ICH-harmonised guidances on genotoxicity testing of pharmaceuticals: evolution, reasoning and impact

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has convened an expert working group which consisted of the authors of this paper and their respe ctive committees, consulting soups and task forces. Two ICH guidances regar ding genotoxicity testing have been issued: S2A, 'Guidance on Specific Aspe cts of Regulatory Genotoxicity Tests' and S2B, 'Genotoxicity: A Standard Ba ttery for Genotoxicity Testing of Pharmaceuticals.' Together, these guidanc e documents now form the regulatory backbone for genotoxicity resting and a ssessment of pharmaceuticals in the European Union, Japan, and the USA. The se guidances do not constitute a revolutionary new approach to genotoxicity testing and assessment, instead they are an evolution from preexisting reg ional guidelines, guidances and technical approaches. Both guidances descri be a number of specific criteria as well as a general test philosophy in ge notoxicity testing, Although these guidances were previously released withi n the participating regions in their respective regulatory communiques, to ensure their wider distribution and better understanding, the texts of the guidances are reproduced here in their entirety (see Appendix A) and the ba ckground for the recommendations are described. The establishment of a stan dard battery for genotoxicity testing of pharmaceuticals was one of the mos t important issues of the harmonisation effort. This battery currently cons ists of: (i) a test for gene mutation in bacteria, (ii) an in vitro test wi th cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mouse lymphoma ik assay, (iii) an in vivo test for chromosomal dam age using rodent hematopoietic cells. A major change in testing philosophy is the acceptance of the interchangeability of testing for chromosomal aber rations in mammalian cells and the mouse lymphoma rk assay. This agreement was reached on the basis of the extensive review of databases and newly gen erated experimental data which are in part described in this publication. T he authors are fully aware of the fact that some of the recommendations giv en in these ICH guidances are transient in nature and that the dynamic qual ities and ongoing evolution of genetic toxicology makes necessary a continu ous maintenance process that would serve to update the guidance as necessar y. (C) 1999 Elsevier Science B.V. All rights reserved.