Injection-Site Sarcomas in Rodent Carcinogenicity Studies: Human Relevance and Labeling Implications

The two-year rodent carcinogenicity bioassay, often using the subcutaneous (SC) route for parenterally administered drugs, is a regulatory standard for evaluating carcinogenic potential. However, repeated SC injections of nongenotoxic agents or implantation of inert materials frequently induce injection-site sarcomas in rodents due to a species-specific response to chronic inflammation. This contrasts with humans, who rarely develop such tumors at injection sites, highlighting the limited relevance of these rodent findings for human risk. Extensive literature documents that rodents are uniquely susceptible to developing injection-site sarcomas following chronic local irritation and exaggerated fibroblastic proliferation responses. Marketed drugs, including pegvisomant and insulin glargine, have caused injection-site sarcomas in rodent studies but pose no corresponding risk to humans. These findings are noted in drug labeling but do not restrict marketing. Given the species-specific nature of this phenomenon and the practical challenges of dosing in long-term rodent studies, SC route of administration should be avoided for rodent carcinogenicity studies whenever feasible.