Tackling Early Phase Development Challenges With Effective First-In-Human Studies

First-in-human (FIH) trials in the early phases of drug development represent a critical milestone in the approval of medicines. Their purpose is to study the human pharmacology, pharmacokinetics (PK) and pharmacodynamics (PD), tolerability, and safety of an investigational medicinal product (IMP) having already gone through preclinical studies, and to evaluate how the effects translate from animals to humans. They may also include the collection of data on food or drug interactions, different age groups or gender, proof of concept, and relative bioavailability of different formulations. FIH trials allow sponsors to determine potential risks associated to the drug at each step of its development, and determine the safe dose range in the course of its clinical progression.

Both the FDA and the EMA have strict guidelines when it comes to FIH studies. Following two incidents that occurred in the past two decades (Parexel in 2006 and Biotrial in 2016), the EMA revised its guidance on early FIH clinical trials to further help stakeholders identify and mitigate risks to ensure the safety of trial participants. These revisions focused mainly on dosing levels and the improvement of strategies in the overall conduct of the clinical trial, including the introduction of sentinel dosing to ensure subject safety.

In recent years, trial protocols have become increasingly complex. In the past, FIH clinical trials consisted of a single ascending dose (SAD) design, which was followed by a multiple ascending dose (MAD) study. Today, most FIH trials combine a number of different study parts (e.g., SAD, MAD, and food effects) which require that the information generated in previous parts be analyzed by the safety review group and integrated into an assessment within a shorter timeframe, prior to making a decision on whether to proceed to the next part.