By Judy Stone

A Phase 1, or first-in-human clinical trial run by Biotrial, a long-standing French-based clinical research organization, ended disastrously. One healthy volunteer is brain-dead and others are seriously—and perhaps permanently—left with serious neurologic damage, according to Dr. Pierre-Gilles Edan, head of the neurology department at the hospital in Rennes where the volunteers were taken, and France Health Minister Marisol Touraine. Edan said that MRIs of the affected patients show deep cerebral hemorrhage and necrosis and that the “handicap that could be irreversible.”

What we know

The volunteers all apparently received a Bial⁠ pharmaceutical novel compound BIA 10-2474⁠, designed to target pain relief by acting on cannabinoid receptors. Bial is also a long-established company, founded in 1924 in Portugal, but also having a large international presence. A potential study volunteer provided study related documents that described the investigational drug BIA 10-2474 as a “product in development for the treatment of different medical conditions from anxiety to Parkinson’s disease, but also for the treatment of chronic pain of sclerosis, cancer, hypertension or the treatment of obesity.” This translates more simply to mood and motor disorders complicating neurologic diseases—epitomizing a problem with consent forms or recruitment materials—which are often so deliberately broad as to be uninformative.

All six volunteers received the oral drug on January 7; five became ill on January 10. Surprisingly, the trial has been ongoing since July and at least 90 participants completed the trial uneventfully, receiving various doses of drug. Presumably the doses escalated over time, as typically occurs in Phase 1 trials. There were an additional 38 who received placebo, very unusual in a Phase 1 trial, where the goal is to test the safety of increasing doses.

The investigational drug reportedly is thought by Bial to inhibit the FAAH enzyme⁠ and works by targeting the endocannibinoid system which helps a person sense harm.

Clinical trial phases—how every drug is tested

With any drug in development, the compound begins with animal, or pre-clinical testing for safety. Phase 1 trials examine the safety of increasing doses, and are the first time an experimental drug is given to people. If the drug survives Phase 1, Phase 2 looks at efficacy and dosing for the intended indication. More people take part in this phase, but it is still a very limited population. Next, Phase 3 broadens the population to include those with more underlying diseases, and compares the study medication either to placebo or to one already on the market. After approval by the FDA, Phase 4 trials are often marketing driven. If done properly, they will continue to look for safety issues.

What we don’t know

There are so many questions, as little information has been released. We don’t know what doses this group of ill volunteers received, or how that was different from earlier groups. It was likely the first of a higher dosage. We don’t know if or how food affected the drug’s metabolism.

Could there have been a contaminant causing disaster in one batch of drug? While much less likely with an oral than IV drug, an error in manufacturing or the concentration of drug could perhaps have affected one batch and not others.

Why was there a large placebo group, given that is atypical in Phase 1 trials?

Did these patients all receive the drug at the same time (in parallel) or sequentially? It appears that they all received it on January 7. In the last disastrous clinical trial, TeGenero TGN1412 in London, in 2006, six Phase 1 healthy volunteers almost died with multi-organ failure from a cytokine storm. This became known as the “Elephant Man” trial, for how bad the victims looked. One of the major lessons was that volunteers should be dosed sequentially, allowing time between each to detect a serious adverse reaction. Why didn’t that happen here?

Perspective

First, any clinical trial, especially first-in-human testing, comes with unpredictable risks. There is no way that animal studies can successfully predict them all. Even after clinical testing and approval of new agents, serious side effects are found all the time, as the drug is given to thousands or millions of people. Infrequent adverse events may be readily overlooked or not seen in clinical testing with small numbers of subjects.

The TeGenero trial taught us—or should have—the importance of going slowly, in a step by step manner. Was that followed here? Preliminary reports suggest that it wasn’t. If true, why not?

Serious adverse events on Phase 1 trials are very rare—on the order of “once every 26.3 years of individual subject exposure.” But sometimes bad things happen even when everything was done correctly, as exemplified by the NIH FIAU trial⁠10, with serious adverse events. The Institute of Medicine reviewed all and commended the investigators, concluding “their subsequent response to the crisis was exemplary.”

Are these trials ethical? With many in poverty, there is an inherent coercion in this type of trial. How well did the investigators or the consent explain possible risks?

Do subjects have any recourse? In France, these victims will receive compensation. That is not always the case. One needs to read the fine print carefully. This is one argument for a clinical trial injury fund, as a safety net for volunteers, who are critically important for drug development.

It’s one thing to take a risk of a Phase one trial if you have metastatic cancer or another fatal disease. It is quite another for a healthy volunteer to do so.

What is imperative is that we conduct trials transparently and ethically, follow safety procedures rigorously, provide a clear and thorough consent process, and minimize the coercion of financial incentives. We still have a lot to learn.