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. inspection générale des affaires sociales reports the inspection générale des affaires sociales (igas) released a preliminary report on 5 february 2016. the french minister of health indicated that the cause of the death of one of the subjects had not been identified; it claimed biotrial failed three major issues: the study should have been stopped when the first subject was hospitalized so the drug would not have been given to five others; the incident should have been reported immediately, namely january 10, not four days later; all other subjects should have been notified right away asking them if they would like to continue in the study. 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. the minister announced that all clinical trials in france in the event of a serious, unexpected adverse event such as this would be explicitly required to re-consent the remaining trial participants. 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. 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. it stated the trial was halted as soon as it became apparent that the first volunteer had a serious adverse event, and that the man's initial symptoms on 10 january had been mild enough that he was expected to return to the trial facility on 11 january which is why it did not re-consent all volunteers. chu informed biotrial at 10:00 am on 11 january that the man had likely had a stroke, at which point the trial was halted, though it was not known whether the stroke had anything to do with the study drug. this was after further doses had been given to the other volunteers (at 8:00 am that morning). biotrial's statement offered no comment on the time taken between the trial halt at 10:00 am on the 11th and the notification of the authorities three days later on the 14th. ansm comité scientifique spécialisé temporaire the final report from the ansm committee appointed to investigate the matter concluded in april 2016 that: he most likely hypothesis to date is that of toxicity specific to the molecule via its binding to other brain cell structures, facilitated by (1) its low specificity for its target enzyme; (2) use of multiple doses a lot higher than those leading (at least in humans) to complete and lasting faah inhibition, and; (3) its probable gradual accumulation in the brain, undoubtedly related to the specific pharmacokinetic features of bia 10‐2474. the committee also criticised the clinical study design which "probably significantly contributed to the accident", noting that administration of the top multi-dose groups did not and could not take into account emerging pharmacokinetic data from latest dose groups and offered no chance to adjust the dose as adverse events emerged. the choice of dose escalation levels (20 to 50 to 100 mg) was based on pharmacokinetic data from the 10 mg group and data from the 50 mg dose group (that would have clearly shown non-proportional dose kinetics) were not yet available when administration to the 100 mg multi-dose group commenced. the committee made six recommendations, which it invited european and international regulators to consider (reproduced here in brief): justification and demonstration of pharmacological activity predictive of efficacy in humans cannot be considered to be secondary. harmacology studies to establish a dose‐effect curve (where appropriate) to be reasonably predictive of real‐life, future therapeutic efficacy. a neuropsychological assessment with clinical interview and cognitive tests should be a compulsory part of assessment during volunteer screening, inclusion and clinical monitoring in a phase 1 trial for drugs with "central nervous system" tropism. all first‐in‐human and phase 1 protocols should, unless unnecessary, provide for the doses to be tested in volunteers to be adjusted according to the data collected in volunteers already having been exposed during the trial. during first‐in‐human and phase 1 trials, volunteer safety should take precedence over any practical, economic or regulatory considerations. dose escalation strategies in first‐in‐human and phase 1 trials should take account of considerations based on common clinical and pharmacological sense. the committee would like to see a debate opened at european and international level, on access to data from ongoing or previous first‐in‐human and phase 1 trials. agencies outside france a european medicines agency (ema) spokesperson said in january 2016 that "eu authorities will look carefully at the findings to determine if further measures are needed to protect health of clinical trial participants. until eu authorities have the full picture, it is not possible to say whether any revisions to eu guidelines are required". later, in july 2016, the agency proposed to revise its key first-in-human clinical trial guideline, the last significant revision having been published in response to the 2006 tgn1412 clinical trial that had had similarly dire effects in its trial volunteers. the ema stated the proposal aimed to address risks posed by complex trials, such as the one undertaken in rennes, having 'several steps of clinical development within a single clinical trial protocol'. 