EMA updates first-in-human trial guidance to tighten volunteer safety

Biotrial

The European Medicines Agency has followed through on plans to update its guidance on first-in-human clinical trials in light of a fatality in a French study earlier this year.

The revised guideline aims to improve the safety of patients volunteering for early-stage trials and is open for comment until the end of February, said the EU regulator. It follows an incident in January, in which one patient died and five more were hospitalized after taking an anxiety drug developed by drugmaker Bial in a first-in-human study run by contract research organization Biotrial. 

The incident sparked an investigation by the French authorities which claimed the two companies "lacked common sense" in not stopping the trial quickly enough when it became clear things were going awry, and also resulted in an involuntary manslaughter probe by French prosecutors. 

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The companies deny any wrongdoing, insisting they acted in accordance with the current rules on these studies, while France's drugs regulator—the ANSM—has been forced to defend itself from allegations that it concealed information related to the incident. 

The case prompted the EMA and European Commission to take a closer look at the 2007 guideline, concluding earlier this year that it was no longer fit for purpose given the increasing complexity of trial protocols.

In particular, there has been a trend towards greater deployment of trials which involve giving multiple ascending doses of the test compound straight away, rather than starting with a single ascending dose design. Trial sponsors are also more likely to bundle in multiple analyses within a single trial, for example by including different age groups and conducting studies on food interactions.

The revisions to the guide include the addition of advice on mitigating the risk posed to trial volunteers, for example by laying out the principles used to calculate starting doses, stepwise increases, the interval between administrations, and maximum doses. It also says sponsors should define "unambiguous stopping rules which result in an immediate stop to dosing" if side effects are seen.

For its part, France has already implemented interim measures to prevent a recurrence of this type of incident, including a requirement that hospitalization of any volunteer in a first-in-human trial should result in a suspension in dosing and a re-inspection of all clinical centers running this type of study.

The revised guideline was adopted last week by EMA's Committee for Medicinal Products for Human Use (CHMP).

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