Determining the value of subchronic or chronic animal toxicity testing in identifying new target organ findings

Toxicity studies supporting FIH clinical entry were compared with those of 13-week (subchronic) and ≥26 weeks (chronic) duration for 38 small molecule (non-oncology), 58 small molecule oncology and 13 biological drug candidates. New target organs, seen as new findings, occurred in subchronic studies in rodents and non-rodents for 32% and 29% small molecule (non-oncology) drug candidates, respectively or 48% and 36% small molecule oncology drug candidates, respectively. New findings occurred in chronic studies in rodents and non-rodents for 32% and 36% small molecule (non-oncology) drug candidates, respectively or 44% and 22% small molecule oncology drug candidates, respectively. New findings occurred for 23% biological drug candidates taken into chronic testing. However, none of the new findings prevented drug candidates continuing in Phase 2 and/or 3 clinical development, although other published work has shown that new findings can lead to compound termination. Overall, this evaluation showed that toxicity studies still have a vital role in supporting safety assessment but discussion is presented on how opportunities exist to change our current testing paradigm. From a 3Rs perspective, drug companies should be applying a scientific justification and/or WoE approach if they plan performing multiple studies, especially 2 species use for small molecule drug candidates.