The utility of two rodent species in carcinogenic risk assessment of pharmaceuticals in Europe.

For the past 20-30 years, lifespan carcinogenicity studies for pharmaceuticals have been required to be carried out in two rodent species. Due to scientific progress, the necessity/justification of lifespan studies in two species for the assessment of carcinogenic risk of pharmaceuticals is currently under discussion. A study in one species (either rat or mouse) might suffice. To appraise the need for a study in a second species, a database was compiled of all pharmaceuticals tested for carcinogenicity for which a marketing authorization was applied for in Germany and The Netherlands since 1980. The incidence of treatment-related tumor findings was determined in either rat or mouse or in both. Tumor findings occurred for nearly 50% of all compounds, with the rat being more sensitive than the mouse. Specific attention was given to the question whether tumor findings in mice ever caused the regulatory authorities to refuse registration, to restrict the proposed therapeutic indication of a pharmaceutical, or to apply a cautionary label. It was found that no tumor findings in mice alone ever led to such a regulatory action. In addition, whether mouse studies had been important in interpreting the results of rat studies was determined. A negative mouse study (no tumors found) was rarely used to declare the rat findings irrelevant to humans. A mechanistic explanation was used as a much more important argument in the assessment of tumor findings in rats. In case of transspecies findings, the target organs were the usual ones, such as lung and liver, or the tumors occurred as a result of an exaggerated pharmacodynamic action expected from the pharmacology of the compound. The results of the database thus question the need of maintaining the requirement of rodent carcinogenicity studies in two species.