Integrating Human Intestinal Organoids into FDA's New Approach Methodologies for Drug Discovery

Reliance on cell lines and animal models for toxicity testing has long been the cornerstone of preclinical drug discovery for intestinal diseases, but the physiology, genetics, and disease etiology of animals differ significantly from those of humans. Species-specific differences contribute to high drug attrition rates at early stages of clinical trial, particularly in complex disorders such as inflammatory bowel disease (IBD), in which such a rate is over 85%. Regulatory shifts by the FDA with the Modernization Act 2.0 and subsequent New Approach Methodologies (NAMs) guidance are accelerating the transition toward human-relevant systems by emphasizing AI-integration, organoid-based assays, and organ-on-chip technologies. Human intestinal organoids (HIOs) have emerged as transformative tools that faithfully replicate the architecture, function, and cellular diversity of the human gut. Advances in the HIOs allow study of drug absorption, metabolism, and toxicity in a dish, providing a bridge between in vitro assays and clinical outcomes to offer new opportunities for improving the prediction of toxicokinetics and pharmacokinetics. Emerging clinical trials employing patient-derived intestinal organoids (PDO) underscore their potential to bridge preclinical and clinical drug development. HIOs, as a disease model, fit well with the FDA's NAMs roadmap, and they will improve drug safety assessment and reduce the use of animal models.