Editor—After the apparent recovery of a patient with suspected variant Creutzfeldt-Jakob disease when she was treated with quinacrine, the Department of Health is reported as planning a clinical trial to evaluate the drug's effectiveness as a potential treatment for the disease.1 Should an ethics committee approve such a trial?
There is clearly considerable uncertainty about the effect of quinacrine in variant Creutzfeldt-Jakob disease and other prion diseases,2 but we find it almost inconceivable that a rational patient with suspected prion disease would be in equipoise—that is, indifferent—between quinacrine and placebo. The side effects of quinacrine are well known and are comparatively minor over a wide dose range; the drug penetrates the blood-brain barrier moderately well and has high activity against prions in vitro and in some animal studies.3
Prion diseases are invariably fatal when untreated. The balance of risks and benefits is clearly in favour of taking quinacrine (which is cheap and easily available). Any patient prepared to be randomised in a trial of quinacrine versus placebo is likely not to have understood properly what the implications are. Such a trial should not, therefore, be sponsored at present, or be approved by ethics committees. It has already been recognised that recruiting patients would be difficult, if not impossible.4
The alternative to a randomised trial is a “historically controlled trial.” Although diagnosis is tricky, patients classified by the National Creutzfeldt-Jakob Disease Surveillance Unit in Edinburgh as having possible Creutzfeldt-Jakob disease are thought to have a 50-60% chance of having the disease. Those classified as having probable Creutzfeldt-Jakob disease are thought to have a 95% or greater chance of having the disease (R Knight, National Creutzfeldt-Jakob Disease Surveillance Unit, personal communication).
An ethically acceptable approach would be to offer quinacrine to all patients classified as having possible or probable Creutzfeldt-Jakob disease. It will quickly become apparent, even allowing for the potential biases that can arise from using historical controls, whether quinacrine is preventing the deaths of a large proportion of patients with the disease.
If quinacrine is preventing deaths then trials comparing doses, or combinations of quinacrine and other drugs, could proceed. If, however, it is clearly not saving a majority of patients—for example, if the first 50 patients treated follow courses only a little better than those of historical controls—then the balance of risks and benefits for patients becomes much more equal. Only when an ethics committee judges that fully informed, rational patients would be prepared to enter a trial is it reasonable to allow a trial to proceed.5
References
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