Navigating First‐in‐Human and Early‐Phase Patient Studies: Study Designs, Risk Mitigation, and Population Selection Challenges

Abstract First–in‐human (FIH) and early‐phase clinical studies have increasingly become an integral part of the entire clinical development process, applying integrated protocols and robust risk mitigation strategies to enhance participant safety and development efficiency. This manuscript focuses on the diverse study designs employed in FIH studies, strategies for effective risk mitigation, suitable study population selection, and the methodologies and considerations unique to early‐phase patient trials. FIH studies typically include single ascending dose (SAD) and multiple ascending dose (MAD) cohorts that may be conducted in healthy volunteers (HVs) or with relevant patient populations. An analysis of 193 compounds approved by the FDA's Center for Drug Evaluation and Research between 2020 and 2023 revealed that 47.7% (92 out of 193) conducted FIH or initial SAD/MAD studies in healthy volunteers, while 39.4% (76 out of 193) initiated their FIH studies in the relevant patient population. The status for 12.9% (25 out of 193) was unknown. Among the programs that did not involve healthy volunteers for FIH or initial SAD/MAD studies, 65.8% (50 out of 76) were developed for oncology indications, whereas the remaining 34.2% (26 out of 76) were involved in therapeutic areas such as rare disease, genetic disorders, and ophthalmology. This manuscript highlights the importance of tailoring scientific and operational approaches to specific molecules, indications, and patient relevance. It provides tools, strategies, and a mind map to effectively navigate challenges during this phase of the development.