VII.C.5. EU-specific requirements for periodic safety update reports

The scientific evaluation of the risk-benefit balance of the medicinal product included in the PSUR detailed in VII.B.5. shall be based on all available data, including data from clinical trials in unauthorised indications and populations according to the provisions of DIR Art 107b and IR Art 34(1).

The EU-specific requirements should be included in the PSUR EU regional appendix.

VII.C.5.1. PSUR EU regional appendix, sub-section “Proposed product information”

The assessment of the need for amendments to the product information is incorporated within the PSUR assessment procedure in the EU. The regulatory opinion/position should include recommendations for updates to product information where needed. Marketing authorisation holders should provide the necessary supportive documentation and references within the PSUR or in this appendix to facilitate this.

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 and/or actions, including implications for the approved SmPC(s) for the product(s) for which the PSUR is submitted [IR Art 34 (5)].

In this sub-section, the marketing authorisation holder should provide the proposals for product information (SmPC and package leaflet) based on the above mentioned evaluation. These should be based on all EU authorised indications.

A track change version of the proposed SmPCs and package leaflets based on the assessment and conclusions of the PSUR should be provided. For centrally authorised medicinal products, the proposed product information should also be submitted to Module 1.3.1 of the Electronic Common Technical Document (eCTD).

All the SmPCs and packages leaflets covered by the PSUR and in effect at the data lock point, should be reviewed to ensure that they reflect the appropriate information according to the cumulative data included and analysed in the PSUR.

Amendments to the product information should not be postponed or delayed until the PSUR submission and amendments not related to the information presented in the PSUR, should not be proposed within the PSUR procedure. It is the obligation of the marketing authorisation holder to submit a variation in accordance with the Regulation (EC) No 1234/2008 on variations to the terms of a marketing authorisation.

A brief description of ongoing procedures (e.g. variations) to update the product information should be provided in this section.

VII.C.5.2. PSUR EU regional appendix, sub-section “Proposed additional pharmacovigilance and risk minimisation activities”

Considering the provision established in IR Art 34 (5), this sub-section should include proposals for additional pharmacovigilance and additional risk minimisation activities based on the conclusions and actions of the PSUR, including a statement of the intention to submit a RMP or an updated RMP when applicable.

VII.C.5.3. PSUR EU regional appendix, sub-section “Summary of ongoing safety concerns”

In order to support the information provided in the PSUR section 16.1 “Summary of safety concerns” (see VII.B.5.16.1.), Table 1.10 (according to the current RMP template) “Summary – Ongoing safety concerns” should be included in this PSUR sub-section. This table should be extracted from the version of RMP available at the beginning of the PSUR reporting interval (see Module V).

VII.C.5.4. PSUR EU regional appendix, sub-section “Reporting of results from post-authorisation safety studies”

Findings from both interventional and non-interventional (for further guidance see Module VIII) postauthorisation safety studies (PASS) should be reported in the PSUR. While the marketing authorisation holder should inform competent authorities in Member States and the Agency as applicable about any new information that may impact on the risk-benefit balance immediately, the PSUR should provide comprehensive information on the findings of all PASS, both interventional and non-interventional, in PSUR sections 7 and 8 respectively.

Final study reports for studies conducted with the primary 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 which were completed during the reporting interval should also be included as an annex to the PSUR. For such studies discontinued during the reporting interval, the reasons for stopping the study should also be explained.

If an important safety concern has been identified in the course of a study, regardless of whether it has been detected through pre-specified methods and whether the study is considered a PASS, the marketing authorisation holder and specifically the qualified person responsible for pharmacovigilance (QPPV) will have informed the relevant competent authorities in Member States immediately. PSURs should not be used as the initial communication method either for the submission of final study reports to the competent authorities in Member States or for the notification of any new information that might influence the evaluation of the risk-benefit balance.

VII.C.5.5. PSUR EU regional appendix, sub-section “Effectiveness of risk minimisation”

Risk minimisation activities are public health interventions intended to prevent the occurrence of an adverse drug reaction(s) associated with the exposure to a medicinal product or to reduce its severity should it occur. The success of risk minimisation activities in delivering these objectives needs to be evaluated throughout the lifecycle of a product to ensure that the burden of adverse reactions is minimised and hence the overall risk-benefit balance is optimised. In accordance with section VII.B.5.16.5., evaluation of broad global experience should be reflected in the body of the report, when provides insights into the effectiveness of risk minimisation activities in any country or region that may have utility in other countries or regions are of particular interest .

This sub-section should additionally provide an evaluation of the effectiveness of routine and/or additional risk minimisation activities specifically relevant to an EU context. This should take account of regulatory imposed obligations for implementation of risk minimisation measures in addition to the overall requirement for monitoring of safety and benefit-risk. Results of any studies to assess the impact or other formal assessment(s) of risk minimisation activities in the EU should be included when available. As part of this critical evaluation, the marketing authorisation holder should make observations on factors contributing to the success or weakness of risk minimisation activities. If a particular risk minimisation strategy proves ineffective, then alternative activities need to be put in place. In certain cases, it may be judged that risk minimisation cannot control the risks to the extent possible to ensure a positive risk-benefit balance and that the medicinal product needs to be withdrawn either from the market or restricted to those patients in whom the benefits outweigh the risks. More extensive guidance on monitoring the effectiveness of risk minimisation activities is included in Module XVI. As a principle, the marketing authorisation holder should distinguish in their evaluation between implementation success and attainment of the intended outcome.