WHO 9 Policy Perspectives on Medicines Pharmacovigilance: ensuring the safe use of medicines October 2004 World Health Organization Geneva odern medicines have changed the way in Why pharmacovigilance Mwhich diseases are managed and controlled. is needed However, despite all their benefits, evidence con- tinues to mount that adverse reactions to medicines The processes involved in the clinical development are a common, yet often preventable, cause of of medicines are illustrated in Figure 1. Once put onto illness, disability and even death. In some countries, the market, a medicine leaves the secure and pro- adverse drug reactions (ADRs) rank among the tected scientific environment of clinical trials and top 10 leading causes of mortality. Aside from the is legally set free for consumption by the general intrinsic dangers associated with the products them- population. At this point, most medicines will only have selves, individual patients may exhibit particular and been tested for short-term safety and efficacy on a unpredictable sensitivities to certain medicines. In limited number of carefully selected individuals. In addition, if more than one medicine is prescribed, some cases as few as 500 subjects, and rarely more there is always a risk of negative interactions. The than 5000, will have received the product prior to its selection and use of the best and safest medicine(s) release. for a given individual out of the many choices avail- able thus requires considerable skill on behalf of the For good reason, therefore, it is essential that new and prescribing practitioner. medically still evolving treatments are monitored for their effectiveness and safety under real-life condi- In order to prevent or reduce harm to patients and tions post release. More information is generally thus improve public health, mechanisms for evaluat- needed about use in specific population groups, ing and monitoring the safety of medicines in clinical notably children, pregnant women and the elderly, use are vital. In practice this means having in place a and about the efficacy and safety of chronic use, well-organized pharmacovigilance system. Pharma- especially in combination with other medicines. covigilance – an umbrella term used to describe the Experience has shown that many adverse effects, processes for monitoring and evaluating ADRs – is a interactions (i.e. with foods or other medicines) and key component of effective drug regulation systems, risk factors come to light only during the years after clinical practice and public health programmes. the release of a medicine (see Table 1). Figure 1 Clinical development of medicines Box 1 What is pharmacovigilance? Phase I Phase III 20 – 50 healthy volunteers 250 – 4000 more varied to gather preliminary data patient groups. – to determine WHO defines pharmaco- short-term safety and efficacy vigilance as the science Animal experiments for Phase II acute toxicity, organ 150 – 350 subjects Phase IV and activities relating to damage, dose dependence, with disease – to Post-approval studies metabolism, kinetics, determine safety to determine specific the detection, assessment, carcinogenicity, and dosage safety issues mutagenicity/teratogenicity recommendations understanding and prevention of adverse Preclinical Phase IV Spontaneous Animal Phase I Phase II Phase III effects or any other Experiments Post-approval Reporting medicine-related problem. Registration Development Post Registration Page 1: WHO Policy Perspectives on Medicines — Pharmacovigilance: ensuring the safe use of medicines Over the last decade, it has been increasingly Table 1 Classical examples of serious and unexpected recognized that the scope of pharmacovigilance adverse reactions needs to be extended beyond the strict confines of detecting new signals of safety concerns. Globaliza- Medicine Adverse reaction tion, consumerism, the resulting explosion in free trade and communication across borders, and increasing Aminophenazone (amidopyrine) Agranulocytosis use of the Internet have all contributed to a change Chloramphenicol Aplastic anaemia in the way people access medicinal products and Clioquinol Myelooptic neuropathy (SMON) information about them. These changing patterns Erythromycin estolate Cholestatic hepatitis in drug use require a shift in the approach to Fluothane Hepatocellular hepatitis pharmacovigilance, more specifically, towards one Methyldopa Haemolytic anaemia that is more closely linked, and thus better able to Oral contraceptives Thromboembolism respond, to the prevailing patterns of drug use within Practolol Sclerosing peritonitis society. Reserpine Depression Statins Rhabdomyolysis Thalidomide Congenital malformations Partners in pharmacovigilance The management of the risks associated with the use of medicines demands close and effective collaboration between the key players in the field Box 2 Adverse drug reactions: the example of pharmacovigilance. Sustained commitment to of thalidomide such collaboration is vital if the future challenges in pharmacovigilance are to be met, and if the disci- Thalidomide was introduced in 1957 and widely prescribed pline is to continue to develop and flourish. Those as an allegedly harmless treatment for morning sickness responsible must jointly anticipate, describe and and nausea. It was soon linked to a congenital abnormality which caused severe birth defects in children of women respond to the continually increasing demands and who had been prescribed this medicine during pregnancy. expectations of the public, health administrators, By 1965, thalidomide had been removed from the market policy officials, politicians and health professionals. in most countries. Nevertheless, it continued to be used However, there is little prospect of this happening in for the treatment of leprosy, and in more recent years, its the absence of sound and comprehensive systems indications have been extended to a much wider range which make such collaboration possible. The con- of medical conditions. These uses are allowed only under strict supervision and specialist advice. Despite these straints typically include lack of training, resources, precautions, between 1969 and 1995, 34 cases of political support, and most especially scientific infra- thalidomide embryopathy were registered in leprosy structure. Understanding and tackling these are an endemic areas in South America by the Latin American essential prerequisite for future development of the Collaborative Study of Congenital Malformations. science and practice of pharmacovigilance. The aims of pharmacovigilance Box 3 Monitoring the safety of medicines: key partners Events such as the thalidomide tragedy highlight the extreme importance of effective drug monitor- • Government • Health professionals ing systems for all medicines. The principal aims of • Industry •Patients pharmacovigilance programmes are: • Hospitals and academia • Consumers • Medical and pharmaceutical • to improve patient care and safety in relation •The media associations to the use of medicines, and all medical and •World Health •Poisons and medicines Organization paramedical interventions; information centres • to improve public health and safety in relation to the use of medicines; • to contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging Pharmacovigilance in national drug their safe, rational and more effective (including cost-effective) use; policy • to promote understanding, education and clinical The provision of good quality, safe and effective medi- training in pharmacovigilance and its effective cines and their appropriate use is the responsibility of communication to health professionals and the national governments. The establishment of a national public. medicine regulatory agency and a designated Page 2: WHO Policy Perspectives on Medicines — Pharmacovigilance: ensuring the safe use of medicines centre for the study of adverse reactions are central other, regulators need to understand the specialized to the achievement of these functions. Multi- and pivotal role that pharmacovigilance plays in disciplinary collaboration is of great importance; in ensuring the ongoing safety of medicinal products. particular, links need to be forged between various departments of the ministry of health and also with other stakeholders, such as the pharmaceutical in- dustry, universities, nongovernmental organizations Box 5 Pharmacovigilance in practice: (NGOs) and those professional associations having the example of cerivastatin responsibility for education on rational use of medicines and pharmacotherapy monitoring. Cerivastatin was first approved as a lipid-regulating agent in 1997. By 2000 a total of 549 cases of rhabdomyolysis associated with cerivastatin use had been reported to the WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden. Consequently a signal was Box 4 Key elements of pharmacovigilance issued regarding an association between cerivastatin, in national drug policy myopathy and rhabdomyolysis. • Establishment of national pharmacovigilance systems In November 1999 in the United States, and in March 2000 for the reporting of adverse events, including national in Canada, prescribing information was changed to include and, if appropriate, regional pharmacovigilance centres. a contraindication for the combined use of cerivastatin and gemfibrozil, another lipid-regulating medicine. A similar • Development of legislation/regulation for medicine action was taken in Australia in February