Rosalie Elespuru, PhD - Testimony

Rosalie Elespuru, PhD FDA/CDRH/OSEL/DB Genomics Lab Chair, FDA GeneTox Network 1. The ICH revision weakens safety assessment standards for cancer risk of drugs. There is no standard method for assessment of cancer risk in humans. Thus it is our public health duty to apply a conservative standard, and the original ICH genotoxicity test battery, including in vitro mammalian mutagenicity and chromosomal damage assays, was designed to do this. The in vitro mammalian assays detect the broadest set of known genotoxins and carcinogens. The ICH revision moves away from this goal, substituting in vivo assays that are less sensitive and not yet validated. 2. The ICH revision will slow the FDA review process. Having 2 options is problematic for FDA reviewers when there is no guidance (and no way to judge) which option should be used in what circumstance. The options clearly are different, particularly in sensitivity and in the classes of genotoxins detected. Having 2 options would create additional internal and sponsor - FDA discussions and debates. 3. The ICH revision short-circuits ongoing international collaborative efforts (e.g. ILSI, IWGT) on follow-up tests to in vitro positive results and development and integration of new technologies. The ICH revision should wait until the newer tests are validated, accepted internationally, and have well-understood utility. There are not a lot of choices for alternative assays. The Comet assay is still an unknown quantity (e.g. what carcinogens are detected or missed). 4. The ICH revision dis-harmonizes the other FDA product centers, other federal agencies, and international standards groups regarding genotoxicity assessments, all of which use a similar genotoxicity test battery that includes in vitro mammalian tests. Alterations in the protocol and interpretation of mammalian assay data, as well as policy interpretations (CDER WOE guidance, 2006) largely obviate the need to change the ICH guidance.