Nonclinical development of advanced therapies: Best practices for translational and regulatory success

Advanced therapeutics-including cell and gene therapies, antibody-drug conjugates, and RNA-based medicines-present unique in vivo pharmacology, safety, and translational challenges that require tailored nonclinical programs aligned with global regulatory expectations. This review synthesizes best practices for designing IND/CTA-enabling studies, integrating biodistribution, pharmacokinetics/pharmacodynamics, immunogenic assessment, safety pharmacology, toxicology, and dose selection into a cohesive strategy. Regulatory frameworks from the FDA, EMA, and PMDA emphasize early engagement, modality-specific risk assessment, and harmonization through ICH guidance (e.g., S12). Key recommendations include using relevant animal models, novel analytical methods, and conservative first-in-human dosing to mitigate translational uncertainties. Distinct considerations for oncology versus non-oncology indications are highlighted, reflecting differing risk tolerances and data requirements. Case studies of clinical holds and successful submissions underscore the importance of anticipating regulatory concerns, ensuring manufacturing readiness, and implementing robust risk mitigation. By adopting these integrated scientific and regulatory strategies, developers can streamline translation from preclinical studies to human trials, ultimately accelerating the delivery of safe, effective advanced therapies.