Commentary on the EMA Guideline on strategies to identify and mitigate risks for first‐in‐human and early clinical trials with investigational medicinal products

The European Medicines Agency (EMA) published in July 2017 a guideline for first-in-human (FIH) drug studies [1]. The purpose of this document is to assist investigators, pharmaceutical companies, ethics committees and other regulators and stakeholders with the design and performance of early clinical studies of new compounds in humans. The focus of the guideline is on risk mitigation and promotion of safety. The guideline is a revision of an earlier version dated 2007 and extends the existing EU guidance to address FIH and early phase clinical trials (CTs) with integrated protocols [2]. The first edition of the EMA guideline on FIH studies followed the devastating events that occurred during the FIH study of TGN1412 in March 2006. The first administered dose of this CD28 superagonistic antibody caused a cytokine release syndrome in all healthy volunteers. The causes of these unexpected severe effects were carefully analysed by different authorities and experts in the field [3–5]. This resulted in guidelines that put an increased emphasis on the relevance of animal models; a revision of strategies to determine the starting dose (including the concept of MABEL, the minimally active biological effect level in humans); and an adaptation of safety measures for FIH studies (e.g. ‘sentinel’ cohort and intensive care access). Further research of TGN1412 revealed interspecies differences between the biological function of CD28 and led to the development of a bioassay that was predictive for humans. As a result, in 2014, the compound could be reintroduced at much lower doses in human development [6]. Ten years after its first publication the EMA guideline on FIH studies has now been revised. This revision followed a tragic event that happened in January 2016 during an FIH programme with BIA 10-2474, a fatty acid amide hydrolase (FAAH) inhibitor that enhances endogenous endocannabinoid concentrations being developed by BIAL [7]. Although BIA 10-2474 had never been administered to humans, FAAH inhibitors had been examined in numerous clinical trials. Other compounds of the class had generally failed to show therapeutic effects in a number of indications, but no concerns had been raised for safety. The study –which included several parts under the same ‘umbrella’ protocol – had an apparently uncomplicated single ascending dose (SAD) part, on which several lower multiple ascending doses (MAD) cohorts had followed before the events unrolled. It was therefore quite unexpected that severe neurological symptoms occurred in the third cohort on the fifth day of administration, which caused the death of one of the volunteers and neurological toxicity in four others. The root cause analysis of these tragic outcomes has not yet been completed, largely because of the ongoing legal proceedings that impose limitations on sharing the data and the results. The French authorities have issued a report, which outlines a number of factors that may have been involved [8]. Despite strong public appeal from both clinical researchers [9, 10] and regulators [11], the pharmacokinetic (PK), pharmacodynamic (PD) and clinical data obtained in the SAD and MAD studies have not been published, and many questions regarding the preclinical characteristics of the compound remain unanswered. Irrespective of the ongoing debate about transparency and access to the BIAL data, EMA amended its guidance dated British Journal of Clinical Pharmacology Br J Clin Pharmacol (2018) 84 1401–1409 1401