Global strategies for non-clinical evaluation of radiopharmaceuticals: comparing regulatory pathways and international harmonization efforts

Radiopharmaceuticals (RPs) require a dual-component non-clinical risk assessment strategy that simultaneously evaluates both molecular targeting characteristics and radiobiological effects. Regulatory authorities worldwide (the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China National Medical Products Administration (NMPA)) have established distinct evaluation frameworks, reflect different scientific perspectives and risk-benefit philosophies. The International Atomic Energy Agency (IAEA) complements these frameworks by providing harmonized technical guidance and capacity-building tools. This review identifies the common scientific foundations shared by the three regulatory frameworks: the dual‑component risk paradigm, reliance on the core non-clinical study types (pharmacology, biodistribution, toxicology, dosimetry), acceptance of GLP principles, and agreed flexibilities. It then systematically compares the philosophical and methodological divergences, characterizing the FDA’s radiation‑proportionate precautionary approach, the EMA’s risk‑proportionate strategy, and the NMPA’s hybrid integrative model. Key differences in species selection, toxicology program scope, and dosimetry role are analyzed. The IAEA is also discussed as a distinct harmonization body that provides technical standards, capacity‑building tools, and practical protocols without acting as a regulatory authority. Finally, emerging trends for advancing the 3Rs, varying GLP expectations, and the clinical shift toward personalized dosimetry, are discussed alongside potential pathways for global alignment. By clarifying shared principles and strategic divergences across jurisdictions, this analysis offers a practical roadmap for global RP development. It highlights the need for tiered, risk-proportionate quality frameworks, validation of alternative models, and incorporation of personalized dosimetry into future regulatory guidance under a future harmonized ICH framework specifically tailored for radiopharmaceuticals.