Introduction

The thalidomide disaster, which caused the development of phocomelia in nearly 10 000 children whose mothers took thalidomide during pregnancy,1 was the stimulus for the establishment of systems to monitor suspected adverse drug reactions (ADRs) and the development of modern pharmacovigilance. The reasons for monitoring postmarketing drug safety were summarized in 1970 in a report of the Committee on Safety of Drugs in the UK (which later became the Committee on Safety of Medicines, CSM):

No drug which is pharmacologically effective is entirely without hazard. The hazard may be insignificant or may be acceptable in relation to the drug’s therapeutic action. Furthermore, not all hazards can be known before a drug is marketed; neither tests in animals nor clinical trials in patients will always reveal all the possible side effects of a drug. These may only be known when the drug has been administered to large numbers of patients over considerable periods of time.

Premarketing clinical trials are effective in studying the efficacy of medicines. However, while they define many aspects of the safety profiles of medicines, premarketing clinical trials have limitations in defining the clinically necessary safety profiles of drugs. These limitations include:

• The small numbers of patients, in epidemiologic terms, included in premarketing clinical trial programs;
• The large numbers of patients in these programs who receive the study products for short durations (many only receive a single dose); this limits the power of premarketing clinical trials to detect rare ADRs or ADRs with long latency;
• Premarketing development programs are dynamic; doses and formulations can change during drug development; in some programs, large numbers of patients studied receive lower doses or different formulations from those eventually marketed;
• The exclusion from clinical trials of special populations such as the young, the old, women of childbearing age, and patients with concurrent diseases, eliminates many patients who may be at higher risk for developing ADRs, limiting the generalizability of the results of such trials.

Therefore, there has been general agreement for more than 30 years that the clinically necessary understanding of drug safety depends on postmarketing monitoring and postmarketing safety studies. This has resulted in not only the establishment of voluntary systems for reporting suspected ADRs (see Chapters 9 and 10) but the development of a range of other methods to monitor and study postmarketing drug safety.

Soon after the establishment of spontaneous reporting systems, it was recognized that, while such systems have many real advantages for detecting and defining ADRs, particularly rare ADRs, they also have limitations.

The theoretical basis for establishing a system to monitor events regardless of relatedness to drug exposure was proposed by Finney in 1965.5 This and the limited contribution of the spontaneous reporting system in detecting hazards such as the oculomucocutaneous syndrome with practolol led Inman to establish the system of Prescription-Event Monitoring (PEM) at the Drug Safety Research Unit (DSRU) at Southampton in 1981.6 Subsequently the CSM, wishing to consider monitoring the postmarketing safety of medicines, established a committee under the chairmanship of Professor David Grahame-Smith. The committee reported in June 1983 and again in July 1985, and in these reports showed an appreciation of the need for prescription-based monitoring. It also specifically recommended that postmarketing surveillance (PMS) studies should be undertaken “on newly-marketed drugs intended for wide-spread long-term use.”7 PEM is one form of pharmacovigilance that, with the development and harmonization of drug regulation in the European Community, has its basis in Directives 65/65 and 75/319, and in Regulation 2309/93.