Bioequivalence and Bioavailability Forum

Dear MGR,

in a three-period replicate design (e.g. TRT/RTR) you get not only CV_intra (like in a 2x2 cross-over), but also the reference's (and test's) variability - which may be used in Reference Scaled ABE. Similarly in a four-period replicate design (e.g. TRTR/RTRT) you get the variability of both formulations, which may be used in Population and Individual BE.
Even in a conventional evaluation (ABE) of a replicate study, you are less prone to be hit by outliers. If a subject shows an irregualar response to a treatment compared to the rest of the study's subjects in one period only, you have strong evidence that a subject-by-formulation can be excluded. Sometimes FDA allows exclusion of the subject in such a case (the EU is more strict in this respect).

If you want to go with an extended acceptance range for C_max (0.75-1.33) in the EU, you must demonstrate high variability of the reference in a replicate design pilot study (Q&A document):
8. What is a "highly variable drug or drug product?"
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. However, a replicate design is needed to assess within-subject variability.

Regards,
Hermann