What can we learn from the recent tragic events unfolding in Rennes, France as a result of a clinical trial involving an assessment of the safety of a novel molecule and the subsequent death of a healthy male individual, one of a cohort of 128 people participating voluntarily in the trial?
On January 15th, a statement by Madame Touraine, the French Minister of Health, formally denied that cannabis was involved. The initial reports in the UK press and elsewhere had referred to the possible involvement of cannabis thus allowing the more imaginative journalists to launch diatribes about the dangers of marijuana being used for medical purposes. What are the facts of this incident and in particular what is the French media reporting on the trial? In the light of the reported death, the relevant French authorities have initiated an official investigation into the circumstances surrounding the trials.
Some basic background facts: a Portuguese pharmaceutical company, Bial-Portela SA, based in Porto, contracted Biotrials, a private French organisation [officially approved by the state] based in Rennes offering services to the international pharmaceutical industry, to carry out Phase 1 trials in humans on a new compound synthesised in Bial’s laboratories. A Phase 1 drug trial is the first time an experimental drug is given to humans after a series of exhaustive laboratory and animal studies. Phase 1 trials are conducted in healthy volunteers who do not have the medical condition in question. It is believed that the compound had been granted a US patent in June 2015 with 41 medical conditions being cited. The compound, code-named BIA 10-2474 and administered orally, is apparently based on a urea salt and was intended to treat mood and motor disorders associated with neurodegenerative disorders and anxiety. It is a member of a class of organic compounds known as fatty acid amide hydrolase (FAAH) inhibitors.
Why the interest in the FAAH mechanism?
The human body makes several fatty acid amides including anandamide, a natural stimulator of the cannabinoid receptors upon which chemicals in cannabis can act. Anandamide is referred to as being endogenous, described as an endocannabinoid and is responsible for controlling pain. The underlying thought is that a drug inhibiting FAAH will permit anandamide to act on cannabinoid receptors in a manner such that any potential psychoactive effects of cannabis would not accompany the inhibitive effect. A brief word on cannabinoids of which there are three types: one group of vegetable origin and found in cannabis plants; another prepared synthetically from chemical entities; the final one is made internally by the body and is thus endogenous. In this specific case it is the last group that is of interest. Some of the UK press reports failed to understand this basic point and immediately talked of cannabis being involved. They were wrong!
Such is the medical interest in this basic inhibition process that several pharmaceutical companies have been developing their own FAAH inhibitors. According to “Forbes” these include Janssen/Johnson & Johnson’s JNJ-42165279 for social anxiety disorder, Merck’s MK-4409, and Pfizer’s PF-04457845 both aimed at osteoarthritis pain, insomnia, Tourette syndrome as well as treatment of the symptoms of cannabis withdrawal, and finally Vernalis’ V158866. The diversity of envisaged medical effects reflects the wide range of actions that endocannabinoids appear to have in animal research models. To date none of these potential drugs has been associated with any type of brain injury in human research volunteers taking part in other Phase 1 trials.
The “Bial” compound along with other structurally related compounds has previously been tested in murine species and on non-human primates with results showing significant FAAH inhibition. Based on these laboratory results Phase I trials were initiated in July 2015 under the terms of a contract between Bial and Biotrials. The aim of these trials was to assess basic safety and human tolerance levels to specific dose levels administered orally and in a well-controlled manner. Initially single doses were provided and then in multiple amounts with careful observation and monitoring of each individual. The clinical trial was initiated last July with the objective of testing a total of 128 male volunteers, aged between 28 and 49, since then the experimental compound drug has been administered to a total of 90 volunteers in different doses, with the remaining participants given a placebo. On January 10th one man out of the 90, who as a member of a cohort of eight – two were given the placebo – had been given repeated doses at higher concentrations, was taken to hospital as he was in a serious condition. His health deteriorated rapidly and he died the following day. Out of five other participants, who also received higher-level doses, four also were hospitalized subsequently with neurological problems being described as serious and the damage possibly irreversible. The trials were suspended on January 11th and, in view of the death, both local police and state health authorities started a formal investigation.
Formal comments by both Bial and Biotrials did not cast any light on the reasons for this unexpected and tragic event. Other experts in this field of pharmaceutical research were totally surprised by this turn of events as previously there had been no reports of similar effects being observed in Phase 1 trials with related compounds. One curious feature of the clinical trials scene is that as many as 30% of the results of such trials are never reported in the literature [at least not within 5 years of their completion] and this in spite of legislation in the USA and also in Europe calling for immediate publication of all such results. A review of this anomalous situation seems to be essential as well as of the general regulations covering all three phases of medical trials. Risks are always present in any innovative medical treatment involving novel molecules but who should decide on the level of risk to be accepted? Animal trials are often contested on the grounds of animal protection and in-vitro work should perhaps be increased but ultimately in-vivo testing in humans must take place.
What can we learn from this “accident”? Informed public understanding of the general subject of pharmaceutical developments must be improved. Mass media must be prudent in their interpretation of such important issues and related events. In this specific case the immediate attribution to cannabis as the cause was clearly wrong. Education can help to avoid such misunderstandings and pharmaceutical suppliers should give more comprehensible information to consumers of new “drugs”.