(W1130-01-02) Bioequivalence Approaches Utilized in Generic Drug Applications for Topical Drug Products Applied to the Skin

Purpose: The Office of Generic Drugs (OGD) at the U.S. Food and Drug Administration ensures high-quality, affordable generic drugs are available to the American public. Historically, there have been three types of bioequivalence (BE) approaches used to support generic drug approval for topical drug products applied to the skin: comparative clinical endpoint bioequivalence (CCEP BE) studies, vasoconstrictor (VC) studies, or a waiver of in vivo BE studies. Currently, OGD recommends characterization-based BE approaches as an alternative, efficient method to support a demonstration of BE for topical products. The purpose of this work is to summarize the distribution of BE approaches utilized in abbreviated new drug applications (ANDAs) for topical products received during fiscal years (FYs) 2018 to 2023 and how the approaches have contributed to generic drug approval.

Methods: In this work, received ANDAs, ANDA status, and the BE approach used in each ANDA were obtained from the Agency’s internal databases. Received ANDAs for the topical route of administration were defined as those submitted to the Agency between FY 2018 and FY 2023 (October 1, 2018-September 30, 2023) that did not have a refuse-to-receive or unacceptable submission status determination. ANDA application status in the current work were summarized for the received ANDAs (withdrawn ANDAs were excluded from the application status analysis) as of March 19, 2024. Within the scope of this work, ANDAs with an approved or tentative approval status were categorized as approved ANDAs. ANDAs with a pending or complete response status were categorized as pending ANDAs. The application status (e.g., approved, pending, etc.) analysis is based on the FY that the ANDA was received. The BE approach used in the received ANDAs were categorized into the four most common BE approaches: characterization-based BE approach, CCEP BE study, VC study, and waiver of in vivo BE studies. ANDAs that only conducted an in vivo pharmacokinetic BE study were not categorized into these four BE approaches and are outside the scope of the current analysis. ANDAs using a combination of in vivo BE approaches were categorized into the least efficient in vivo BE approach (e.g., ANDAs that conducted both CCEP BE and VC studies were categorized into the CCEP BE group). ANDAs that included physiochemical and structural (Q3) characterization in addition to a CCEP BE or VC study were categorized into the characterization-based BE approach group.

Results: The number of received ANDAs using efficient characterization-based BE approaches has generally increased since FY 2018 (Figure 1). Among the approved ANDAs that were received between FY 2018 and FY 2022, a characterization-based BE approach was the most used among the four most common BE approaches (approximately 38% of approved ANDAs), and the percent of approved ANDAs that used this approach has increased since FY 2018. An in vitro release test (IVRT) and an in vitro permeation test (IVPT) are two studies utilized for comparison of product performance between a perspective generic topical drug product and reference standard (RS). An IVRT study is commonly recommended as part of the characterization-based BE approach for most semisolid topical drug products (e.g., topical cream, gel, ointment). An IVPT study is recommended for subset of topical drug product depending on the complexity and/or site of action of the drug product. Among the approved topical ANDAs that were received between FY2018 and FY 2022 that utilized a characterization-based BE approach, approximately 64% and 20% of the approved topical ANDAs utilized IVRT and IVPT studies, respectively.

Conclusion: These data suggest the generic drug industry has generally adopted characterization-based BE approaches in topical ANDAs, and OGD has begun approving topical ANDAs that have utilized this approach. Characterization-based BE approaches, along with other BE approaches, serve an essential role to support the development and approval of generic topical drug products, leading to increased availability of high-quality generic drugs for patients.

Acknowledgements: This project was supported in part by an appointment (Lingxiao Xie) to the Research Participation Program at the U.S. Food and Drug Administration administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.


Figure 1. Topical ANDAs received between FY 2018-FY 2023 by the four most common BE approaches for topical products. Bars represent ANDAs received using a given BE approach normalized by the number of topical ANDAs received in a given FY.