Addressing Positive Findings in Carcinogenicity Studies

Cancer risk assessment is a major part of establishing the safety profile of investigational pharmaceuticals intended for chronic use. Because the nonclinical carcinogenicity assessment program is typically conducted in the later stage of clinical development and requires extensive resources, careful consideration must be given to its design, timing, conduct, interpretation, and reporting in order to protect patients. Positive results in carcinogenicity studies are not uncommon and can have a significant impact on the overall development program. Toxicologists interpreting carcinogenicity results and their relevance to human safety should use a multifaceted approach including statistical and exposure considerations. While for some investigational products the human relevance of a positive result can readily be discounted, others require follow-up assessments in order to characterize their relevance to human risk. Ultimately, even if a positive signal is concluded to be relevant to humans and occur at low or no margins of clinical exposures, its impact on the overall development program is shaped by the clinical indication, targeted population and its demonstrated therapeutic benefits. This chapter discusses some practical factors to consider when establishing whether a carcinogenicity study is ‘positive’, and establishing the path forward by determining the impact of positive findings on patient safety and the overall clinical development program, both from a Sponsor and FDA perspective.