Integration of safety pharmacology endpoints into toxicology studies - A survey of GLP institutions in China.

Abstract

Integrating safety pharmacology (SP) endpoints into repeated-dose toxicology studies enables the simultaneous assessment of organ toxicity and determination of functional safety risks within a single study, a practice endorsed by regulatory guidelines. Initiated by the Chinese Safety Pharmacology Society, this questionnaire-based survey assessed the implementation of such integrated studies across 19 Chinese institutions compliant with good laboratory practice and qualified to support submissions to the National Medical Products Administration (NMPA, China), FDA, and EMA. The survey compared integration practices for new chemical entities (NCEs) versus biopharmaceuticals, including animal models, monitoring technologies, statistical design, regulatory acceptance, and technical challenges. Furthermore, the survey solicited recommendations regarding revisions to the current ICH S7A guideline. For biopharmaceuticals, integration was common, with 16 of 19 institutions applying it in more than 75% of projects, primarily using non-human primates. Endpoint coverage in these studies included the cardiovascular system in all 19 institutions, the respiratory system in 16 of 19, and the central nervous system in 11 of 19, alongside an average 18% reduction in animal use. Respondents reported that data from these studies were fully accepted by the NMPA, FDA, and EMA in regulatory submissions. Conversely, integration was rarely used for NCEs, with 18 of 19 institutions reporting limited implementation. The primary barriers cited were interference with toxicokinetic sampling and lower statistical power compared to standalone crossover designs. As the first systematic survey of SP-integration practices across Chinese GLP institutions, these findings provide valuable real-world evidence to optimize non-clinical safety assessment strategies and support future revisions of the ICH S7A guideline.