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". the us food and drug administration issued a statement that it was in contact with its counterparts the ansm as well as the ema and announced investigations into faah inhibitors as a drug class."fda is in the process of collecting and reviewing safety information pertinent to faah inhibitors under investigation in the us. fda will work with sponsors to ensure the safety of participants in clinical studies and take regulatory action as appropriate." later, in august 2016, the agency issued a further statement: "the agency has found, based on the available information, that bia 10-2474 exhibits a unique toxicity that does not extend to other drugs in the class, called fatty acid amide hydrolase (faah) inhibitors." the german drug regulator, the bundesinstitut für arzneimittel und medizinprodukte (bfarm) issued a statement 19 january that no clinical trials with faah inhibitors were underway in germany, but that it had authorised seven such trials previously, which were completed without serious incidents. outcome for trial participants the rennes university hospital provided updates on the remaining volunteers in the study and the treating specialists later published a medical report describing the sickened volunteers in november 2016 in the new england journal of medicine. the published medical report described the adverse events as "an acute and rapidly progressive neurologic syndrome the main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness". the authors were of the view that "the toxic effects we observed were related to drug accumulation. this hypothesis is supported by the nonlinear pharmacokinetics of bia 10-2474 for doses higher than 40 to 100 mg" and as reported by the ansm's expert committee. the authors were not however granted access to information from the post-mortem of the man who died. of the five survivors from the top dose group and the other trial participants: two of the top dose group survivors with serious neurological injuries were discharged to care facilities closer to their homes on 18 january 2016, and a third on the 20th. as of 26 january 2016, one of these men was being treated as an outpatient; one had developed an intercurrent illness and had not yet been discharged, and a third had improved enough to go home. the last of the patients had improved enough to be discharged to home 21 january 2016. all five survivors were due to have a follow-up evaluation at the hospital in rennes at the end of february 2016. the hospital contacted the other 84 volunteers who received bia 10-2474 and found no clinical or radiological abnormalities on re-examination of 75 of the volunteers in january 2016. an ansm investigation into these 84 volunteers looked for evidence of brain abnormalities on mri and any report of neurological symptoms experienced during or after the trial. the ansm report, published in november 2016, concluded that the findings reported in these individuals were consistent with the typical incidence in the wider population and were not similar in characteristics to those seen in the top dose group. the participant from the top dose group who was hospitalised for observation did not develop any symptoms, nor any findings by mri, and returned home on 18 january 2016. the individual had remained asymptomatic as of november 2016. according to the published medical report, at least two of the top dose group survivors continued to suffer effects as of november 2016 - "residual memory impairment" in one case, and "a residual cerebellar syndrome" in another. in december 2016, a bial representative at a british pharmacological society conference in london confirmed that the four symptomatic survivors who received the top dose were continuing to suffer neurological side-effects. news reports from march 2016 described the condition of stéphane schubhan (42), a professional photographer from la flèche, sarthe and participant of the top dose cohort. mr. schubhan "sleeps badly, has nightmares, sees double at all times, walks with difficulty, and succumbs to dizziness and nausea if he stands more than 10 minutes at a time" and does not know if he will be able to work again. mr. schubhan said he had participated in a previous clinical trial, but in this case he was never informed about the animal deaths that were later revealed and would never have consented to take part had he known. doctors have told schubhan that they hope he will improve over the coming 6–12 months but that they do not know what the outcome will be. under french law, all clinical trial participants are protected by the 1988 huriet law on the protection of persons in clinical research. the bia 10-2474 trial participants are therefore entitled to financial compensation as well as recourse to civil and criminal proceedings. the family of guillaume molinet commenced manslaughter proceedings in late january 2016. implications for other faah inhibitors other pharmaceutical companies, including merck, pfizer, johnson & johnson, sanofi, and vernalis, have previously taken other faah inhibitors into clinical trials without experiencing such adverse events (e.g., respectively, mk-4409, pf-04457845, jnj-42165279, ssr411298, and v158866. related enzyme inhibitor compounds such as urb-597 and ly-2183240 have been sold illicitly as designer drugs. following the events in rennes, janssen announced that it was temporarily suspending dosing in two phase ii clinical trials with its own faah inhibitor, jnj-42165279, headlining the decision as "precautionary measure follows safety issue with different drug in class". janssen was emphatic that no serious adverse events had been reported in any of the clinical trials with jnj-42165279 to date. janssen did not state whether the suspension, though voluntary, was at the request of the fda. the suspension was to remain in effect until more information is available about the bia 10-2474 study. pfizer had previously been developing an faah inhibitor pf-04457845 for indications including osteoarthritis pain and trauma. a spokesperson commented after the events in rennes that "we did explore the potential of a faah-inhibitor for osteoarthritic pain in phase 2 trials, however, no significant efficacy was observed. the faah-inhibitor was recently being evaluated in post-traumatic stress disorder but this trial was discontinued in 2015 for business reasons. we do not have any active trials in this area". sanofi also had been developing an faah inhibitor candidate ssr411298 for the treatment of depression. however, a spokesperson stated in january 2016 that "we have no projects in development that target this enzyme".