VII.C.4. Processes for PSUR Assessment in the EU network

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VII.C.

The competent authorities in the Member States shall assess PSURs to determine whether there are new risks or whether risks have changed or whether there are changes to the risk-benefit balance of the medicinal product [DIR Art 107d].

For purely nationally authorised medicinal products authorised in one Member State, the assessment of PSURs is conducted by the competent authority in the Member State where the product is authorised (see VII.C.4.1.).

For medicinal products authorised in more than one Member State, containing the same active substance or the same combination of active substances whether or not held by the same marketing authorisation holders and for which the frequency and dates of submission of PSURs have been harmonised in the list of EU reference dates, an EU single assessment of all PSURs is conducted with recommendation from the PRAC in accordance with the procedure described in VII.C.4.2.1. and VII.C.4.2.2..

Further to assessment of the PSUR and opinion from the CHMP or position from the CMDh, as applicable, following the recommendation from the PRAC, the competent authorities in Member States, or the European Commission for centrally authorised products, shall take the necessary measures to vary, suspend or revoke the marketing authorisation(s), in accordance with outcome of the assessment [DIR Art 107g(2)] [REG Art 28(4) and (5)] (see VII.C.4.2.3. and VII.C.4.2.4.).

The outcome of the PSUR assessment results in a legally binding decision or position in case of any action to vary, suspend, revoke the marketing authorisations of the medicinal products containing the concerned active substance or combination of active substances, on the basis of the position of the CMDh or the opinion of the CHMP following the recommendations from the PRAC. Furthermore, marketing authorisation holders are reminded of their obligation to keep their marketing authorisation up to date in accordance with REG Art 16(3) and DIR Art 23(3). The recommendations are therefore implemented in a harmonised and timely manner for all products within the scope of the procedure across the EU.

Amendments to the SmPC, package leaflet and labelling as a result of the PSUR assessment should be implemented without subsequent variation submission for centrally authorised products and through the appropriate variation for nationally authorised products, including those authorised through the mutual recognition and decentralised procedures.

When the proposals for the product information include new adverse reactions in section 4.8 (“Undesirable effects”) of the SmPC, or modifications in the description, frequency and severity of the existing reactions, marketing authorisation holders should provide in the relevant sections of the PSUR appropriate information to allow the adequate description and classification of the frequency of the adverse reactions. If other sections of the SmPC (e.g. SmPC section 4.4 “Special warnings and precautions for use”) are considered to be updated, clear proposals should be provided for the competent authorities in the Member States to consider during the PSUR assessment22. The proposals should be included in the PSUR regional appendix (VII.C.5.).

Harmonisation of the entire product information in all the Member States where the product is authorised is not one of the objectives of the PSUR assessment procedure. Instead, the outcome of the assessment should incorporate the new safety warnings and key risk minimisation recommendations, arising from the assessment of the data in the PSUR, to be included in the relevant sections of the product information.

VII.C.4.1. PSURs for purely nationally authorised medicinal products

It is the responsibility of the competent authority in the Member State where the product is authorised to evaluate the PSURs for these medicinal products and the assessment is conducted in accordance with the national legislation.

Listings of individual cases may be requested in the context of the PSUR assessment procedure for adverse reactions of special interest and should be provided by the marketing authorisation holder within an established timeframe to be included in the request. This may be accompanied by a request for an analysis of individual case safety reports, (including information on numbers of cases, details of fatal cases and as necessary, analysis of non-serious cases), where necessary for the scientific evaluation. Information on the context or rationale for the request should generally be provided.

Following the assessment of PSURs, the competent authority in the Member State should consider whether any action concerning the marketing authorisation for the medicinal product concerned is necessary. They should vary, suspend or revoke the marketing authorisation when applicable according to the appropriate procedure at national level.

The assessment report and conclusions of the competent authority in the Member State should be provided to the marketing authorisation holder.

VII.C.4.2. Medicinal products authorised in more than one Member State

VII.C.4.2.1. Assessment of PSURs for a single centrally authorised medicinal product

This section describes the assessment of PSURs where only one centrally authorised medicinal product is involved according to the procedure set up in Article 28 of Regulation (EC) No 726/2004 (see figure VII.6.).

