French Prosecutors' Case May Alter Drug Trial Process

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The worst fear of any clinical trial is causing harm, or even death, in trial participants and unfortunately, for Portuguese pharmaceutical company BIAL, and one of its trial subjects, this fear was recently realized.

In Phase I of a clinical trial for a drug being investigated for treatment of chronic pain (most likely known as BIA 10-2474, though unconfirmed), the death of one participant after being declared brain dead was recently announced, along with the hospitalization of five others, with four of them showing neurological disorders. The other participant was without symptoms, but under observation.

It seems now that French prosecutors are beginning a manslaughter investigation in this case. This would be a devastating blow to research and development as any drug manufacturer has to now worry about criminal charges in the rare instance that a subject dies or is permanently disabled. The Phase I trial is one of the most important steps in getting a new drug or medical device approved: these early clinical tests are designed to test different doses for toxicity and tolerance, and follow animal testing.

The drug being investigated was an inhibitor of an enzyme known as a fatty-acid amide hydrolase, which is responsible for the breakdown of endocannabinoids. The endocannabinoid system is known for modulating several different physiological processes in the body such as the regulation of appetite, pain sensation, mood and memory as well regulating the psychoactive effects of cannabis. Receptors for endocannabinoids, CB1 and CB2 are found predominantly in the brain and nervous system, but they are also present in other organs and tissues outside of the nervous system.

The level of interest in the endocannabinoid system is not novel. In 2009 Sanofi-Aventis withdrew its drug, Rimonabant (Acomplia), due to its risk of dangerous psychological side effects, including suicidality. Rimonabant made it to Phase III clinical trials in the United States but never made it to the market. It was a CB1 receptor blocker that was going to be used in the treatment of obesity and diabetes. In fact, France toughened its medical safety laws when this medication was suspected of causing hundreds of deaths in Europe where the drug was on the market.

The European version of the Food and Drug Administration, the European Medicines Agency, is roughly parallel to the FDA with respect to investigational drug approval process. In the United States, the FDA has safeguards in place to protect the health and welfare of study participants. Companies usually conduct extensive animal studies prior to beginning human trials and once the company has supplied the FDA with sufficient evidence of the drug or device s safety will they receive an Investigational New Drug (IND) number and be allowed to proceed to testing in human subjects.

What can work and show promise in animal models is not always the case in humans as evidenced by the tragedy in France. Recently, I wrote about Right to Try (RTT) laws, that enable states to bypass the FDA in allowing terminally ill patients access to Phase I investigational drugs. The concern is always going to be protecting the safety of participants in experimental drug trials. However, when it comes to terminally ill patients the situation is more about weighing harms versus benefits, with the benefit of extending life or potentially saving a life trumping any potential harm in an individual who will die soon.

The ultimate goal of a Phase I trial is determining a drug s safety in the treatment of human subjects. Of the 128 healthy volunteers aged 18-55 who took part in the BIAL trial, 90 received the treatment whereas the rest of the participants received placebo. This trial was conducted after 108 healthy people had already received the study drug without major adverse reactions granted it is not that many people. One industry insider stated that he was "very surprised to see this reaction in a Phase I trial" and that in his 20-plus years he has never seen mortality before in this stage of clinical trials. Phase I clinical trials are primarily to check for side effects and dosing range he relayed.

Seeing as how the entire process had followed all safety protocols, not only is it ludicrous to charge anyone with manslaughter but entirely unfounded. With the prescription pain killer abuse epidemic being what it is, any attempt at discovering new drugs is welcome. Drug approval is a process and the results may not be what we would hope for but before we send out a lynch mob, it s important to reflect on where we would be if we criminalized the process.