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Bias of two one‐sided tests procedures in assessment of bioequivalence
Author(s) -
Liu JenPei,
Weng ChungSing
Publication year - 1995
Publication title -
statistics in medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.996
H-Index - 183
eISSN - 1097-0258
pISSN - 0277-6715
DOI - 10.1002/sim.4780140813
Subject(s) - bioequivalence , sample size determination , normality , statistics , parametric statistics , mathematics , nominal level , econometrics , confidence interval , medicine , pharmacology , bioavailability
The current applications of Schuirmann's two one‐sided tests procedure for the original scale ignore the variability of the least squares mean of the reference formulation when it substitutes for the unknown reference average of pharmacokinetic responses. We propose a modified two one‐sided tests procedure that takes into account the variability of the least squares mean of the reference formulation. The non‐parametric version of the modified procedure is also available. We conducted a simulation study to examine the true level of significance and empirical power of four current parametric and non‐parametric two one‐sided tests procedures under a 2 × 2 crossover design with different combinations of sample size, intrasubject variability, and correlation between the two responses from a subject. Both theoretical results and empirical evidence show that the true level of significance of the current two one‐sided tests procedures converges to 0·5 when the correlation of the two responses approaches 1. However, not only is the modified two one‐sided tests procedure a test of size α, but empirical evidence indicates it is also an unbiased test. The modified non‐parametric procedure also controls the size of the tests and is competitive even under normality assumption.