The assessment of PSURs for a single centrally authorised medicinal product is coordinated by the Agency and shall be conducted by a Rapporteur appointed by the PRAC [REG Art 28(3)] (hereinafter referred to as “PRAC Rapporteur”).

Upon receipt, the Agency should perform a technical validation of the report to ensure that the PSUR application is in a suitable format.

Listings of individual cases from EudraVigilance database may be retrieved to support the PSUR assessment.

Further to the above verifications, the procedure starts in accordance with the official starting dates published on the Agency’s website. The detailed procedural timetables are published as a generic calendar on the Agency’s website.

The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.

During the assessment, additional listings of individual cases may be requested by the PRAC Rapporteur through the Agency for adverse reactions of special interest and should be provided by the marketing authorisation holder(s) within an established timeframe to be included in the request. This may be accompanied by a request for an analysis of individual cases safety reports, (including information on numbers of cases, details of fatal cases and as necessary, analysis of non-serious cases), where necessary for the scientific evaluation. Information on the context or rationale for the request should generally be provided.

During the drafting of the assessment report, the PRAC Rapporteur shall closely collaborate with the CHMP Rapporteur [REG Art 28(3)].

The PRAC Rapporteur shall prepare an assessment report and send it to the Agency and to the members of the PRAC [REG Art 28(3)] within 60 days of the start of the procedure.

The Agency shall send the PRAC Rapporteur’s preliminary assessment report to the marketing authorisation holder [REG Art 28(3)].

By Day 90, the marketing authorisation holder and members of the PRAC may send comments on the PRAC Rapporteur’s preliminary assessment report to the Agency and the PRAC Rapporteur. Those comments should also include responses to outstanding issues or questions raised by the PRAC Rapporteur in the preliminary assessment report and which can be addressed within the timeframe of the comments phase.

Following receipt of comments, the PRAC Rapporteur shall prepare an updated assessment report [REG Art 28(3)] within 15 days (i.e. by Day 105). The updated assessment report is made available to the members of the PRAC and should be forwarded to the marketing authorisation holder by the Agency.

An oral explanation to the PRAC can be held at the request of the PRAC or the marketing authorisation holder in case of recommendation for a revocation or suspension of the marketing authorisation, a new contraindication, a restriction of the indication or a reduction of the recommended dose.

The PRAC shall adopt the updated assessment report with or without further changes at its next meeting [REG Art 28(3)], together with a recommendation on the maintenance of the marketing authorisation or the need to vary, suspend or revoke the marketing authorisation. The PRAC recommendation may also highlight the need to conduct a post-authorisation safety study, request an update of the RMP, review of safety issues and/or close monitoring of events of interest.

Divergent positions of PRAC members and the grounds on which they are based shall be reflected in the recommendation issued by the PRAC [REG Art 28(3)].

The Agency shall include the PRAC recommendation and adopted assessment report in the repository, and forward both to the marketing authorisation holder [REG Art 28(3)].

Further to adoption at the PRAC meeting, in case of any regulatory action is recommended, the assessment report and PRAC recommendation are sent to the CHMP for adoption of an opinion for the centrally authorised product concerned as described in VII.C.4.2.3.

VII.C.4.2.2. Assessment of PSURs for medicinal products subject to different marketing authorisations containing the same active substance (EU single assessment)

This section describes the assessment of PSURs for medicinal products subject to different marketing authorisations, authorised in more than one Member State, containing the same active substance or the same combination of active substances whether or not held by the same marketing authorisation holder and for which the frequency and dates of submission of PSURs have been harmonised in the list of EU reference dates. This could include a mixture of centrally authorised products, products authorised through the mutual recognition, decentralised and national procedures. [DIR Art 107e to 107g] (so-called PSUR “EU single assessment” procedure).

The assessment of PSURs for medicinal products, also called “EU single assessment”, shall be conducted by [DIR Art 107e(1)]:

a “Member State” appointed by the CMDh where none of the marketing authorisations concerned has been granted in accordance with the centralised procedure;
a “Rapporteur” appointed by the PRAC, where at least one of the marketing authorisations concerned has been granted in accordance with the centralised procedure (hereinafter referred to as “PRAC Rapporteur”).

