Revised Guidelines on FiH Clinical Trials

The European Medicines Agency (EMA) has revised its guidance on first-in-human (FiH) clinical trials to further help stakeholders identify and mitigate risks for trial participants which will be in effect from 01 February 2018. The release of the revision follows a review of the guideline launched back in May 2016 by EMA, after a Phase I, first-in-human trial in France left one patient dead and five others hospitalized.

A FiH study is a clinical trial where a medical procedure, previously developed and assessed through in vitro or animal testing, or through mathematical modelling is tested on human subjects for the first time. Sometimes, this is called a Phase 0 study. Participants in these trials, often healthy volunteers, face an element of risk as the ability of researchers to predict the effects of a new medicine on people is limited before it is actually studied in humans. The safety and well-being of trial participants should always be the utmost priority when designing early clinical trials. 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 current guideline focuses on non-clinical aspects of drug development, only considers SAD studies while revised guideline

  • Gives considerably more information on design of FiH studies
  • Explicitly covers the “umbrella-protocol” practice, including considerations for moving from SAD to MAD parts
  • More concrete guidance on choice of starting dose
  • Calls for maximum dose / dose range / exposure margin to be defined in the protocol
  • Precautions to apply between treating subjects within a cohort and between cohorts

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.

Frequent mention of modelling (PK/PD, PBPK) throughout several sections of guidance increases opportunities for use of STATISTICS in FiH trials.

GCE would be happy in lending a hand to understand and implement revised guidance in your FiH trials.

Link to revised guidance: