The Basis of Pharmacovigilance

THE BASIS OF PHARMACOVIGILANCE

Introduction

 ‘Not all hazards can be known before a drug is marketed’.

Committee on Safety of Drugs, Annual Report 1969, 1970.

Pharmacovigilance – the study of the safety of marketed drugs under the practical conditions of clinical use in large communities – involves the para-dox that what is probably the most highly regulated industry in the world is, from time to time, forced to remove approved and licensed products from the market because of clinical toxicity. Why is such close regulation not effective in preventing the withdrawal of licensed products? The question has been with us from the very early days of the 1960s and remains with us today, and its consideration tells us a great deal about pharmacovigilance.

The greatest of all drug disasters was the thalido-mide tragedy of 1961–62. Thalidomide had been introduced, and welcomed, as a safe and effective hypnotic and anti-emetic. It rapidly became popular for the treatment of nausea and vomiting in early pregnancy. Tragically, the drug proved to be a potent human teratogen that caused major birth defects in an estimated 10 000 children in the countries in which it was widely used in pregnant women. Figure 1.1 shows a child with thalidomide-induced amelia of the upper limbs and phocomelia of the lower limbs fitted with the kind of prostheses available at that time. The story of this disaster has been reviewed elsewhere (Mann, 1984).

Figure 1.1. Child with thalidomide-induced deformities of the upper and lower limbs fitted with pneumatic prostheses. 

The thalidomide disaster led, in Europe and else-where, to the establishment of the drug regulatory mechanisms of today. These mechanisms require that new drugs shall be licensed by well-established regu-latory authorities before being introduced into clini-cal use. This, it might be thought, would have made medicines safe – or, at least, acceptably safe. But Table 1.1 summarizes a list of 39 licensed medicines withdrawn, after marketing, for drug safety reasons since the mid-1970s in the United Kingdom.

Table 1.1. Drugs withdrawn in the United Kingdom by the marketing authorization holder or suspended or revoked by the Licensing Authority.  

Why should the highly regulated pharmaceutical industry need, or be compelled, to withdraw licensed medicines for drug safety reasons? Why do these problems of licensed products being found toxic continue despite the accumulated experience of more than 45 years since the thalidomide tragedy?

Partly, the problem is one of numbers. For example, the median number of patients contributing data to the clinical safety section of new drug licensing applications in the United Kingdom is only just over 1500 (Rawlins and Jefferys, 1991). Increasing regulatory demands for additional information before approval have presumably increased the average numbers of patients in applications, especially for new chemical entities; nevertheless, the numbers remain far too small to detect uncommon or rare adverse drug reactions (ADRs), even if these are serious.

The size of the licensing applications for impor-tant new drugs cannot be materially increased without delaying the marketing of new drugs to an extent damaging to diseased patients. Thus, because of this problem with numbers, drug safety depends very largely on the surveillance of medicines once they have been marketed.

A second reason for difficulty is that the kinds of patients who receive licensed medicines are very different from the kinds of volunteers and patients in whom pre-marketing clinical trials are undertaken. The patients in formal clinical trials almost always have only one disease being treated with one drug. The drug, once licensed, is likely to be used in an older group of patients, many of whom will have more than one disease and be treated by polypharmacy. The drug may also be used in paediatric patients, who are generally excluded from initial clinical trials. The formal clinical trials may be a better test of efficacy than they are of safety under the practical conditions of everyday clinical usage.

A third problem is that doctors may be slow or inef-fective in detecting and reporting adverse drug effects. Many of the drugs summarized in Table 1.1 were in widespread, long-term use before adverse reactions were detected, and even now, hospital admissions due to ADRs have shown an incidence of between 2.4% and 3.6% of all admissions in Australia with simi-lar or greater figures in France and the United States (Pouyanne et al., 2000). Even physicians astute in detecting adverse drug effects are unlikely to identify effects of delayed onset.

A fourth reason for difficulty is that drugs are often withdrawn from the market for what may be very rare adverse effects – too infrequent by far to have shown up in the pre-licensing studies – and we do not yet have effective means in place for monitoring total post-marketing safety experience. This situation may well change as large comprehensive databases such as the General Practice Research Database (GPRD) become more widely used for signal detection and evaluation. These databases record, in quite large and representative populations, all usage of many specific medicines and clinical outcomes and can be used to systematically screen for and evaluate serious adverse events. Because they contain comprehensive infor-mation on some important information, such as age, sex, dose and clinical events on all patients in the represented population, they are systematic compared with spontaneous reporting systems. They may offer a better chance of detecting long-latency adverse reac-tions, effects on growth and development and other such forms of adverse experience.

