New pharmacovigilance legislation (Regulation (EU) No 1235/2010 and Directive 2010/84/EU) was adopted by the European Parliament and European Council in December 2010. The legislation was the biggest change to the regulation of human medicines in the European Union (EU) since 1995. It has significant implications for applicants and holders of EU marketing authorisations. The European Medicines Agency is responsible for implementing much of the new legislation, which has been effective since July 2012.
The legislation is accompanied by the implementing regulation. This is a legally binding act published by the European Commission in June 2012 that provides details on the operational aspects for the new legislation:
Role of the European Medicines Agency
The European Medicines Agency, the EU Member States and the European Commission are responsible for implementing much of the new legislation. The Agency plays a key role in coordinating activities relating to the authorisation and supervision of medicines, including safety monitoring, across this network.
The Agency is working with a wide range of stakeholders including the European Commission, pharmaceutical companies, national medicines regulatory authorities, patients and healthcare professionals to ensure effective implementation. Most of the legislation had to be implemented within 18 months of becoming law or by July 2012.
Background to the new legislation
A strong factor in the development of the new Directive and Regulation is the incidence of so-called adverse drug reactions (ADRs) - responses to a medicine that are ‘noxious and unintended’. ADRs are estimated to cause 197,000 deaths per year in the EU. A strengthened European safety monitoring system aims to reduce the number of ADRs.
The European Commission began a review of the European system of safety monitoring in 2005 including an independent study sponsored by the European Commission and extensive public consultation in 2006 and 2007. The legislation was adopted by the European Parliament and Council of Ministers in December 2010.
Impacts of the new legislation on marketing-authorisation holders
Marketing-authorisation applicants and holders are impacted by the legislation in a number of key areas. The legislation aims to:
- make roles and responsibilities clear;
- minimise duplication of effort;
- free up resources by rationalising and simplifying periodic safety update reports (PSURs) and adverse-drug-reaction (ADR) reporting;
- establish a clear legal framework for post-authorisation monitoring.
Examples of impacts on marketing authorisation holders and applicants include:
EudraVigilance / ADR reporting
- Following a successful audit, marketing authorisation holders submit ADR reports only into EudraVigilance – previously, reports went via the individual national competent authority. This includes reporting of medication errors that result in an adverse reaction.
Simplified safety monitoring
- PSURs have a single assessment for the same active substance or a combination of active substances.
- Routine PSUR reporting is no longer necessary for products with low risk or for old or established products unless concerns arise.
- PSUR reporting is electronic following the establishment of an EU repository. PSURs are sent directly to the European Medicines Agency.
- There is a strengthened legal basis for requesting post-authorisation safety and efficacy studies (PASSs / PAESs) from the pharmaceutical industry.
- Risk-management systems are required for all newly authorised medicines.
- All pharmacovigilance referrals are discussed by the Pharmacovigilance Risk Assessment Committee (PRAC) and the Committee for Medicinal Products for Human Use (CHMP) or the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh). Opinions are adopted as a result.
Inspections and pharmacovigilance systems
- Marketing-authorisation holders are required to maintain a pharmacovigilance system master file (PSMF) permanently available for submission or inspection by the national competent authority. The PSMF replaced the detailed description of the pharmacovigilance system (DDPS).
Supply of medicinal product information to the Agency
- Regulation 1235/2010 states that by 2 July 2012, marketing-authorisation holders had to have submitted information to the Agency on medicinal products for human use authorised or registered in the EU using an electronic format provided by the Agency. Marketing-authorisation holders are also responsible for maintaining this information once submitted.
For background information on the legislation and its impacts for the EU public, see 2010 pharmacovigilance legislation.
2012 amendments to the legislation
The pharmacovigilance legislation was amended in October 2012 by Regulation (EU) No 1027/2012, which applies as of 5 June 2013 and Directive 2012/26/EU, which applies as of 28 October 2013. The amendments aim to further strengthen of the protection of patient health by allowing the European medicines regulatory action promptly and appropriately.
Notification requirements for cessation of marketing and withdrawal
Marketing-authorisation holders of human medicines now have to notify the EU regulators of any action to withdraw a product from the market, together with the reason for this action.
These notifications need to be sent to the European Medicines Agency both for centrally and for nationally authorised medicines, and also to the concerned Member States for nationally authorised medicines, when the decision to withdraw the product 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.
Article-107i referral procedures are now triggered automatically if a Member State or the European Commission suspends or revokes a marketing authorisation, prohibits the supply of a marketing authorisation or refuses a renewal of a marketing authorisation as a result of the evaluation of data resulting from pharmacovigilance activities. They are also triggered if marketing-authorisation holder interrupts the placing on the market of a medicine or takes action to have a marketing authorisation withdrawn, or that it intends to do so, on the basis of safety concerns.
For Article-31 referral procedures, the Commission or a Member State can now decide to suspend or prohibit the use of a medicine at any stage of the procedure when it considers this necessary to protect public health, as a temporary measure until a definitive decision on the referral is adopted. Centrally authorised medicines can also be included in Article-31 procedures containing a range of medicines, whether the grounds for the procedure are based on safety, efficacy or quality issues.
More information is available on referral procedures.
Translation exemptions now include cases of severe issues of availability, including shortages of medicines. In these cases, the marketing-authorisation holder can request an exemption to translate the package leaflet, and now also the labelling, of the medicine into the official languages of the Member State concerned.
For more information, see the guideline on the packaging information of medicinal products for human use authorised by the Union.
The mandatory scope of the medicines subject to additional monitoring has been extended to include:
- medicines given conditional approval or authorised under exceptional circumstances and medicines authorised with specific obligations on the recording or monitoring of suspected adverse drug reactions;
- medicines for which the marketing-authorisation holder is required to carry out a post-authorisation safety study (PASS).
Impact of the legislation on EU citizens and patients
For patients and EU citizens, the new legislation has a number of goals:
- to inform them on the benefit-risk aspects of taking a medicine;
- to provide the opportunity for them to report perceived problems with a medicine through online reporting forms and take part in public hearings;
- to raise awareness of safety issues through the creation of new websites with information on medicine safety issues;
- to increase public confidence in the safety-monitoring system and the positive-risk benefit of medicines.
The activities introduced with the new legislation fall into four main areas:
- Directive 2010/84/EU
- Regulation (EU) No 1235/2010
- Consolidated version of Directive 2001/83/EU
- Consolidated version of Regulation (EC) No 726/2004
- Commission Implementing Regulation (EU) No 520/2012
- European Commission: Pharmacovigilance - major developments
- New European Union pharmacovigilance legislation – Key concepts (08/02/2013)
- Better vigilance for public health protection - Overview of the new European Union pharmacovigilance legislation (22/05/2013)
- Communication with stakeholders as part of the European Union's new pharmacovigilance legislation (25/03/2013)
- Collection of key information on medicines as part of the European Union's new pharmacovigilance legislation (25/03/2013)
- Better analysis and understanding of data and information as part of the European Union's new pharmacovigilance legislation (25/03/2013)
- Regulatory action to safeguard public health as part of the European Union's new pharmacovigilance legislation (25/03/2013)