The processes involved in the clinical development of medicines are illustrated in Figure 1. Once put onto the market, a medicine leaves the secure and protected scientific environment of clinical trials and is legally set free for consumption by the general population. At this point, most medicines will only have been tested for short-term safety and efficacy on a limited number of carefully selected individuals. In some cases as few as 500 subjects, and rarely more than 5000, will have received the product prior to its release.
For good reason, therefore, it is essential that new and medically still evolving treatments are monitored for their effectiveness and safety under real-life conditions post release. More information is generally needed about use in specific population groups, notably children, pregnant women and the elderly, and about the efficacy and safety of chronic use, especially in combination with other medicines. Experience has shown that many adverse effects, interactions (i.e. with foods or other medicines) and risk factors come to light only during the years after the release of a medicine (see Table 1).
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Box 1 What is pharmacovigilance?
WHO defines pharmacovigilance as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem.
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Figure 1 Clinical development of medicines
Table 1 Classical examples of serious and unexpected adverse reactions
Medicine |
Adverse reaction |
Aminophenazone (amidopyrine) |
Agranulocytosis |
Chloramphenicol |
Aplastic anaemia |
Clioquinol |
Myelooptic neuropathy (SMON) |
Erythromycin estolate |
Cholestatic hepatitis |
Fluothane |
Hepatocellular hepatitis |
Methyldopa |
Haemolytic anaemia |
Oral contraceptives |
Thromboembolism |
Practolol |
Sclerosing peritonitis |
Reserpine |
Depression |
Statins |
Rhabdomyolysis |
Thalidomide |
Congenital malformations |
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Box 2 Adverse drug reactions: the example of thalidomide
Thalidomide was introduced in 1957 and widely prescribed as an allegedly harmless treatment for morning sickness and nausea. It was soon linked to a congenital abnormality which caused severe birth defects in children of women who had been prescribed this medicine during pregnancy. By 1965, thalidomide had been removed from the market in most countries. Nevertheless, it continued to be used for the treatment of leprosy, and in more recent years, its indications have been extended to a much wider range of medical conditions. These uses are allowed only under strict supervision and specialist advice. Despite these precautions, between 1969 and 1995, 34 cases of thalidomide embryopathy were registered in leprosy endemic areas in South America by the Latin American Collaborative Study of Congenital Malformations.
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