Development challenges for carcinogenicity risk assessments of topical drugs.

ABSTRACT

The nonclinical safety package to support development and approval of drugs intended to be administered by topical application generally follows International Council for Harmonisation multidisciplinary 3 (ICH M3) and topic specific safety (ICH S) guidances. However, some aspects of topical drug development may require case-by-case determination of nonclinical safety strategies. The necessity to conduct a dermal rodent carcinogenicity study is one such example that is not considered an obligate component of a nonclinical safety data package for drug approval. While absence of systemic exposure, as stated in ICH M3, is a primary reason to forego a dermal carcinogenicity assessment, there may also be other factors for consideration in determining the need for a life-time carcinogencity study by dermal route to aid in the overall human cancer risk assessment. We therefore reviewed nonclinical carcinogencity data packages from drugs approved by the FDA or PMDA over a ~25 year time period to evaluate outcomes of oral versus topical carcinogencity studies and to understand their utility for informing the overall human risk assessment. We also discuss various other properties of topical small molecules that could impact the decisions to conduct a dermal life-time rodent carcinogenicity study. Collectively, the need to conduct 2-year dermal carcinogenicity studies in rodents should be determined case-by-case and consider scientific factors such existing systemic toxicity and carcinogenicity study data, anticipated drug exposures in skin, skin evaluation from the chronic minipig toxicity study, and genetic toxicity profile.