[2] A clinical trial with this drug was underway in Rennes, France, in January 2016, in which serious adverse events occurred affecting five participants, including the death of one man.

[8] BIA-10-2474 is a long-acting inhibitor of fatty acid amide hydrolase (FAAH) that increases levels of the neurotransmitter anandamide in the central nervous system and in peripheral tissues (that is, the rest of the body other than the brain and spinal cord).

[1][8] In normal tissues, the enzyme FAAH degrades anandamide and other endocannabinoid neurotransmitters, which relieve pain and can affect eating and sleep patterns.

[13] The patent discloses limited details about BIA 10–2474, mainly the screening assay results for each of the several hundred candidate compounds to evaluate the effect on FAAH activity.

Publication of the chemical structure created considerable interest among chemists, with some sharing online their assessment of likely binding interactions between BIA 10-2474 and in vivo targets.

[14][16] At least one analysis using standard software modelling packages found that although FAAH emerged as the primary target for BIA 10–2474, a number of other proteins rated highly as well.

[7] According to a company statement, a project to develop FAAH inhibitors was initiated by Bial in 2005, and studies with this compound began in 2009 with pre-clinical in vitro and in vivo pharmacological and toxicological evaluation.

[18] An expert committee, established by the French medicines regulator after the trial, requested clarification from Bial of a range of preclinical issues.

[15] In terms of animal pharmacodynamics, the trial protocol reports that the biological activity of BIA 10-2474 was tested in models of predictive efficacy in treating pain.

[8] The expert committee of the ANSM took the view that this was insufficient basis for commencing human trials, and that further evidence of BIA 10-2474 as an analgesic was warranted.

Around two-thirds of the total dose was eliminated in the urine, about one-fifth in the faeces and the remainder was heavily metabolized in all species studied (rat, mouse, dog, monkey).

[15] The final report by the ANSM Committee noted the drug had a very steep dose-effect curve in humans "going from absence of to almost complete inhibition" over a narrow concentration range.

[8][24] On these issues, the French regulator's expert committee pointed out, based on the company's IC50 data, that complete FAAH inhibition should have been achieved with a dose of 1.25 mg in humans.

[15] The preliminary report from the IGAS investigation, released by the French Minister for Health in February 2016, found there was no legal requirement in France for the trial sponsor to disclose all pre-clinical data to the ANSM.

"[6] In 2015 Biotrial, a contract research organization, initiated a first-in-human trial of BIA 10–2474 in healthy volunteers, with secondary endpoints to investigate neuropathic pain.

Participants of the study were to receive €1,900 and, in turn, asked to stay at Biotrial's facility for two weeks during which time they would take the drug for ten days and undergo tests.

[5] Four of the other five men in the same dosage group were also hospitalized between 10 and 13 January[33] suffering injuries similar to the man who died, including deep haemorrhagic and necrotic lesions seen on brain MRI.

A neurologist at the University of Rennes Hospital Center, Professor Pierre-Gilles Edan, stated in a press conference with the French Minister for Health, that 3 of the 4 men who were displaying neurological symptoms "already have a severe enough clinical picture to fear that even in the best situation there will be an irreversible handicap" and were being given corticosteroids to control the inflammation.

[3] The man who died was later named by local news media as Guillaume Molinet, 49, an artist and father of four from Guilliers, a town in the Breton department of Morbihan.

[48][49][50] All these reports drew comparisons between this incident and the TGN1412 trial at Northwick Park, London in which six volunteers developed life-threatening drug reactions during a Phase I study in 2006.

[52] Bial also denounced the unauthorised release of the trial protocol and was critical of the wide-ranging speculation by scientists and the media about the possible cause of the incident.

[29] In July 2016, Bial's Executive Director António Portela confirmed his company's decision to permanently abandon development of the molecule.

[55][56] As of March 2016 it remained unclear whether Bial disclosed the adverse animal findings to Biotrial, including the deaths of monkeys and dogs in several studies.

[18] The French health minister Marisol Touraine, who visited the trial site in Rennes and spoke with the victims' families, called the events "an accident of exceptional gravity" and promised to investigate the matter via the Inspector General for Social Affairs (IGAS), with a final report due end of March.

[58] In May 2016, the French Health Minister announced several new measures for clinical trials in France, including the establishment of an expert group within the ANSM for review of first in human and early phase studies.

[27][60] The Health Minister noted further that a number of the trial protocol provisions had been too vague and not precise enough; that the eligibility criteria should have been more explicit regarding substance use habits of the volunteers and that there was no legal requirement for the sponsor to disclose all pre-clinical data to the ANSM.

[27] The Comité de Protection des Personnes (CPP) in Brest, a research ethics committee, has asked Bial for the exclusion criteria on the consuming cannabis and other psychoactive substances.

[61] Biotrial published a detailed response on its website, expressing its disappointment to learn of the report via the media and not prior to its publication from the Health Ministry.

[64] The European Investment Bank, which provided 110 million euros in funding for Bial's FAAH inhibitor programme stated it had been in contact with the company about the incident, but that "it would be premature to consider recall of the EIB loan at this stage".

A spokesperson commented after the events in Rennes that "we [Pfizer] did explore the potential of a FAAH-inhibitor for osteoarthritic pain in Phase 2 trials, however, no significant efficacy was observed.