The pharmaceutical landscape is constantly evolving, and regulatory updates are crucial to maintaining patient safety and compliance. The latest updates to Implementing Regulation (EU) 520/2012 mark a significant shift in pharmacovigilance processes, impacting marketing authorization holders (MAHs), national competent authorities (NCAs), and the European Medicines Agency (EMA). Understanding these changes is essential for organizations aiming to stay ahead of regulatory requirements.
Commission Implementing Regulation (IR) (EU) No 520/2012, adopted on 19 June 2012, establishes detailed procedures for the performance of pharmacovigilance activities within the European Union.
It supplements Regulation (EC) No 726/2004 and Directive 2001/83/EC, focusing on the monitoring, detection, assessment, and prevention of adverse effects of medicinal products for human use. The regulation aims to enhance patient safety by ensuring that MAHs, NCAs, and the EMA adhere to consistent and effective pharmacovigilance practices.
Since its implementation, the regulation has been instrumental in standardizing pharmacovigilance activities across EU member states. However, with advancements in technology and the accumulation of practical experience, the need for targeted amendments has been identified. In 2021, the European Commission initiated a targeted stakeholder consultation to gather feedback on proposed updates to the regulation.
In December 2024, feedback on the draft act was again requested, with the consultation period concluding on January 15, 2025. These proposed amendments aim to optimize pharmacovigilance activities by incorporating lessons learned since the regulation’s initial adoption and by integrating new technical standards.
These proposed amendments aim to optimize PV activities by incorporating lessons learned since the regulation’s initial adoption and by integrating new technical standards. They would become effective after Commission adoption of the IR, which is expected in second quarter of the year.
Key Proposed Changes
EudraVigilance (EV) Monitoring Changes
This is perhaps the most significant anticipated change being proposed. The updated IR would remove the obligation for MAHs to monitor EV for safety signals, which will officially mark the end of the pilot project on signal detection in EV by MAHs.
Under the current regulation, at the end of the pilot project all MAHs were to become responsible for monitoring EV and informing NCAs and the EMA of any validated signals from that source. To implement this legal requirement, a pilot phase was launched in 2018, initially focusing on a limited number of active substances. Over time, the pilot duration was extended several times. However, based on stakeholder feedback, it was ultimately agreed the requirement to monitor EV would remain with NCAs and EMA, and MAH responsibilities would be removed from the IR.
As a result, the revised regulation (Chapter III) proposes that MAHs use EV as an additional source of information to support existing PV processes and enhance signals detected through other sources. However, they should not be responsible for detecting or validating signals detected from EV. This responsibility should remain solely with EU regulatory authorities. GVP Module IX on Signal Management would be amended accordingly.
Subcontractors and Audits
The current legislation and guidance allow MAHs to subcontract certain activities of the PV system to third parties. However, the full responsibility for the performance of PV activities is still retained by MAHs.
Since the existing IR is lacking details on how to ensure the MAHs have subcontracted activities under their control and EU inspectors have frequently raised findings in the area of contracts/agreements with third parties performing certain PV services for MAHs, it was considered beneficial to strengthen the IR in order to enhance MAHs’ oversight regarding compliance controls of third parties.
Where the PV tasks have been subcontracted by the MAH to a third party (or by this third party to another third party), delegation arrangements, each party’s responsibilities, and audit and inspection arrangements should be clearly documented. Third parties should agree to be audited by or on behalf of marketing authorisation holders and inspected by the competent authorities to guarantee and verify compliance concerning all aspects of the PV system.
Additional paragraphs have been incorporated, and the text has been revised in Article 6 (Subcontracting) and Article 13 (Audit).
PSMF Maintenance
Article 4 was updated to emphasise that any significant deviations from the PV procedures, their impact and their management shall be documented in the pharmacovigilance system master file until resolved (compared to prior wording “any deviations”).
This was proposed to avoid unnecessary administrative burdens for applicants and competent authorities. It would mean a significant shift as currently all open deviations are being presented in the PSMF, including less relevant and non-significant ones. The shift will reduce administrative task while increasing visibility of deviations that might significantly impact the PV systems.
