Abstract
Purpose. The FDA has proposed replacing the current averagebioequivalence criterion with population and individual bioequivalence criteriathat consider variances in addition to the difference of averages. Oneof these variances in the individual bioequivalence criterion measuressubject-by-formulation interaction, the extent to which thetest-reference difference varies from person to person. This paper discussesconceptual and statistical issues raised in various publications andpresentations with respect to the presence and estimation of such aninteraction.
Methods. We focus on the importance of subject-by-formulationinteraction, an understanding of what is a large interaction, and theassessment of the magnitude of this interaction in bioequivalence studies.Simulation studies, examples from the literature, and data from FDAfiles are used to demonstrate the magnitude of the interaction and itsdistribution under various conditions.
Results. The concept of a large interaction is tied to the concept of alarge mean difference. We suggest that an interaction greater than0.15 is a conservative criterion for a large interaction. Magnitudes ofestimated interaction are affected by variability, sample size, and theselection of data sets that pass average bioequivalence.
Conclusions. Examples of substantial interactions are beginning toappear. More data is needed before reaching definitive conclusionsregarding the frequency and importance of observed interactions.
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Hauck, W.W., Hyslop, T., Chen, ML. et al. Subject-by-Formulation Interaction in Bioequivalence: Conceptual and Statistical Issues. Pharm Res 17, 375–380 (2000). https://doi.org/10.1023/A:1007508516231
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DOI: https://doi.org/10.1023/A:1007508516231