Guidance for Industry - S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for human Use

Introduction:
This guidance document, S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for human Use, provides recommendations for testing and interpreting genotoxicity data for pharmaceuticals. The guidance combines and replaces two previous ICh guidelines and aims to improve risk characterization for carcinogenic effects that have their basis in changes in genetic material. The guidance applies to products being developed as human pharmaceuticals and provides internationally agreed-upon standards for follow-up testing and interpretation of positive results in vitro and in vivo in the standard genetic toxicology battery.

Key Points:

* The guidance outlines a standard genetic toxicology battery consisting of a bacterial reverse gene mutation test, a cytogenetic test for chromosomal damage in vitro or in vivo, and an in vivo test for genotoxicity using rodent hematopoietic cells.
* The guidance provides recommendations for the selection of top dose levels and study design/test protocols for in vitro and in vivo tests.
* The guidance discusses modifications to the standard battery for certain situations, such as testing compounds that are toxic to bacteria or have structural alerts for genotoxic activity.
* The guidance also covers the detection of germ cell mutagens and provides recommendations for in vivo dose selection and demonstration of target tissue exposure for negative in vivo test results.
* The guidance includes a section on the evaluation of test results and follow-up test strategies, including the assessment of biological relevance and the evaluation of results obtained in in vitro and in vivo tests.
* The guidance provides recommendations for follow-up strategies for positive results, including mechanistic/in vivo follow-up and the use of appropriate endpoints and tissues for in vivo assays.
* The guidance includes a glossary of terms and references for further reading.

Main Message:
The guidance provides comprehensive recommendations for genotoxicity testing and data interpretation for pharmaceuticals intended for human use. By following the recommendations in this guidance, sponsors can ensure that their genotoxicity testing strategy is scientifically sound and regulatory acceptable. The guidance emphasizes the importance of appropriate dose selection, demonstration of target tissue exposure, and the evaluation of results in the context of the overall toxicological profile of the compound. By using a standardized approach and following the recommendations in this guidance, sponsors can improve risk characterization for carcinogenic effects that have their basis in changes in genetic material, ultimately leading to safer pharmaceuticals for human use.

“Guidance for Industry - S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for human Use.” FDa Center for Biologics Evaluation and Research (CBER), June 2012.