(T1130-03-18) Bioequivalence Deficiencies Observed in Sucralfate Oral Suspension Generic Applications: An In-Depth Analysis of the Deficiencies Identified to Help Improve the Quality of Future Submissions

Purpose: Sucralfate oral suspension is a locally acting and only minimally absorbed gastrointestinal (GI) product for short term treatment of active duodenal ulcer. Due to limited systemic exposure of this product, in vivo study with pharmacokinetic (PK) endpoints is not a viable option for determination of bioequivalence (BE). Based on totality of evidence approach, FDA recommended an alternative in vitro BE option in October 2017 (revised in February 2023) comprising drug substance sameness, formulation characterizations, dissolution and four in vitro bioassays: 1. in vitro equilibrium binding study with bile salts, 2. in vitro kinetic binding study with bile salts, 3. in vitro equilibrium binding study with human serum albumin (HSA) or bovine serum albumin (BSA) and 4. in vitro enzyme (pepsin) activity study. Unlike other locally acting GI products indicated for reducing serum phosphate and cholesterol levels, for which in vitro phosphate and/or bile salt binding assays are recommended¹, inclusion of in vitro equilibrium binding study with serum albumin and in vitro pepsin activity study made BE determination of sucralfate oral suspension unique. This research was undertaken to analyze and compare the different approaches/ways the applicants have performed these four bioassays and identify common deficiencies in these applications. Thus, the main purpose of this study is to help generic sponsors to pay more attention to some of the key parameters of these in vitro studies to avoid the identified deficiencies discussed here. This in turn would help the Agency to approve these applications with fewer review cycles.

Methods: BE reviews of abbreviated new drug applications (ANDAs) for sucralfate oral suspension received from 2016 through 2022 were evaluated. Deficiencies were compiled for each bioassay and further classified into four categories, i. Method development and optimization. Under this category, we assessed if there is any missing or insufficient optimization data for parameters required for a sensitive biorelevant condition, (e.g., adsorbate-adsorbent concentration, pretreatment and incubation media, pH and duration etc.), whether the range of tested parameters selected rationally, and whether the reaction reached equilibrium; ii. Pre-study analytical method validation and sample analysis. Key parameters fall under this category are acceptability of all analytical method validation parameters including stability, dilution integrity, sensitivity, detailed report of rejected/ failed runs, raw data/ chromatogram etc. iii. Pivotal study and data analysis. This category covers accuracy of calculation, units of parameters, data presentation, discrepancy in observations between method development and pivotal study phases etc. iv. Miscellaneous.

Results: The study with maximum BE deficiencies issued for sucralfate oral suspension is found to be in in vitro equilibrium binding study with BSA/ HSA (38%), followed by equilibrium and kinetic binding study with bile salts (28% + 7% = 35%) and enzyme activity (pepsin) assay (27%) (Figure 1). Breakdown of deficiencies of each bioassay into four categories indicate that most of the deficiencies are related to method development and optimization in all four bioassays. The next categories with more deficiencies identified are pre-study analytical method validation and sample analysis and pivotal study and data analysis respectively (Figure 2). Under each category, most deficiencies are common among bioassays. For example, most frequently observed deficiency in BSA/HSA and bile equilibrium binding assay is inadequate equilibrium mean binding profile. The underlying reason for this deficiency appears to be non-optimal adsorbent/adsorbate concentration and range selection due to inadequate method development and optimization. Other notable deficiencies under first category of method development and optimization include missing or insufficient optimization data of acid pretreatment media/pH and duration, incubation media/pH and duration.

Conclusion: Most generic sponsors adopted BE recommendations outlined in the product specific guidance (PSG) for sucralfate oral suspension for product development. However, numerous inadequacies are being occurred repeatedly that unexpectedly prolongs the ANDA review and approval process. A comprehensive and in depth understanding of frequently occurring deficiencies and addressing these deficiencies prior to ANDA submission will notably reduce the review cycle and thus expedite the approval process.

References: 1. Lu D, Vivian D, Ren P, Yang Y, Zhang H, Jiang X, Stier E. Common Deficiencies of in vitro Binding Bioequivalence (BE) Studies Submitted in Abbreviated New Drug Applications (ANDAs). AAPS J. 2018 Jan 11;20(2):26. doi: 10.1208/s12248-017-0182-5.

Figure 1: Distribution of BE deficiencies among bioassays expressed in percentage of total deficiencies.

Figure 2: Breakdown of BE deficiencies based on category; Binding studies include in vitro equilibrium binding study with bile salts, in vitro kinetic binding study with bile salts, and in vitro equilibrium binding study with HSA and BSA.