[co-author: Eftychia Sideri]

The European Medicines Agency (EMA) has released a new Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products. The Guideline was adopted by the CHMP on 20 July 2017. It will come into effect on 1 February 2018. The revised Guideline is the outcome of EMA’s initiative to update the previous guideline on first-in-human clinical trials. The revision is intended to assist stakeholders in the transition from non-clinical to early clinical development and in identifying factors influencing risk for new investigational medicinal products.

According to EMA, despite the fact that it is very rare for participants in first-in-human trials to experience serious harm, there is, nevertheless, an element of risk. This is due to the fact that the ability of researchers to predict the effects of a new medicine on people is limited before it is actually studied in humans. The new Guideline emphasises the trial sponsor’s responsibility to define the degree of uncertainty associated with the medicinal product to be tested and to provide a description of how the risk associated to this will be handled within the design and conduct of the trial. The sponsor must provide documents that are adequate in format and scientific content to permit a meaningful assessment of the adequacy of the risk minimisation efforts.

The revised Guideline also takes into consideration the increasing complexity of protocols of first-in-human clinical trials in recent years. The Guideline outlines strategies for mitigating and managing risks for trial participants. This includes principles concerning the calculation of the starting dose to be used in humans, the subsequent dose escalations, the criteria for maximum dose and the conduct of the trials that have multiple parts. The revised Guideline also addresses the overall risk assessment of non-clinical issues. This is due to the fact that non-clinical data in pharmacodynamics, pharmacokinetic and toxicology are important basis for planning and conduct of a first-in-human trial.

The Guideline provides criteria on how to suspend or cancel a clinical trial. Furthermore, the Guideline mentions that the trial design should provide a specific plan for monitoring for adverse events or adverse reactions.