It is generally accepted (e.g. Amery, 1999) that it is not possible to detect all the adverse effects of a medicine during the pre-marketing clinical trials, because of a number of factors. First, trials are generally small (on average 1500 patients for a new drug substance); although they will detect common side effects, particularly those that are predictable from the pharmacology of the drug, they are too small to detect side effects that occur rarely (incidence of 1 in 10 000 or less). Additionally, medicines are used in clinical trials in a very controlled manner—they are given for a limited duration, to carefully selected patients who are closely monitored. This is in complete contrast to the manner in which the medicine may be used once marketed, when it may be used in patient populations for which it was not intended, may be given for long periods of time, and in combination with other medicines.
It is therefore vital to monitor the safety of medicines as used in routine clinical practice throughout their marketed life, in order to detect those side effects that are not identified through clinical trials. The best established way to do this is to collect reports of suspected adverse drug reactions (ADRs) via a spontaneous reporting scheme such as the Yellow Card Scheme.
All spontaneous reporting schemes, including the Yellow Card Scheme, have a number of limitations, perhaps the most significant of which is under-reporting (e.g. Griffin and Weber, 1992; see the section on weaknesses below). Despite this, such schemes have a proven track record as an "early warning'' system for the identification of new drug safety hazards. Examples of drug safety hazards identified through spontaneous reporting have been described previously (e.g. Rawlins, 1988b; Griffin and Weber, 1992); recent examples of ADRs identified through the Scheme are shown in Table 15.1.
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