For decades, preclinical drug development has relied on animal testing as the regulatory gold standard. Yet nearly 90% of drug candidates that succeed in animal studies ultimately fail in human trials, underscoring a persistent translational gap. Advances in stem-cell–derived organoids, microengineered organs-on-chips, 3D-constructed tissues, and computational modeling - collectively termed New Approach Methodologies (NAMs) - offer human-relevant insights that could transform drug discovery and development. Regulatory frameworks are also shifting, with initiatives from the FDA, EMA, and NIH supporting NAM integration. Early studies show potential for improved prediction of efficacy and safety, but challenges remain in reproducibility, scalability, and regulatory acceptance. This Editorial highlights the scientific promise, regulatory momentum, and practical considerations surrounding NAMs, arguing that their future depends not on hype, but on evidence-based implementation that earns trust across stakeholders.

Animal testing has long been a cornerstone of preclinical development, providing data to advance investigational new drugs into clinical trials. Yet species differences severely limit predictive power: approximately 90% of drug candidates that pass animal studies fail in human trials. Most failures trace back to two major factors:1.

Lack of efficacy – animal disease models often fail to capture the true complexity of human biology and pathology.

2.

Safety issues – particularly those driven by human-specific mechanisms or idiosyncratic reactions, such as drug-induced liver injury (DILI), where animal models cannot replicate the physiological and genetic diversity of patient populations.

At their core, both challenges reflect the same underlying problem: the poor predictability of traditional preclinical models when it comes to human outcomes.

A new generation of systems - collectively termed New Approach Methodologies (NAMs) - is reshaping the preclinical landscape. Organoids derived from human stem cells, microphysiological systems (MPS) such as organs-on-chips and 3D-constructed tissues, and advanced computational models capture aspects of human biology more faithfully than animal surrogates. By improving prediction of efficacy and safety, NAMs could reduce attrition, accelerate timelines, and lower costs while also addressing ethical concerns around animal testing.

Momentum is also being driven by regulatory changes, which signal that regulatory infrastructure is beginning to align with technological innovation. These developments make this an opportune moment to examine both the promise and the limitations of NAMs.

This Editorial therefore highlights the scientific advances, regulatory initiatives, and practical implications of NAMs. It aims to stimulate discussion among researchers, regulators, and industry stakeholders about credible integration. By placing NAMs into the broader context of translational science and regulatory policy, the Editorial argues that their future depends not on hype, but on building robust systems that can reliably inform human drug safety and efficacy.