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Amendment of EU PV Regulation in 2025
Written by Martti Ahtola | Jan 30, 2025
Introduction
The European legislation for performing pharmacovigilance activities, Implementing Regulation (EU) No 520/2012, is likely to be amended during 2025. A draft version of the Amendment was shared for public feedback in December 2024.
The key changes include expanded scope of pharmacovigilance activities and risk management plans, a focus on significant deviations, introduction of subcontracting requirements, removal of signal validation responsibilities by marketing authorization holders (MAHs), emphasis on regular audits and third-party audits, expansion of data monitoring sources, broader signal detection, changes in signal management and terminology, updated reporting requirements, and introduction of post-authorization study requirements.
The implementing regulation is being amended and the public feedback collection related to the proposed amendments to legislation ended on 15th of January 2025.
The official page where you can find the draft of the amendment is here. This post will guide you through the “reasons and goals” of the proposed amendments with Tepsivo’s commentary. We recommend you also download our presentation listing the proposed amendments with specific text changes highlighted and analyzed.
What to expect?
One of the main changes in the legislation is related to signal detection. Once the updated legislation is effective, it will end the EMA signal pilot that has been extended several times since 2018.
But this is not the only area that seem to be affected by future changes, the list is quite extensive – see our quick overview below.
Expanded scope of pharmacovigilance activities and risk management plans: The new legislation requires a more detailed description of the organizational structure and a focus on the preparation, implementation, and maintenance of risk management plans.
Focus on significant deviations in PSMF: The deviation documentation requirement now applies only to significant deviations from pharmacovigilance procedures, streamlining the documentation process.
Introduction of subcontracting requirements: Clear roles, responsibilities, and data exchange methods are now mandatory in subcontracts, ensuring compliance and data integrity.
Emphasis on regular audits and inspections: The new rules stress the importance of regular risk-based audits of the quality system, including audits conducted by third parties, and inspections of PV subcontractors.
Removal of signal validation by MAHs: The compliance management section no longer explicitly mentions signal validation by MAHs, indicating a shift in responsibility or process.
Removal of continuous EV monitoring by MAHs: Continuous EudraVigilance (EV) monitoring still required by EMA and NCAs.
Description of data monitoring sources related to EV downloads: MAHs are required to monitor data from multiple sources, including the Eudravigilance database, for comprehensive signal management and risk assessment.
ICSR and Literature Report requirements highlighted and strengthened: The content of individual case safety reports and periodic safety update reports has been amended for clarity and comprehensiveness. DOI is recommended for articles.
Post-authorization study requirements: New provisions outline the submission of study protocols and reports to an electronic register (ENcEPP).
EMA Signal Pilot is Ending Soon
The EMA Signal Pilot, which has been running since 2018 and was supposed to last for one year only, has once again been extended but now there is end in sight.
According to the updated EMA signal management website, the new amendment to the Implementing Regulation (EU) No 520/2012 will likely be published in the first half of 2025. The pilot on signal detection by MAHs in EV will be terminated with the update of the Implementing Regulation. According to the EMA website the requirements established in the updated Implementing Regulation will be applicable to all MAHs with medicinal products authorised in the EEA. What those amended requirements will be, is still unknown. The updated EMA website also states that the GVP Module IX on Signal Management will be amended in due course to reflect this update.
Pharmacovigilance Risk Assessment Committee (PRAC): Work Plan 2025 Adopted by the Committee on 12 December 2024 does mention the regulation update and PRAC’s upcoming work related to the guideline update. Signal detection and management working group plans to revise GVP Module IX (revision 2) on ‘Signal management’ in line with the revised Implementing Regulation. The signal management GVP module was previously revised in 2017.
Complete removal of signal validation by MAHs seems to be close to happening thanks to the amendment of the regulation. This would also explain how the EMA signal pilot can be finally ending. If the legislation would not be amended this way, the signal “pilot” would either have to continue forever placing certain companies in an “unfair” position, or the requirement would finally become applicable for all MAHs. The latter would have caused a huge amount of unnecessary additional work for all MAHs who would have to start performing thorough signal validation without any significant benefit to the patient safety, as shown by the collected evidence from the pilot.
The only sensible option was to amend the legislation, as was requested by EMA several years ago and communicated first by Tepsivo in 2022.
