Implementation of the pharmacovigilance legislation
HumanRegulatory and procedural guidancePharmacovigilance
The pharmacovigilance legislation, which came into effect in 2012, introduced a range of tasks and streamlined existing responsibilities for regulators and the pharmaceutical industry in the European Union (EU).
Information on EU pharmacovigilance fees to be charged for human pharmacovigilance activities is available on Pharmacovigilance fees payable to the European Medicines Agency (EMA).
Multi-annual reports on pharmacovigilance activities
EMA and the Heads of Medicines Agencies (HMA) publish multi-annual reports on the pharmacovigilance activities of the European medicines regulatory network.
These reports provide an overview of the longer-term impact of the pharmacovigilance legislation.
The report covering 2019 to 2022 contains an overview of the measures implemented to ensure the safety of all authorised medicines in the EU during the COVID-19 pandemic.
These included intensified monitoring of COVID-19 vaccines complemented by the use of real-world evidence and enhanced international collaboration.
The report also describes how the network carried out its core regulatory activities by prioritising tasks during the pandemic.
Previous reports
Collection of key information on medicines
Risk-management plans
The pharmacovigilance legislation strengthened procedures concerning risk-management plans. This includes requiring a risk-management plan for all new medicines and the publication of summaries of risk-management plans, which the Agency began in March 2014. Risk-management plans ensure that proactive planning of data collection and of risk minimisation takes place. They are essential for the safe introduction of new products for patients.
- For more information, see Risk-management plans.
Periodic safety update reports
The legislation sets out the format and content for periodic safety update reports (PSURs) and foresees the 'single assessment' of PSURs for multiple products that contain the same active substance or combination of active substances.
Single assessments of PSURs for centrally authorised medicines began in July 2012. Single assessment was expanded to nationally authorised medicines in April 2013.
Routine PSUR reporting is no longer necessary for generic products, although regulatory authorities can request PSURs if concerns arise.
- For more information, see Periodic safety update reports.
PSUR repository
In accordance with the pharmacovigilance legislation, EMA launched an electronic central repository for PSURs and their assessment reports on 26 January 2015.
On 12 June 2015, the EMA Management Board gave its green light for the repository to be used as the single, central platform for all information related to PSURs in the EU. The use of the repository is mandatory since 13 June 2016.
The repository facilitates the pharmaceutical industry's submission of PSURs electronically, and gives secure access to authorised users from national competent authorities in EU Member States, EMA, EMA committees, and the European Commission. This ensures that all parties involved in benefit-risk assessments of medicines have timely access to all relevant documents in one location.
Post-authorisation safety and efficacy studies
The legislation strengthened the legal basis for requesting post-authorisation safety studies (PASSs) and post-authorisation efficacy studies (PAESs) from the pharmaceutical industry.
The Pharmacovigilance Risk Assessment Committee (PRAC) now has the task of approving PASS protocols. It can also require and enforce PASSs or PAESs, in order to improve the benefit-risk monitoring of medicines.
- For more information, see Post-authorisation safety studies.
Data submission for authorised medicines
The legislation requires marketing-authorisation holders to submit structured electronic information to the Agency on medicines authorised in the European Union (EU) and European Economic Area (EEA).
This is to ensure that the pharmacovigilance systems of the Agency, national competent authorities and industry are driven by accurate, complete and reliable information on medicines, substances and organisations.
During 2014, the pharmaceutical industry was required to re-submit data to the Agency to ensure that it is up-to-date, complete and of high-quality.
Since the start of 2015, the focus is on maintaining the data. Marketing-authorisation holders must notify EMA on:
- new marketing authorisations within 15 calendar days from the date of notification of the granting of the marketing authorisation by the national competent authority;
- any amendments to the terms of marketing authorisations following variation, transfer, renewal, suspension, revocation or withdrawal no later than 30 calendar days from the date on when the amendments were authorised.
For more information, see Data submission for authorised medicines.
Adverse-drug-reaction reporting by patients and healthcare professionals
The legislation introduced the right of individual European citizens to report suspected side effects directly to national medicine regulatory authorities and marketing-authorisation holders.
Information on suspected side effects of medicines is available to view in the European database of suspected adverse drug reaction reports.
For more information, see 'Guideline on good pharmacovigilance practices: Module VI – Management and reporting of adverse reactions to medicinal products' on good pharmacovigilance practices.
