Are we ready to replace animal models? A perspective on regulatory challenges of human-relevant drug testing systems

This perspective examines whether animal models can be gradually replaced by human-relevant New Approach Methodologies (NAMs) in drug development and regulatory evaluation, synthesizing recent advances across hepatology, oncology, neurotoxicology, and cardiac safety assessment. Although the relevant technologies have become increasingly mature, their acceptance at the regulatory level is still lagging due to factors such as limited standardization, insufficient reproducibility of results, and unclear approval pathways. Building on a systematic comparison of existing evidence, this article proposes a three-stage transition pathway: the first stage (auxiliary stage)-using NAMs in parallel with animal experiments; the second stage (partial replacement stage)-using NAMs as the preferred efficacy evaluation model for human-specific diseases; and the third stage (regulatory integration stage). Only through gradual validation can animal models be replaced responsibly, thereby increasing the success rate of translational research and reducing the use of animal experiments. Overcoming the persistent challenges of limited standardization, poor reproducibility, and unclear regulatory pathways is the central prerequisite for this transition.