On 18 December 2024, the European Commission published a proposed implementing regulation relating to pharmacovigilance (“PV”) requirements for human medicines marketed in the EU (“Proposal”), which will update European Commission Implementing Regulation (EU) 520/2012 (“Implementing Regulation”). While the core PV requirements, including the obligation to establish and operate a PV system and the key reporting requirements, are set out in Regulation (EC) No 726/2004 and Directive 2001/83/EC, the Implementing Regulation provides detailed requirements on the performance of PV activities, including the need for a PV system master file (“PSMF”), more comprehensive requirements for the PV quality system, and detailed provisions relating to periodic safety update reports (“PSURs”).
The proposed changes aim to harmonize the performance of PV activities by marketing authorization holders (“MAHs”), national competent authorities and the European Medicines Agency (“EMA”), and in some cases widen the scope of the Implementing Regulation’s PV requirements. Other changes are clarificatory in nature.
Proposed Changes
Among other changes, the Proposal will amend the Implementing Regulation by providing additional detail in certain areas. For instance:
- Article 1(3) of the Proposal builds out Article 6 of the Implementing Regulation, adding further detail for MAHs subcontracting PV duties to third parties. This additional detail includes the requirement for MAHs to incorporate into subcontracting agreements: (i) a “clear description of the roles and responsibilities of the third parties;” (ii) the obligation of third parties to exchange safety data with the MAH and the method for this exchange; (iii) arrangements for the inspection and auditing of such third parties; and (iv) the obligation on third parties to agree to be audited by or on behalf of the MAH and inspected by competent authorities. The Proposal also requires that third parties do not subcontract any PV task without the MAH’s written consent.
- Article 1(16) of the Proposal imposes additional obligations on MAHs in relation to the scope of post-authorization safety studies involving their medicines (Article 36, Implementing Regulation): the MAH would be required to enter the study protocol, abstract of the final study report and the final study report itself in the electronic post-authorization study register maintained by the EMA. The MAH must electronically submit the study protocol to the register before beginning data collection and the abstract of the final study report within one month after the finalization of the final study report.
Similarly, the Proposal widens the scope of several provisions under the Implementing Regulation, including:
- Article 19(1) of the Implementing Regulation (Identification of changed risks and new risks) – Article 1(8) of the Proposal would extend the scope of signals taken into consideration for the purposes of monitoring data in the Eudravigilance database from signals related only to an adverse reaction to those also relating to a “suspected” adverse reaction. The Implementing Regulation defines “signals” in this context as “information arising from one or multiple sources, including observations and experiments, which suggests a new potentially causal association, or a new aspect of a known association between an intervention and an event or set of related events, either adverse or beneficial, which is judged to be of sufficient likelihood to justify verificatory action.”
- Article 28(1) of the Implementing Regulation (Content of the individual case safety report) – Article 28(1) of the Implementing Regulation provides the criteria for a valid individual case safety report (“ICSR”), namely: an identifiable reporter, an identifiable patient, one suspected adverse reaction, and the medicinal product(s) concerned. Article 1(14) of the Proposal would extend this definition to apply not only “in the case of expedited reporting,” as originally drafted under the Implementing Regulation, but rather to “reporting” generally.
- Article 28(3) of the Implementing Regulation (Content of the individual case safety report) – Article 28(3) of the Implementing Regulation sets out an extensive list of information that the MAH is expected to provide with ICSRs, if available. Article 1(14) of the Proposal seeks to add the digital object identifier (“DOI”) for any literature references in relation to suspected adverse reactions reported to this list of required information.
By contrast, the Proposal would also narrow the scope of Article 4(3) of the Implementing Regulation, which relates to an MAH’s maintenance of a PSMF for each of its medicinal products. Currently, the MAH must document “any deviations” from the MAH’s PV procedures, including their impact and how they are managed, in the PSMF until resolved. Under Article 1(2) of the Proposal, this obligation would be restricted only to “significant deviations.”
Alongside these changes, the Proposal also contains various clarifying updates. For instance:
- Article 1(15) of the Proposal updates Article 34 of the Implementing Regulation to expressly require PSURs to include “updates on the implementation of risk minimisation measures.”
- Article 1(5)(a) of the Proposal amends Article 13(1) of the Implementing Regulation, which relates to audits of an MAH’s PV quality system, to clarify that the audits must cover all PV activities for a defined period and verify that those activities comply with the policies, processes and procedures of the quality system.
- Articles 1(12) and 1(13) of the Proposal also update the references in Articles 25 (Use of internationally agreed terminology) and 26 (Use of internationally agreed formats and standards) of the Implementing Regulation to refer to the most up-to-date relevant harmonized standards issued by the International Organization for Standards (“ISO”).
Next Steps
The consultation on the Proposal will close on 15 January 2025. Organizations wishing to respond to the Proposal may give feedback here.
Covington will continue to follow developments and provide further updates.
If you would like to discuss the latest developments and what they may mean for your company’s operations, please contact: Grant Castle, Robin Blaney, Adem Koyuncu or Marie Doyle-Rossi.