CDER Researchers have been investigating how pharmacokinetic (PK) modeling can support a determination of bioequivalence (BE) for topical drug products. In the case of a generic diclofenac sodium topical gel, 1%, CDER found that physiologically based pharmacokinetic (PBPK) modeling supported an alternative BE approach that does not include a comparative clinical endpoint BE study. The abbreviated new drug application (ANDA) that was approved using this approach is a significant milestone for the Generic Drug User Fee Amendments (GDUFA) regulatory research program that is supported by FDA.
Locally acting drug products deliver their active ingredient at or near the site of action which may be in or on the body. These products include, for example, orally inhaled, nasal, ophthalmic, and topical drug products applied directly to the skin and oral products that act locally in the gastrointestinal tract.1 To demonstrate BE between a brand name product (reference) and its generic (test), there must be an “absence of significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”2
FDA’s recent approval of generic diclofenac sodium topical gel, 1%, was a successful example of PBPK modeling supporting an alternative BE approach for an ANDA. This is the first time a virtual BE assessment leveraging dermal PBPK modeling and simulation supported a “totality of evidence” BE approach that led to drug approval. The decision to approve this generic drug was based on 1) qualitative and quantitative sameness and physical and structural similarity to the reference product, 2) an in vivo BE study with PK endpoints, and 3) a virtual BE assessment leveraging dermal PBPK modeling and simulation instead of a comparative clinical endpoint study in patients. Evidence from additional PBPK modeling and simulation activities conducted by CDER assessors bridged the gap between the in vitro evidence for comparable (upstream) bioavailability through the skin and the in vivo evidence for comparable (downstream) bioavailability in the systemic circulation so that a comparative clinical endpoint study was not needed.
The Scientific Challenge
Establishing BE for topical drug products by conducting comparative clinical endpoint studies can be costly, and the studies may not be sufficiently sensitive to detect certain formulation differences. Quantitative methods and modeling (e.g., PBPK) can support alternative BE approaches with reduced or no human testing. However, to be used for regulatory decision-making, these mathematical models need to be sufficiently verified and validated (V&V) for their intended purpose.
Verification and Validation of a Dermal PBPK model for Diclofenac Sodium Topical Gel, 1%
For this ANDA, the applicant implemented an innovative two-level approach for verifying and validating the fit-for-purpose dermal PBPK model developed for diclofenac sodium topical gel, 1%. Briefly, the first level V&V focused on assessing the performance of the developed models for topical products with diclofenac sodium as the active pharmaceutical ingredient (API). The dermal PBPK model for diclofenac sodium topical gel, 1%, incorporated product-specific formulation attributes generated by the applicant as part of its product characterization program and was validated leveraging clinical PK data supporting the ANDA submission.
The second-level V&V aimed at assessing the performance of the computational platform that was used (i.e., the Multi-Phase Multi-Level Mechanistic Dermal Absorption model within the Simcyp® Simulator, version 17). The performance of the platform was evaluated by the ANDA applicant and CDER assessors validating a significant number of PBPK models for dermatological products using published data. The dermal PBPK models supporting the second-level validation included dermatological products with APIs other than ...
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