US FDA issues new guidance to pharma industry on Genotoxicity tests of new small molecule drug substances

The US FDA has issued fresh guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals meant for human use. The focus of this guidance is testing of new small molecule drug substances and it does not apply to biologics. This guidance combines and replaces two ICH guidances namely, S2A Specific Aspects for Regulatory Genotoxicity Tests for Pharmaceuticals (ICH S2A guidance) and S2B Genotoxicity, a Standard Battery for Genotoxicity Testing of Pharmaceuticals (ICH S2B guidance). The purpose of the revision is to provide guidance on optimizing the standard genetic toxicology for prediction of potential human risks and on interpreting results. The key objective is to improve risk characterization for carcinogenic effects that have their basis in changes in the genetic material. The revised guidance describes internationally agreed-upon standards for follow-up testing and interpretation of positive results in vitro and in vivo in the standard genetic toxicology. The guidance is intended to apply only to products being developed as human pharmaceuticals. The regulatory authority has issued the norms for testing of new small molecule drug substances guidance and is not for the biologics. Recommendations on the timing of the studies to clinical development is provided in the ICH guidance referred to as Non-clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (ICH M3(R2) guidance). The recommendations in the guidance should be applied in conjunction with other ICH guidances. Genotoxicity tests can be defined as in vitro and in vivo tests designed to detect compounds that induce genetic damage by various mechanisms. These tests enable hazard identification with respect to damage to DNA and its fixation. Registration of pharmaceuticals requires a comprehensive assessment of their genotoxic potential, stated the global drug regulator. There is also a set of rules for the evaluation of test results and on follow-up test strategies. The regulator has stated that comparative trials have shown conclusively that each in vitro test system generates both false negative and false positive results in relation to predicting rodent carcinogenicity. Genotoxicity test of in vitro and in vivo tests detect carcinogens that are thought to act primarily via a mechanism involving direct genetic damage, such as the majority of known human carcinogens. Therefore, tests are not expected to detect non-genotoxic carcinogens. Experimental conditions, such as the limited capability of the in vitro metabolic activation systems, can lead to false negative results in vitro tests. The test approach is designed to reduce the risk of false negative results for compounds with genotoxic potential. On the other hand a positive result in any assay for Genotoxicity does not always mean that the test compound poses a genotoxic/carcinogenic hazard to humans, said the global regulatory authority. Although positive in vitro data could indicate intrinsic genotoxic properties of a drug, appropriate in vivo data determine the biological significance of these in vitro signals in most cases. Pharma industry is of the view that such a formal direction allows the researchers carrying Genotoxicity testing to follow a more systematic interpretation of data. Source:Pharmabiz