Pharmacovigilance is the scientific process of monitoring the safety of medicines, as well as acting to both reduce the risks and increase the benefits of medicines. It comprises the following key activities: (i) collecting and managing data on the safety of medicines; (ii) identifying any new safety issues or changes to existing safety issues that may arise); (iii) evaluating the data and making decisions with regard to safety issues; (iv) acting to protect public health (including regulatory action); (v) communicating with stakeholders; (vi) audit, both of the outcomes of any action taken and of the key processes involved. Stakeholders directly involved in pharmacovigilance include: (i) patients as the users/consumers of medicines; (ii) doctors, pharmacists, nurses and all other health care professionals working with medicines; (iii) regulatory authorities, including the EMA and those in the Member States responsible for monitoring the safety of medicines; and (iv) pharmaceutical companies and companies involved in importing or distributing medicines.
On 31 December 2010 the Commission published in the Official Journal of the European Communities Regulation (EC) No 1235/2010 (“the Regulation”) and Directive 2010/84/EC (“the Directive”) amending as regards pharmacovigilance Regulation (EC) No 726/2004 concerning medicinal products authorised through the centralised procedure (including advanced therapy medicinal products under Regulation (EC) No 1394/2007) and Directive 2001/83/EC concerning medicinal products authorised through the national, decentralised and mutual recognition procedure. The Regulation entered into force on 1 January 2011 and will apply from2 July 2012. The Directive will enter into force on 20 January 2011 and will be applicable from 21 July 2012.
These legal texts, which amend the existing pharmacovigilance legal framework for medicinal products marketed within the EU, originate from an initial legislative proposal dated 2008. This was adopted after a number of significant weaknesses in the existing EU system of pharmacovigilance were identified through an independent Commission sponsored study, extensive public consultation (in 2006 and again in 2007) and detailed analysis by the Commission services.
These weaknesses included: (i) a lack of clear roles and responsibilities for the key responsible parties and a lack of clear obligations against which they perform their roles (resulting in poor compliance); (ii) slow EU decision-making on drug safety issues particularly for nationally authorised products and frequent disharmony in action taken by the Member States; (iii) low levels of transparency relating to pharmacovigilance and relatively limited EU coordination of communication about the safety of medicines, plus complex product information with poor penetration of key warnings; (iv) cumbersome oversight of companies’ pharmacovigilance systems by the authorities; (v) a lack of proactive and proportionate monitoring including a lack of risk management and structured data collection in the form of post authorisation safety studies and duplicative reporting rules for the industry and authorities relating to both 15-day, literature and periodic reporting of ADRs; and (vi) lack of inclusiveness of stakeholders including a lack of direct patient reporting of ADRs and their virtual absence from decision-making.
Based on the results of the above studies and public consultations, on 26 February 2007 Commission Vice-President Günter Verheugen announced a strengthening of the EU’s pharmacovigilance system. On 10 December 2008 the Commission adopted a legislative proposal - as part of the broader “pharmaceutical package” - aiming to better protect patients by strengthening the EU’s system for the safety monitoring of medicines.
The proposals focused on the following aspects: (i) maintaining the current split of competences between the Member States and the EMA, while making clear their respective roles and responsibilities and minimising the duplication of effort; (ii) strengthening the rules on transparency relating to pharmacovigilance data, assessment and decision-making and involving stakeholders (e.g. patient and health care professional groups) in the processes, including reporting (including patient reporting); (iii) establishing clear standards (“Good Vigilance Practices – GVP”) for the conduct of pharmacovigilance by both the industry and the regulators; (iv) freeing up resources by rationalising and simplifying the reporting of suspected adverse drug reactions (ADRs), both expedited and periodic reporting, optimising current information technology (including Eudravigilance) and matching the reporting requirements with the level of knowledge about the safety of a specific product; and (v) establishing a clear legal requirement to conduct post-authorisation safety studies, including those in risk management systems.
The final text of the newly adopted legislation, consistent with the original proposal, strengthens and rationalises the Community system of pharmacovigilance for medicinal products for human use and in particular it:
- Clarifies roles and responsibilities for the parties concerned, including the role of the supervisory authority for pharmacovigilance, which is the competent authority of the Member State in which the pharmacovigilance system master file (see further below) is located. Such authority shall be responsible for verifying, on behalf of the EU, that the marketing authorisation holder (MAH) for the medicinal product satisfies the pharmacovigilance requirements laid down in Titles IX and XI of Directive 2001/83/EC and it may, if considered necessary, conduct pre-authorisation inspections to verify the accuracy and successful implementation of the pharmacovigilance system described by the applicant in support of his application for authorisation.
- Introduces a Pharmacovigilance Risk Assessment Advisory Committee which shall be responsible for the provision of pharmacovigilance assessments and of a number of recommendations on the safety of medicines at the EU level, for example:
- On risk management systems and monitoring their effectiveness; and
- On the mandatory conduction of post-authorisation efficacy studies where concerns relating to some aspects of the efficacy of the medicinal product are identified, and can be resolved only after the medicinal product has been marketed and/or when the understanding of the disease or the clinical methodology indicate that previous efficacy evaluations might have to be revised significantly.