Pharmacovigilance system master files
Marketing-authorisation holders are now required to maintain a pharmacovigilance system master file (PSMF) permanently available for submission or inspection by regulatory authorities.
Notification requirements for cessation of marketing and withdrawal
Since the 2012 amendments to the pharmacovigilance legislation, marketing-authorisation holders of human medicines have to notify EU regulators of any action to withdraw a product from the market, together with the reason for this action, when the decision is based on any of the following grounds:
- the medicine is harmful;
- the medicine lacks therapeutic efficacy;
- the risk-benefit balance of the medicine is not favourable;
- the qualitative and quantitative composition of the medicine are not as declared;
- manufacturing or inspection issues have been identified.
For more information, see Withdrawals and cessation of centrally and nationally authorised medicines: questions and answers.
Medical literature monitoring
The legislation requires the Agency to provide a service to monitor selected medical literature on suspected adverse reactions to medicinal products containing certain active substances. This ensures that individual cases are entered into EudraVigilance in the required electronic format for adverse reaction reporting. These reports are subsequently forwarded to the national competent authority of the respective European Economic Area (EEA) Member State.
This is in line with the reporting principles set out in module VI of the guideline on good pharmacovigilance practices.
The pharmaceutical industry are able to download Individual case safety reports (ICSRs) from the system. This allows marketing-authorisation holders to process these ICSRs in their safety databases and meet their reporting obligations outside the EEA as applicable.
EMA has published the MLM substance and herbal substance groups covered by the medical literature monitoring service. The list contains active substances, including herbals, with high numbers of marketing authorisations granted to various marketing-authorisation holders in the EEA.
The service became fully operational on 1 September 2015, covering 300 chemical active substance groups and 100 herbal active substance groups monitored by EMA.
- For more information, see Monitoring of medical literature and entry of adverse reaction reports into EudraVigilance
Analysis and understanding of data and information
Strengthened signal detection
The legislation brought in a stronger process for detecting safety signals for centrally authorised medicines by the Agency and strengthened the coordination of Member State signal detection for nationally authorised medicines.
- For more information, see Signal management.
Enhancement of EudraVigilance
On 22 November 2017, EMA launched a new and improved version of EudraVigilance (human).
The new system has enhanced features for the reporting and analysis of suspected adverse reactions, to support stronger safety monitoring of medicines and a more efficient reporting process for stakeholders.
- For more information, see EudraVigilance.
Additional monitoring of medicines
The legislation introduced the concept of additional monitoring for medicines that are being monitored particularly closely by regulatory authorities. These medicines have an inverted black triangle printed on the product information.
- For more information, see Medicines under additional monitoring.
Regulatory action to safeguard public health
Changes in scientific committees and decision-making
The legislation established the PRAC, which began meeting in July 2012.
It also changed the mandate of the existing Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh). This Group now leads on decision-making based on recommendations from the PRAC for nationally authorised medicines, ensuring harmonised implementation of safety recommendations across the EU.
Strengthened referral procedures
The legislation introduced the Article 107i procedure for safety-related issues to rapidly assess significant emerging safety issues linked with a medicine available in the EU. This procedure can be used regardless of the medicine's initial authorisation route, either central or national.
All pharmacovigilance referrals are assessed by the PRAC, whose recommendations are relied upon by the Committee for Medicinal Products for Human Use (CHMP) or the CMDh.
The legislation also increased transparency for safety referrals procedures, with the publication of more information on each referral online and the opportunity for the public to engage with the Agency through public hearings.
- More information is available on Referral procedures.
Communicating with stakeholders
Publishing of information on medicines
The Agency publishes the agendas and minutes of all of its committees, including the PRAC and CHMP in line with the legislation.
The Agency is also working towards the launch of the European medicines web portal, which will include information on all medicines authorised in the EU. Until the launch of the fully functional portal, this website (ema.europa.eu) publishes all relevant information in accordance with the legislation.
Coordination of safety messages
The legislation gives the Agency a central role in coordinating announcements on the safety of medicines across the EU, including nationally authorised medicines. This aims to ensure consistent and coherent safety advice on medicines that are available in more than one Member State.
For more information, see:
Public hearings
The legislation gives the Agency the ability to organise public hearings for safety-related referral procedures. When considered necessary by the PRAC, members of the public can take part in public hearings on specific issues relating to the safety of medicines, either in person or online.
The PRAC adopted the rules of procedure for public hearings in April 2016, after they were endorsed by EMA's Management Board:
For more information, see Public hearings.