(T1130-05-27) Bioequivalence Recommendations for Tretinoin-Containing Topical Products

Purpose: In 1971, tretinoin topical solution and swab, 0.05% were approved under new drug application (NDA) 016921 as the first retinoid topical product for the treatment of acne vulgaris by the U.S. Food and Drug Administration (FDA). Since then, topical retinoids, either alone or in combination with benzoyl peroxide, clindamycin phosphate, etc. have been approved in various dosage forms including solution, gels, creams, and lotion. Formulations containing microparticles suspended in the gels and creams, thus leading to additional complexity, have also been utilized to deliver tretinoin. Based on the complexity of the microstructure of these tretinoin-containing topical dosage forms, among other factors, FDA has recommended various approaches for establishing bioequivalence (BE) of prospective generic tretinoin-containing topical products. The purpose of the current work is to provide a comprehensive review of the microstructural complexity of tretinoin-containing topical products and the development of science-based BE approaches recommended in the FDA’s product-specific guidances (PSGs).

Methods: Based on the complexity of the microstructure, tretinoin-containing topical products were categorized as single-phase, conventional multiphasic and complex multiphasic systems in this work. The relationship between a product’s microstructural complexity and the recommended BE approaches obtained from the FDA’s published PSGs were reviewed for 17 tretinoin-containing topical products. Trend analysis was conducted on the components of BE approaches recommended for these products. Additionally, research was conducted to understand the relationship between a drug product’s microstructure and performance.

Results: As of April 2024, there are 19 approved reference listed drugs for tretinoin-containing topical products. Among the 19 products, 17 have published PSGs. Comparative clinical endpoint BE studies have been recommended in all 17 PSGs, except for the PSG for tretinoin topical solution (an in vivo BE study can generally be waived for a topical solution under 21CFR 320.22(b)(3)). At this time efficient characterization-based approaches have been recommended for single-phase systems (e.g., tretinoin topical gels), but not for the conventional multiphasic (e.g., tretinoin creams and lotions) or complex multiphasic (e.g., tretinoin gels containing microparticles) systems. As a component of the characterization-based BE approaches, as the structural complexity increases, additional physicochemical and structural tests may be recommended. For example, compared to single phase tretinoin topical gels, characterization of globule size distribution and other tests may be relevant for multiphasic tretinoin topical creams and lotions. For more complex multiphasic systems, such as Retin-A micro (tretinoin) topical gel, Generic Drug User Fee Amendments (GDUFA)-funded research demonstrated that a microparticle’s morphology, particle size, spatial distribution of tretinoin and the interaction of tretinoin with polymer matrix play an important role in controlling drug release which may in-turn affect tretinoin bioavailability. As a separate matter, for tretinoin-containing topical products that are available in multiple strengths, the release of tretinoin from the drug product is expected to be proportional to the product strength. Waiver of in vivo studies for intermediate strength(s) of tretinoin-containing topical products have been recommended for conventional multiphasic tretinoin products (i.e., products referencing Retin-A cream) and similar approaches may also be applicable for complex multiphasic tretinoin products.

Conclusion: In addition to comparative clinical endpoint BE studies, characterization-based BE approaches are designed based on the microstructural complexity of the drug products, supported by scientific research on the drug products’ physiochemical and structural (Q3) characteristics and performance. GDUFA-funded research demonstrated that the microstructure of tretinoin-containing topical products such as rheology, globule size, etc. may impact the release of tretinoin from the drug products, and thereby the bioavailability. Therefore, the formulation and the microstructural properties for a given formulation are carefully considered during the development of BE approaches. Ultimately, available efficient characterization-based BE approaches and the waiver approaches, in addition to the comparative clinical endpoint BE studies, are anticipated to streamline generic product development.

Acknowledgements: This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.