Modeling and Simulation in Development and Regulatory Approval of Chimeric Antigen Receptor T-Cell Therapies: An...

Chimeric antigen receptor (CAR) T-cell therapies represent a major advancement in oncology. These therapies have demonstrated therapeutic potential, particularly in hematological malignancies where patients have relapsed or are refractory to prior treatments. Despite their promise, the development of CAR-T cell therapies is challenging. Manufacturing processes are complex and individualized for each patient, the eligible patient population is small, and conventional clinical trial designs are often not well suited. This study investigates the use of modeling and simulation for CAR-T cell therapies approved in Europe between 2014 and 2024. Regulatory documents for six authorized products were analyzed to identify and categorize regulatory questions relating to pharmacokinetics, efficacy, safety, and benefit-risk assessment. These questions were systematically organized into a structured repository spanning multiple biological levels. Fewer than half of these questions were addressed at initial marketing authorization, with additional data submitted through post-marketing commitments. Most modeling efforts were devoted to pharmacokinetics, with fewer relating to efficacy and safety being rarely explored. A structured credibility framework was employed to benchmark these modeling approaches against conventional analytical methods. The study revealed inconsistent methodological maturity for modeling and simulation approaches used across submissions. Compared with models described in the scientific literature, those used in regulatory applications were generally simpler and lesser, indicating a more limited implementation of M&S approaches in regulatory contexts so far. The repository developed herein may facilitate improved consistency and transparency in regulatory evaluation and support the broader adoption of model-based approaches throughout the development lifecycle of complex therapies.