The revised guideline will come into effect on 1 February 2018.
First-in-human trials are a key step in medicine development, where a medicine already tested in vitro, in animals or in other preclinical studies is administered to people, often healthy volunteers, for the first time. Even if participants in these trials face an element of risk that is difficult to predict, they have only on very rare occasions experienced serious harm. It was the case of the Bial Pharmaceuticals-sponsored Phase I trial (occurred in France in 2015), that triggered the release, on 21 July 2016, of the EMA’s concept paper on the revision of the 2007 “Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products”. The concept paper anticipated the issuance of this revised guideline, published in the draft version for consultation on 15 November 2016 and now, in the final version, on 25 July 2017.
As explained by the EMA, the guideline puts emphasis on the sponsor’s responsibility to define the uncertainty associated with the medicine tested at each step of the development and to describe how the potential risks that might arise from this uncertainty will be addressed within the design and conduct of the trial. The approach must be supported by a well-documented scientific rationale from the outset and be responsive to data emerging over the course of the trial itself.
The strategies to mitigate and manage risks for trial participants described in the guideline refer specifically to the calculation of the starting dose to be used in humans, the subsequent dose escalations and the criteria for maximum dose. Guidance is also provided on criteria to stop a study, the rolling review of emerging data with special reference to safety information for trial participants, and the handling of adverse events in relation to stopping rules and rules guiding progress to the next dosing level.