Points to consider for revising the ICH S7A guideline on safety and secondary pharmacology.

Abstract

Although the ICH S7A guideline on safety pharmacology largely achieved its objective, a proportion of remaining adverse drug reactions and attrition can be attributed in part to gaps in safety and secondary pharmacology assessments. Advances in science, technology, drug development paradigm and regulatory practices necessitate revisiting and evolving ICH S7A to address these limitations. The anticipated completion of the ICH S7B Q&As by end of 2025 provides an opportunity to integrate its outcomes with ICH S7A into a comprehensive, modality-agnostic sustainable over time framework. Such consolidation could streamline guidance, enhance usability, and align regulatory expectations globally. This proposed revision should aim to address key aspects of safety and secondary pharmacology, including the definition of adversity, the integration of human-relevant in vitro and in silico models, and the adoption of state-of-the-art in vivo platforms. Further considerations should include the development of principles for model and assay validation, the promotion of integrated risk assessment frameworks, and incorporation of weight of evidence approaches. Revised guideline would also emphasize sustainable practices by adapting to evolving therapeutic modalities, while reducing reliance on animal testing through New Approach Methodologies. The revision seeks to enhance the benefit-risk evaluation of drug candidates, refine clinical monitoring, foster regulatory acceptance, and streamline drug development. This comprehensive update has the potential to not only optimize drug safety evaluations but also to align industry practices with modern scientific advancements and ethical considerations, ensuring a more robust and efficient pathway for therapeutic innovation.