The PSUR EU single assessment procedure is coordinated by the Agency. Upon receipt, the Agency should perform a technical validation of the reports to ensure that the PSURs applications are in a suitable format.

Upon establishment of the list of all medicinal products for human use authorised in the EU referred to in REG Art 57, the Agency should ensure that all marketing authorisation holder(s) of the given substance have submitted PSUR(s), as required. In the event where a PSUR has not been submitted, the Agency should contact the concerned marketing authorisation holder(s). However, this will not preclude the start of the single assessment procedure for other PSUR(s) of the same active substance.

Listings of individual cases from EudraVigilance database may be retrieved to support the PSURs assessment.

The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure.

Further to the start of procedure, the PRAC Rapporteur or Member State conducts the single assessment of all PSURs submitted for the given active substance.

During the assessment, additional listings of individual cases may be requested by the PRAC Rapporteur or Member State through the Agency for adverse drug reactions of special interest and should be provided by the marketing authorisation holder(s) within an established timeframe to be included in the request. This may be accompanied by a request for an analysis of individual cases safety reports, (including information on numbers of cases, details of fatal cases and as necessary, analysis of non-serious cases), where necessary for the scientific evaluation. Information on the context or rationale for the request should generally be provided.

The PRAC Rapporteur or Member State shall prepare an assessment report and send it to the Agency and to the Member States concerned [DIR Art 107e(2)] within 60 days of the start of the procedure. This preliminary assessment report should be circulated to the members of the PRAC.

The Agency shall send the PRAC Rapporteur’s/Member State preliminary assessment report to the concerned marketing authorisation holder(s) [DIR Art 107e(2)]. This assessment report should be circulated amongst all the marketing authorisation holders whose medicinal product(s) are part of the EU single assessment.

By Day 90, the marketing authorisation holder(s), Member States and members of the PRAC as applicable may send comments on the PRAC Rapporteur’s/Member State’s preliminary assessment report to the Agency and the PRAC Rapporteur/Member State, as applicable. Those comments should also include responses to outstanding issues or questions raised by the PRAC Rapporteur/Member State in the preliminary assessment report and which can be addressed within the timeframe of the comments phase.

Following receipt of comments, the PRAC Rapporteur/Member State shall prepare an updated assessment report [DIR Art 107e (3)] within 15 days (i.e. by Day 105). The updated assessment report is forwarded to the members of the PRAC and should be circulated by the Agency amongst all the marketing authorisation holders whose medicinal product(s) are part of the EU single assessment.

The PRAC shall adopt the updated assessment report with or without further changes at its next meeting [DIR Art 107e(3)], together with a recommendation on maintenance of the marketing authorisation or the need to vary, suspend or revoke the marketing authorisation. The PRAC recommendation may also highlight the need to conduct a post-authorisation safety study (see Module VIII), request an update of the RMP (see Module V), review of safety issue and/or close monitoring of events of interest.

Divergent positions of PRAC members and the grounds on which they are based shall be reflected in the recommendation issued by the PRAC [DIR Art 107e(3)].

The Agency shall include the PRAC recommendation and adopted assessment report in the repository, and forward both to the marketing authorisation holder(s) [DIR Art 107e(3)].

Further to adoption at the PRAC meeting, in case of any regulatory action is recommended, the assessment report and PRAC recommendation are sent to:

the CHMP where at least one centrally authorised product is included in the single assessment, for adoption of an opinion as described in VII.C.4.2.3.;
the CMDh where no centrally authorised product is included in the single assessment, for agreement of a position as described in VII.C.4.2.4..

VII.C.4.2.3. Single assessment including at least one centrally authorised product leading to a CHMP opinion

The CHMP acknowledges receipt of the PRAC recommendation and assessment report, in case of any regulatory action, at their next meeting following the PRAC adoption. Within 30 days from receipt, the CHMP shall consider the PRAC assessment report and recommendation and adopt an opinion on the maintenance, variation, suspension, revocation of the marketing authorisation(s) concerned [DIR 107g(3)].