See our previous blog posts about the topic:
🗞️ EMA report echoes our calls on MAHs to stop signal detection activities in EudraVigilance
🗞️ Signal detection performed by pharmaceutical companies should stop
News about the amending of the implementation regulation was scarce and it took some real detective work to find industry news that would refer to the actual announcement from the European Commission.
The EMA website did not contain anything else than what is described above. One of the news pieces found with extensive Google search contained a link to the public consultation page for Performance of pharmacovigilance activities for human medicines (update of Implementing Regulation (EU) 520/2012).
Public Feedback for the Amendment
Unfortunately, due to what we view as lack of public communication by the Committee combined with the vacation period, we had already missed our chance to give our feedback.
The public consultation was open from 18th of December 2024 to 15th of 2025. In total, 14 parties gave their feedback on the proposal.
There probably would have been quite a few pharmacovigilance experts around Europe who would have been willing to give their say about amending the legislation that affects the core pieces of their work. Maybe next time.
The type and level of feedback varied from analysis papers that are many times longer than the amendment itself to short comments about a specific sentence.
For example, this is how Medicines for Europe commented on the amendment of article 18 paragraph 2:
Current legislation:
Marketing authorisation holders shall monitor the data available in the Eudravigilance database to the extent that they have access to that database.
Proposed Amendment:
Marketing authorisation holders shall monitor the data available in the Eudravigilance database together with data from other available sources, as part of their pharmacovigilance responsibilities for data monitoring, signal management and risk assessment.
Suggestion from Medicines for Europe:
Marketing authorisation holders shall use the data available in the Eudravigilance database as needed together with data from other available sources, as part of with their pharmacovigilance responsibilities for data monitoring, signal management and risk assessment.
There is a good reason this sentence was pointed out in the feedback. EV downloading is one of the largest PV tasks for MAHs in Europe and currently it is not completely clear from the legislation or the EU GVP what monitoring the data available in EV actually means in practice.
The amendment puts the EudraVigilance monitoring into context with monitoring other sources of data (literature, internal communication pathways, studies etc.), but the proposed version of the amendment does not clarify what the monitoring of Eudravigilance should in practice look like.
Many companies download daily or weekly the available reports and analyze them. But this is not clearly required by the legislation and what Medicines for Europe suggested is a more open interpretation of using the data as needed, moving to an even hazier requirement but also to more flexibility for different kinds of products with different benefit-risk profiles.
A more significant change seems to be the removal of the MAH requirement to continuously monitor Eudravigilance in the following paragraph. This would seem to suggest that the daily and weekly manual downloads could be stopped in case the product contains a low-risk safety profile.
In general, the feedback given on the amendment was relevant and high level. Tepsivo would have shared feedback on the same points and requested the same type of clarifications to the suggested wording.
Amendment reasons and goals
The proposal for Amendment contains two lists describing the proposed changes. The first 12 points are something that could be considered to be reasoning and goals of the amendment and the next 18 points are exact ways how the amendment tries to achieve those goals by changing, adding or removing parts of the regulation.
The “reasons and goals” description of the proposed amendments to the implementing regulation are listed below with initial comments, questions and feedback.
To see the exact changes to the legislative text with the current legislative text and analysis of the proposed change, download our presentation.
Amendment 1
“Commission Implementing Regulation (EU) No 520/2012 sets out certain implementing measures for the performance of pharmacovigilance activities.
In light of practical experience in applying that Implementing Regulation, technical and scientific progress, and international harmonisation in pharmacovigilance, it is appropriate to review it, while guaranteeing the same level of public health protection.”
Tepsivo’s comment: The amendments proposed now are based on experience and feedback on the existing legislation that has been in place for a long time.
Amendment 2
“Implementing Regulation (EU) No 520/2012 sets out, among other things, the content of the pharmacovigilance system master file.
To avoid unnecessary administrative burdens for applicants and competent authorities, only significant deviations from the pharmacovigilance procedures, their impact and their management should be documented in the pharmacovigilance system master file until resolved.”
Tepsivo’s comment: Wording has been changed from “Any deviations” to “Any significant deviations”.
This change suggests a shift in focus towards documenting only those deviations that have a notable impact on the pharmacovigilance process and implies that minor or insignificant deviations may not require documentation in the pharmacovigilance system master file (PSMF).
