A Japanese view on a global toxicology testing program before ICH1 and after ICH4

Many unharmonized points on the toxicological evaluation on pharmaceuticals have been solved by the discussion for 8 years in the ICH. The following issues are representative ones in which the Japanese view on a toxicology testing program after ICH4 is different from that before ICH1: (1) a new guideline and pre-mating treatment period in reproductive toxicity; (2) 9-month chronic studies for non-rodent species; (3) a new guideline of toxicokinetics; and (4) selection of high dose levels and a new guideline using short-term alternative tests in carcinogenicity. Hazard evaluation of pharmaceuticals to man in toxicological studies in Japan before ICH1 has been conducted on the basis of the traditional toxicological evaluation. After ICH4, in line with the ICH strategy, Japan will adopt the analytical/integrative toxicological evaluation taking into account the 'weight of evidence' approach, exposures of the test drug and species differences between experimental animals and humans. However, since there still remain many things that need to be clarified for the better understanding of the guidelines, Japan should take more flexible regulatory approaches for the evaluation.