EVALUATION OF THE CARCINOGENIC POTENTIAL OF PHARMACEUTICALS - OPPORTUNITIES ARISING FROM THE INTERNATIONAL-CONFERENCE ON HARMONIZATION

The evaluation of the carcinogenic potential of pharmaceuticals is cur rently undergoing dramatic changes. For the past 25 years the regulato ry expectation for agents intended for long term use has been that lif espan studies (usually lasting 2 years) in 2 rodent species be conduct ed. These studies take at least 3 years to plan, execute and interpret , and use over 1200 animals. It is now recognised that the quality of the information obtained from these studies is unreliable for predicti on of carcinogenic risk to humans. Over the past 4 years, the Internat ional Conference on Harmonisation (ICH) has recommended changes in app roaches to assessing the carcinogenic potential of pharmaceuticals. In future, only one long term rodent study will be routinely required (u sually in rats), provided this is complemented with a short or medium term test in one of the emerging new models for carcinogenicity, such as transgenic mice or newborn mice. However, the relevance of these ne w models to human cancer and their use in risk assessment is still lar gely unknown and this situation must be kept under review as knowledge accumulates. A long term study in a second rodent species is still an option. Dose selection has also been improved inasmuch as there are n ow several alternatives to the use of the maximum tolerated dose (MTD) . In the past, the use of the MTD, when the normal homeostasis of the test animals is disturbed, has been considered one of the major proble ms with the rodent carcinogenicity bioassay. However, one of the alter native end-points to the use of the MTD, i.e. the comparison of plasma concentrations in rodents and humans, must be viewed with caution. Wh ile this may contribute to limiting the high dose level for agents of very low toxicity, the concept should not be interpreted as signifying that plasma concentrations provide a sound basis for comparing the ca rcinogenic activity of agents in different species. Recognition of the 4 properties (genotoxicity, immunosuppression, steroid hormonal activ ity and long term tissue damage), at least one of which is associated with each of the pharmaceuticals known to be carcinogenic to humans, s hould focus more attention on a search for these properties in patient s. Absence of these properties at clinically relevant dose levels indi cates that a pharmaceutical is highly unlikely to be carcinogenic to h umans.