One person is brain-dead and five more have been hospitalized after a phase I clinical trial in France went horribly wrong. At least three of the patients may suffer irreversible brain damage if they survive, a doctor treating them said today.
The patients were previously healthy volunteers who participated in a study, conducted by Biotrial, a private company in the city of Rennes, to test the tolerability of a candidate drug. French officials haven't announced which drug, and it's not yet clear why many others who participated in the study since it began in July apparently haven’t experienced similarly severe side-effects.
Details about the accident have been slow to emerge. Biotrial, a well-known contract research firm established in 1989, put a one-paragraph notice on its website today that said, without providing details, that during a first-in-man study, "serious adverse events related to the test drug have occurred in some subjects." (A few hours later, the company issued another statement saying: "Our thoughts go out to the volunteers and their families. We are working hand in hand with the Health Authorities to understand the cause of this accident.")
At a press conference in Rennes this afternoon, French health minister Marisol Touraine said Biotrial was testing a compound acting on the body's endocannibanoid system, a group of receptor proteins that responds to compounds naturally made in the body as well as components in cannabis. The drug, tentatively aimed at multiple disorders, including neurodegenerative diseases and anxiety, was developed by Portuguese pharmaceutical company Bial. Contacted by Science today, a Bial spokesperson said that she could not comment but that the company would issue a press statement about the matter later today.
Speculation on the Internet focuses on a compound named BIA 10-2474, which, according to Bial's website, is a candidate drug for "neurological and psychiatric pathologies" that is currently in phase I testing.
Speaking on radio news station France Info today, neurologist Gilles Edan of the University of Rennes Hospital Center said that the first patient from the study arrived on Sunday with very severe symptoms that Edan's team initially thought might be caused by a stroke. The patient soon deteriorated further and is now brain-dead, Edan said. Four other patients have neurological symptoms of varying severity, he added, but are not in a coma. "Of these four, three already have a severe enough clinical picture to fear that even in the best situation there will be an irreversible handicap," Edan said. Because the drug's effects on humans are unknown, the patients need to be monitored very closely, he said. "We cannot make a definitive prognosis." The sixth patient does not have symptoms but is under surveillance.
Touraine, who visited the hospital today, said all six are men aged between 28 and 49 years old. She said the drug had been tested on animals, including chimpanzees, and that France's National Agency for Medicine and Health Products Safety (ANSM) approved the trial on 26 June 2015. The plan was to enroll 128 volunteers aged between 18 and 55; the trial would first test a single dose, then multiple doses, and finally the combination of the drug with a meal. So far, 90 people have received varying doses of the drug while others had received a placebo, Touraine said. (Phase I studies don't usually have a placebo group; it's not clear why this one did.)
The six volunteers that were hospitalized all received multiple daily doses, the first one of which was given on 7 January. The first symptoms appeared on 10 January, Touraine said, and the trial was halted the next day.
Touraine didn't speculate on why symptoms only appeared in this group and not in previous volunteers; it's possible that the six were the first to receive multiple doses of the drug, or that a batch of drug was contaminated in some fashion. (All six were "in the same trial group," Edan said.) Every volunteer who has taken the drug since the trial began will be contacted, Touraine said, presumably to be checked for any adverse events that might have gone unnoticed.
Touraine said that prosecutors in Rennes have opened an investigation and that ANSM will conduct an investigation as well. Meeting the victims and their families today was "a moment of intense emotion," Touraine said. "The shock is even greater because people who participate [in phase I trials] are healthy, not sick, and obviously they don't expect to be confronted with such accidents."
Phase I studies are designed to test safety and tolerability of a drug, as well as how, and how fast, the chemical is processed by the human body. Most of these studies are carried out by specialized research contract companies; the subjects are usually healthy volunteers who receive modest financial compensation.
Serious incidents in phase I studies are rare, but they can never be completely excluded because a drug's behavior in animals isn't always a good predictor of its effects in humans. The last publicly known similar incident occurred in 2006, when six men in the United Kingdom suffered severe organ dysfunction after receiving small doses of a monoclonal antibody named TGN1412.
With reporting by Tania Rabesandratana.