Bioequivalence and Bioavailability Forum

Hi Winnie,

❝ If the RSABE method is performed on the highly variable drug with the 4-way crossover design (not the NTI drug), is the homoscedasticity assumption always holden?

It’s an assumption. In many cases it was proven outright false (quite often CV_wT < CV_wR). In RSABE (and ABEL as well) regulators are not interested in CV_wT.

❝ And I think if a 3-way crossover design is used, there is no way to assume the homoscedasticity since the test drug is administered once and we can not calculate the WSV of the test drug.

You are right for the partial replicate TRR|RTR|RRT. No problems in the 3-period full replicates TRT|RTR or TRR|RTT.

❝ A further question is, when do we assume the reference and test product have equal variances, i.e. CVwT ≡ CVwR? And why?

If we have only information from a pilot study in a partial replicate design that’s all we can do.
If the true CV_wT < CV_wR, the study will be overpowered, which is economically and ethically questionable. If it will be the other way around, bad luck. See also this article about heteroscedasticity in RSABE and that one for ABEL.