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A Death and Other Adverse Events in French Drug Trial Raise Questions About Testing Safety and Ethics

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Excerpt

A trial testing the safety of an experimental agent in healthy volunteers resulted in a death and neurologic impairments. Bioethicists discuss what may have gone wrong with the trial and what principles should apply to safe and ethical research conduct.
A phase 1 drug trial in France that left one healthy volunteer dead and three others with neurologic impairments has focused attention on how to build more safeguards into drug testing and better promote the sharing of early testing results with the scientific community.
The drug trial gone awry is the focus of a November 3 report in The New England Journal of Medicine (NEJM) that provides clinical and radiological details on volunteers who were given consecutive daily doses of a drug being tested for safety as an analgesic and anti-inflammatory agent, possibly for neurologic pain. The experimental drug, which was referred to as BIA 10-2474, was a fatty acid amide hydrolase inhibitor intended to target the endocannabinoid system; the agent was manufactured by Bial, a Portuguese pharmaceutical company.
The case has been reviewed by French authorities, and those investigations have turned up some shortcomings in the clinical trial design and execution. But precisely how a drug that seemed to be safe in animal testing and other early testing in people turned out to be deadly is still unclear.
“An unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial,” said the NEJM report. “The underlying mechanism of this toxic cerebral syndrome remains unknown.”
Independent physicians and bioethicists interviewed by Neurology Today agreed that the case provides an opportunity to explore issues related to clinical trial design, informed consent, trial oversight, and the sharing and publication of early testing results. The question of potential risks versus benefits always needs to be carefully weighed, even in phase 1 trials where the emphasis is on safety not efficacy, they said. [For more on the principles deemed necessary for ethical clinical research, see “The 7 Ethical Requirements of Clinical Research.”]
As was the case with the French study, phase 1 studies typically involve healthy volunteers who have nothing to gain from the drug being tested. Other drug companies had tested molecules similar to BIA 10-2474 and abandoned their efforts due to insufficient evidence of efficacy, and even earlier findings on BIA 10-2474 were not impressive, noted Jonathan Kimmelman, PhD, associate professor in the biomedical ethics unit at McGill University in Montreal, who was not associated with that research.
“How did a drug that has so little promise make it into phase 1 studies? It's a little bit unsettling,” he told Neurology Today.
The untoward results occurred as part of a “first-in-human” phase 1 clinical trial in January involving eight people, six of whom received 50 mg daily of BIA 10-2474 and two of whom received placebo. According to an April report by an inquiry committee in France, a total of six volunteers were hospitalized with adverse events: one had neurologic symptoms on day five of drug administration, two on day six, two others on the day after the last day of drug administration, and one other had adverse effects two days after the last administration of the drug. The testing, which occurred as a clinical trial unit run by Biotrial, a drug testing company, continued even after volunteers began to be transferred to the hospital with neurologic symptoms.
The NEJM report, written by doctors at Rennes University Hospital in France, where the study participants were taken, contains details on four of the six volunteers (men aged 27 to 49 years) who were given the drug.
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