On the other hand, “significant” is not defined and unless it is further explained in GVP this might not be as straightforward as it initially seems. amendments proposed now are based on experience and feedback on the existing legislation that has been in place for a long time.
Amendment 3
“Marketing authorisation holders may subcontract certain activities of the pharmacovigilance system to third parties, for example to specialised service providers.
Where the pharmacovigilance tasks have been subcontracted by the marketing authorisation holder 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 in order to guarantee and verify compliance concerning all aspects of the pharmacovigilance system.”
Tepsivo’s comment: Specific elements must be included in subcontracts in the future. This means that if the MAH has subcontracted PV activities, those agreements must be reviewed and in some cases updated to reflect this legislative change. Same applies for agreements between the subcontractors and third parties that they have contracted to perform tasks.
The new paragraph that the agreements must include clear description of roles and responsibilities, an obligation to third parties to exchange safety data with the MAH, arrangements for inspections and auditing of third parties and an obligation for third parties to agree to audits by (or on behalf) of MAH and inspections by competent authorities.
The other new paragraph defines an obligation for MAH’s written consent in case third parties subcontract pharmacovigilance task(s) assigned to them. These are not exactly new requirements and have been in other terms included in some parts of the legislation and have been part of the best practices in drug safety space.
Amendment 4
“Marketing authorisation holders are to establish quality systems for the performance of pharmacovigilance activities pursuant to Article 8(1) of Implementing Regulation (EU) No 520/2012.
In accordance with Article 13 of that Regulation, those quality systems are to be audited. In order to ensure better efficiency of audits, the content of those audits should be further defined in this Regulation.
The third party subcontracted to carry out pharmacovigilance tasks in whole or in part on behalf of or in conjunction with marketing authorisation holders should be audited by or on behalf of the marketing authorisation holder and may be inspected by the competent authorities, irrespective of whether or not this obligation is mentioned in the subcontract.
It is important that subcontractors have clarity about their obligations, which should be set out in the subcontract, but a subcontract’s shortcomings should not affect the performance of audits and inspections.”
Tepsivo’s comment: The new, extended wording of requirements for conducting audits of the quality (management) system (QMS) relates to audit intervals, ensuring compliance with articles about quality system, human resources management, compliance management and record management and data retention, scope of the audit in regards the topics and that it should be looking at the compliance of the performed activities in relation to the controlled documents.
The new paragraph 1a regulates auditing of subcontractors highlighting the requirements for the MAHs to audit subcontractors and points out that the subcontractor may be inspected by the authorities.
This is one of the points that was commented the most in the public feedback. Comments from AESGP and EFPIA questioned the added value of conducting audits on predefined intervals, regardless of their risk level.
They pointed out that this requirement could cause significant operational disruptions to a PV system that is already subject to extensive internal audits, external partner audits, and inspections by competent authorities at high frequency. One of the concerns was that the allocation of resources would be substantial, necessitating a significant expansion of audit teams and resulting in considerable cost implications for companies.
EFPIA also pointed out that this revision would limit the ability to operate an effective risk-based audit program by only applying risk to the frequency of audit. This would not be aligned with the well-established standards executed across multiple industries and defined in well-respected global standards such as ISO 9001:2015 that support risk-based methods being applied throughout the audit lifecycle (planning, execution, reporting and closure).
By removing the ability to operate all aspects of an audit program in a risk-based manner, the value and outcome of audits will be diluted as the same effort will be applied to areas of high and low risk, instead of focusing on the areas representing the highest risk and impact to PV processes and patient safety.
EFPIA suggested that clarity on acceptable risk-based practices be further defined in GVP Module IV Pharmacovigilance Audits, which has not undergone any revision since August 2015.
Amendment 5
“The Eudravigilance database is the system for managing and analysing information on adverse reactions to medicines that have been authorised or are being studied in clinical trials.
The European Medicines Agency (ʻthe Agencyʼ) and national competent authorities continuously monitor the data in the Eudravigilance database. The database is also accessible to marketing authorisation holders to the extent necessary for them to fulfil their pharmacovigilance obligations.
Based on the experience acquired from marketing authorisation holders’ monitoring of the data in the Eudravigilance database, the requirements for marketing authorisation holders should be clarified, including the requirements for signal validation and subsequent notification to the Agency and national competent authorities.”
