Draft guidelines on mutagenicity testing of new drugs issued by the CPMP. A four test screen

In 1977 the Committee on Proprietory Medicinal Products (CPMP) decided that in order to further the harmonisation of data requirement required for marketing authorization an expert working party should be set up to draw up safety guidelines. Amongst other guidelines produced for the CPMP has been one on mutagenicity which has been issued as a consultative document. This paper outlines the philosophy underlying the working party's recommendations that a "four-test screen" comprising of a bacterial test, an in vitro test to determine chromosome breakage in mammalian cells, a test to demonstrate gene damage in vitro in mammalian cells, and finally a mammalian in vivo test to demonstrate chromosomal damage in proliferating tissue (bone marrow). It is not suggested that other tests are less suitable or that evidence from other tests would not be acceptable as alternatives to part of the package. However in these circumstances the use of the alternative may need to be justified. No single test can at the present time be accepted as a sufficient screen to investigate all possible mechanisms by which genetic damage can be produced. The four-test system greatly improves the probability of demonstrating any mutagenic hazard.