An oral explanation to the CHMP can be held at the request of the CHMP or the marketing authorisation holder(s) only in case of differences with the PRAC recommendation where CHMP considers the possibility of adopting an opinion on the suspension or revocation of the marketing authorisation(s), a new contraindication, a restriction of the indication or a reduction of the recommended dose.

The opinion will contain the following:

the final assessment report and recommendation adopted by the PRAC;
detailed explanation of the scientific grounds for differences with the PRAC recommendation, if applicable [DIR Art 107g(3)];
in the case of a CHMP opinion to vary the marketing authorisation(s):
- the scientific conclusions and grounds recommending the variation to the terms of the marketing authorisation;
- for centrally authorised products, revised product information and if applicable, conditions imposed to the marketing authorisation holder and where appropriate, the conditions or restrictions imposed to the Member States for the safe and effective used of the medicinal product, in accordance with the provision provided in DIR Art 127a;
- for nationally authorised products, including those authorised through the mutual recognition and decentralised procedures, an annex indicating the new safety warnings and key risk minimisation recommendations to be included in the relevant sections of the product information as applicable.
in the case of a CHMP opinion to suspend the marketing authorisation(s), the scientific conclusions together with the grounds for suspension and conditions for lifting the suspension;
in the case of a CHMP opinion to revoke the marketing authorisation(s), the scientific conclusions together with the grounds for revocation;
divergent positions of CHMP members, where applicable.

Further to adoption, the Agency should send the CHMP opinion together with its annexes and appendices to the European Commission, marketing authorisation holder(s) and competent authorities in Member States.

The final assessment conclusions and recommendations are published in the European medicines webportal (VII.C.7.).

a. Post CHMP opinion – Centrally authorised products

Where the CHMP opinion states that the terms of the marketing authorisation(s) needs to be varied, the marketing authorisation holder(s) of centrally authorised products should provide the translations of the product information and the scientific conclusions and grounds recommending the variation to the terms of the marketing authorisation, in all EU official languages, in accordance with the translation timetable adopted by the CHMP.

Further to receipt of a CHMP opinion stating that regulatory action to the concerned marketing authorisation is necessary, the European Commission shall adopt a decision addressed to marketing authorisation holders to vary, suspend or revoke the marketing authorisation(s) of centrally authorised product(s) [DIR Art 107g(4b)].

Further to adoption, the European Commission should notify the decisions amending the terms of the marketing authorisation of centrally authorised products to the marketing authorisation holder(s).

b. Post CHMP opinion – Nationally authorised products, including those authorised through the mutual recognition and decentralised procedures

Further to receipt of a CHMP opinion stating that regulatory action to the concerned marketing authorisations is necessary, the European Commission shall adopt a decision addressed to the competent authorities in Member States concerning the measures to be taken [DIR Art 107g(a)] in respect of nationally authorised products, including those authorised through the mutual recognition and decentralised procedures.

Further to the receipt of the decision from the European Commission, the competent authorities in Member States shall take the necessary measures to vary, suspend or revoke the marketing authorisation(s) within 30 days [DIR Art 107g(4)].

VII.C.4.2.4. Single assessment not including centrally authorised product leading to a CMDh position

The CMDh acknowledges receipt of the PRAC recommendation and assessment report, in case of any regulatory action, at their next meeting following the PRAC adoption.

Within 30 days from receipt, the CMDh shall consider the PRAC assessment report and recommendation and reach a position on the maintenance, variation, suspension, revocation of the marketing authorisation(s) concerned [DIR Art 107g(1)].

An oral explanation to the CMDh can be held at the request of the CMDh or the marketing authorisation holder(s), only in case of differences with the PRAC recommendation where the CMDh considers the possibility to reach a position on the suspension or revocation of the marketing authorisation(s), a new contraindication, a restriction of the indication or a reduction of the recommended dose.

