Robert H. Heflich, Division of Genetic and Reproductive Toxicology, U.S. FDA/NCTR - Testimony

New assays being recommended for the core ICH battery. Robert H. Heflich, Division of Genetic and Reproductive Toxicology, U.S. FDA/NCTR. The proposed ICH S2(R1) Guidance on Genotoxicity Testing and Data Interpretation contains the option of using either of two ‘equally suitable’ test batteries, both of which include an assay not part of the original core battery. Option 1 generally uses the same test battery structure described in the S2B Guidance; however Option 1 includes the in vitro micronucleus (MN) assay as an alternative for fulfilling the requirement of an in vitro mammalian cell assay. The in vitro MN assay is widely used, and has been subjected to several multilaboratory validation studies. Also, it provides data on potential aneugenicity as well as clastogenicity, can be automated and miniaturized, and a standardized, internationally agreed-upon protocol will soon be available in the form of an OECD Test Guideline (TG487). Finally, MN frequency (measured in a different context) bears a quantitative relationship to human cancer risk (Bonassi et al., 2007). On balance, the inclusion of the in vitro MN assay in Option 1 of the revised Guidance is a positive development that has a good chance of improving drug safety assessment. The picture is less positive with regard to the second new test added to the battery. The test battery for Option 2 essentially replaces the in vitro mammalian cell assay with a second in vivo assay. The first in vivo assay will usually be a MN assay on rodent hematopoietic cells, and several possibilities are listed for the second test (Comet assay, alkaline elution assay, transgenic mouse mutation assay, DNA adduct assay, liver unscheduled DNA synthesis (UDS) assay). While in vivo MN assay is suitable as one of the in vivo assays, there is a major problem with identifying a second in vivo assay for Option 2. The most likely tests that are named have two concerns: 1. The nature of the test 2. The stage of test