New alternate methods for clinical trials: Discussion of the use of human induced pluripotent stem cells for drug development

  • Overview of recent regulatory shifts (FDA Modernization Act 2.0, April 2025 FDA policy) enabling non-animal methods for oncology IND submissions.
  • Addressing tumor heterogeneity and efficacy challenges through isogenic iPSC-derived tumor models engineered with specific mutations (e.g., KRAS, TP53, EGFR) using CRISPR/Cas9, enabling precise assessment of variant effects.
  • Utilizing human induced pluripotent stem cells (iPSCs) for predictive toxicology (e.g., CARTOX assays) and disease modeling to enhance safety assessments and clinical trial efficiency, particularly in small molecule and antibody-based therapies.
  • Employing differentiated iPSC-derived healthy tissue models (e.g., cardiomyocytes, hepatocytes, neurons) to evaluate off-tumor/on-target toxicities in CAR-T therapies, mitigating risks of unintended tissue damage.
  • Operational considerations, validation strategies, and practical lessons from developing scalable iPSC biobanks supporting New Approach Methodologies (NAMs) in oncology drug development.