One Death, Three Serious Brain Injuries in Phase 1 Trial

Jean-Bernard Gervais

January 15, 2016

UPDATED January 18, 2016 // A participant in the phase 1 trial of an investigational analgesic medication who was reported as brain dead on January 15 has subsequently died on January 17. This individual and five other previously healthy volunteers were hospitalized at the University Hospital of Rennes in France after developing serious neurologic problems.

The clinical condition of the five volunteers who remain hospitalized is stable, the hospital announced in press release on January 18.

"Four patients are showing neurological disorders and the fifth patient, who has no symptoms, is under observation. Three patients are in a very serious condition, raising fears of irreversible disability. The MRI revealed necrotic and hemorrhagic brain lesions," said Pierre-Gilles Edan, MD, professor of neurology at Rennes University Hospital.

Marisol Touraine and Dr Pierre-Gilles Edan. Source: David Vincent/AP

"This trial concerns a molecule for treatment of motor disorders, neurodegenerative disorders, and anxiety disorders. It acts on the endocannabinoid system," said Marisol Touraine, France's Minister of Social Affairs, Health, and Women's Issues, at a press conference in Rennes on January 15. The five hospitalized volunteers are men aged 28 to 49 years, she said.

There were two other participants in this part of the trial, but they were taking placebo, did not have any neurological symptoms, and have not been hospitalized.

Touraine called the development "unprecedented" in France.

The clinical trial application was filed on April 30 with the National Agency of Drug Safety (MSNA) by Biotrial, a clinical trials laboratory.

The MSNA authorized this trial on June 25, 2015, and it began on July 8. Investigators planned to include 128 volunteers. So far, 90 people have participated, but earlier participants had received lower doses of the experimental drug than the six people hospitalized.

On January 10, one of the volunteers presented to Rennes University Hospital in serious condition. "We first thought he was the victim of a stroke," said Dr Edan.

Biotrial decided to discontinue the trial on January 11 because four patients were hospitalized. On January 14, the Ministry of Health was informed of this incident.

In the coming days, the Regional Health Agency will have the task of recalling the other participants in this study.

Furthermore, the MSNA "decided to conduct a technical inspection of these clinical trials. The French minister has asked the General Inspectorate of Social Affairs to conduct an inspection of the organization, the means and the conditions of intervention of this institution in the completion of the clinical trial." The healthcare division of the Paris prosecutor's office opened an investigation in flagrante delicto for "involuntary injury."

The Biotrial laboratory that conducted the phase 1 trial had proper authorization and positive results, added Touraine. Founded in 1989 by pharmacist Jean-Marc Gandon, PharmD, and Hervé Allain, MD, professor of pharmacology at Rennes University, Biotrial conducts 20 to 25 simultaneous studies each year without incident.

A message on the Biotrial site says, "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."

Similar Past Incident in UK

As pointed out by the health minister, this type of incident is totally "unprecedented" in France.

In Europe, a similar event occurred in 2006 in London, United Kingdom, when six male previously healthy volunteers participating in a phase 1 clinical trial had to be hospitalized, two in a critical condition and one in a serious state. They had received an investigational anti-CD28 monoclonal antibody intended for use in cancer or immune system diseases. That drug was being developed by TeGenero, a German biotech company, and the trial was being conducted by the Parexel company, a clinical trials specialist. As with the incident in Rennes, the only two people who experienced no symptoms were those who had been given placebos.

Another incident in the past occurred in a later stage of drug development. In Nigeria, in 1996, a test run by the Pfizer laboratory led to the deaths of 11 children. The laboratory was testing its new antibiotic, Trovan, in the final phase of clinical trials. Following legal action an agreement was finally reached between Pfizer and the Nigerian government, and the company was required to pay €75 million (US$82 million) compensation.

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