Human Relevance of Pharmaceutical Drug‐Induced Thyroid Tumors in Rats, Labeling Implications, and Carcinogenicity Study Requirements

ABSTRACT In rats, thyroid tumors are common age‐related findings with reported incidence rates up to 8.1% and 11.86% for follicular and C‐cell adenomas, respectively. Increases of thyroid follicular neoplasms in rodents via the induction of hepatic UDP‐glucuronosyltransferase (UGT) enzymes, resulting in elevated thyroid hormone (TH) metabolism, excretion, and subsequent follicular cell proliferation are generally accepted to have little or no relevance to humans due to species differences in sensitivity to this pathophysiologic process. In this analysis, we reviewed approved drugs that resulted in thyroid tumors in 2‐year rat carcinogenicity studies and summarized the positioning of these findings in product labeling language and human risk assessments in the United States and Europe. Overall, although thyroid follicular cell tumors are commonly observed, the labels reviewed listed no suspected human risk or directly state the absence of human relevance for these findings. Like follicular cell tumors, thyroid C‐cell tumors are common background findings in rats but comparatively are not as commonly increased in frequency as drug‐related findings in 2‐year rodent carcinogenicity studies. These findings are most notably observed with GLP‐1 agonists and their human relevance is a topic of ongoing clinical safety surveillance analysis. Thyroid follicular cell hyperplasia, when specifically occurring through hepatic enzyme induction and/or enhanced TH clearance, should be evaluated for anticipated human translational relevance using nonclinical and clinical data. If no human relevance is anticipated, this rationale should be incorporated into a weight of evidence approach for carcinogenicity studies as outlined in the ICH S1B addendum.