From The Editor | January 25, 2016

Did Poor Protocol Design Lead To The Clinical Accident In France?

Ed Miseta

By Ed Miseta, Chief Editor, Clinical Leader

Did Poor Protocol Design Lead To The Clinical Accident In France?

Did the clinical trial in France that has left one person dead and several others hospitalized have flaws in the protocol design? While we continue to await new information on what may have caused the tragedy, some researchers are already speculating on whether or not the design of the trial may have been a factor, and are demanding more information be released.

The researchers, including some from the UK’s Royal Statistical Society (RSS), have examined the trials protocol and are concerned about the lack of information appearing in the report. According to an article appearing on, researchers have noted a lack of information about whether the trial included adequate time intervals between the dosing regimens on study participants. The intervals are an important part of trials, as they allow investigators to monitor participants for possible side effects before exposing others to the drug. 

The incorporation of these delays was identified as an important aspect of trials by both the RSS and the European Medicines Agency almost 10 years ago, when a trial in the UK produced serious adverse events.

In that 2006 London trial, six men were left ill after taking part in a study testing a drug designed to fight auto-immune disease and leukemia. Within hours of taking the drug, TGN1412, all experienced a serious reaction, were admitted to intensive care, and had to be treated for organ failure. Two became critically ill, with one eventually losing all of his fingers and toes. All were told they would have a higher risk of developing cancers or auto-immune diseases.

The Duff Report, written in response to the TGN1412 trial, noted the medicine should have been tested in one person at a time. It also helped to put additional safety measures in place. The Medicines and Health Products Regulatory Agency (MHRA) now requires committees to look at pre-clinical data to determine the proper initial dose, and rules are in place to stop the trial if unintended reactions occur.

The RSS has called upon Bial, the Portuguese company that sponsored the trial, to release further information about its design and any previous tests. We know from the French health minister that the drug being tested acted on natural receptors found in the body known as endocannibinoids, which regulate mood and appetite. All six trial participants were reportedly administered the doses simultaneously.

Per the protocol, participants were to receive one dose daily for ten consecutive days. The protocol does not state whether there were intervals between the individuals beginning the treatment, nor the dosage received.

According to the timeline laid out by French health minister Marisol Touraine, those injured in the trial all began taking the medicine on January 7th. Adverse events appeared in the first subject three days later, and in shortly thereafter in the others.    

Catherine Hill, a biostatistician who previously served on the ANSM's scientific advisory board, is quoted in the Nature as saying it was “a big mistake” to begin giving the six volunteers the drug on the same day. She notes a delay should have incorporated, and the lack of it created an “unreasonable protocol.”

The British Pharmacological Society has also released a statement calling for data from catastrophic clinical trials to be made available for review earlier.

The trial was being performed at Biotrial, a French-based firm that was formed in 1989 and has conducted thousands of trials. Bial has disclosed the drug was a FAAH (fatty acid amide hydrolase) inhibitor, which is an enzyme produced in the brain and elsewhere that breaks down neurotransmitters called endocannabinoids. It is now believed the culprit is referred to by the codename BIA 10-2474, which appeared on a recruitment form that was given to a volunteer. Little more is known about it, and there does not appear to be any entry for it in clinical trial registries.  

The French health ministry has reporting the six patients were all in good health prior to taking the oral medicine, which was administered to 90 male volunteers between the ages of 28 and 49. The trial recruited 128 individuals, and the remaining participants received a placebo. Touraine, who has described the situation as a very serious accident, noted the patients were taking part in a trial in Brittany, Rennes involving a medicine developed by a “European laboratory”, refusing to comment further until additional information became available.

Touraine has also asked the Inspector General of Social Affairs to lead an investigation into the circumstances around the trial, which has been suspended. She notes the drug had been tested on animals, including chimpanzees; the trial had been approved in 2015 by France's National Agency for Medicine and Health Products Safety. The drug was intended to treat mood disorders such as anxiety. While the men were administered varying doses, the patients who are hospitalized were taking the drug “regularly”. Pharmaceutical giant Johnson & Johnson has voluntarily suspended testing on a similar drug until more information on the tragedy comes to light.