Legal Basis, Principles and Organisation of the EU Pharmacovigilance System

LEGAL BASIS, PRINCIPLES AND ORGANISATION OF THE EU PHARMACOVIGILANCE SYSTEM

The concept of pharmacovigilance was introduced into the legislation at EU level in 1993 through a Council Directive (Council Directive 93/39/EEC amending Council Directive 75/319/EEC). EU medicines legislation has since been codified into a single Directive (2001/83/EC) in which pharma-covigilance is covered in Title IX (Articles 101–108). Directives of the European Parliament and the Council have the objective of harmonising the national legis-lation of the EU Member States, and Member States are bound to implement these legal provisions into their national legislations. However, pharmacovigi-lance systems already existed in most countries which were Member States in 1993 and also in many of those joining the EU through the enlargement process in 2004. These systems vary according to differences in historical development and the organisation of health-care at national level. Table 14.2 summarises the organisational features of the national pharmacovigi-lance systems. All are an integral part of the respective national drug regulatory authority (except in Luxem-bourg for which spontaneous reports are submitted to one of the French regional centres located in Nancy). Through the EU legislation, their activities are speci-fied with regard to medicinal products authorised for use on their territory as follows:

·    to collect information about suspected ADRs that occur under normal conditions of use;

·    to obtain information on consumption data;

·    to collate information on misuse and abuse;

·    to evaluate this information scientifically; and

·    to ensure the adoption of appropriate regulatory decisions.

Practice has shown that pharmacovigilance needs to be conducted with a view to how the product is used in ordinary clinical practice. This includes use outside the terms of the marketing authorisation. Experience gained during the post-authorisation phase may also provide valuable input into the evaluation of medici-nal products at the stage of application for marketing authorisation, if there are chemical or pharmacologi-cal similarities with authorised products.

The national pharmacovigilance systems of the Member States together form the pharmacovigilance system in the EU, co-operating in a network structure under the co-ordination of the EMEA and in liaison with the European Commission. Also included are Norway, Iceland and Liechtenstein, which are not members of the EU but are part of the European Economic Area (EEA) (EEA Joint Committee, 1999). Within this network structure, all parties have their roles and responsibili-ties for the surveillance of medicinal products. These roles and responsibilities vary depending on the route of marketing authorisation of the product in the EU and are defined in Directive 2001/83/EC, as amended in 2004 as a result of an intensive legislative review process, and Council Regulation (EEC) No. 2309/93, replaced, likewise through the review process, as of 20 November 2005 by Regulation (EC) No. 726/2004. They are further described in guidance documents which were developed at EU level during the 1990s for the competent authorities and marketing authorisa-tion holders in consultation with Member States and interested parties (Table 14.3). These guidelines are in accordance with recommendations agreed at the Inter-national Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). They have been amended in the light of experience and are available in a compiled format (European Commission, 2006).

The EMEA is a Community agency, that is a public authority of the EU, set up by a Community act of secondary legislation (Council Regulation (EEC) No. 2309/93) with its own legal personality (European Union institutions and other bodies, 2005). The objec-tive of the EMEA is the protection and promotion of human and animal health in the EU by fulfilling, inter alia, the following tasks with respect to human medicines:

·    the co-ordination of the scientific evaluation of qual-ity, safety and efficacy of medicinal products that have been applied for a central marketing authorisa-tion with the aim of facilitating the access to effective and safe innovative medicinal products throughout the EU; and

·    the co-ordination of post-authorisation safety of medicinal products through the pharmacovigilance network.

·    The EMEA pools scientific expertise from the Member States for the evaluation of medicinal prod-ucts, and to provide advice on drug research and development programmes (European Medicines Agency, 2005). More specific to pharmacovigi-lance, the tasks of the EMEA include the following:

–       co-ordination of the supervision (including phar-macovigilance activities) of medicinal products authorised in the EU;

–       provision of access to information on suspected ADRs reported for medicinal products marketed in the EU by means of a database and data-processing network (EudraVigilance);

–       maintenance of and variations to the terms of the marketing authorisation for centrally authorised products and

–       management of referral procedures for nationally authorised products leading to Commission Deci-sions binding in all Member States when there is a safety concern which impacts on public health in the Community; and provision of recommen-dations on measures necessary to ensure safe and effective use of these products.

EudraVigilance was put in place by the EMEA from December 2001 (European Medicines Agency, 2004), enabling the electronic transmission of ADR case reports to a central point accessible by all competent authorities in the EU and exchange of pharmacovig-ilance information between all stakeholders (market-ing authorisation holders, national competent authori-ties and EMEA). In addition to the case reports aris-ing worldwide post-marketing, EudraVigilance was extended to include clinical trials data as of May 2004. These developments are in line with international devel-opments at ICH level (Tsintis and LaMache, 2004) and proactive pharmacovigilance and risk management (Waller and Evans, 2003). Guidance for the electronic submission of case reports on ADRs in relation to medicinal products authorised in the EU is provided (European Commission, 2006).

Much of the work of the EMEA is done within its scientific committees. For medicines used in humans this is the CHMP. This committee is supported by several expert working parties, one of which is the PhVWP. The PhVWP currently meets eleven times per year at the EMEA. Its mission is to provide advice on the safety of medicinal products and the investigation of ADRs to enable effective risk identification, assessment and management, in the pre- and post-authorisation phase, leading to recommendations on harmonised and synchronised action. These are ultimately imple-mented either by the European Commission following a CHMP Opinion for centrally authorised products or by national competent authorities. The PhVWP also takes the lead in the development of pharmacovigilance guidelines.

To facilitate, in addition, a continuous exchange of information between regulators in the EU, in particu-lar with regard to changes in the benefit–risk balance possibly requiring major regulatory action, but also for signal evaluation, the so-called rapid alert-non-urgent information system has been established. Records of this information flow are maintained centrally by the EMEA and followed up by the PhVWP at each of their meetings. The principles and procedures of this system are presented in a guideline (European Commission, 2006).

Pharmaceutical companies holding marketing autho-risations in the EU have various obligations in the area of pharmacovigilance that are laid down in Title IX of Directive 2001/83/EC and Regulation (EC) No 726/2004 and elaborated further in guidelines (Euro-pean Commission, 2006). In particular, marketing authorisation holders must employ a qualified person who is responsible for

·     establishing and maintaining a system that collects and collates all suspected ADRs;

·     the preparation of periodic safety update reports;

·     responding to requests for additional information from competent authorities; and

·     provision to competent authorities of any other infor-mation relevant to the risk-benefit evaluation.

In addition, marketing authorisation holders are obliged to report serious suspected ADRs in accordance with the legislation and guidance cited above to competent authorities within 15 days (‘expedited reports’).