EMA Revises Guideline on First-in-Human Trials

Regulatory NewsRegulatory News | 15 November 2016 |  By 

The European Medicines Agency (EMA), in cooperation with the European Commission and the EU member states, on Tuesday proposed revisions to its 2007 guideline on first-in-human clinical trials as part of an effort to further improve the safety of participants as trial protocols become increasingly complex.

The revised guideline, which is open for public consultation until 28 February 2017, is intended to further assist sponsors in the transition from non-clinical to early clinical development.

While identifying factors influencing risk for new investigational drugs, the document also includes considerations on quality aspects, non-clinical and clinical testing strategies and designs for first-in-human trials, as well as early phase trials.

“Strategies for mitigating and managing risks are given, including principles on the calculation of the starting dose to be used in humans, the subsequent dose escalation, the criteria for maximum dose and the conduct of the CT [clinical trial] including the conduct of multiple parts,” the guidance reads.

The release of the revisions follows a review of the guideline launched back in May by EMA, after a Phase I, first-in-human trial in France last January left one patient dead and five others hospitalized.

But as EMA has noted, adverse reactions in healthy volunteers such as those observed in the trial in France are extremely rare. Since 2005, approximately 14,700 Phase I trials (with 305,000 subjects) have been run in the EU, including 3,100 first-in-human studies. Only one other severe incident has been previously reported in that time.

Prior to the release of this revision, EMA released for public consultation a concept paper outlining the major areas for revision and to reflect the evolution of practices in the last 10 years. The consultation served as the basis for the revision, which was carried out by an EU-wide group of experts from national competent authorities who authorize trials in the EU.

In particular, the guidance is focused on non-clinical aspects, such as the better integration of pharmacokinetic and pharmacodynamic data and toxicological testing into the overall risk assessment, as well as the role of non-clinical data in the definition of the estimated therapeutic dose, maximal dose, and dose steps and intervals.

EMA also delves into clinical aspects in the guidance, including 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.

EMA says it will make public all comments received, both on the concept paper and the revised guideline, after the final guideline is released. The agency said it’s aiming to publish a final revised guideline in the first half of 2017.

Draft guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products


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