Stratified Safety Evaluation Framework for Natural Products Based on New Approach Methodologies in Integrative Medicine: A Narrative Review

The widespread assumption that “natural” equals “safe” has been repeatedly challenged by adverse events associated with medicinal plant-derived products. Unlike synthetic pharmaceuticals, these natural products present distinct safety concerns because of their compositional complexity, inherent variability, and batch-to-batch inconsistency. Consequently, a one-size-fits-all approach to toxicological assessment is insufficient. In this narrative review, we propose a pragmatic “classify-then-evaluate” framework that stratifies natural products into three operational categories according to compositional complexity and degree of chemical characterization—TCM compound formulae, active fractions/extracts, and purified single compounds. This framework enables safety evaluations to be tailored to product complexity by integrating conventional toxicological assays with emerging new approach methodologies. By linking chemical characterization, hazard identification, quality control, and risk assessment within a tiered system, this framework bridges the gap between evidence generation and regulatory decision-making, offering a scientifically grounded and proportionate pathway for evaluating the safety of natural products used in integrative medicine, with a primary focus on herbal and TCM-related products. The review does not aim to provide a comprehensive systematic evidence map; further validation of the proposed framework is required