PII-192 - SAFETY CONSIDERATIONS OF SUBJECT POPULATION SELECTION IN BIOEQUIVALENCE STUDIES FOR GENERIC DRUG DEVELOPMENT.

T. Tran¹, J. Bae¹, D. Nguyen², J. Shon², M. Kim³, S. Borges², K. Li²; ¹ORISE, 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, ³Division 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: In general, healthy volunteers (HV) are recommended for pharmacokinetic (PK) bioequivalence (BE) studies in the product-specific guidances (PSGs) for generic drug development. If safety considerations preclude the use of HV for ethical reasons, patients for whom the drug is intended to treat are recommended. However, conducting BE studies in patients may pose some potential challenges (e.g., recruitment, cost, duration, intrinsic variability). This project aimed to retrospectively analyze the nonclinical toxicology and clinical safety profiles to understand the rationale behind study population selection in PSGs developed by the U.S. Food and Drug Administration (FDA).

Methods: FDA’s PSG database was used to compile a list of PSGs for oral drug products that recommend PK BE studies in patients. PSGs recommending comparative clinical endpoint BE studies in patients were excluded. To identify common factors, PSGs were classified using United States Pharmacopeia (USP) therapeutic categories as well as nonclinical toxicology profile (i.e., cytotoxicity, carcinogenicity, genotoxicity) and other pertinent safety elements (e.g., hepatotoxicity, cardiotoxicity) from the reference listed drug (RLD) labeling. Available corresponding product-specific BE guidances from the European Medicines Agency (EMA) were reviewed as comparison.

Results: Fifty-seven PSGs (55 RLDs; 49 active pharmaceutical ingredients) were identified. The most common USP therapeutic categories were antineoplastics (N=40), immunological agents (N=3), anticonvulsants (N=3), and antipsychotics (N=3). Of 55 RLDs, risks for genotoxicity (N=37), cytotoxicity (N=34), carcinogenicity (N=28), and hepatoxicity (N=19) were mentioned in their labeling. Among 55 RLDs, seven have product-specific BE guidances available from the EMA, four of which are non-cytotoxic antineoplastics and recommended BE studies in HV, different from FDA recommendation.

Conclusion: Genotoxicity, cytotoxicity, and carcinogenicity were the most common risk factors identified for RLDs in FDA’s PSGs recommending PK BE studies in patients. Further analysis into the differential level of safety data is needed to justify enrollment of patients instead of HV. These findings will be used to develop a decision framework for the proper selection of study population for PK BE studies.