Analysis on the Impact of U.S. FDA’s Narrow Therapeutic Index Bioequivalence Criteria on Generic Drug Applications

Since 2012, the U.S. Food and Drug Administration (FDA) has developed classification criteria of narrow therapeutic index (NTI) drug products and tightened bioequivalence (BE) standards for these 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, as well as the average BE criterion of 80.00%-125.00%. Currently, the BE study design and criteria for NTI drugs are somewhat different across regulatory agencies. The objective of this study is to survey pharmacokinetic BE data of abbreviated new drug applications (ANDAs) of NTI drugs submitted to the FDA with initial submission dates between January 1, 2013 and October 1, 2022 to identify the impact of FDA's current BE approach on generic NTI approval. Thirty-three NTI drug products from 100 ANDAs were identified with 93 ANDAs included in analysis. Eighty-seven ANDAs had four-way crossover studies, with 69 and 106 fed and fasting BE studies, respectively. For all NTI drugs, the range of average S_WR for C_max, AUC_t, and AUC_inf was between 0.05 and 0.27. Of the 20 studies that failed BE, 90%, 5%, and 5% failed reference scaled criteria only, variability comparison criteria only, and both, respectively. Further communication of this work with global regulatory agencies and the scientific community will help better understand current FDA NTI BE criteria and review experiences. These efforts will support the development of harmonized BE criteria for NTI drugs, in turn improving patient access to generic NTI drugs.