Five men were hospitalized and 1 died after a drug trial in France, the country’s health minister announced on January 15.
Marisol Touraine, the minister for social affairs, health, and women’s rights, said in a statement that her office was informed the evening of January 14 about a “serious accident” that resulted in the hospitalization of 6 men at the Centre Hospitalier Universitaire de Rennes, in eastern Brittany.
The New York Times reported that the participants, all men, were 28–49 years old. The head of the hospital’s neurology department said that 3 men may have suffered irreversible brain damage, based on magnetic resonance imaging analyses.
The drug, a fatty acid amide hydrolase (FAAH) inhibitor, was administered orally to healthy volunteers as part of a Phase 1 clinical trial by Biotrial, a drug evaluation company based in Rennes, on behalf of the drug manufacturer, Bial. The drug was intended to help with mood, anxiety, and motor problems linked to neurodegenerative diseases via the endocannabinoid system.
Of 128 participants, 90 were given the drug, and the rest a placebo. Nature news reported that the trial had tested escalating single doses of the drug without observing any serious adverse side effects. The 6 participants who became ill were the first to receive repeat higher doses over the course of several days.
The first participant to become ill experienced adverse symptoms on January 10 and died on January 17. Biotrial halted the trial on 11 January. One of the patients has since been discharged from the hospital, and the condition of the other 4 was said to be serious but stable.
Authorities are contacting the 84 other people who received the drug at lower doses to arrange medical examinations.
Janssen Pharmaceuticals announced on January 17 their voluntary suspension of dosing in 2 Phase 2 clinical trials of their FAAH inhibitor, wrote Forbes magazine. However, the magazine says that Janssen’s drug, as well as Pfizer’s FAAH inhibitor have shown considerable safety in both Phase 1 and Phase 2 trials.
Biotrial released a statement saying that the trial had been conducted in full compliance with the international regulations, and that proper procedures were followed at every stage throughout the trial— in particular the emergency procedures for the transfer of subjects to the hospital. They said “we are in close and regular contact with the health authorities and ministry in France.”
Bial, based in Coronado, Portugal, also said that it had followed all guidelines and regulations for clinical trials.
The French Agency for the Safety of Health Products, the country’s drug regulator, authorized the trial on June 26, and it began on July 9. Touraine said the drug had previously been tested on animals, including chimpanzees.
The New York Times wrote that contrary to several reports in the French news media, the drug was not a cannabisbased painkiller.
Neither the French authorities nor Biotrial has disclosed the identity of the molecule, but Bial did state that the drug was a FAAH inhibitor. A news story in Science proposed that the drug could be BIA 10-2474, a compound that Bial lists as being in phase I tests on its drug pipeline.
FAAH is an enzyme produced in the brain and elsewhere in the body that breaks down neurotransmitters known as endocannabinoids. FAAH inhibitors cause endocannabinoids — which activate the same neural receptors as the active chemical in cannabis, and might have painkilling properties — to accumulate in the body.
Daniele Piomelli, professor of anatomy and neurobiology, pharmacology and biological chemistry at the University of California, Irvine, told the New York Times that it was difficult to comment on the drug because its structure and pharmacological properties are unknown. He said that the main problem with other FAAH inhibitors, which have been tested by Pfizer, Sanofi, Organon and others, has been that they do not work very well—not that they were unsafe.
It’s possible that BIA 10-2474 drug has completely unexpected effects because it binds to another target besides FAAH, molecular pharmacologist Stephen Alexander of the University of Nottingham, said in a statement distributed by the Science Media Center (SMC). “Another option is a dosing accident, where patients were given far more than clinicians thought was in the dosage form,” added neuropharmacologist Ben Whalley of the University of Reading, also in an SMC statement.
Experts in clinical trials told the Times that serious injuries involving early-stage clinical trials were rare but must be completely investigated since they typically involve healthy subjects who would not otherwise have fallen ill.
Nature reported that the subjects were paid €1900 (US $2073) each. “Many Phase 1 trial volunteers are poor and unemployed, and they volunteer for trials like this because they are desperate for money,” Carl Elliott, a bioethicist at the University of Minnesota, told the New York Times. “This means they are easily exploited.”
Nature reported that days after the first public acknowledgement of the incidents, a lack of official information left outside experts and the public in the dark as to what happened.
“The French authorities have not been very rapid nor transparent in their response,” said Catherine Hill, a specialist in clinical-trial design and a former member of the scientific advisory board of France’s National Agency for Medicines and Health Products Safety. She explained that French investigations into other medical accidents have often been opaque.
Along with the French drug regulation agency, the country’s General Inspectorate of Social Affairs, the Rennes prosecutor’s office and the health branch of the Paris prosecutor’s office have opened investigations.
Calling the incident “unprecedented” at a news conference in Rennes, Touraine said: “I have no knowledge of a comparable event.”
“Toxicity deaths in Phase 1 trials are rare,” said Daniel P. Carpenter, a professor of government at Harvard and an authority on the United States Food and Drug Administration, told the New York Times. Some deaths were reported in Phase 1 trials early in the effort to treat AIDS, he said, but “nothing like this in a long time.”