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The University of Rennes Hospital Center.

The University of Rennes Hospital Center.

Electzik/Wikimedia Commons

France tightens rules in wake of fatal clinical trial

The French government is taking measures to lower the health risks to volunteers in clinical trials in the wake of the final report about a study that killed one person and landed five others in the hospital in January. Furthermore, the contract research company that conducted the study, Rennes, France–based Biotrial, must within a month provide a "plan of action" explaining how it will avoid a repeat of its mistakes during the trial or lose its operating license, French health minister Marisol Touraine said today at a press conference on the report’s release.

The 127-page report by France's General Inspectorate of Social Affairs (IGAS) doesn't pinpoint why or how the potential drug caused brain damage in previously healthy control subjects; it calls on the government to "mobilize the international scientific community" to find out what went wrong and suggests a range of scientific approaches, such as testing whether the drug hits other brain targets than the intended one and a study of the potential toxicity of the compound's metabolites.

In the fatal trial, Biotrial tested a drug, named BIA 10-2474, that acts on the body's endocannabinoid system, a network of receptors and other molecules in the nervous system, some of which play a role in the response to cannabis. The drug's developer, Portuguese pharmaceutical company Bial, believed it might be of use in a wide range of conditions, including anxiety, mood disorders, and Parkinson's disease. The problems surfaced in a group that received multiple doses of 50 milligrams daily as part of a phase I trial, in which a drug's safety is studied in healthy people. Ninety subjects who had previously received single doses of up to 100 milligrams or multiple doses of up to 20 milligrams had not suffered from any dangerous side effects.

IGAS's new report confirms many of the conclusions of an interim report released in February. The inspectors say that Biotrial's study design complied with French regulation and current standards, and animal tests did not raise any red flags. But the company made major mistakes after the first volunteer—a 49-year-old singer, painter, and composer who would later die—was taken to a hospital with headaches and blurry vision on 10 January. The remaining participants in the trial were given another dose of the drug the next morning, for instance, and were not properly informed of what had happened. Biotrial didn't alert French authorities until 14 January.

Touraine today announced several measures aimed at improving safety and strengthening the response when a trial goes awry. France's Regional Health Agencies will be asked to carry out inspections at all clinical trial centers in the country, together with the National Agency for Medicines and Health Products Safety (ANSM). The latter agency will start producing monthly reports of all serious, unexpected side effects in phase I and II studies, and a new expert group at ANSM will review and approve each study, Touraine said.

Touraine did not address one key criticism in the report, however. Biotrial started giving 50-milligram doses of the drug to all the subjects at the same time, rather than using a staggered participation schedule. The latter setup would have taken more time, but would have allowed monitoring each volunteer's health before moving on to the next one.

In a press release, Bial stressed that the trial protocol had been approved by ANSM and that it had no reason to expect problems with the 50-milligram dose. "There were no alerts, or signals in any of the safety parameters collected from any of the previous cohorts that could have anticipated the tragic accident," the company says.

Biotrial, meanwhile, issued a statement saying that it is "shocked" to only receive the report this morning after Touraine's press conference, although copies were leaked to French newspapers Le Monde and Libération over the weekend. The company says it has already filed the plan of action requested by Touraine, and harshly criticized IGAS's investigation, which it says didn't respect the "adversarial principle" or the rights of people interviewed. The company didn't elaborate, however, and did not dispute any of the specific charges in the report.

Although it doesn't call the overall study unethical, the IGAS report questions whether healthy people should have been exposed to a drug whose proposed benefit was never very clear. "In the eyes of some experts, the potential added value of the product in the therapeutic arsenal was questionable," the report says. And although Bial had promised "a large panoply of potential future therapeutic benefits," it hadn't explained why BIA 10-2474 would be better than other molecules. Similar questions arise with other candidate drugs however; the report says the issue merits a "public debate at the international level."