Duration of Acute and Chronic Toxicity Testing in Animals (ICH S4A and S4B)

Abstract

AbstractTo support approval of pharmaceuticals for long-term use in humans, it is required that product safety is supported by acute and chronic toxicity studies in rodents and non-rodents. The duration of acute toxicity studies (S4A) and chronic rodent studies (S4B) was harmonised between the three ICH regions in 1991, whereas the process of harmonising the duration of non-rodent studies was initiated. The US FDA originally required studies of at least 12-month duration, whereas in Japan and EU studies of 6-month duration were considered acceptable as an ICH objective. In this chapter, the background for the ICH S4B guideline regarding the duration of non-rodent repeated-dose toxicity studies is explained and lessons learned are discussed. Since the guideline was issued in 1997, changes occurred in, e.g. the language of the European legislation, and the requirements for non-clinical studies to support clinical development have progressed within the ICH (M3): we therefore consider options such as prospective evaluation, biomarker-based mechanistic understanding, toxicokinetics and the use of evidence-based medicine to support further joint activities to harmonise the duration of non-rodent toxicity studies at the global level.KeywordsToxicity StudyMarketing AuthorisationChronic Toxicity TestingChronic Toxicity StudySafety Pharmacology StudyThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.