Some of the difficulties due to numbers, patient populations and so on were recognized quite early. The Committee on Safety of Drugs in the United Kingdom (established after the thalidomide disas-ter, originally under the chairmanship of Sir Derrick Dunlop, to consider drug safety whilst the Medicines Act of 1968 was being written) said – quite remarkably – in its last report (for 1969 and 1970) that ‘no drug which is pharmacologically effective is without hazard. Furthermore, not all hazards can be known before a drug is marketed’. This then has been known for over 35 years. Even so, many prescribers still seem to think that licensed drugs are ‘safe’, and they are surprised when a very small proportion of licensed drugs have to be withdrawn because of unex-pected drug toxicity. Patients themselves may have expectations that licensed drugs are ‘completely safe’ rather than having a safety profile that is acceptably safe in the context of the expected benefit and nature of the underlying health condition.

The methodological problems have been long recognized. The Committee on Safety of Medicines, the successor in the United Kingdom to the Dunlop Committee, investigating this and related problems, established a Working Party on Adverse Reactions. This group, under the chairmanship of Professor David Grahame-Smith, published its second report in July 1985. The report supported the continuation of methods of spontaneous reporting by professionals but recommended that post-marketing surveillance (PMS) studies should be undertaken on ‘newly-marketed drugs intended for widespread long-term use’; the report also mentioned record-linkage meth-ods and prescription-based methods of drug safety surveillance as representing areas of possible progress (Mann, 1987).

Similar reviews and conclusions have emerged from the United States since the mid-1970s. A series of events in the United States recently created a resurgence of interest in drug safety evaluation and management. The Prescription Drug User Fee Act (PDUFA) of 1992 provided additional resources at the Food and Drug Administration (FDA) for drug reviews through user fees and established target time-lines for FDA reviews. The shorter approval times lead to some medications being approved sooner in the United States than that in Europe in contrast to the pre-PDUFA experience. A few highly visible drug withdrawals led to a perception that perhaps drugs were being approved too quickly. Lazarou, Pomeranz and Corey (1998) published the results of a meta-analysis that estimated that 106 000 fatal adverse reac-tions occurred in the United States in 1994. This and other articles (Wood, Stein and Woosley, 1998) stimulated considerable public, congressional and regulatory attention on reducing the societal burden of drug reactions and medication errors (Institute of Medicine, 1999; U.S. Food and Drug Administra-tion, 1999; United States General Accounting Office, 2000). As a result, greater attention and resources are currently being devoted to signal generation and eval-uation by the FDA, industry and academic centres. Moreover, efforts are underway to develop better tools to manage recognized risks through a variety of inter-ventions, such as communications with healthcare providers and patients, restricted product distribution systems and other mechanisms. Additional effort is being focused on measuring the success of these risk-management interventions. This new initiative repre-sents a fundamental shift in the safety paradigm in the successor in the United Kingdom to the Dunlop Committee, investigating this and related problems, established a Working Party on Adverse Reactions. This group, under the chairmanship of Professor David Grahame-Smith, published its second report in July 1985. The report supported the continuation of methods of spontaneous reporting by professionals but recommended that post-marketing surveillance (PMS) studies should be undertaken on ‘newly-marketed drugs intended for widespread long-term use’; the report also mentioned record-linkage meth-ods and prescription-based methods of drug safety surveillance as representing areas of possible progress (Mann, 1987).

Similar reviews and conclusions have emerged from the United States since the mid-1970s. A series of events in the United States recently created a resurgence of interest in drug safety evaluation and management. The Prescription Drug User Fee Act (PDUFA) of 1992 provided additional resources at the Food and Drug Administration (FDA) for drug reviews through user fees and established target time-lines for FDA reviews. The shorter approval times lead to some medications being approved sooner in the United States than that in Europe in contrast to the pre-PDUFA experience. A few highly visible drug withdrawals led to a perception that perhaps drugs were being approved too quickly. Lazarou, Pomeranz and Corey (1998) published the results of a meta-analysis that estimated that 106 000 fatal adverse reac-tions occurred in the United States in 1994. This and other articles (Wood, Stein and Woosley, 1998) stimulated considerable public, congressional and regulatory attention on reducing the societal burden of drug reactions and medication errors (Institute of Medicine, 1999; U.S. Food and Drug Administra-tion, 1999; United States General Accounting Office, 2000). As a result, greater attention and resources are currently being devoted to signal generation and eval-uation by the FDA, industry and academic centres. Moreover, efforts are underway to develop better tools to manage recognized risks through a variety of inter-ventions, such as communications with healthcare providers and patients, restricted product distribution systems and other mechanisms. Additional effort is being focused on measuring the success of these risk-management interventions. This new initiative repre-sents a fundamental shift in the safety paradigm in the United States and offers new challenges to phar-macovigilance professionals. In fact, the shift is not restricted to the United States as both the FDA and the EMEA in 2005 issued guidance documents for industry on signal detection, evaluation, good pharma-covigilance practice and recommendations for manag-ing risks after the approval (EMEA, 2005; U.S. Food and Drug Administration, 2005a–c).

We have long recognized then that the safety of patients depends not only on drug licensing by regu-latory bodies but also on post-marketing drug safety surveillance, pharmacovigilance. It is also important to note that the same post-marketing information needed to confirm new safety signals is also needed to refute signals and protect the ability of patients to benefit from needed medicines that may be under suspicion due to spurious signals.