(M1430-02-11) Common Bioequivalence (BE) Deficiencies Identified in ANDAs Associated with Solid Oral Extended-Release Drugs in Various Therapeutic Areas: A Retrospective Survey of BE Study Data Submitted to the FDA

Purpose: The timely availability of generic versions of these products offers significant financial and health benefits to the American public, as they are frequently prescribed in various therapeutic areas and hold substantial market shares. However, abbreviated new drug applications (ANDAs) for solid oral extended-release (ER) drug products often exhibit multiple preventable bioequivalence (BE) deficiencies. These issues unnecessarily delay generic drug development and strain both regulatory Agency and the generic industry. The findings of this current study aim to assist the generic pharmaceutical industry in improving the quality of ANDA submissions, further accelerating regulatory review process, ultimately providing earlier and greater access to healthcare for the American public.

Methods: The evaluated drug products included: 1) Memantine ER Tablet (anti-dementia), 2) Oxymorphone ER Tablets (opioid pain killer), 3) Tramadol ER Tablets (non-opioid pain killer), 4) Metoprolol Succinate ER Tablets (cardiovascular agent), 5) Paliperidone ER Tablets (antipsychotic), 6) Glipizide ER Tablets (anti-diabetic), 7) Oxybutynin Cl ER Tablets (antispasmodics) and 8) Quetiapine Fumarate ER Tablets (atypical antipsychotic). The investigation focused on ANDAs, specifically 158 ANDA submissions that referenced the aforementioned ER drug products and were submitted from 2001 to 2023. The BE deficiencies identified were categorized into four different areas: 1) pharmacokinetics (PK); 2) bioanalysis; 3) dissolution; and 4) formulation.

Results: Category 1: The common deficiencies identified in the PK category for these ANDAs include i) Subjects were excluded or included in the statistical analysis without proper justification; ii) Information on the failed or pilot BE study were missing or inadequate; iii) Electronic data files required for statistical analysis were missing or submitted improperly; iv) Significant differences in Tmax or Tlag between test product and reference product were observed; v) Subjects who were assumed “statistical outliers” were dropped from the final statistical analysis without adequate justification. Category 2: The common deficiencies identified in the bioanalysis category for these ANDAs include i) Analytical raw data from the study runs of all the subjects and/or chromatograms for 20% of study subjects were incomplete; ii) sample re-analysis was inadequate; iii) Standard Operating Procedure (SOP) and/or validation report used in the application were not submitted; iv) The long-term frozen storage stability data were not submitted or were insufficient to cover the entire biological sample storage time period; v) Bioanalytical reports were incomplete (e.g., missing dilution integrity data, stock stability data, recovery data). Category 3: The common deficiencies identified in the dissolution category for these ANDAs, using to support waiver requests, include i) Dissolution data in multi-pH media were considered inadequate due to non-comparable profile, missing data and discrepancies in data; ii) Dissolution data using scored tablets were missing or inadequate; iii) dissolution method used in the application was considered inadequate due to lack of discriminatory ability. iv) Dissolution data for alcohol dose-dumping (ADD) study were considered inadequate due to increase of drug release of test product in media with alcohol and missing data; v) Similarity factors (i.e., f2) of dissolution data between bio-strength and other strength were less than 50; vi) Explanation or investigation on unusual high variability in dissolution data was missing. Category 4: The common deficiencies identified in the formulation category for these ANDAs include i) The information on colorant, flavor or shell used in the test formulation was missing or incomplete; ii) proposed used the excipients were over the limit used in the approved drug product under same context of use; iii) Formulation proportionality between bio-strength and other strength was inadequate; iv) Information on bio-batch were incomplete (e.g., missing potency and content uniformity). The frequency of occurrence of the above four (4) common deficiency categories during the first review cycle is summarized as follows: i) 16% of deficiencies were related to PK; ii) 32% of deficiencies were related to bioanalysis; iii) 42% of deficiencies were related to dissolution data; and iv) 11% of deficiencies were related to formulation. It is worth noting that some ANDAs had deficiencies in multiple categories. Deficiencies related to the alcohol dose dumping were identified in 13 ANDAs. These deficiencies were primarily due to partial or non-submissions of ADD data or an increase of drug release from test product comparing to that of reference drug product. Six (6) ANDAs had deficiencies due to significant differences in Tmax or Tlag between test product and reference product. Among these 6 ANDAs, one (1) ANDA was recommended to reformulate due to potential negative clinical impact of Tlag difference.

Conclusion: Various deficiencies identified during BE review for oral ER products are avoidable and occur repeatedly. Some deficiencies are related to their clinical impact (e.g., Tlag difference), while others (e.g., ADD testing deficiencies) appear to be associated with drug product formulation design. The submission of acceptable, complete and well-organized BE submissions for ANDAs will be of significant value to the generic drug industry, as well as the American public, who will benefit from the earlier access to generic drugs.

Acknowledgements: The views and opinions presented here represent those of the presenters and should not be considered to represent advice or guidance on behalf of the U.S. Food and Drug Administration.