Standardized Terminology and Formats
Chapter IV on use of terminology, formats and standards was updated to align with new technical standards, such as the mandatory adoption of the ISO Individual Case Safety Report (ICSR) standard based on the ICH E2B(R3) modalities, effective from 30 June 2022, as well as new ISO standards versions. The alternative format to XEVMPRM was introduced, to support the electronic submission of medicinal product and substance information based on the ISO IDMP standards.
Transmission of Suspected Adverse Reactions
Article 28(2) has been revised to include the following text:
In reporting, the individual case safety report shall include at least one identifiable reporter, one identifiable patient, at least one suspected adverse reaction and the medicinal product(s) concerned.
“An identifiable reporter, an identifiable patient” were replaced with “one identifiable reporter, one identifiable patient”.
The term ‘expedited’ was deleted to ensure applicability of the minimum reporting requirements to all individual case safety reports (ICSRs).
When it comes to literature referencing in ICSR, it is now expected that the digital object identifier (DOI) shall also be provided where available by Member States and marketing authorisation holders when reporting suspected adverse reactions.
Content of Periodic Safety Update Reports (PSURs)
Article 34 was updated to include the need to cover implementation of risk minimisation measures in PSUR, not only the results of their effectiveness:
’The periodic safety update report shall contain updates on the implementation of the risk minimisation measures and the results of assessments of the effectiveness of risk minimisation activities relevant to the risk-benefit assessment.’
Annex II which covers the format of periodic safety update reports was updated to reflect the same expectation.
Post-Authorization Safety Studies (PASS)
New paragraph was added in Article 36 mandating the registration of all imposed non-interventional post-authorization studies in the EU Register before commencing data collection. This requirement is already included in the GVP Module VIII.
The concept of public registration of post-authorisation studies allows to provide transparency on studies initiated to address questions about the safety of medicinal products and to facilitate peer review of study protocols by third parties.
‘The marketing authorisation holder shall enter the study protocol, the abstract of the final study report and the final study report in the electronic post-authorisation study register maintained by the Agency. The marketing authorisation holder shall submit electronically to the register the study protocol before the start of the data collection and the abstract of the final study report within one month after the finalisation of the final study report.’
Next Steps and Adoption Timeline
As of February 2025, the EC has not yet announced a specific adoption date for the proposed amendments to IR. While there is anticipation that the Commission may adopt the regulation in the second quarter of 2025, this timeline remains tentative. Consequently, the implementation timelines will be determined following the formal adoption of the regulation. Stakeholders are advised to monitor official communications from the European Commission and the European Medicines Agency for the latest updates.
It is worth noting that the Agency aims to publish revised GVPs in close proximity to respective legal articles coming into force, without the public consultation step. The Modules expected to be updated are:
- GVP Module I on ‘Pharmacovigilance systems and their quality systems’,
- GVP Module II on ‘Pharmacovigilance system master file (revision 2)’,
- GVP Module III on ‘Pharmacovigilance inspections’,
- GVP Module IV on ‘Pharmacovigilance audits (revision 1)’,
- GVP Module VI on ‘Collection, management and submission of reports of suspected adverse reactions to medicinal products (Rev. 2)’ and
- GVP Module VII on ‘Periodic safety update report’
- GVP Module VIII on ‘Post-authorisation safety studies‘ is also to be updated, however it should be released for public for public consultation, but only after amended Implementing Regulation has been published. Update of the related documents (templates for format and content of PASS protocol and report) is also expected.
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How PrimeVigilance Can Help
Navigating regulatory changes can be complex, but staying compliant is critical. PrimeVigilance’s team of pharmacovigilance experts is at the forefront of global regulatory updates, ensuring that our partners remain aligned with evolving legislation. Our regulatory affairs specialists provide tailored support, from compliance audits to strategic guidance on meeting new IR 520/2012 requirements.
Stay ahead of regulatory changes with confidence—contact PrimeVigilance today to discuss how we can support your organization’s pharmacovigilance needs.
