The European Medicines Agency (EMA) has issued new, stricter rules for studies that test drugs in people for the first time. They aim to better protect participants in such first-in-human studies—often healthy volunteers who receive a financial reward.
The guideline, which was issued on 25 July, will take effect in February 2018. It comes in the wake of a tragedy in a French drug study last year that led to the death of one man and serious neurological damage in four others. But some say the revision isn't going for enough.
The new guideline emphasizes that drug developers must perform comprehensive preclinical tests of a new compound, including how it binds to its target and whether it has so-called off-target effects; experts argue such studies fell short for the French study. EMA also provides more detailed guidance on dosing and how to monitor subjects' safety. Trial sponsors need to have strategies to minimize risks at every step and have to deal with adverse events timely and adequately.
Also new in the guideline are provisions for trials consisting of multiple substudies, which have become far more common the past decade. (The French trial, run by Biotrial in Rennes for a Portuguese drug company named Bial, used multiple groups of volunteers to test many different dosing regimens and interactions with food.) In some cases, drug developers need to analyze all the results of an earlier part before moving on to the next.
Neuropharmacologist Daniele Piomelli from the University of California, Irvine, welcomes several of the new rules. Bial and Biotrial made the “incomprehensible decision” to test daily doses of up to 100 milligrams, he says, when much smaller doses had been shown to completely inhibit the target enzyme; the new rules would have prevented that.
But the guideline doesn't sufficiently address another mistake, Piomelli says. After the first volunteer was hospitalized with strokelike symptoms, the remaining subjects received another dose the next morning. Under EMA's new rules, a serious adverse reaction in even one subject should be considered a reason to stop if it is “at least possibly related” to the drug candidate. But Piomelli says that with healthy volunteers, any serious adverse event should be presumed to be drug-related. “In doubt, you stop,” he says.
EMA “certainly tried to improve” the guideline, says Joerg Hasford of Ludwig Maximilians University of Munich in Germany, the chair of the Association of German Research Ethics Committees. But the wording is “supersoft,” Hasford says. Drug developers want studies to go fast, and EMA appears to accommodate them, he says. Studies with multiple parts, for instance, are attractive to trial sponsors because they have to apply for approval and produce participant information only once. But Hasford says such setups should not normally be allowed for first-in-human trials.
The guideline also lacks sufficient ethical guidance on weighing the benefits against the risks before a trial starts, he adds. Some researchers criticized the Bial trial because the company had not shown that the test drug, called BIA 10-2474, was a promising drug candidate. “It was not clear that this compound was useful for anything,” Piomelli says.
In an email to ScienceInsider, an EMA spokesperson says that the guidelines need to cover many different scenarios and that the agency can't produce an “omni-comprehensive document.” Trial sponsors have to interpret and apply the provisions in a manner “that is proportionate to the level of uncertainty linked to the novel drug and the characteristics of the subjects,” he says. And the revision focuses on technical aspects, he emphasizes; ethics committees are responsible for weighing studies' ethical questions.