PWIV-001 - EXPLORATION FOR EXCLUSION OF FEMALES OF REPRODUCTIVE POTENTIAL AS A BIOEQUIVALENCE STUDY POPULATION IN PRODUCT-SPECIFIC GUIDANCES FOR GENERIC DRUG DEVELOPMENT.

C. Paleracio¹, D. Nguyen², K. Li², C. Tsui³, M. Frost², M. Kim², J. Shon²; ¹University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, ²US Food and Drug Administration, Silver Spring, MD, USA, ³US Food and Drug Administration, San Francisco, CA, USA.

Background: Female subjects are generally recommended for pharmacokinetic (PK) bioequivalence (BE) studies in product-specific guidances (PSGs) for generic drug development if such drug product is intended for use in females. However, one major safety consideration for including females of reproductive potential (FRP) in PK BE studies is reproductive and genotoxic risks. This project aimed to retrospectively analyze the type and level of toxicological evidence supporting excluding FRP for PK BE studies in currently published PSGs.

Methods: A list of oral drug product PSGs recommending the exclusion of FRP in healthy subjects or general population in PK BE studies was obtained from the FDA PSG databases using search terms such as reproductive potential, childbearing, and teratogenicity. PSGs for reference listed drugs (RLDs) indicated only for males or for postmenopausal females were excluded. Nonclinical toxicology profiles (i.e., embryofetal toxicity [EFT], genotoxicity [GT], and fertility impairment [FI]) and contraception recommendations were collected from the RLD labeling.

Results: PSGs for 59 RLDs met the criteria for evaluation. Twenty-seven RLDs had EFT potential, 9 RLDs had both EFT and GT potential, 13 RLDs had both EFT and FI potential, and 9 RLDs had EFT, GT, and FI potential. Of the 27 RLDs with EFT potential, 13 RLDs exhibited EFT at doses ≤ the (maximum) recommended human dose, and 11 RLDs recommended contraception for at least one month after the final dose.

Conclusion: The current analysis provided insights into the rationale for recommending the exclusion of FRP as a PK BE study population in current PSGs. This collective information will be used to develop a decision framework for the selection of PK BE study population based on reproductive and genotoxic risks to ensure consistency and subject safety in PK BE studies.