Drug trial regulation in question following Bial tragedy

An investigation into the drug trial that killed one volunteer and left five others hospitalised has concluded that a catalogue of misjudgements caused the tragedy.

The phase 1 trials of Bial’s BIA 10-2474 were being carried out by French clinical research organisation Biotrial in January when things went disastrously wrong. The trial ended in one volunteer being brain dead, and five more with serious neurological symptoms.

However the investigation says the exact pharmacological reason for the disaster remains a mystery.

The committee is nevertheless calling for stricter controls for CNS drug studies, specifically regarding preclinical studies, participant screening, maximum dose evaluation, dose escalation, and overall trial design. Most importantly, they want to stricter requirements put in place to ensure pre-clinical pharmacological studies demonstrate that a drug has potential.

The drug was being developed to treat pain, despite there being no evidence from its pre-clinical studies (or those of others in the FAAH inhibitor class) that the drug was effective for this indication.

The special committee assembled by France’s National Agency for Medicines and Health Products Safety (ANSM) says there is no single clear reason for the catastrophic side-effects to be found in previous animal studies, but said Bial needed to answer questions about some decisions. Among these was the very unusual decision to test the drug in four different animal species, (rats, mice, dogs and primates), plus unexplained causes of death in numerous animals.

It also found that the phase 1 trial recruited several volunteers who should have been excluded from the trial because of risk factors, including one who had suffered a severe head injury in the past, and another with high blood pressure.

Other FAAH inhibitors, such as PF-3845 (Pfizer) and JNJ-42165279 (Janssen) had already been abandoned because of lack of efficacy, particularly in analgaesia.

Unlike its competitors however, BIA 10-2474 was being billed as a reversible FAAH inhibitor which, through testing, was found to be the opposite, irreversible. Not only could this mechanism cause a dangerous increase in anandamide – and resultant potential issues with brain circulation – the drug also showed signs of lower specificity than others in its class, increasing the chances of interaction with other compounds in the brain.

Director general of Biotrial Dominique Martin, was reported in French newspaper Le Monde as singling out the drug itself, stating how it is “clearly the molecule that is the cause”. He also added that there were no toxicity concerns in first volunteers, likening the sudden health incidents “as if a dam had burst somewhere.”

In relation to Martin’s comments, current explanations suggest that the lack of specificity of the drug is responsible for the adverse events in patients, with a likely probability that the drug was affecting other molecules in the brain. The investigation also concluded that one trial cohort received a very high dose of the drug, around 40 times that needed to fully inhibit FAAH.

Read the Temporary Specialist Scientific Committee (TSSC) report here

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