variation IA_IN under category C.I.3.a if harmonised national translations are available and no further adaptation of the currently approved wording of the decision (EC Commission Decision or CMDh position) is necessary. In cases where the wording has to be adapted, a type IB under category C.I.3.z has to be submitted. In case the MAH wants to submit new data for assessment, a type II variation should be submitted.

For generic products or others not directly involved in the PSUSA procedure itself, the changes have to be submitted via a variation procedure according to the timelines indicated in the table below.

For NAPs, further guidance on implementing variation can be found on the CMDh website (Question Answers, Pharmacovigilance legislation).

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

⁴ See also Q 3.3 of the QA list for the submission of variations according to Commission Regulation (EC) 1234/2008

PSURs, PSUR addendums, summary bridging reports and line listings should no longer be submitted as part of a renewal application. The clinical overview submitted in the renewal application should include relevant information to support the benefit-risk re-evaluation of the medicinal product. Please refer to the Guideline on the processing of renewals in the centralised procedure.

Reference

• Guideline on the processing of renewals in the centralised procedure
• Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report

For centrally authorised products (CAPs), if you cannot find the answer to your question in the Q&A when preparing your application or during the procedure, please contact the Product Lead responsible for your product.

For nationally authorised products (NAPs), please submit your query using the Ask EMA feature.

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 word 'PSUR' as a minimum 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 (the procedure number of the PSUR single assessment as per the EURD list, the name of the product and the name of the active substance/combination of active substances) 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.

PSURs for NAPs will be handled by the Risk Management Specialist . You will be able to contact the RMS throughout the procedure.

For PSUR repository interface, eSubmission Gateway and/or the Web Client questions, issues, change requests and requests for services, please contact us through the Service Desk portal. This portal improves the efficiency of the technical support by allowing users to report issues, track progress of their queries and obtain answers to frequently asked questions. This portal replaces the following mailboxes (gatewaysupport@ema.europa.eu eCTD@ema.europa.eu, and PSURrepository@ema.europa.eu) which are to be used for all technical queries concerning these IT systems, such as e.g. Web Client/Gateway set-up, registration details or the transmission failures of files in the production or test environment.

The Agency aims to respond to your query within 5 working days. To help us deal with your enquiry, please provide as much information as possible including whether your query refers to a NAP or a CAP, the procedure number of the PSUR single assessment as per the EURD list, the name of the product and the name of the active substance/combination of active substances in your correspondence.

Please refer to the e submission webpage and the PSUR Repository MAH user guide for additional information.

For information on how to submit requests for amendments of the EURD list or any other questions related to the EURD list, please refer to the EURD list submission requirements.

For queries on fees and QPPV advice notes (please refer to question “What fee do I have to pay?”), you can contact us using the designated EMA fees query form available on the Pharmacovigilance fees: questions and answers webpage.

For queries on invoices already issued, please go to the Agency's How to pay page.

The Agency aims to respond to your query within 5 working days. To help us deal with your enquiry, please provide as much information as possible including whether your query refers to a NAP or a CAP, the procedure number of the PSUR single assessment as per the EURD list, the name of the product and the name of the active substance/combination of active substances in your correspondence.

Reference

• How to pay