From animal models to new approach methodologies: Opportunities and challenges
Animal testing has long served as a foundational aspect of drug development. Since the US Food and Drug Administration (FDA)'s April announcement to phase out mandatory animal testing, health and regulatory agencies worldwide—including the NIH, European Commission, European Medicines Agency, and the United Kingdom’s Health and Safety Executive—have signaled efforts to promote new approach methodologies (NAMs) and reduce reliance on animal testing. Although NAMs have developed rapidly in recent years, there is considerable debate regarding whether they can truly replace animal experiments. Here, we provide a comprehensive analysis of the latest research comparing the strengths and limitations of NAMs with those of traditional animal testing while exploring potential paradigm shifts in global drug development strategies.
Transition to new approach methodologies
The current scientific consensus emphasizes the urgent need to accelerate the development of alternative models and technological approaches that more accurately reflect the authentic human biology. Meanwhile, the US Food and Drug Administration (FDA) explicitly encourages the adoption of organoids and microphysiological systems (MPSs) to enhance drug safety and reduce reliance on animal models.
Organoids for efficient drug screening
Organoids are advanced in vitro 3D human microtissue models that replicate organogenesis, disease progression, and individualized responses, providing a transformative alternative to animal models. For instance, only 35.3% of genes expressed in the human liver are shared with mice, which requires human-based systems to model development and disease. Earlier multicellular liver organoid models lacked key features such as functional bile ducts and physiological liver zonation. In recent years, increasingly complex and physiologically precise organoid models have been continuously developed. Hasan et al. developed highly structured, self-assembling hepatic organoids derived from induced pluripotent stem cell (iPSC)-derived liver progenitor cells within optimized culture systems. These organoids successfully replicate multi-zonal liver development and disease pathology, providing a physiologically relevant, humanized platform for drug screening.1 Furthermore, recent advances have been achieved in modeling the significantly greater complexity of the liver system. Research led by Wu et al. recently developed a methodology for differentiating human pluripotent stem cells (hPSCs) into vascularized cardiac and hepatic organoids, directly evaluating pharmaceutical effects on human liver development while significantly improving liver vascularization techniques.2 Similarly, researchers have generated adult liver cell organoids with metabolic functions, capable of lipid elimination following treatment with compounds implicated in metabolic dysfunction-associated fatty liver disease.
Beyond hepatic models, organoid technology extends to a wide range of applications. For instance, human gastroids have been developed to model gastric fundic-antral patterning in vitro, and study reveals that multilayered co-development depends on non-endodermal cells, particularly neural clusters.3 Methodologies for generating fetal epithelial organoids from amniotic fluid cells may overcome long-standing ethical and legal barriers in fetal tissue research. These organoid systems, with high physiological fidelity and translational potential, are reshaping research from fundamental studies to personalized therapies.
