Posted 12 August 2016
By Zachary Brennan
The U.S. Food and Drug Administration (FDA) on Friday said that after reviewing the safety information of a first-in-human clinical trial in Rennes, France that resulted in the death of one healthy volunteer and the hospitalization of five others in January, the agency found that the toxicity exhibited in the trial does not extend to other drugs in the class, known as fatty acid amide hydrolase (FAAH) inhibitors.
Working alongside the European Medicines Agency (EMA) and the French national medicines agency (ANSM), FDA said it found that the investigational drug (BIA 10-2474) in the study, conducted by the contract research organization Biotrial for the Portuguese pharmaceutical company Bial, “exhibits a unique toxicity that does not extend to other drugs in the class.”
And since there are no clinical trials with BIA 10-2474 underway in the US, FDA says it is working with sponsors to establish the appropriate path forward for FAAH inhibitors.
“We are also working to ensure healthy subjects, patients, and investigators participating in FAAH inhibitor clinical trials are fully informed of the risks and potential benefits of these experimental therapies,” FDA said in a statement on Friday.
In March, ANSM released a report outlining how its Temporary Specialist Scientific Committee (TSSC) evaluated what went wrong with the French trial, though questions on what happened remain.
According to a report of the committee’s minutes, Bial planned to develop the compound as an analgesic, though clinical development of several similar compounds “was abandoned after Phase 2 clinical trials due to insufficient effectiveness (analgesic especially) without any specific toxicity being noted in humans or animals.”
In terms of toxicology, TSSC says the BIA 10-2474 animal studies “were carried out properly in accordance with current standards (those of the ICH especially),” and “no toxicity, especially neurological (central or peripheral) comparable to that observed in the accident in Rennes, [France] appears to have been demonstrated in animals, despite the use of 4 different species and high doses administered over long periods.”
Also, the committee noted that “the fact that the toxicology studies, although conducted on four animal species with doses up to 650 times the dose absorbed by the hospitalised volunteers, do not apparently show any lesions or picture likely to predict such toxicity.”
The TSSC outlined the following recommendations to move forward: The demonstration of pharmacological activity, comparative whenever possible, should be a requirement in the future before in‐human administration or even before continuing toxicology studies; A neuropsychological assessment with clinical interview and cognitive tests should be a compulsory part of assessment during volunteer screening and inclusion in a Phase 1 trial for drugs with "central nervous system" tropism; Detailed and well‐supported arguments for the choice of maximum dose to be tested in volunteers with respect to the presumed effective dose should be provided.
“For example, in this case, it appears unjustified to plan to test a dose (100 mg) 80 times higher than that presumed to induce complete and prolonged FAAH inhibition (claimed mechanism of action of the drug tested),” the committee said.
In May, EMA said it's reviewing its standards for first-in-human clinical trials because of the fatal trial, though the regulator noted that since 2005, about 14,700 Phase I 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.
And in order to meet FDA regulatory requirements, the agency noted that study sponsors collect rigorous laboratory and animal data and must submit such safety data to FDA in an IND application before any human volunteers may be enrolled in a Phase 1 study.
“Furthermore, sponsors may not initiate phase 1 studies until 30 days after submitting an IND application to the agency. This period of time allows FDA scientists to review the safety data and determine if the proposed study is reasonably safe to proceed... Catastrophic adverse events in phase 1 studies conducted in the U.S. are extremely rare,” FDA said.
FDA finds drugsunder investigation in the U.S. related to French BIA 10-2474 drug do not pose similar safety risks