Genotoxicity testing: current practices and strategies used by the pharmaceutical industry.

Current guidelines and recommendations for genotoxicity testing of pharmaceuticals are disparate, both in terms of the most appropriate tests to use and the protocols to follow. Recent attempts have been made to standardise genotoxicity testing procedures, coinciding with the current review of the OECD guidelines and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). However, as with other aspects of non-clinical safety assessment of pharmaceuticals, guidelines have been prepared by evaluation of general chemical data due to the lack of specific information on pharmaceuticals. To address this, a project was undertaken to collect and collate information specifically pertaining to the genotoxicity testing of pharmaceuticals in order to obtain a clear understanding of international strategy and procedures in the pharmaceutical industry. It is clear that the practices and regional variations are strongly influenced by national guidelines and do not necessarily follow companies' preferences. However, there is a surprising amount of variation in approach between companies on some issues. This is evident in how companies define a genotoxin. This ranges from a positive result in an in vivo assay as indicative of a genotoxin (43%) to any positive result in vitro or in vivo (30%). Indeed many companies (particularly in Japan) will terminate development on the strength of a clear positive result in an Ames test. There is much debate within the ICH process concerning tests to detect gene mutations in mammalian cells as part of a primary test battery. This survey shows that in general, the pharmaceuticals industry has severe doubts about these assays. Thirty-seven (78%) of the 47 participating pharmaceutical companies include an in vitro test to detect gene mutation in mammalian cells as part of their routine test battery. The HPRT test using Chinese hamster cells has the most widespread use, although there is only limited use of such tests in Japan. Compound development has been affected by the results of such tests, but usually only in terms of clarification of equivocal results in other genotoxicity tests in the test battery. The majority (63%) of companies do not support its use as a primary regulatory requirement, and 83% do not consider the mouse lymphoma assay (L5178Y) an acceptable replacement for in vitro mammalian cytogenetics. In conclusion, this survey has provided valuable information on the current modus operandi of the international pharmaceutical industry for consideration in current harmonisation initiatives.