Tepsivo’s comment: The Committee acknowledges that clarifications are required, but the actual changes in the text do not really bring much clarity to the requirements.
It is quite easy to guess that the interpretation will be that the signal validation is no longer required to be performed by MAHs but what do the removal of “continuous monitoring of EV” requirement and the addition of other relevant data sources alongside with EV mean?
It is noted that there will be an update to the signal detection module of GVP, that can be expected to clarify the future requirements. This was another point that was frequently commented on in the feedback.
Amendment 6
“In order to facilitate the interoperability of systems, avoid the duplication of encoding activities concerning the same information and allow for an easier exchange of information, this Regulation takes into account developments in international standards used by marketing authorisation holders, national competent authorities and the Agency for the performance of pharmacovigilance activities, as well as the need for certain updates to terminology.“
Tepsivo’s comment: This part refers to the use of ISO IDMP as dictionaries for coding product information etc. The standards have been updated since the effective version of the legislation was published.
Amendment 7
“Suspected adverse reactions to a medicinal product are reported to the Eudravigilance database by means of individual safety reports. The reports should be as complete as possible, but in order to ensure some standardisation of reports, minimum reporting requirements should apply in all cases.“
Tepsivo’s comment: These changes highlight the need to report valid ICSR in all situations. The quality of reports in EV is known to be low and any attempt to lower the amount of trash in the system is welcome.
The text change generalizes the context to “reporting” without specifying “expedited” and it also suggests the possibility of reporting multiple reactions.
Amendment 8
“For better literature referencing in individual case safety reports, Member States and marketing authorisation holders should provide the digital object identifier (DOI), if available, when reporting suspected adverse reactions.“
Tepsivo’s comment: This is related to the data quality point same as the point above. The quality of literature reports can be very low in EudraVigilance.
There is a very high proportion of articles that are from “local literature screening” and refer to “articles” that are not available online and cannot be found by anyone else except the reporter.
Addition of DOI might help a little bit, but we know that most of these obscure references do not have a DOI either.
Amendment 9
“In order to clarify and strengthen the content of the periodic safety update report, that report should include updates on the implementation of risk minimisation measures.“
Tepsivo’s comment: While the previous document only required the results of assessments of the effectiveness of these activities, the new version emphasizes the need to also report on how these measures are being put into practice.
The PSUR template is amended to mention not only the effectiveness of risk minimization measures, but emphasizes their implementation.
It is understandable why PSUR content improvement is requested, but it is also easy to see how this adds to administrative work around periodic reporting. Is this the direction we want to go?
Shouldn’t we build smart systems for adverse event reporting that would make periodic reporting obsolete instead of relying on documents that live outside of the actual data systems (EV and safety database of the MAH)?
Amendment 10
“If national competent authorities, the Agency or the Commission have concerns about the safety of a medicinal product, they may oblige a marketing authorisation holder to initiate, manage and finance non-interventional post-authorisation safety studies.
In order for them to be transparent, the marketing authorisation holder should put such studies in the electronic post-authorisation study register maintained by the Agency.“
Tepsivo’s comment: This update makes complete sense and it seems that the main point of this update is to highlight the role of the PASS register ENCePP.
Next steps
It seems that this year, there will be the biggest change to EU PV legislation and practices since 2017. While it initially seemed like a minor amendment to the signal detection requirements with no impact for most MAHs (EMA’s signal pilot ending), after a more thorough review and assessment it seems that many changes will need to be made to pharmacovigilance processes and possibly to the agreements with partners.
While the amendment is not final, it seems that it will impact not only signal detection, but also EV downloads (if that can be considered a separate process from signal detection), PSMF maintenance, risk minimization measure effectiveness documentation, PV auditing and receiving audits and inspection, PSUR preparation process etc.
The goal is that this amendment will be finalized during the first half of 2025. We will see if that happens, and what the final text will look like. It might still be too early to start working on changes, but at this point it is already good to acknowledge that change is coming and probably make notes to whatever your change control and/or regulatory requirements or regulatory intelligence process requires.
This will most likely impact a large number of PV and quality processes and the actual services delivered by PV subcontractors related to EU PV.
Tepsivo is of course ready with our unique Tepsivo OnePV integrated PV system.
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