Investigation of the relationship between a starting dose in first-in-human studies and no observed adverse effect level in nonclinical studies

摘要

Objective: A starting dose in first-in-human (FIH) studies has been determined carefully to guarantee the safety of participants in the study but sometimes it seems to be too conservative. The objective of the present study is to investigate a reasonable safety factor to enable effective drug development without serious safety problems in study participants. Methods: No-observed-adverse-effect levels (NOAELs) in nonclinical studies, starting doses in FIH studies, and approved doses in Japan were reviewed by documents disclosed by health authorities, and the relationships among each parameter were analyzed retrospectively. Results: The present study suggested that the starting doses in the past FIH studies had been determined very prudently, and revealed that there were significant differences between the starting dose and approved dose. Conclusion: It would be possible to develop new drugs effectively without serious safety risks if a reasonable safety factor had been applied to determine a starting dose in FIH studies.