Regulatory Case Studies Encountered by Project Toxicologists in Drug Development

Today, toxicologists have a diverse role in drug development and function in multidisciplinary teams with unique expertise. This article summarizes presentations from a continuing education (CE) course at the 2024 Annual Meeting of the American College of Toxicology (ACT), discussing different case studies with regulatory input. The six case studies from the CE course on regulatory toxicology in pharmaceutical drug development span small molecules, biologics, and gene therapy and illustrate key nonclinical challenges encountered across the development continuum, including formulation changes, impurities and degradants, route-specific toxicology, local tissue risk assessment, and interpretation of unexpected toxicity findings. Additional topics include evaluation of residual solvents, application of weight-of-evidence approaches, and integration of nonclinical and clinical data to support regulatory decision making. The case studies reflect real-world regulatory and scientific considerations across multiple stakeholder perspectives, including industry, contract research organizations, and regulatory agencies. Collectively, they demonstrate how toxicologists must integrate data from chemistry, manufacturing and controls (CMC), nonclinical studies, and clinical pharmacology to support risk assessment and clinical development strategies. Across the cases, common themes emerge, including increasing reliance on exposure-based assessments, application of integrated weight-of-evidence frameworks, adaptation of study designs to novel therapeutic modalities, and the importance of early and proactive regulatory engagement. These examples further highlight the need for toxicologists to manage uncertainty, interpret incomplete datasets, and provide scientifically justified recommendations within compressed development timelines. Overall, these case studies illustrate the evolving role of the toxicologist responsible for translating multidisciplinary data into regulatory strategies that enable safe and efficient drug development.