078: Survey of Bioequivalence Data of Abbreviated New Drug Applications of Narrow Therapeutic Index Drug Products

Statement of Purpose: In 2012, the US Food & Drug Administration (FDA) tightened bioequivalence (BE) standards for generic narrow therapeutic index (NTI) drug products by recommending a fully replicated, two-sequence, two-treatment, four-period crossover study design where BE is based on passing both scaled average BE criterion and within-subject variability comparison criterion. Meanwhile, most other regulatory agencies recommend conventional two-way crossover studies and directly tighten BE limits. The objective of this study is to survey BE data of abbreviated new drug applications (ANDAs) of NTI drug products submitted and/or approved after 2013 by the FDA to identify the impact of FDA’s current BE approach on generic NTI approval. The results will help support the future international harmonization in NTI BE standards for International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M13 development.

Description of Methods & Materials: ANDAs for NTI drug products with first submission dates on or after January 2013 to October 2022 were collected. ANDAs were reviewed for whether BE data were deemed adequate based on a two-way crossover BE study or four-way crossover BE study. Individual applications were further reviewed to determine the number of passing and failed four-way crossover BE studies. Additionally, pharmacokinetic (PK) parameters: AUC_t, C_max, and AUC_inf were collected. The point estimate, 90% confidence interval (CI), critical bound, sWT, sWR, sWT/sWR ratio, and upper sWT/sWR 90% CI were collected for each PK parameter. Test product and reference standard potency assay values as well as the number of subjects included in the PK analysis were gathered for each ANDA.

Data & Results: In total, 33 NTI drug products with 14 active pharmaceutical ingredients (API) in 100 ANDAs were identified. 88 ANDAs with locatable BE data were included in analysis. Of the 88 surveyed ANDAs: 5 ANDAs contained two-way crossover studies only, 73 ANDAs included four-way crossover studies only, and 10 ANDAs contains both two-way and four-way crossover studies. From the 83 ANDAs with four-way crossover studies, there were 67 fed BE studies and 103 fasting BE studies submitted. For all NTI drug products, the range of average sWR for C_max, AUC_t, and AUC_inf was between 0.05 and 0.28. For the same API with distinctly different dosage forms, differences in average sWRs were observed. Of the 20 studies that failed BE criteria, 90%, 5%, and 5% failed reference scaled limits only, variability comparison criteria only, and both criteria, respectively. Overall, there was a slight increase of failed studies with a decrease in sWR.

Interpretation, Conclusion or Significance: This work helps better understand the impact of 2012 FDA NTI BE criteria on the approval of generic NTIs submitted to FDA. Further exchange of this work with global regulatory agencies and scientific community will clarify the strengths and limitations of different BE approaches for NTI drugs and promote the development of harmonized BE criteria for NTI drugs, in turn improving patients access to generic NTI drugs.

Disclosures: The contents in this abstract reflect the views of the authors and should not be construed to represent FDA’s views or policies.