Key considerations for dose selection in first-in-human studies of cell and gene therapy products.

Abstract

Advancements in science and technology have led to the development of cell and gene therapy (CGT) products with diverse modalities and mechanisms of action (MOAs). However, this diversity presents significant challenges for standardizing dose selection in clinical studies based solely on nonclinical data. Moreover, extrapolating nonclinical efficacy and safety data to humans is often unreliable. In first-in-human (FIH) studies, these limitations necessitate robust quality characterization, nonclinical proof-of-concept (POC) studies, and a comprehensive understanding of each product's MOA, with dose determination tailored to each product. In this review article, we aim to examine the critical factors influencing the extrapolation of nonclinical data to humans, highlight limitations of such extrapolation, and present specific examples of dose-setting approaches for FIH studies of CGT products. We outline key considerations for dose selection, emphasizing the importance of considering product-specific characteristics and MOA. Understanding these aspects of CGT products facilitates the design of appropriate nonclinical studies and supports accurate interpretation of their outcomes, ultimately contributing to the safe execution of FIH studies involving CGT products.