The US Food and Drug Administration (FDA) announced it has released new, harmonized guidance for sponsors looking to conduct genotoxicity testing and data interpretation for human drug products.
The guidance, originally put forth in 2008 by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), combines and replaces two existing ICH guidance documents: S2A Specific Aspects for Regulatory Genotoxicity Tests for Pharmaceuticals and S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals.
"The purpose of the revision is to provide guidance on optimizing the standard genetic toxicology battery for prediction of potential human risks, and on interpreting results, with the goal of improving risk characterization for carcinogenic effects that have their basis in changes in the genetic material," FDA explained in the guidance.
The guidance only applies to small-molecule, non-biological pharmaceutical products intended to be used in human subjects.
Genotoxicity tests are used to determine whether a pharmaceutical compound induces genetic damage to a subject, which can cause a wide range of problems including cancer and heritable birth defects. The guidance notes a "battery approach" to genotoxicity testing is preferable given the broad spectrum of potential events and the limits of single-test analysis, and describes the requirements of conducting genotoxicity battery tests.
The guidance also describes recommendations for conducting in vitro testing, which include best practices for test repetition and interpretation, and recommended protocols for various assays. Further recommendations are provided for in vivo testing, including detecting chromosomal damage, dose selection, demonstration of target tissue exposure, sampling, statistical significance, testing sex-specific drugs and the routes of administration.
Test result evaluation and follow-up test strategies are also described in the guidance, including assessing biological relevance and evaluating results obtained in both in vitro and in vivo tests.
FDA - Guidance for Industry - S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use