The position will contain the following:

the final assessment report and recommendation adopted by the PRAC;
detailed explanation of the scientific grounds for differences with the PRAC recommendation, if applicable [DIR Art 107g(2)];
in the case of a CMDh position to vary the marketing authorisation(s), the scientific conclusions and grounds recommending the variation to the terms of the marketing authorisation and an annex indicating the new safety warnings and key risk minimisation recommendations to be included in the relevant sections of the product information, as applicable;
in the case of a CMDh position to suspend the marketing authorisation(s), the scientific conclusions together with the grounds for suspension and conditions for lifting the suspension;
in the case of a CMDh position to revoke the marketing authorisation(s), the scientific conclusions together with the grounds for revocation;
divergent position(s) for the CMDh members, where applicable.

The final assessment conclusions and recommendations shall be published by the Agency in the European medicines web-portal [DIR Art 107l] (VII.C.7.).

If the CMDh position is reached by consensus:

The position agreed including the action to be taken is recorded by the chairperson in the minutes of the CMDh meeting where agreed.

The chairman shall send the agreed CMDh position [DIR Art 107g(2)] and its appendices to the marketing authorisation holder(s) and competent authorities in Member States.

Further to receipt of the CMDh position stating that regulatory action to the concerned marketing authorisation is necessary, the competent authorities in Member States shall adopt necessary measures to vary, suspend or revoke the marketing authorisation(s) concerned in accordance with the timetable for implementation determined in the agreed position [DIR Art 107g(2)].

In case the position of the CMDh agreed that variation to the terms of marketing authorisation is required, the marketing authorisation holder(s) shall submit the relevant variation to that effect within the timetable for implementation [DIR Art 107g(2)] as appended to the agreed position.

If the CMDh position is reached by majority vote:

The majority position on the action to be taken is recorded by the chairman in the minutes of the CMDh meeting where agreed.

The majority position of the CMDh together with its annexes and its appendices, including translations in all EU official languages where applicable, shall be forwarded to the European Commission [DIR Art 107g(2)]. The position of the CMDh should also be forwarded to the competent authorities in Member States.

Further to receipt of a CMDh position stating that regulatory action to the concerned marketing authorisation is necessary, the European Commission shall adopt decision(s) [DIR Art 107g(2)] addressed to the competent authorities in Member States in order for them to vary, suspend or revoke the marketing authorisation(s) of nationally authorised product(s) which is addressed to marketing authorisation holders.

Further to receipt of the decision from the European Commission, the competent authorities in Member States shall take the necessary measures to maintain, vary, suspend or revoke the marketing authorisation(s) within 30 days [DIR Art 107g(2)].

VII.C.4.3. Relationship between PSUR and risk management plan

The general relationship between the risk management plan (RMP) and the PSUR is described in Module V, while an overview of the common RMP/PSUR modules is provided in VII.C.4.3.1.

During the preparation of a PSUR, the marketing authorisation holder should consider whether any identified or potential risks discussed within the PSUR is important and requires an update of the RMP. In these circumstances, updated revised RMP including the new important safety concern should be submitted with the PSUR and assessed in parallel, following the timetable for the assessment of PSUR as described above.

If important safety concerns are identified by the national competent authorities in the Member States during the assessment of a PSUR and no updated RMP or no RMP has been submitted, recommendations should be made to submit an update or a new RMP within a defined timeline.

VII.C.4.3.1. PSUR and risk management plan – common modules

The proposed modular formats for the PSUR and the RMP aim to address duplication and facilitate flexibility by enabling common PSUR/RMP sections to be utilised interchangeably across both reports. Common sections with the above mentioned reports are identified in Table VII.1.:

PSUR section	RMP section
Section 3 – “Actions taken in the reporting interval for safety reasons”	Part II, module SV – “Post-authorisation experience”, section “Regulatory and marketing authorisation holder action for safety reason”
Sub-section 5.2 – “Cumulative and interval patient exposure from marketing experience”	Part II, module SV – “Post-authorisation experience”, section “Non-study postauthorisation exposure”
Sub-section 16.1 – “Summary of safety concerns”	Part II, module SVIII – “Summary of the safety concerns” (as included in the version of the RMP which was current at the beginning of the PSUR reporting interval)
Sub-section 16.4 – “Characterisation of risks”	Part II, Module SVII – “Identified and potential
Sub-section 16.5 – “Effectiveness of risk minimisation (if applicable)”	Part V – “Risk minimisation measures”, section “Evaluation of the effectiveness of risk minimisation activities”