PII-187 - ASSESSMENT OF MALE INFERTILITY RISKS TO SUPPORT PRODUCT-SPECIFIC GUIDANCE DEVELOPMENT FOR GENERIC ORAL PRODUCTS.

S. Park¹, D. Nguyen¹, T. Tran¹, K. Li¹, M. Kim², J. Shon¹; ¹Division of Therapeutic Performance II, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, ²Division of Therapeutic Performance II, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.

Background: Product-specific guidances (PSGs) describe the Food and Drug Administration (FDA)’s current thinking on the most appropriate method for establishing therapeutic equivalence between generic drugs and their reference listed drugs (RLDs). Exclusion of males of reproductive potential (MRPs) in pharmacokinetic (PK) bioequivalence (BE) studies has been recommended in PSGs on a case-by-case basis to avoid male infertility risks. This project aimed to retrospectively analyze the nonclinical toxicology and other factors (e.g., enrollment of healthy MRPs in the RLD programs) supporting this recommendation in currently published PSGs of oral dosage forms to develop a standard decision framework for potentially excluding MRPs in PSG-recommended PK BE studies.

Methods: A list of PSGs for oral dosage forms recommending exclusion of MRPs or any males in PK BE studies was compiled using an internal FDA search engine with keywords (e.g., fertility, reproductive, sterile, surgical). PSGs for RLDs with approved indications only in females were excluded. Nonclinical toxicology profiles (i.e., male fertility impairment, genotoxicity) and enrollment of healthy MRPs in the RLD programs were collected and analyzed from the labeling and regulatory submissions.

Results: Thirteen PSGs of oral dosage forms (13 RLDs; 11 active pharmaceutical ingredients) recommended exclusion of MRPs or any males in PK BE studies. Per the labeling and regulatory submissions, all RLDs exhibited potential for male infertility (e.g., degeneration of reproductive organs and decreased semen volume and/or sperm count) in chronic animal studies. Eleven out of 13 RLDs had no-observed-adverse-effect levels within the maximum recommended human dose. Eight out of 13 RLDs showed potentially irreversible effects. In addition, per the labeling, five RLDs exhibited potential for genotoxicity. Eleven out of 13 RLD programs allowed enrollment of healthy males, of which eight RLD programs allowed enrollment of MRPs.

Conclusion: This analysis identified factors supporting the exclusion of MRPs in currently published PSGs. These findings will be leveraged to develop a standard decision framework for potentially excluding MRPs in PSG-recommended PK BE studies, thereby improving PSG consistency while ensuring subject safety in PK BE studies for generic drug development.