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Author Spotlight: Advancements in CAR-T Cell Manufacturing and Gene Therapy Production
Published on: August 18, 2023
Key considerations for dose selection in first-in-human studies of cell and gene therapy products
Misaki Naota1, Yusuke Nozaki1, Fumito Mikashima1
1Pharmaceuticals and Medical Devices Agency (PMDA), Tokyo, Japan.
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.
Insights
Dose selection for cell and gene therapy (CGT) products in early trials faces challenges due to diverse product types and unreliable nonclinical data extrapolation. Tailored approaches considering product specifics are crucial for safe first-in-human (FIH) studies.
Area of Science:
- Biotechnology
- Pharmacology
- Clinical Research
Background:
- Cell and gene therapies (CGT) exhibit diverse modalities and mechanisms of action (MOAs), complicating standardized dose selection.
- Extrapolation of nonclinical efficacy and safety data to human subjects is often unreliable for CGT products.
- Standardizing dose selection for CGT products based solely on nonclinical data presents significant challenges in clinical studies.
Purpose of the Study:
- To examine critical factors influencing nonclinical data extrapolation to humans for CGT products.
- To highlight limitations in extrapolating nonclinical data for CGT products.
- To present specific dose-setting approaches for first-in-human (FIH) studies of CGT products.
Main Methods:
- Review of existing literature and regulatory guidance on CGT dose selection.
- Analysis of factors influencing nonclinical to human data extrapolation.
- Case examples of dose-setting strategies for FIH CGT studies.
Main Results:
- Nonclinical data extrapolation for CGT products is limited by product diversity and unique MOAs.
- Robust quality characterization and nonclinical proof-of-concept studies are essential for FIH trials.
- Product-specific characteristics and MOA must guide dose determination in FIH studies.
Conclusions:
- Tailored dose-setting approaches are necessary for safe and effective FIH studies of CGT products.
- A comprehensive understanding of CGT product characteristics and MOA is vital for study design and interpretation.
- Addressing extrapolation challenges ensures the safe execution of early-phase CGT clinical trials.
