[Global trends in drug development using alternatives to animal testing]

In recent years, declining success rates and rising development costs have posed major challenges in drug development, highlighting the need for more efficient and rational approaches to evaluating drug efficacy and safety. Although non-clinical studies have traditionally relied primarily on animal experiments, adverse events that are difficult to predict continue to emerge during clinical trials and post-marketing, underscoring limitations in human extrapolation. In this context, new approach methodologies (NAMs), including human cell-based models and in silico analyses, have gained increasing international attention for improving predictivity while contributing to the 3Rs principles. This review outlines international and domestic regulatory trends in NAMs and highlights recent advances in organ-specific toxicity assessment using human-relevant models. For cardiotoxicity, contractility assays using human iPSC-derived cardiomyocytes have demonstrated the ability to predict chronic contractile dysfunction and are expected to support anticancer drug safety assessment. In neurotoxicity, platforms combining rat cortical neurons and human iPSC-derived neurons with multi-electrode array system have improved sensitivity for detecting seizure risk. In hepatotoxicity, three-dimensional culture systems and hepatocytes derived from humanized liver chimeric mice have shown promise for predicting drug-induced liver injury. Future efforts should focus on defining context of use and establishing reproducibility and reliability to enable broader regulatory acceptance of NAMs. As regulatory frameworks continue to evolve worldwide, guidelines are expected to be developed or updated based on a weight-of-evidence approach integrating in vitro and in silico data.