Causality assessment of adverse effects - When is re-challenge ethically acceptable?

One of the most difficult tasks in the evaluation of a medicine is whether it causes a particular rare and unusual (idiosyncratic) adverse effect. Suc h causality assessments are sometimes done by drug de-challenge and re-chal lenge. When the adverse effect is potentially serious, there is clearly an important decision to be made as to whether the re-challenge is justifiable and hence ethical. The recent controversy about the potential cardiotoxici ty of fexofenadine, the fatalities associated with penicillin re-challenge and the fatalities associated with abacavir re-challenge highlight some of the potential serious risks of drug re-challenge. The associated important ethical issues are discussed. In particular, there is the need to ensure re spect for the patient and to consider the scientific and social value of th e re-challenge. A framework for evaluating and assessing the appropriatenes s of a particular drug re-challenge is proposed in the light of recent as w ell as long-standing discussions of drug re-challenge, patient informed con sent and the ethics of human experimentation, in general. It is suggested t hat a drug re-challenge should be approached with the same rigour and stand ards of documentation as are currently required of clinical trials. Given t he potential conflicts of interest inherent with any drug study, it is argu ed that the safeguards, as may be provided by scrutiny by an ethics committ ee, are necessary for a drug rechallenge. For the investigator contemplatin g the conduct of a drug re-challenge we would recommend the following: (i) a careful risk-benefit assessment as part of the decision-making process; ( ii) careful scientific preparation, including appropriate expert support an d emergency back-up facilities, if re-challenge is deemed necessary; (iii) the writing of a detailed protocol for independent approval and for safegua rding all concerned; and (iv) meticulous record keeping.