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][4][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 studywhich included several parts under the same 'umbrella' protocolhad 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 regu...

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (C max ), to be included within the tighter acceptance range of 90.00-111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one-size-fits-all" criterion is particularly questionable when the within-subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the withinsubject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00-125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00-111.11% when the within-subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within-subject variability are frequently exposed to bioavailability differences larger than 10%.

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Bioequivalence (BE) of products containing narrow therapeutic index (NTI) drugs in the European Union is currently established by demonstrating that the 90% confidence interval for the ratio of the population geometric means of the test compared to the reference product’s AUC, and in certain cases Cmax, is included within the tighter acceptance range of 90.00–111.11%. An alternative criterion, consisting of narrowed limits based on the within-subject variability of the reference product, was recently proposed. Its performance for a three-period partial replicate design was tested by simulation in terms of power to show BE, type I error (T1E) and sample size requirements. A new condition, a constraint on the test-to-reference geometric mean ratio (cGMR) to be contained within the range of 90.00–111.11%, was also tested. The probability of showing BE when the products differ more than 10% was increased, but only if the reference product’s within-subject variability was moderate-to-high. The inclusion of the additional cGMR limited this. An increase in the T1E (<7%) was observed. The inclusion of the additional cGMR did not change the highest inflation of the T1E. Finally, a significant sample size reduction was observed and the inclusion of the cGMR usually did not increase the required sample size.

Scientific advice (SA) is an important tool offered by regulators to help developers generate robust evidence on a medicine's benefits and risks. Drawing on accumulated experience and looking at the SA provided by the European Medicines Agency in 2018 to advanced therapy medicinal products originally developed by public bodies, we discuss most commonly raised issues and the complexity and timings of the questions posed. Earlier and more frequent SA could help advanced therapy medicinal product developers to pre-empt delays at the marketing authorisation stage.Carefully addressing quality and nonclinical issues before entering the pivotal phase of development will clear the path for a smooth clinical development and successful marketing authorisation.