EMA looks to improve safety of first-in-human trials

Reflection on changes to best practices begins in wake of French clinical trial tragedy

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LONDON—There hasn’t been a lot of news lately about a controversial death and five hospitalizations related to a clinical trial in France in January, but May 27 saw an announcement from the European Medicines Agency (EMA) that it has started a review of the guidelines that describe first-in-human clinical trials and the data needed to enable their appropriate design and allow initiation—and has signaled clearly that the French trial was a key catalyst for that decision.
The review of guidelines is being done in cooperation with the European Commission and the member states of the European Union (EU).
The incident in question was a Phase 1 clinical trial in Rennes, France, conducted by the company Biotrial on behalf of the Portuguese pharmaceutical firm Bial. Under evaluation in the trial was an analgesic drug candidate called BIA 10-2474 that inhibits fatty acid amide hydrolase enzymes. In mid-January, the reports came out that one man had died and five others hospitalized for severe health problems. Some scientists and other concerned parties voiced concerns shortly after the news broke about a lack of information regarding whether the design included adequate time intervals between patients being given the multiple-dose regimen of the drug—these intervals allow investigators to watch for possible side effects in one volunteer before they give the drug to subsequent trial participants.
As the EMA said in its announcement that it would review trial guidelines in the EU, “The review will identify which areas may need to be revised in the light of the tragic incident which took place during a Phase 1 first-in-human clinicial trial in Rennes, France, in January 2016. The trial led to the death of one participant and hospitalization of five others.
“EMA’s review will take into account the findings from two in-depth investigations into what went wrong during this trial, one carried out by the Temporary Specialist Scientific Committee set up by the French medicines agency ANSM and the other by the Inspection Générale des Affaires Sociales (IGAS), the inspectorate for social affairs in France.
“Both reports include a series of recommendations regarding the requirements for authorization and conduct of first-in-human clinical trials for further examination by the international regulatory and public health community.”
EMA’s work will focus on best practices and guidance, with a goal to agree a concept paper by July that would identify areas for change and proposals to further minimize the risk of similar accidents. The concept paper will form the basis for an EU-wide review of the guidelines. This process will include targeted discussions with stakeholders and a public consultation on proposed changes later in 2016.
The EMA review has begun with a pair of expert groups doing preparatory work. One group is looking at preclinical aspects with an eye toward the data needed from lab tests or animal studies to safely initiate first-in-human tests. The other group will look at clinical aspects of the design of first-in-human trials and how these could be improved to better ensure the safety of human volunteers taking part in these trials.
The EMA notes that severe adverse reactions in healthy volunteers such as those observed in the trial in Rennes are extremely rare during clinical trials, and “Since 2005, approximately 14,700 Phase 1 clinical trials (with participation of 305,000 subjects) have been conducted in the EU, including 3,100 first-in-human studies. Only one other severe incident has been previously reported in that time in the EU.”
On May 23, Bial responded to the issuance of the final IGAS report in a news release that read, in part, “The report does not question the clinical trial protocol’s approval by the French National Agency for Medicines and Health Products Safety (ANSM), stating that it complies the existing legislation and recommendations, namely on the evolution of the forecasted doses.
“Thereby, Bial reinforces that the decisions on the escalating doses were properly taken. Towards the report conclusion regarding the escalating doses, including the passage from 20 mg to 50 mg, Bial notes that the safety and tolerability profile of BIA 10-2474 was favorable up to 20 mg. There were no alerts, or signals in any of the safety parameters collected from any of the previous cohorts that could have anticipated the tragic accident. The integrated analysis of single (up to 100 mg) and multiple doses of drug exposure did not reveal any unexpected behavior of the molecule.
“Therefore, given the data collected in the previous phases of the trial, there was no reason to modify the escalation of doses forecasted and approved by the authorities in the trial protocol.”
Until the death and hospitalizations occurred, Bial noted, there were no previous signs “that could have prevented what happened were detected, nor did any comparable toxicity occur in the preclinical trials in animals.”
Bial concluded by saying that its key priority is “to accurately and exhaustively understand what happened in the clinical trial with the experimental molecule BIA 10-2474” and that, “Although deeply shaken by this regrettable accident,” it maintains its commitment to research and to the quality of life and people’s health.

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