French clinical trial tragedy “astonishing and unprecedented”, says report
A report into the clinical trial tragedy in France in January has called the event “astonishing and unprecedented” but did express numerous concerns, including that the incident occurred with a molecule similar to other compounds previously abandoned due to their insufficient effectiveness.
The news broke in January that six patients had been hospitalised as a result of a Phase I clinical trial, conducted by clinical research organisation Biotrial on behalf of Portuguese company Bial. One would die later in hospital. The French Health Minister, Marisol Touraine, criticised the trial, saying “Faced with such a serious situation, we would expect the laboratory to approach the health authorities more quickly.”
The report, published by the French National Agency for Medicines and Health Products Safety, highlighted several issues with the trial, as well as providing several hypotheses as to the cause of these adverse events, and made a set of recommendations to take forward in future.
In regards to the specific compound used, the FAAH (fatty acid amide hydrolase – believed to relieve pain) inhibitor, BIA 10-2474, was believed to “appear to be a lot less specific to FAAH than its predecessors, making binding to other cerebral enzymes plausible.”
In regards to the animal testing of the compound, the report calls for clarification from Bial on a number of important issues which are a major cause of concern. The report indicates that testing on rats and primates would have expected for a product with potential effect on the central nervous system. They indicate: “the reasons for using four different species for the toxicology studies; the results of any microscopic examinations of the brains of deceased primates; and the reasons for the apparent lack of preclinical pharmacology studies for confirming, before transfer to humans, the analgesic effect of BIA 10-2474, especially compared to benchmark analgesics.”
When it came to the Phase I trial, itself, the report indicates that the trial adhered to most normal standards but did raise a few more points to highlight. These include the failure to stop the trial immediately when the first person was hospitalised.
The common factor between all those hospitalised was indeed the BIA 10-2474. All 6 received multiple doses of the compound at 50mg. The symptoms they felt were of very rapid onset in five of the six volunteers. MRI scans showed damage of variable severity but all possessing similar characteristic, affecting the hippocampus and the pons. Clinically, they point out, there were neither peripheral neurological symptoms, nor seizures, nor biological, metabolic or immunological anomalies, making the entire picture “completely unusual” and like “nothing potentially seen before.”
These adverse events occurred in only one of the 14 cohorts in this study, meaning that there are very few features that could have caused this to happen, according to the report. These include: “an administration error or procedure specific to this cohort; a common feature among the six subjects having presented with signs of toxicity; or an effect relating to the total BIA 10-2474 dose that the subject received.”
In regards to dosage, the report particularly highlights that the 50mg dose given to these volunteers was at a rate 10 to 40 times higher than that to supposedly induce complete FAAH inhibition.
The report closes with several recommendations, but clarifies that these will be presented in more depth at the formal presentation of their conclusions on 24 March. They suggest, among others, the provision of detailed and well-supported arguments for the choice of maximum dose to be tested in volunteers relative to the presumed effective dose; and also a large-scale consensus process should cover Phase I dose-escalation strategies to establish recommendations for more reasonable and careful practises than those applied in the case of BIA 10-2474.
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