The final regulatory report into a fatal French drug trial run by a drugmaker and its CRO partner earlier this year was "clearly linked to the compound tested"--but the report’s lead author claims common sense was lacking from researchers.
The report, ordered from the French National Agency for Medicines and Health Products Safety (ANSM), said in its final conclusions that Portuguese drugmaker Bial, the lab producing the drug, and French CRO Biotrial, the company which conducted the experiments, had made errors--but had not broken any regulatory rules.
In all, more than 100 patients had taken the drug in Rennes, France, but in January, 6 trial participants took a higher-dose form of the treatment, with one becoming brain dead and later dying. Five others were seriously ill, but reports suggest that they are recovering. The drug being tested was BIA 10-2474, a medicine that blocks the enzyme FAAH to treat anxiety.
One of the most crucial issues identified by the report was that two doses of the BIA 10‐2474 molecule tested were given in too quick a succession to the trial participants.
The trial was designed so that 6 doses (2.5 mg up to a maximum of 100 mg) would be tested on one group of volunteers. The researchers would then multiply the quantity by two each time a new dose was administered--but this was not applied between dosages of 20 mg and 50 mg.
The participant who died fell ill after reaching the 50 mg dose threshold. But at the time, the scientists had not associated his symptoms to the fact he had been given the molecule, and kept giving other patients the drug for several days afterwards.
The report concludes that: “The symptoms presented by the volunteers can be linked to the BIA 10-2474 dose which they received daily and repeatedly […] The most credible hypothesis is that the molecule itself was toxic.”
The experts said the problem with the drug was likely its poor ability to bind to its target, the FAAH enzyme.
Their report added that "a likely gradual accumulation in the brain" would explain "why the accident only occurred on the fifth day of the administration of a dose of 50mg and not in the volunteers who had received a single dose that was twice as strong."
The report also points out there were fundamental problems with the documents--given by Bial to gain approval for human trials--as they turned out to contain a number of inaccuracies and translation mistakes.
Lead author Bernard Begaud said the rules "generally seem to have been respected" in the trial run by Bial, even if "common sense" appeared to have been neglected.
The trial was testing a compound less efficient than another already on the market, and was "no more effective than several others from the same family that had already been abandoned because they were ineffective," Begaud told news wire AFP.
The report also adds that this will likely require new best practice codes for all future drug trials to reduce any similar accidents and fatalities.
The authors urged a tougher selection process for volunteers when testing drugs on humans for the first time, given that the dead man had previously suffered a head injury, and another of the victims had hypertension--ailments that should have ruled them out, the report said.
"The seriousness of the accident at Rennes justifies changes to the regulations and international best practice," the report noted.
Bial has welcomed the findings, noting that it had "identified no failure to comply with current rules and guidelines."
- check out the ANSM report (in French)