Properties of the estimated variance component for subject-by-formulation interaction in studies of individual bioequivalence

Laszlo Endrenyi, Nathan Taback, Laszlo Tothfalusi

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Characteristics of the variance component for the subject-by-formulation interaction (σ(D)/2) estimated in simulated studies of individual bioequivalence and in three- and four-period cross-over trials reported by the FDA, were compared, σ(D)/2 was estimated by (i) restricted maximum likelihood (REML) and (ii) the method of moments (MM). Variation of the variance component, estimated by both procedures (s(D)/2) and for both the simulated and FDA data, increased with rising intra-individual variation. Consequently, a constant level of s(D)/2 (such as 0.0225 suggested by the FDA) may not be regarded as a basis for demonstrating substantial interactions. Features of the FDA and simulated parameters were similar. The results suggested that the FDA data were compatible with assuming σ(D) = 0.05 or perhaps 0.00. Therefore, there is no foundation for concerns about public health. Both simulations and calculations demonstrated that s(D)/2 estimated by MM was unbiased and its variance was proportional to σ(WF)/4 when σ(D)/2 = 0. Copyright (C) 2000 John Wiley and Sons, Ltd.

Original languageEnglish
Pages (from-to)2867-2878
Number of pages12
JournalStatistics in Medicine
Issue number20
Publication statusPublished - Oct 30 2000


ASJC Scopus subject areas

  • Epidemiology
  • Statistics and Probability

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