Details of French trial must be released urgently, say UK expertsBMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i319 (Published 18 January 2016) Cite this as: BMJ 2016;352:i319
British specialists have called for further information to be made available urgently about a drug trial in France that has claimed one life and left another five volunteers in hospital, three with serious brain damage.
Three separate inquiries have been launched into the disaster, by the French social affairs inspectorate, the national medical safety agency, and the gendarmerie, but details about the product under test and the trial’s protocol and dosing regimen have not been disclosed. Given that 90 people are reported to have been given the experimental treatment in various doses and that drugs with a similar mode of action have been tested by other manufacturers, Carl Heneghan of Oxford University said that an urgent need for transparency transcended any prosecution.
Munir Pirmohamed of the University of Liverpool said that it was possible that the adverse reactions were an off-target effect, in which the drug was interacting with a receptor other than that intended, but that without further information it was impossible to be sure. “It is therefore vitally important that as much information as possible is made available to the scientific community as soon as possible by the manufacturer,” he said.
Sheila Bird, a statistician and expert in trial design who retired recently from the UK Medical Research Council’s Biostatistics Unit in Cambridge, has appealed directly to the French licensing authorities, the National Agency for the Safety of Medicine and Medical Products (ANSM), asking for the study design and protocol to be made available. Like the TGN1412 trial at Northwick Park Hospital in north London in 2006,1 these details have potential implications for the design of phase I studies internationally, she said.
What is known is that the product, BIA 10-2474, belonged to a class known as fatty acid amide hydrolase (FAAH) inhibitors. It was developed by the Portuguese company BIAL and was being tested in a “first in man” trial in Rennes by the company Biotrial when the adverse effects emerged.
The target of the product was one or both of the enzymes that break down the fatty acid amides that act as transmitters to brain receptors such as those targeted by cannabinoids. This mode of action is intended to increase the activity of these receptors, achieving the pain killing effects of cannabis based drugs without the side effects (such as memory loss). At least five FAAH inhibitors have been developed by drug companies, including Pfizer, Sanofi-Aventis, and Merck, without so far producing a successful treatment. None has shown the adverse effects seen in the French trial.
The trial involved 90 healthy volunteers aged between 18 and 55 who were given the drugs in different doses and another 28 who were given a placebo. An email provided to the online news site Breizh-info.com by a man who had volunteered but who in the event was not selected for the trial said that participants were to be paid €1900 (£1455; $2075) for a two week stay at the Rennes centre, which involved daily oral administration of the product and a series of tests on blood, urine, and vital signs. The trial was authorised by ANSM on 26 June 2015 and began on 7 January this year.
Three days later one of the volunteers fell ill and was admitted to hospital with symptoms that doctors first attributed to a stroke. Five others followed in subsequent days. Pierre Gilles Edan, head of the neurology department at the University Hospital in Rennes, where the five surviving volunteers, all men, are being treated, said that three had brain damage including bleeding and necrosis that “could be irreversible.” A fourth had neurological problems but of lesser severity, and a fifth man had experienced no adverse effects but was being monitored.
All six had been in the same trial group, which according to BIAL was the group given the highest dose in the third phase of the trial, when multiple doses were being given. The compound had been tested in the normal way, including in chimpanzees, said the French health minister, Marisol Touraine. UK experts have questioned this claim, as chimpanzees are very seldom used in drug trials.
“If one went to primates one would usually test on macaques rather than chimpanzees, so it appears to indicate there is something different about this compound if this report is true,” said Jackie Hunter, chief executive of the Biotechnology and Biological Science Research Council, in a comment elicited and distributed by the Science Media Centre.
What could have gone wrong? Experts providing guidance through the centre suggest contamination and off-target effects as the most plausible explanations. Another possibility, suggested by Hunter, was an accumulating metabolite that is found in humans but not in animals. The French inquiries will need to establish whether enough time was allowed between the high doses to be sure that adverse effects were not emerging.
French press reports said that the man who died was 49, the oldest of the six. He has not been named. Trial records from Biotrial were seized by the gendarmerie over the weekend, and leaks to French media indicate that investigators have focused on contamination. The samples used in the trial were made in Italy, using ingredients manufactured in Hungary.
Touraine has said that she expects a preliminary report from the three parallel investigations by the end of the month.
Cite this as: BMJ 2016;352:i319