The European Medicines Agency (EMA) endorsed a new approach methodology (NAM) to generate early toxicity data using virtual control groups derived from historical animal controls, marking a first step toward replacing live animal controls in regulatory toxicity testing. While initially limited, the endorsement lays groundwork for inclusion in future marketing-approval applications. In parallel, the FDA is pushing to reduce reliance on animal models in preclinical development through guidance and policy that support “new approach methodologies” (NAMs). The U.S. direction reinforces adoption of human-relevant models—such as organoids and microphysiological systems—earlier in development pipelines. Taken together, the EMA and FDA moves signal regulators are beginning to formally recognize datasets produced without traditional contemporaneous animal control arms, potentially changing how toxicity studies are structured, validated, and submitted.