Four months after a clinical trial in France left one person dead and five others hospitalized, French authorities blamed the clinical research organization and drug maker for various lapses and moved to tighten procedures for testing medicines. The CRO, however, castigated authorities for their findings and blamed the medicine for causing the serious patient reactions.
In a 271-page report released Monday, France’s social affairs inspectorate, known as IGAS, concluded that Biotrial, the CRO that oversaw the early-stage study, failed to properly manage the testing. Notably, the agency found that Biotrial continued to administer the drug even after one patient was sent to the hospital, and it failed to confirm patient consent before running the trial (if you read French, here is part one and here is part two).
Overall, the CRO failed to “implement the optimal level of protection for volunteers,” the report stated. Compounding matters, the drug maker, Bial, and the CRO were both accused of taking too long to inform French health authorities of the serious adverse events, although the report cleared the National Agency of Drug Safety of wrongdoing.
This failing was traced, in part, to an unclear division of roles between the companies, according to the report. Although authorities noted that Biotrial was compliant with existing laws, French authorities gave the CRO, which is based in Rennes, France, one month to submit a plan to avoid a repeat of what were described as “major breaches.”
Beyond the immediate tragedy, the episode focused attention on the lack of public reporting of early-stage clinical trials. There was little known about the drug that was being tested and anxieties were heightened because Bial, the Portuguese drug maker, disclosed very little about its medicine even after the patient reactions came to light.
As we noted previously, however, the drug that was being tested is an inhibitor of fatty acid amide hydrolase, or FAAH, an enzyme produced in the brain that breaks down neurotransmitters known as endocannabinoids. The drug was being developed as a treatment for chronic pain for people with cancer and other ailments. A Phase I, or early-stage trial, began on Jan. 7 in healthy volunteers to gauge drug safety and dosing. About 90 people had been given the tablet at varying doses.
Nonetheless, there is still concern that French authorities are also not disclosing enough information.
“I don’t think they’ve addressed the problem with the drug, other than saying there seems to be a dosing issue,” said Sean Ekins, an expert in computational toxicology and industry consultant who has written about transparency issues. “They’re looking at the big picture. But scientifically, they haven’t disclosed what was going on. We still don’t know why patients had these reactions. It’s a big unanswered question. We still don’t know about the science.”
The drug maker has, so far, not responded publicly to the report. [UPDATE: The drug maker sent us a statement saying that, “Until the date of the accident, no previous signs that could have prevented what happened were detected, nor did any comparable toxicity occur in the pre-clinical trials in animals.”
The drug maker also maintained it did not have access to the patient autopsy in order to investigate possible causes, there was no reason to modify dosing, and that trial protocol was approved and followed. “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 said.]
For its part, Biotrial issued a scathing statement, saying the company “deplores this situation,” especially since it “respected” the trial protocol that was approved by French health authorities. And the CRO blamed the drug for its “unexpected and unpredictable toxicity, which is at fault for the accident.”
The CRO also criticized authorities for their findings, as well as for allegedly leaking the report to the media without giving the company an opportunity to first review the contents. The CRO further accused French authorities of failing to include input provided by the company and “deplores the methods, contrary to legal procedures, that were used to put together the report.”
The company also alleged that French authorities did not mention any “possible conflicts of interest,” but did not elaborate. We asked Biotrial to explain this comment and will update you accordingly. In any event, the CRO maintained that these failures undermined the “credibility” of the report.
Finally, Biotrial maintained that an action plan has already been in place and that the company did not wait “to make volunteer care improvement its utmost priority.” The CRO added that it will submit its plan to the authorities.
[ANOTHER UPDATE: A Biotrial spokeswoman wrote us that two IGAS investigators used to work at the Public Assistance-Paris Hospital, and of them is now the head of Rennes University Hospital, which is involved in the case and is where the patient died in January. And the other investigator used to work for the head of ANSM, the French regulator. “They used to work all together and today, we fear that the inquiry was not conducted in a strictly fair way,” she explained.]
Thank Goodness for CFR 21 Part D section 313.52 which exculpates sponsors from CRO screw UPS, which I could start a second career writing a book about.
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