Abstract
Purpose: Reflecting the extended scope of the valid EMA regulation, this analysis intends to contribute to the knowledge about risk for participants in first-in-human (FiH) multiple-dose studies. Materials and methods: All FiH multiple-dose studies in healthy subjects performed by the Bayer Department of Clinical Pharmacology, Cardiovascular, between 2006 and 2019 were analyzed. Study reports were reviewed for study designs, demographics, treatment-emergent adverse events (TEAEs), and safety laboratory results above the 1.5-fold of the upper limit of normal (aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), amylase, lipase, glutamate dehydrogenase (GLDH), gamma glutamyl transpeptidase (GGT), total bilirubin, and creatinine in serum), and data were analyzed. Results: 12 out of 16 studies were included. Indications for development were cardiovascular (7), pulmonary (3), kidney (1), and hematological (1) diseases. 496 healthy male subjects (mean age 33.8 years, mean BMI of 24.7 kg/m2) received treatment (370 active, 126 placebo). 293 subjects had at least 1 TEAE (59.1%): 231 (62.4%) after active treatment and 126 (49.2%) after placebo. Subjects with a maximum TEAE intensity of moderate did not differ between active and placebo. The only severe TEAE was unrelated to the study, the only serious TEAE on active treatment was not considered drug-related. Subjects had a significantly higher relative risk on active treatment versus placebo to experience an overall TEAE. No relevant differences between active and placebo for the analyzed laboratory increases were seen. Conclusion: Subjects were not exposed to an undue risk in the analyzed studies. Adverse events and laboratory value increases occur frequently under placebo treatment. The results can help in the risk stratification for and interpretation of other phase I studies.
Highlights
An important extension in the scope of the valid guideline for early clinical trials with investigational medicinal products of the European Medicines Agency (EMA) is the coverage of studies beyond single-dose first-in-human (FiH) trials [1]
Study reports were reviewed for study designs, demographics, treatmentemergent adverse events (TEAEs), and safety laboratory results above the 1.5-fold of the upper limit of normal (aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), amylase, lipase, glutamate dehydrogenase (GLDH), gamma glutamyl transpeptidase (GGT), total bilirubin, and creatinine in serum), and data were analyzed
Indications for development were cardiovascular (7), pulmonary (3), kidney (1), and hematological (1) diseases. 496 healthy male subjects received treatment (370 active, 126 placebo). 293 subjects had at least 1 TEAE (59.1%): 231 (62.4%) after active treatment and 126 (49.2%) after placebo
Summary
An important extension in the scope of the valid guideline for early clinical trials with investigational medicinal products of the European Medicines Agency (EMA) is the coverage of studies beyond single-dose first-in-human (FiH) trials [1]. The death case in the Bial trial in 2016, which happened in the multiple-dose part of this FiH study [3], illustrates dramatically the importance of paying particular attention to safety in this step of early clinical development. In order to contribute to the general knowledge for risk stratification, we analyzed safety data of our in-house FiH multiple-dose studies in healthy subjects for all compounds that went into human development between 2006 and 2019. A similar result was demonstrated for previous FiH studies [8] The aim of this analysis was to determine if a relevant increase of risk occurs at the important step from first single- to multiple-dose administration in humans
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