An Industry Perspective on the 2017 EMA Guideline on First‐in‐Human and Early Clinical Trials

Abstract

The European Medicines Agency (EMA) in 2017 issued a revised guideline on nonclinical and clinical aspects of first-in-human (FIH) and early clinical trials (CTs). External input was solicited during a draft comment phase, and although some industry suggestions were adopted, others were not. We agree that subject safety is of utmost priority, and believe that minimizing risk must be balanced with efficient and informative study designs to bring new medicines to patients.

The Role of Quantitative Systems Pharmacology in the Design of First‐in‐Human Trials

“…To the Editor: In a recent issue of Clinical Pharmacology & Therapeutics , representatives from the European Medicines Agency (EMA) and the pharmaceutical industry provide their perspectives on the new 2017 EMA guideline on nonclinical and clinical aspects of first‐in‐human (FIH) and early clinical trials. This guideline was a response of the EMA to the tragic outcomes of the FIH trial with the fatty acid amide hydrolase (FAAH) inhibitor, BIAL 10‐2474, in 2016.…”

“…The EMA and the pharmaceutical industry appear to be in agreement on how this applies to selecting a safe starting dose, but their perspectives seem to diverge when it comes to defining the pharmacodynamic range and maximum dose that can be explored in an FIH study . The industry perspective states that “…the predicted therapeutic range at the time of FIH conduct is based on translational PK/PD (pharmacokinetic/pharmacodynamic) data, which in many cases is adjusted on emerging clinical data” and “…the exposure maximum is typically defined by mean animal exposure.” This view, as well as the new EMA guideline, seems to suggest that FIH doses can only be estimated on the basis of preclinical data and appear to ignore the potential role of mechanistic model‐based approaches, such as quantitative systems pharmacology (QSP), which may or may not use preclinical data. This point is particularly relevant for the BIAL 10‐2474 case, in which an available QSP model could have been used to set stopping criteria well below the (fatal) highest dose tested based on understanding of the pharmacodynamic range.…”

Safety, Tolerability, and Pharmacokinetics of an Oral Small Molecule Inhibitor of IL‐17A (LY3509754): A Phase I Randomized Placebo‐Controlled Study

“…Similarly, based on well-characterized preclinical data, LY3509754 was not considered to require a sentinel dosing approach. 21 The considerable delay between administration and liver signal onset meant that these safety data were not available for the dose escalation meetings; hence, it was agreed that dose escalation criteria had been met and further cohorts were enrolled per study protocol.…”

“…The NOAELs established in the 1‐month and 3‐month rat and dog studies supported the planned clinical dose range and no liver injury was observed in animals, consistent with the biopsy histopathology or the latent, prolonged effects observed in the clinical trial. Similarly, based on well‐characterized preclinical data, LY3509754 was not considered to require a sentinel dosing approach 21 . The considerable delay between administration and liver signal onset meant that these safety data were not available for the dose escalation meetings; hence, it was agreed that dose escalation criteria had been met and further cohorts were enrolled per study protocol.…”