title: A Bioequivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-Scaled Approach and Variability Comparison Criterion.
abstract: Various health communities have expressed concerns regarding whether average bioequivalence (BE) limits (80.00-125.00%) for the 90% confidence interval of the test-to-reference geometric mean ratio are sufficient to ensure therapeutic equivalence between a generic narrow therapeutic index (NTI) drug and its reference listed drug (RLD). Simulations were conducted to investigate the impact of different BE approaches for NTI drugs on study power, including (1) direct tightening of average BE limits and (2) a scaled average BE approach where BE limits are tightened based on the RLD's within-subject variability. Addition of a variability comparison (using a one-tailed F test) increased the difficulty for generic NTIs more variable than their corresponding RLDs to demonstrate bioequivalence. Based on these results, the authors evaluate the fully replicated, 2-sequence, 2-treatment, 4-period crossover study design for NTI drugs where the test product demonstrates BE based on a scaled average bioequivalence criterion and a within-subject variability comparison criterion.
authors.affiliation: Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Wenlei
authors.initials: W
authors.lastname: Jiang
authors.forename: Fairouz
authors.initials: F
authors.lastname: Makhlouf
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Schuirmann
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Nan
authors.initials: N
authors.lastname: Zheng
authors.forename: Dale
authors.initials: D
authors.lastname: Conner
authors.forename: Lawrence X
authors.initials: LX
authors.lastname: Yu
authors.forename: Robert
authors.initials: R
authors.lastname: Lionberger
mesh_terms: D003198:Computer Simulation; D018592:Cross-Over Studies; D016568:Drugs, Generic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D013810:Therapeutic Equivalency
chemical_list: D016568:Drugs, Generic
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