Risk Management in First-in-Human Trials of Intravenous Drugs: Current Practices and Future Perspectives.

In the first-in-human (FIH) study, the intravenous (IV) administration represents a critical juncture where preclinical data meet human physiology, characterized by immediate systemic exposure and an extremely narrow margin for safety. The current management measures for these trials are fragmented and lack a systematic framework. This narrative review, informed by a structured synthesis of peer-reviewed literature, regulatory guidance documents, and systematic institutional experience from multiple IV FIH trials conducted between 2020 and 2025, summarizes the key risk factors for FIH-IV trials, including pharmacological uncertainties, formulation-related toxicity, infusion rate sensitivity, and participant heterogeneity. It further evaluates preventive strategies such as determination of starting dose, personnel management and ensuring operational readiness, standardization of medication preparation and administration, comprehensive safety monitoring, and emergency response coordination and infrastructure. The primary aim is to propose a conceptual, stratified risk management framework that categorizes trials into low-, moderate-, and high-risk levels based on drug-related, procedural, and participant-specific variables. Corresponding management strategies are then applied to each level: standardized for low risk, enhanced for moderate risk, and advanced for high risk. This structured approach optimizes safety assurance in high-risk trials while avoiding the overutilization of resources in low-risk settings. The proposed framework is intended as a conceptual supplement to existing regulatory guidelines (eg, ICH E6(R3), EMA FIH guideline) and requires prospective multicenter validation before broad implementation.