(M0930-04-24) Developing Efficient Bioequivalence Approaches for Generic Vaginal Drug Products

Purpose: The development of generic vaginal drug products has historically involved in vivo bioequivalence (BE) studies with pharmacokinetic (PK) endpoints and/or clinical endpoint(s). In recent years, the Office of Generic Drugs (OGD) at the U.S. Food and Drug Administration (FDA) has begun recommending efficient characterization-based approaches for generic topical drug products applied to the skin within product-specific guidances (PSGs). The components that are recommended as part of a characterization-based approach often depend on the complexity of the product (e.g., dosage form) and the site/mechanism of action of the drug product. Using a similar framework, efficient characterization-based approaches which may mitigate the risks associated with potential failure modes for BE have been proposed for generic vaginal drug products. The purpose of this work is to assess the current methodologies available for development of (generic) vaginal drug products and to discuss the research efforts underway to support the development of efficient BE recommendations for such products.

Methods: The total number of reference products was obtained from the Orange Book (current through July 2022) by filtering the list of approved drug products by the route of administration (vaginal), market status (prescription or over the counter), and reference standard drug products. Orange Book listings that contained “extended release” or multiple dosage forms (e.g., cream and suppository) were excluded from the analysis. Based on the assessment, creams, gels and suppositories/inserts/tablets are the most commonly used dosage forms for vaginal drug products. Through Generic Drug User Fee Amendments (GDUFA)-funded research, the potential failure modes for BE for such drug products have been identified. In the current work, PSGs for vaginal semisolid drug products published prior to July 2022 were classified based on the recommended BE approaches: 1) characterization-based BE approach, 2) comparative clinical endpoint BE study only, 3) comparative clinical endpoint BE study and PK BE study, or 4) no PSG available. PSGs that include multiple BE approaches were classified based on the approach that is listed first in the current PSG page (characterization-based approaches are typically listed first, when a PSG includes multiple approaches). Gap analysis was conducted for vaginal drug products that do not currently include efficient approaches for establishing BE. Research efforts to address such gaps were developed.

Results: Currently, of the 30 reference products available on the market, 25 drug products (83%) have a published PSG (Figure 1). Efficient characterization-based approaches are currently recommended for 10% of all vaginal drug products. Of the published PSGs, 67% of vaginal gel PSGs include characterization-based approaches and 10% of insert/suppository/tablet PSGs include characterization-based approaches. In vivo approaches comprising of comparative clinical endpoint BE study and/or PK BE study (100% of cream PSGs; 33% of gel PSGs; 100% of ointment PSGs; 90% of insert/suppository/tablet PSGs) are most commonly recommended for vaginal products. Based on an assessment of the microstructure of vaginal reference products, single-phase gels were determined to the least complex dosage form of those evaluated. Emulsion-based drug products, such as creams, generally appear to be more complex in microstructure compared to single phase gels, thereby increasing the potential failure modes for BE for such products. Encapsulated drug products where the release of the drug from the dosage form, and thereby bioavailability, may be influenced by the rate of disintegration of a “shell” also contribute to the complexity. In accordance with the analysis, efficient characterization-based approaches are currently recommended for metronidazole vaginal gels (0.75% and 1.3% strength). The characterization-based approaches included no difference in formulation relative to the reference standard, comparative assessment of the microstructure of the prospective generic and corresponding reference standard, as well as an in vitro release test (IVRT) study for evaluation of product performance. Recent research has demonstrated that methodologies routinely utilized for validation of IVRT methods for topical products applied to the skin can be extrapolated to vaginal drug products (with certain adjustments, e.g., studies for the vaginal drug products are typically conducted at 37°C compared to 32°C for products applied to the skin). Additional research is underway to facilitate the development of biorelevant in vitro methodologies for evaluation of product performance that may be necessary to develop efficient approaches for the creams, suppositories/inserts/tablets, etc.

Conclusion: Efficient characterization-based approaches for vaginal drug products have been developed for single-phase vaginal gels, and previous research has suggested that it may be feasible to develop efficient characterization-based approaches for more complex vaginal drug products, such as emulsions. However, additional research is needed to develop biorelevant performance tests for generic vaginal drug products in order to support development of efficient BE approaches for such products.

Figure 1. Current status of PSGs (n=25) for 30 vaginal reference products (5 vaginal reference products have no PSG). The orange section represents efficient approaches for establishing BE; blue sections represent approaches for establishing BE that are considered to be less efficient or approaches are unavailable.