Eighteen (12.5%) out of the 144 compounds exhibited potential genotoxic properties. For most of these compounds, the genotoxic potential was considered to be weak and a thresheld with regard to the induction of genotoxic effects appeared to exist. Therefore, the relevance of the genotoxic properties to humans was either considered to be low due to a high safety margin in terms of exposure or the clinical benefit was considered to outweigh the potential carcinogenic risk. Based on the negative genotoxicity findings for the majority of compounds, an epigenetic mechanism of carcinogenicity was likely for the majority of compounds with positive carcinogenicity findings.

Long-term carcinogenicity studies in two rodent species were available for 116 compounds (81%), 44 of which were negative and 31 of which were positive in both mice and rats. Data from one long-term carcinogenicity study in rats and a transgenic mouse model were available for eight compounds (6%). For 13 compounds (9%), carcinogenicity data were available in only one rodent species. Six compounds (4%) were tumorigenic in repeat-dose toxicity studies in rats.

Out of the 94 compounds with positive findings in either carcinogenicity or repeat-dose toxicity studies, 33 were positive in both mice and rats (35%), 40 were positive in rats only (43%) and 21 were positive exclusively in mice (22%).
The majority of tumour findings observed in rodent carcinogenicity studies were not considered to be relevant for humans:
A species- or rodent-specific mechanism of carcinogenicity was identified for 38 of the compounds with positive carcinogenicity findings (40%).
A high safety margin between exposures at the NOAEL in rodents and recommended therapeutic doses in humans were established for 17 compounds (18%).
The tumours findings noted in 14 compounds (15%) were either not considered related to treatment based on historical control data, a small effect size and lack of dose-response, relationship and tumours typically observed in rodent strains used, or were not considered relevant for humans based on literature and clinical data or likely differences in metabolism/local concentrations between rodent and humans.
Carcinogenic effects observed for 14 compounds (15%) were considerd to be of unknown relevance for humans. A corresponding wording was included in the SPC section 5.3 for most of these compounds.
A potential carcinogenic risk for humans was noted for four compounds, which was however outweighed by their clinical benefit.
For seven compounds (7%), the tumours observed in rodents were considered to be relevant for humans. These included the anti-retroviral agent cidofovir, which was labelled as a potential human carcinogen in the SPC section 4.4, the immunosuppressive compounds leflunomide, sirolimus, abatacept and tacrolimus, the antifungal agent micafungin, and dexrazoxane. Three of these compounds (cidifovir, micafungin, dexrazoxane) were tumorigenic in repeat-dose toxicity studies and carcinogenicity studies were not performed.
Due to the high number of rodent tumour findings with unlikely relevance for humans, the value of conducting life-time carcinogenicity studies in two rodent species appears questionable. Alternatively, a more flexible and product-specific approach regarding carcinogenicity testing is warranted, taking into account all available information from pharmacology, genotoxicity, repeat-dose toxicity and mechanistic studies and considering species and strain sensitivities towards expected pharmacological/toxicological effects.

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