Category: Formulation and Quality
Purpose: Characterization-based bioequivalence (BE) approaches are efficient methods to establish BE of generic topical dermatological drug products compared to comparative clinical endpoint BE studies, which are considered to be the least accurate, sensitive, and reproducible method of establishing BE for these products. With the advancement in research of advanced analytics and in vitro characterization methods, the Office of Generic Drugs (OGD) has begun recommending these characterization-based approaches within product-specific guidances (PSGs). The first PSG wherein such an approach was comprehensively implemented was for acyclovir topical cream, 5% in 2016, after which these approaches were developed for a handful of topical dermatological drug products. By 2018, characterization-based BE approaches were demonstrated to be a generalizable approach for all classes of topical dermatological semisolid dosage forms. As part of the Generic Drug User Fee Amendments (GDUFA) Regulatory Science Priorities for fiscal year (FY) 2018, OGD intends to “expand characterization-based BE methods across all topical dermatological products.” However, the implementation of this priority has been complex due to technical challenges, scientific unknowns, and limited resources to manage this goal. Therefore, a strategic roadmap was necessary based on a gap analysis of the essential steps for establishing characterization-based methods for all types of generic topical dermatological drug products.
To successfully transition the standards for establishing BE for topical dermatological drug products to characterization-based methods, four critical steps are necessary (Figure 1). Through GDUFA-funded research conducted over the past five years, general critical quality attributes for common topical dermatological dosage forms have been established (Step 1), leading to the identification of ten fundamental properties of semisolid drug products. Filling this gap in knowledge has facilitated the development of characterization-based BE approaches for specific drug products, which are then incorporated into their respective PSGs. The purpose of this study was to assess the progress in this transition by surveying the current recommendations for establishing BE within PSGs for topical dermatological drug products for each dosage form.
Methods: Through GDUFA-funded research, a conceptual framework for identifying the failure modes for BE for generic topical dermatological products was established. The general critical quality attributes of topical semisolid dosage forms were identified and various methods for evaluating these quality attributes were developed. Common trends among the dosage forms were identified and used to develop characterization-based BE approaches within PSGs for various generic topical dermatological drug products. The PSGs for generic topical dermatological drug products published prior to July 2019 were classified based on the recommended approaches for establishing BE and categorized based on common semisolid dosage forms.
Results: By FY 2012 (prior to GDUFA I), approximately 27% of topical dermatological reference products had a published PSG. Currently, 200 PSGs (approximately 62%) have been published for the 322 topical dermatological reference drug products (Figure 2). In vivo studies (e.g., comparative clinical endpoint BE studies and vasoconstrictor studies) are currently recommended in most of the published PSGs and characterization-based BE approaches are recommended for only 6% of topical dermatological reference products overall and within 10% of the published PSGs.
Overall, PSGs are available for 68% (67/99) of topical cream reference products, 80% (39/49) of topical gel reference products, 67% (28/42) of topical ointment reference products, and 68% (21/31) of topical lotion reference products. Within these PSGs, an in vivo comparative clinical endpoint BE study is most commonly recommended (for 51% of cream PSGs and 79% of gel PSGs, for example). A smaller proportion of published PSGs include recommendations for characterization-based BE approaches for topical creams (12%), gels (10%), ointments (14%), and lotions (10%).
Conclusion: Over the last decade, characterization-based BE approaches have been recommended as an alternative in vitro BE approach to in vivo studies for many topical dosage forms based on the knowledge obtained in Step 1 of the roadmap. Incorporation of the characterization-based BE approaches in all PSGs for generic topical dermatological drug products continues to be a priority for OGD. Research has been ongoing to develop various methods of characterizing the critical quality attributes (Step 2). However, it is evident from this analysis that it is imperative to determine the optimal method for each critical quality attribute (Step 3) and develop compendial standards for these methods (Step 4) in the future to establish the infrastructure that is necessary to accomplish the goal of establishing characterization-based BE approaches for all topical dermatological drug products, which in turn will improve patient access to high quality generics.
Megan Kelchen– Silver Spring, Maryland
Megan Kelchen– Silver Spring, Maryland
Priyanka Ghosh– Pharmacologist, US Food and Drug Administration, Silver Spring, Maryland
Tannaz Ramezanli– Pharmacologist, Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA, Silver Spring, Maryland
Sam Raney– Lead for Topical & Transdermal Drug Products, U.S. FDA, Silver Spring, Maryland