Introduction And Historical Perspective

Modern drug regulation in Europe began in the 1960s in the wake of the occurrence of several thousand cases (most of them in Europe) of phocomelia, a congenital limb abnormality which was caused by exposure to thalidomide during pregnancy (Burley, 1988). In response to this tragedy spontaneous adverse drug reaction (ADR) reporting schemes were developed with the aim of providing signals of unexpected hazards. Also legislation was passed to provide regulatory controls on safety, quality and efficacy of medicines through systems of standards for development and manufacturing, authorisation, pharmacovigilance and inspection. In Europe, the first Community Directive on medicines was enacted in 1965 (Council Directive 65/65/EEC) and laid down basic principles relating to these systems, which are still operational at the turn of the millennium. In particular, safety, quality and efficacy are the criteria through which medicines are regulated and other factors, such as cost, are not taken into account in decisions relating to the granting of a marketing authorisation.

Despite the extensive requirements for evidence on quality, efficacy and safety which are necessary to gain a marketing authorisation, pharmacovigi-lance remains a high priority for regulatory authorities in the European Union (EU). Although the quality and efficacy of a medicine are generally well described at the time of authorisation, conclusions on the adverse effect profiles of medicines from clinical trials are limited by the numbers and selectivity of patients included in such trials, their duration, and the relatively controlled conditions under which they are conducted. Safety in practice can only be assessed after marketing and it is well recognised that hazards may emerge at any time during the life of a product. Hence there is a need to monitor continuously the safety of all marketed medicines indefinitely. The overall objectives of regulatory pharmacovigilance (Waller et al., 1996) are summarised in Table 14.1.

Spontaneous reporting schemes continue to underpin such monitoring throughout the EU and have proved successful in identifying many

Table 14.1. Objectives of regulatory pharmacovigilance.

1. Long-term monitoring of drug safety in clinical practice to identify previously unrecognised drug safety hazards or changes in the adverse effect profiles.

2. Assessment of the risks and benefits of licensed medicines, in order to take action to improve drug safety.

3. Provision of information to users to optimise safe and effective use of their medicines.

4. Monitoring the impact of any action taken.

important safety issues. However, both false positives and false negatives have occurred, one of the most striking examples of the latter being the failure to identify the oculomucocutaneous syndrome induced by practolol at an early stage (Felix et al., 1974). Specific limitations of spontaneous reporting schemes include underreporting, and uncertainty about causality and frequency. Thus many other sources of information are also used. There is increasing emphasis on epidemiolo-gical studies and the use of databases such as the UK General Practice Research Database (Wood and Waller, 1996; Walley and Mantgani, 1997) and the Dutch PHARMO system (Herings, 1993) in order to evaluate the safety of marketed medicines.

During the early 1990s closer co-operation between Member States developed as proposals for a more closely integrated regulatory system were formulated. Ultimately this led in 1995 to the establishment of the European Agency for the Evaluation of Medicinal Products (EMEA) and to a new regulatory system that includes procedures for a centralised authorisation and multiple identical authorisations through mutual recognition. These systems have had a considerable impact on the operation of pharmacovigilance in the EU. Although pharmacovigilance continues to be based on national systems, particularly in terms of data collection and expertise, there is central co-ordination through the EMEA and the Phar-macovigilance Working Party (PhVWP) of the Committee for Proprietary Medicinal Products (CPMP). This involves agreed standards and procedures, and systems for exchanging information and decision-making, which are described further below.

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