Responses to Risks

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Chapter: Pharmacovigilance: Keynote Clinical Lessons from Pharmacovigilance

One frustrating problem over the years has been the relatively restricted nature of interventions available to Drug Regulatory Authorities in the event that a licensed medicine turns out to have unsuspected toxicity.


One frustrating problem over the years has been the relatively restricted nature of interventions available to Drug Regulatory Authorities in the event that a licensed medicine turns out to have unsuspected toxicity. These are suspension, revocation or modification to the summary of product characteristics. In these situations the perceived need to take action in rela-tion to the risk from the product is often greater than the apparent risk itself warrants. There is an under-standable tendency to emphasise risk and forget about benefit. An example of this would be the manner in which the recent controversy about the risks of the third-generation oral contraceptive pills and throm-boembolic disease. As well as being of great intrinsic interest, this example emphasises that not all risks relate to new or nearly new drugs. Pharmacovigi-lance needs to remain alert to the potential problems of drugs at all stages in their development and use. Another example of a relatively old drug running into problems in the past was nomifensine, an effective antidepressant in which evidence came to light about the risks of acute haemolysis under unusual circum-stances of use. Given the relatively long-established position of the medicine itself, the company involved found it easier to withdraw it from sale than risk litiga-tion by continuing use with adequate warnings. Was this the right decision? What happened to the long-term recipients who were receiving benefits from this drug? Did they transfer to an older antidepressant, or to a newer one (for which we had no compara-ble information), or discontinue treatment? What were the outcomes in relation to recurrence of depression, suicides and adverse effects to replacement therapies? Unfortunately, we do not know the answers to these questions. Clearly, the company involved in manufac-turing nomifensine was not going to fund such a study.

A more recent example has been the change in drug use patterns that has followed the various safety restrictions and withdrawals in the antipsychotic drugs class. As thioridazine fell from favour due to a combination of demonstrated safety concerns and lack of efficacy in dementia sufferers, so patients were treated with newer (and more expensive) atypical antipsychotics. In due course, drugs from this class prescribed to sufficient numbers of patients showed statistically significant problems with excess cardiac and cerebrovascular events. Now many of those are disallowed. The result? We are using even newer drugs that have not been used in adequate amounts to allow any sort of quantification of risk, or we are using old drugs with very significant tolerability and safety problems, for example chlorpromazine and haloperidol. Has public health been well served by this sequence? A study to assess the balance of risks and benefits over time would need to include not only life-threatening events, but also quality-of-life issues, functional ability and economic aspects too.

The COX-2 story has been covered elsewhere in this book. Regulatory authorities were catapulted into the limelight because of the company deci-sion to withdraw rofecoxib from the marketplace, in turn precipitated by emerging results of an increased risk of myocardial infarction from a (unfinished) randomised placebo controlled trial. What were the main lessons for pharmacovigilance from this still-evolving sequence of events? A number of points are worth mentioning. First, drugs are usually licensed on surrogate endpoints, so we must keep an open mind about all-cause outcomes to ensure that the risk–benefit balance remains positive. In this case, despite the fact that core efficacy was no different from comparators, use of a drug was driven by the rationale that certain side effects might be avoided. This channelling of use was bound to affect the over-all risk–benefit ratio. Secondly, we must be alert to the signals of science. A large outcome study with this drug had shown a very weak signal of cardiovascular events but no notice was taken, while pathophysio-logical plausibility had already been published and discussed. Thirdly, we are reminded that all methods of assessing post-marketing safety have their place. Numerous observational studies on COX-2 drugs had indicated a possible hazard, while it was the ‘gold standard’ RCT (albeit unfinished, with all the prob-lems attendant on that aspect) that brought matters to a head. Finally, the perils of direct to consumer and ‘blockbuster’ marketing are plain to see. Excessive marketing zeal is likely to have exacerbated the chan-nelling phenomenon and may also have stimulated exposure of those who would have been deemed at risk from, and would otherwise have remained unex-posed to, other older drugs.

The issue of regulatory response to signals or demonstrated hazards is one of public health, and thus requires public funding. With the continuing development of multipurpose databases and other data resources, we should be better at managing such events in future. The need for post-withdrawal surveil-lance studies in large databases is likely to persist so that some of these questions can be answered. Sensible collaboration among pharmaceutical compa-nies, academic researchers and regulatory authorities is surely to be encouraged.

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