As to the imposition of mandatory post-marketing studies made by the authority and based on the above recommendations, it should be noted that the MAH will have the opportunity to present written observations. However, in cases where such observations are not finally upheld by the Agency and/or the European Commission, the marketing authorisation shall be compulsorily varied to include the obligation as a condition of the marketing authorisation and the risk management system shall be updated accordingly.
Introduces the possibility for competent authorities to issue marketing authorisation subject to one or more of the following conditions: (a) to take certain measures for ensuring the safe use of the medicinal product to be included in the risk management system; (b) to conduct post-authorisation safety studies (PASS); (c) to comply with obligations on the recording or reporting of suspected adverse reactions which are stricter than those referred to in Title IX of Directive 2001/83/EC; (d) any other conditions or restrictions with regard to the safe and effective use of the medicinal product; (e) the existence of an adequate pharmacovigilance system; and (f) to conduct post-authorisation efficacy studies where concerns relating to some aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed.
Introduces the obligation for MAHs to maintain and make available on request a “Pharmacovigilance System Master File” in respect of one or more medicinal products. This is applicable to central marketing authorisations granted before 2 July 2012 as from either: (i) the date on which those marketing authorisations are renewed; or (ii) the expiry of a period of three years starting from 2 July 2012, whichever is earlier; and applicable to national marketing authorisation (including those authorised through the mutual recognition and decentralised procedure) granted before 21 July 2011 as from either: (i) the date on which those marketing authorisations are renewed; or (ii) the expiry of a period of three years starting from 21 July 2011, whichever is earlier.
Removes the current routine requirement for industry periodic reports (PSURs) for low risk, old and established products. In particular, periodic safety update reporting shall be linked to the risk management system for newly authorised medicinal products and routine reporting shall not be, in principle, required for:
Generic medicinal products;
Medicinal products containing an active substance for which well-established medicinal use has been demonstrated; and
Homeopathic medicinal products or for traditional-use registered herbal medicinal products.
It is foreseen, however, that competent authorities should also require periodic safety update reports with regard to such products when concerns arise relating to pharmacovigilance data or as a result of the lack of available safety data when the use of the active substance concerned is concentrated in medicinal products for which periodic safety update reporting is not routinely required.
- Introduces specific provisions on the supervision of non-interventional post-authorisation safety studies which are applicable as to centrally authorised medicinal products only to studies which have commenced after 2 July 2012 and as to nationally authorised medicinal products (including those authorised through the mutual recognition and decentralised procedure) only to studies which have commenced after 21 July 2011.
- Simplifies adverse reaction reporting and a clear legal basis for the reporting of suspected adverse drug reactions. In particular, a new ADR definition has been provided (“a response to a medicinal product which is noxious and unintended”); medication errors resulting in an ADR will also be reported; after a transitional period, the information on suspected adverse reactions shall be submitted electronically to the Eudravigilance database.
- Strengthens safety, transparency and communications relating to medicines. This is, particularly due to the establishment of a European medicines safety web-portal that contains the conclusions of the scientific assessment as well as any relevant recommendations. It is also foreseen that, at a later stage, both healthcare professionals and the public will have appropriate levels of access to the data contained in Eudravigilance database, but always in an aggregate format.
Based on the estimate provided by the authorities, it seems that full implementation of new legislation may take until at least 2013.
 The legal framework for pharmacovigilance with respect to centrally authorised medicinal products is provided for in Regulation (EC) No 726/2004 and with respect to nationally authorised medicinal products - including those authorised through the mutual recognition and decentralised systems in Directive 2001/83/EC. There are also a number of detailed guidelines on the execution of pharmacovigilance-related procedures (see for example Volume 9A of "The rules governing medicinal products in the European Union - Pharmacovigilance" and in the pharmacovigilance-related guidelines of ICH, E2 series). These legal texts are supplemented by Commission Regulation (EEC) 540/95, which regulates the procedures concerning "suspected unexpected non-serious adverse reactions".
 Both (1) the Commission proposal for a Directive of the European Parliament and of the Council amending Directive 2001/83/EC as regards pharmacovigilance, and (2) the Commission proposal for a Regulation of the European Parliament and of the Council amending, as regards the pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 were adopted on 10 December 2008 and then submitted to the European Parliament and the Council as per the co-decision procedure.
 The pharmaceutical package was made of three different legislative proposals. The first legislative proposal aims to ensure that EU citizens have access to reliable information on medicines (the so-called “information to patients proposal”); the second legislative proposal aims to better protect patients by strengthening the EU’s system for the safety monitoring of medicines (the so-called “pharmacovigilance proposal”); the third legislative proposal aims to strengthen EU legislation to better protect EU citizens from the serious threats posed by fake medicines (the so-called “anti-counterfeiting proposal”).