IGAS report on clinical-trial fatality recommends limited changes to French regulation

France's General Inspectorate of Social Affairs (L'Inspection générale des affaires sociales: IGAS) has published a two-part report (available to view here and here) investigating the clinical-trial fatality – and hospitalisation of five volunteer patients with neurological issues – in a trial examining the efficiency of fatty-acid amide hydrolase (FAAH) enzyme inhibitor BIA 10-2474. The report was commissioned by the French ministry of health in the wake of the high-profile incident (see France: 18 January 2016: Multiple investigations launched in France following drug-trial fatality). Investigators confirmed the findings of an earlier preliminary examination conducted by the National Agency for Medicines and Health Products Safety (Agence Nationale de Sécurité du Médicament et des Produits de Santé: ANSM), which criticised Portuguese manufacturer Bial and French-based clinical-trial organisation (CRO) Biotrial (see France: 8 March 2016: France's ANSM issues report on fatal drug trial involving FAAH inhibitor). According to the IGAS, Bial and the French CRO undertook flawed testing protocols on "several counts". In particular, French authorities cited Biotrial's "failure to implement an optimal level of protection for volunteers", failure to properly confirm patient consent, and responsibility for failing to halt the trials after the first hospitalisations were reported. Both companies were also faulted by the agency for issues related to higher dosages prescribed. Furthermore, the IGAS inspection team was highly critical of the excessive period of time that it took Biotrial and Bial to fully inform national health authorities that a serious adverse event had occurred.

For its part, the ANSM was cleared of regulatory wrongdoing over the approval of the clinical trial, after the IGAS inspectors concluded that the "conditions under which the test was approved [by the drug regulator] did not breach existing legislation". It should be noted, however, that the IGAS has raised significant concerns, noting that the "potential added value of [BIA 10-2474] in the therapeutic arsenal was questionable". The authors of the report raise questions regarding the assessment of the risk level of the drug candidate.

At the time of writing, Bial had not published a response to the IGAS report. Biotrial does not dispute the report's conclusions, but is mounting a robust public defence of its running of the clinical trial, as well as its subsequent handling of the medical emergency. The French CRO accused French authorities of "carefully orchestrated leaks" after copies of the report were circulated to media organisations ahead of the publication and press conference on 23 May; Biotrial claims not to have received a copy of the report until after the health minister's press conference. In a statement, the CRO also noted that it had "always strictly respected" the testing protocol validated by the ANSM, and that claimed that "it has been shown that it is the Portuguese laboratory Bial's compound, by its unexpected and unpredictable toxicity, which is at fault for the accident" – although it should be noted that the IGAS report made no specific conclusions regarding the precise pharmacological causes of the accident.

The French ministry of health has requested that Biotrial submit a "plan of action" to address the alleged major deficiencies identified by the report in the CRO's clinical-trial protocols. Health minister Marisol Touraine warned that unless corrective action was put in place within a month, there was a risk that the laboratory's licence to conduct Phase I trials would be suspended. Biotrial has indicated that documents on its proposals to better safeguard clinical-trial volunteers were submitted to the ANSM prior to the publication of the IGAS inspection report. Assuming this document has been or will be accepted, the ANSM will carry out verifications in the second half of 2016. This may be sufficient to avoid further regulatory penalties against the French CRO; however, a separate judicial inquiry is still being considered. This could address questions of financial compensation packages for clinical-trial participants, and possibly other liability issues.

Outlook and implications

The IGAS has issued 19 recommendations for regulatory and structural changes to early-stage and first-in-human clinical-trial regulation in France. Initially, France will create a new independent expert group, specifically to review and approve early-stage and first-in-human clinical trials. This will create greater in-house expertise on early-stage and first-in-human clinical trials, which should broadly benefit the innovative pharmaceutical industry. The new unit, which will operate within the ANSM, will be tasked with investigating the health records of clinical-trial participants and to exchange information with the European Commission. Regional authorities – under the auspices of the Regional Health Authorities (Agences Régionales de Santé: ARS) – will also be mandated to inspect clinical-trial facilities in the country, as well as to produce monthly reports cataloguing all serious and/or unexpected reactions in Phase I and Phase II trials. It is likely that French approvals of new clinical trials will more carefully weigh the associated potential risk factors, and will probably tend to exercise increased caution in terms of potentially underestimating risk factors.

New regulatory measures for first-in-human trials will involve an automatic high-risk evaluation from the end of 2016 onwards. The main implication for other drug candidates is the likelihood that French regulators will insist that staggered clinical-trial participation schedules be carried out in future first-in-use human trials. This could significantly increase the time required to establish and run trials, as well as the cost of monitoring individual patient health. The main omission in the IGAS report is that it does not examine the precise pharmacological causes for the adverse medical reaction that accrued in some patients receiving BIA 10-2474. Instead, the report's authors advocate the "mobilisation of the international scientific community" to investigate. This could be seen as a failure to establish the root causes of the failure of the FAAH enzyme inhibitor, BIA 10-2474, and specifically whether there was an underlying toxicology or dosing-related issue at play. This could potentially have consequences for other FAAH candidates that are in development, including JNJ-42165279 (Janssen, Belgium), a FAAH candidate (see Belgium: 21 January 2016: Janssen suspends Phase II clinical trials of FAAH inhibitor). France will propose the introduction of new harmonised assessment procedures for first-in-human clinical trials at a European Union (EU)-level, and the adoption of increasingly harmonised rules on the management of serious clinical-trial incidents in Europe. This would first require a comparative analysis of the authorisation procedures for early clinical trials in EU states.