Elizabeth B Andrews

RTI Health Solutions, Research Triangle Institute, Research Triangle Park, NC, USA, and School of Public Health and School of Pharmacy, University of North Carolina at Chapel Hill, NC, USA

''Not all hazards can be known before a drug is marketed."

Pharmacovigilance—the study of the safety of marketed drugs under the practical conditions of clinical usage in large communities—involves a paradox. The nature of the paradox is best explained by glancing back to the very early 1960s and then looking at contemporary experience.

The greatest of all drug disasters was the thalidomide tragedy of 1961-1962. 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 such a child fitted with the kind of prostheses available at that time. The story of this disaster has been reviewed elsewhere (Mann, 1984).

The thalidomide disaster led to the establishment of the drug regulatory mechanisms of today. These mechanisms require that new drugs shall be licensed by the well-established regulatory authorities before being introduced into clinical usage. This, it might be thought, would have made medicines safe—or, at least, acceptably safe. But Table 1.1 shows a list of over 30 licensed medicines withdrawn, after marketing, and for drug safety reasons, over the last 25 years in the United Kingdom.

What is the explanation for the paradox that the highly regulated pharmaceutical industry should need, or be compelled, to withdraw licensed medicines for drug safety reasons? Why do these withdrawals continue despite the accumulated experience of more than 40 years since the thalidomide tragedy?

Partly, the problem is one of numbers. To take but one 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 prior to approval have presumably increased the average numbers of patients in applications, especially for new chemical entities. Nevertheless, the numbers remain far

Pharmacovigilance. Edited by R.D. Mann and E.B. Andrews © 2002 John Wiley & Sons, Ltd ISBN: 0-471-49441-0

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

too small to detect uncommon or rare adverse drug reactions, even if these are serious.

The size of the licensing applications for important new drugs cannot be materially increased without delaying the marketing of new drugs to an extent damaging to diseased patients. Thus, 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 means of polypharmacy. 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 ineffective in detecting and reporting adverse drug effects. Many of the drugs shown in Table 1.1

were in wide-spread, long-term use before adverse reactions were detected and, even now, hospital admissions due to adverse drug reactions have shown an incidence of between 2.4% and 3.6% of all admissions in Australia with similar 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.

An underlying reason 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 just do not have effective means in place for monitoring total post-marketing safety experience. The methodological problem is fundamental and its recognition widespread amongst those who have devoted long periods to the issue of drug safety monitoring.

Some of these difficulties were recognized from quite early on. The Committee on Safety of Drugs in the United Kingdom (established after the thalidomide disaster, 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 30 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 due to unexpected drug toxicity. And 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

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

Brand name (drug substance)

Year action taken

Major safety concerns

Secholex (polidexide)

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