It’s been a year since the clinical trial disaster in France that led to several participants being hospitalized with brain damage. Back in November, the New England Journal of Medicine had an article about the affair, summarizing what was known:
The healthy volunteers described in this article participated in a phase 1 study of BIA 10-2474, a new FAAH inhibitor. They had received the highest cumulative dose (250 to 300 mg) administered to humans. A total of 84 healthy volunteers had previously received cumulative doses of up to 200 mg of BIA 10-2474. No clinical severe adverse event had been reported. The product contained in the capsules administered to all the volunteers was the same as that used for the toxicology studies, and assays confirmed that it was of high purity.These data suggest that the toxic effects we observed were related to drug accumulation. This hypothesis is supported by the nonlinear pharmacokinetics of BIA 10-2474 for doses higher than 40 to 100 mg.
MRI studies and others showed many lesions (microhemorrhages or edema) in the hippocampus and pons of each affected patient, but the exact mechanism for these is still not known. FAAH itself is not expressed in the pons region, and endocannabinoids have not been associated with this sort of toxicity. Whether this was something new in that line, an off-target effect of the compound or a metabolite, or something we haven’t even thought of yet is still unknown.
The latest issue of the journal has a number of letters to the editor prompted by the earlier article. Among them is this from Irwin Nash at Yale, and it’s an idea whose time may be coming:
Kerbrat et al. and Bonini and Rasi describe a phase 1 study that underwent review by an institutional review board. Nevertheless, I question whether it is ethical to enroll healthy persons in phase 1 (toxicity) trials.
According to the principle described in the Belmont Report,1 beneficence implies a reasonable risk-to-benefit ratio. For a healthy volunteer enrolling in a toxicity trial, there is clearly risk but no medical benefit. Monetary compensation or appeals to altruism in the name of humankind are only avenues for ethical abuse. The only cohort that can be considered to derive at least a modicum of medical benefit from volunteering in a phase 1 trial consists of patients who have the condition for which the drug is being developed as a treatment. They should be the only persons who are asked to volunteer for a phase 1 trial.
This sounds a bit radical to people in drug development, but there’s definitely a case to be made. I don’t expect this to change overnight, but it wouldn’t surprise me if Phase I populations do start to shift over. Failing that, we need to get better at estimating pharmacokinetics and pharmacodynamics, because otherwise we may be running greater-than-acceptable risks when drugs go in for first-in-man studies. This topic has certainly come up before (here’s a 2004 article, a clinician’s view from 2008, and another piece from 2011). You’ll notice that all of these assume that there are indeed ethical questions about Phase I trials in healthy volunteers, and work from there to try to find ways to minimize or mitigate the problems.
But problems there are, in any case. How bad would it be, and how much would it slow things down, to go into the intended population in Phase I instead? Thoughts?