In early 2016, global headlines denounced a French clinical trial gone horribly wrong. The study received much media attention after the trial had abruptly concluded with fatal results. The trial was categorized as a Phase 1 Dose Escalation Study of an Investigational New Drugs effects on the endocannabinoid system.
Let’s break that down for a moment.
Phase I → A study designed to test the safety and dosage of an investigational (experimental and not previously tested in humans) product.
Dose Escalation → A study designed to try to establish what is considered “safe” parameters or thresholds for a dose of the investigational product. Such studies are typically done in healthy people (patients or subjects) and in stages. For example, as the researcher, if you enroll 20 subjects to have 5 groups of 4 subjects each, then you start the first group of subjects with a lesser dose. Careful monitoring of the subjects for side effects and adverse (bad) reactions should take place before the dose amount is consequently increased. If the first dose is deemed as safe (none of the subjects in the group experienced any bad effects), the next (higher) dose level is planned for use with the next group of subjects.
Investigational New Drug (IND) → A product that falls under the FDA definition of a drug (Drug substance is an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient.) and has either not been tested in humans or is being used off of its approved labelling, dosage, or indication.
All human subject clinical trials undergo extensive review at the federal, state, and institutional level in the United States if they engage a site (institution, hospital, university) that has filed a federal-wide assurance. Internationally, however, while the requirements and regulations may differ, the basic guiding ethical and historical principles remain the same. As far as investigational drugs go, before use in humans, investigational products are typically tested in animals with several rounds of research. Only 10% of all investigational drugs ever make it to the stage where it may be considered for a Phase I study to be tested in humans.
So What Happened in France?
In this case, the research study was conducted by Biotrial, a French private company, and the investigational drug manufacturer was Bial, a Portuguese pharmaceutical company. The aim of the investigational drug BIA 10-2474 was that it would be able to mitigate and treat a large range of conditions from anxiety disorders to Parkinson’s disease.
In initial testing, the drug tested favorably in several animal studies and raised no concerns in terms of moving the investigational drug research forward.
Within Phase I of the study, the first dose tier consisted of around 90 subjects that were given either a single dose (up to 100 mg) or several doses (no more than 20 mg each). With no evidence of any adverse effects within this group, in the next tier the dose was escalated to 50 mg in multiple doses per day. The first subject in this tier was rushed to the emergency room and hospitalized with the complaint of headaches and blurry vision. Instead of halting drug dosing for other subjects until this adverse event could be monitored and analyzed, the research study continued to provide the escalated dose and chose not to properly inform the remaining subjects or the authorities about the hospitalization incident. The first hospitalized subject’s conditioned eventually deteriorated and was later pronounced brain dead. Four other subjects subsequently were hospitalized with severe neurological symptoms. The study was stopped and national agencies thoroughly investigated how this clinical trial went fatally wrong.
The monitoring of the adverse events needed to have had a more careful examination. Authorities should have been notified as soon as symptoms began manifesting. The study dosing should have been halted to avoid putting more subjects at risk and subjects waiting for the increased dose needed to be properly informed of the incident. In Phase I studies that are studying agents never before used in humans, a data safety monitoring board or committee should frequently review all adverse events and study progress to ensure whether or not the study can feasibly continue without posing undue risks to subjects. In this case this study fell into several conduct and reporting mishaps that, as if the study had been conducted properly, it could have avoided the resulting such negative outcomes. When creating, reading and reviewing human subjects research protocols it is vital that regulatory agencies, research teams, pharmaceutical companies, and subjects pay very close attention to all elements of the study design along with the potential for benefit.
If you are approached to participate in a clinical trial, please always look for the following five criteria:
Ensure that the study is approved by the necessary agencies. Look for an IRB, Ministry of Health, Ethics Review Committee or other such agency approval. If you don’t see it, always ask the study team to ensure that it has been properly reviewed.
Make sure you keep a copy of the consent form or research information sheet at all times as you participate in the study. The risks of the study should be well presented and instructions for how to handle an adverse event or emergency should be provided.
Make sure you report any negative effects you may be experiencing. Your research team needs to know in order to conduct the trial safely and properly.
If there are problems with the research team and/or the trial conduct, always utilize the contact information on the consent forms/research information sheets. The reviewing agency should be able to coordinate and help depending on the situation.
Understand what the study is (phase and products being tested), what is expected of you, and what to expect of the research team. Always feel free to ask questions if there is any confusion.
Reports, reviews, and official determinations are now publicly available for community review and comment. The incident has brought the risks of clinical trials and the importance for good clinical trial conduct, monitoring and regulation to the forefront of public opinion. All in all, globally we can all learn and do our best to avoid and mitigate these tragic scenarios in the future.
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