(W0930-10-63) Alternative Approach to Demonstrate Bioequivalence of Generic Formulations of Sucralfate Oral Suspension

Purpose: Carafate^® (sucralfate) Oral Suspension is a locally acting drug indicated for the short-term treatment of active duodenal ulcer. Sucralfate exerts its effect by multiple mechanisms such as acid neutralization, inhibition of pepsin activity, adsorption to bile salts, and formation of an ulcer-adherent complex for protection of ulcer site. Accordingly, the FDA’s product specific guidance (PSG) for Sucralfate Oral Suspension, recommends the generic formulation (T) to be Qualitatively (Q1) and Quantitatively (Q2) the same as the reference product formulation (R) and perform three in-vitro bioassays for the demonstration of bioequivalence (BE). The purpose of this project is to elucidate with one case study that for non Q2 generic formulations of Carafate^® Oral Suspension, an appropriate alternate approach to the one recommended in current PSG can be utilized for bioequivalence demonstration.

Methods: Abbreviated New Drug Applications (ANDAs) submitted to the Agency for this drug product from 2016 to 2023 were evaluated for approaches employed to demonstrate bioequivalence. The majority of generic applications followed the PSG recommendations except one ANDA which utilized an alternate approach, involving a test formulation that was non Q2 (e.g., differing in the amount of excipient X) compared to the reference product. For this non Q2 test formulation, an alternate BE approach involved conducting new bioassays based on sucralfate’s mechanism of action in addition to the PSG recommended bioassays. These new bioassays included mucoadhesion (stomach) assay, delay in acid diffusion and delay in bile acid diffusion assays, whereas the PSG recommended bioassays included in vitro equilibrium and kinetic binding studies with bile salts, human or bovine serum albumin (HSA/BSA) and in vitro pepsin activity assay. To demonstrate that a non Q2 component does not impact the product performance, these bioassays were conducted on a test formulation along with intentionally altered formulations (including those bracketing the amount of excipient X) in comparison to the reference formulation. Active pharmaceutical ingredient (API) sameness and comparative physicochemical characterization were performed with the final test formulation.

Results: The initial in-vitro bioassays conducted on test formulations with varying amounts of multiple excipients were inconclusive as to the impact of the Q2 difference on the product performance due to the confounding factor of varying other excipients simultaneously. Therefore, these bioassays were considered insufficient to mitigate BE concerns of the Q2 difference. Subsequently, the PSG-recommended and three additional bioassays were conducted on altered formulations differing only in the amount of excipient X. For in vitro HSA binding assay, the study design deviated from the PSG recommended design. In this alternative design, a fixed concentration of HSA and varying concentrations of sucralfate were used instead of a fixed concentration of sucralfate with at least eight different concentrations of HSA. The equilibrium binding affinity constant Kd value was calculated; however, it was not considered a strong predictor of formulation differences. Subsequently, this bioassay was repeated utilizing the study design as recommended in the PSG. The 90% Confidence Interval (CI) of T/R ratio on the Langmuir binding constant (k2) was used to evaluate the equivalence for in vitro equilibrium binding with HSA and bile salts, as recommended in the PSG. The three additional bioassays were statistically evaluated by applying the 90% CI of difference between T and R formulations and comparing against the Equivalence Acceptance Criteria (EAC) constructed from the RLD results. The results from all these bioassays demonstrated that the concentration of excipient X within the evaluated range, did not impact the BE of these test formulations versus the RLD.

Conclusion: An alternative BE approach involving mechanism based additional bioassays with test formulation variants that differ in the amount of non-Q2 excipient along with studies recommended in PSG could provide conclusive evidence that Q2 difference does not affect the BE of this specific generic formulation. Overall, the combined findings from all in vitro bioassays could provide totality of evidence for the bioequivalence of such non Q2 generic drug product to the RLD product. This case study suggests that an alternative approach can be developed by prospective generic applicants for demonstration of BE for non Q2 generic formulations of Sucralfate Oral Suspension.

Acknowledgements: The views expressed are those of the authors and do not reflect official policy of FDA. No official endorsement by the FDA is intended or should be inferred.