Bioequivalence and Bioavailability Forum

Dear Kim, dear Boonchai L.

Reliable information on the intrasubject coefficient of variation is needed for sample size planning, you are right. Unfortunately, this information is usually not presented in publications on bioequivalence studies, and only the pooled inter- and intrasubject coefficient of variation for either test or reference formulation is reported. Thus, the essential information for sample size planning of future studies is not made available to other researchers.
The standard approach to the analysis of a two-treatment, two-sequence, two-period crossover trial is an analysis of variance (ANOVA) for the log-transformed pharmacokinetic parameters, where the factors formulation, period, sequence and subject nested within sequence are used to explain overall variability in the observations. The residual coefficient of variation (CV) is a measure of the variability that is unexplained by the aforementioned factors. Among others, within-subject variability, formulation variability, analytical errors, and subject by formulation interaction can contribute to this residual variance.
A drug product is called highly variable if its intra-individual (i.e. within-subject) variability is greater than 30%. A high CV as estimated from the ANOVA model is thus an indicator for high within-subject variability. Only by using a replicate design it is possible to estimate the within-subject variability of the test and of the reference product as well as the subject × formulation interaction. Please have a look at the revised EMA guideline CPMP/QWP/EWP/1401/98 Rev. 1 "If an applicant suspects that a drug product can be considered as highly variable in ist rate and/or extent of absorption, a replicate cross-over design study can be carried out. Those HVDP for which a wider difference in Cmax is considered clinically irrelevant based on a sound clinical justification can be assessed with a widened acceptance range. If this is the case the acceptance criteria for Cmax can be widened to a maximum of 69.84 – 143.19%. For the acceptance interval to be widened the bioequivalence study must be of a replicate design where it has been demonstrated that the within-subject variability for Cmax of the reference compound in the study is >30%. The applicant should justify that the calculated intra-subject variability is a reliable estimate and that it is not the result of outliers. The request for widened interval must be prospectively specified in the protocol."
I hope this helps
Kind regards
Dan