French minister for health Marisol Touraine describes the situation as "unprecedented" and seeks a comprehensive financial assistance package for affected clinical-trial participants.
IHS Life Sciences perspective | |
Implications | Three parallel investigations have been launched by France's health ministry following the death of a volunteer patient, and the hospitalisation of five others, in an early-stage clinical trial of an oral analgesic drug (BIA 10-2474) developed by the Portuguese pharmaceutical company Bial Portela. |
Outlook | The incident is the most serious of its kind to have occurred in France's medical history. It is likely to lead to tightening oversight of first-in-human trial guidelines. Preliminary investigations are expected to be published in late January and March. European policymakers will also watch the investigations closely to determine whether changes to the regulatory framework are necessary. The incident may prompt increased scrutiny and greater requirements for pre-clinical testing. |
The French government has launched three separate investigations following the death of a healthy clinical-trial volunteer and the hospitalisation of five others (see France: 15 January 2016: French health minister reports serious incident in clinical trial investigating cannabis-based painkiller). France's drug regulatory body (ANSM), the General Inspectorate of Social Affairs (IGAS), and the health division of the Paris Prosecutors Office have opened regulatory and potentially criminal investigations. Speaking on the 16 January 2016, Minister for Health Marisol Touraine stated that results of early investigations examining whether all recommended regulatory, clinical, and medical guidelines were followed were expected to be available by the end of this month (January). A final report by the IGAS is scheduled to be published by the end of March. The minister is reported as stating that it was premature to identify the cause of the incident.
The Phase I study was run by the well-respected drug-evaluation company Biotrial (France), on behalf of Bial Portela (Portugal), and was designed to investigate the safety and efficacy of an oral analgesic drug (BIA 10-2474) in treating mood and anxiety problems associated with neurodegenerative diseases. BIA 10-2474 is an experimental FAAH (fatty-acid amide hydrolase) enzyme inhibitor; FAAH inhibitors have been safely tested for pain relief by other pharmaceutical firms, including Pfizer (US). In a statement over the weekend, Bial announced that the company was co-operating with investigators with "total transparency", and that the trial had been conducted in "full compliance with international regulation…at every stage". The probes will look at whether adverse medical reactions were caused by a clinical error in the trial procedures, or were due to a safety issue with the FAAH enzyme inhibitor that was tested. Trials of the oral analgesic drug were authorised by the ANSM on 26 June 2015, following approval by the ethics commission and animal trials involving chimpanzees. A main area of focus for investigators is likely to be on the dosage levels that were administered in the Phase I trials. In a statement, the Director General of Biotrial has been reported as saying that the clinical-trial authorisation provided for a maximum dose level which the company was "far from reaching". French news outlet Le Monde has reported that the experimental clinical-trial drug was partly manufactured in Hungary and Italy by unnamed companies. According to the ANSM, Biotrial successfully completed two routine inspections in 2014.
The six victims were healthy male volunteers between the ages of 28 and 49 years of age. According to local reports, about 90 persons were administered the experimental molecule at various dosage levels. Relatively large numbers of patients received a placebo in the trial (18). The five hospitalised individuals and the single fatality were administered a higher dose of the oral analgesic drug than the other 84 participants. The condition of the five hospitalised patients is described as stable.
Outlook and implications
There are precedents to this case, with a notable similarity to the 2006 clinical-trial incident involving the former German drug maker TeGenero (see Germany: 5 July 2006: TeGenero Files for Bankruptcy Following Clinical Trial Scandal), in which the German company received unprecedented global medal attention following Phase I clinical trials on anti-inflammatory drug-candidate TGN 1412 that left six healthy volunteers critically ill with severe adverse effects. TenGenero was subsequently forced to file for bankruptcy, having failed to attract significant investment for the company to continue research and development operations. The case also resulted in greater consideration being given to the inclusion of additional phases of preclinical testing. Although financial claims lodged by patients are expected to be handled by medical insurers, it is likely that the recent incident involving Biotrial and Bial will put strain on the reputation and financial resources of both companies as they attempt to manage the high-profile public setback in the coming months. The French government is already pressing Biotrial to make financial compensation packages quickly available to the clinical-trial participants. For its part, France is generally well-equipped to respond to an emergency response to a clinical-trial incident of this nature. However, the scale of the adverse reactions is nevertheless regarded as "unprecedented" and of "extraordinary gravity", according to Touraine. Additionally, the incident is likely to cause distrust of clinical trials in France at a time when the country is looking to facilitate more early-stage research.