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ResourcesHuman Research EthicsAre Phase I Trials Ethical? – In the Pipeline (Derek Lowe | January 2017)

Australasian Human Research Ethics Consultancy Services Pty Ltd (AHRECS)

Are Phase I Trials Ethical? – In the Pipeline (Derek Lowe | January 2017)

 


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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.

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