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 (Stephens and Brynner, 2001).
Regulatory
Pharmacovigilance in the EU
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
(Stephens and Brynner, 2001). 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 quality, safety and efficacy of medicines through
systems of standards for development and manufacturing, autho-risation,
pharmacovigilance and inspection. In the European Union (EU), 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 early in the third millennium. In particular, quality, safety
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, safety and efficacy which
are necessary to gain a marketing authorisation, pharmacovigilance remains a
high priority for regulatory authorities in the EU. Although the quality and
efficacy of a medicine are generally well described at the time of
autho-risation, 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 objec-tives of
regulatory pharmacovigilance (Waller, Coul-son and Wood, 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 important safety issues. However,
both false positives and false negatives have being the failure to identify the
oculomucocuta-neous syndrome induced by practolol at an early stage (Felix, Ive
and Dahl, 1974). Specific limitations of spontaneous reporting schemes include
underreport-ing and uncertainty about causality and frequency. Thus, many other
sources of information are also used. There is increasing emphasis on
epidemiological stud-ies and the use of databases in the EU Member States such
as the UK General Practice Research Database (Walley and Mantgani, 1997, see
Chapter 27) and the Dutch PHARMO system (Herings, 1993) 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 Medici-nal Products (EMEA), since 2004 called the European
Medicines Agency, and to a new regulatory system that includes procedures for a
centralised authori-sation and multiple identical authorisations through a
decentralised procedure and a mutual recognition procedure. These procedures
have had a consider-able 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 Pharmacovigi-lance Working Party (PhVWP)
of the Committee for Medicinal Products for Human Use (CHMP, previ-ously called
CPMP). This involves agreed standards and procedures as well as systems for
exchanging information and decision-making, which are described further below.
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