Bioequivalence and Bioavailability Forum

Hi BEQool,

❝ So the sample size with ABEL is always smaller or equal to ABE right (with the same arguments)? Similarly, power for the same number of subjects is always higher (or equal) with ABEL than with ABE (as shown in my reformulated question at the end of the first post or in your example with n=21 for ABE vs. ABEL)?

Exactly. For details see also this article for a comparison of ABE, ABEL, and RSABE.

❝ 1. So in case regulators (EMA region) ask us to calculate post hoc power (regardless of how irrelevant it is) …

Oh dear! EMA region, really‽ Outright bizarre.

❝ … of a study with 2x3x3 design with CVwr=25%, we should calculate it with power.TOST for AUC and for Cmax when we didnt mention anything about widened limits (ABEL) in the protocol (hypothetical scenario)?

Yes because the study was intended to be assessed by ABE.

❝ And on the other hand, for Cmax we should calculate it with power.scABEL when we mentioned widened limits (ABEL) in the protocol?

Correct again.

❝ 2. Another hypothetical scenario: If we get information from the literature about a drug's CVw (Cmax) of around 30% (lets say a range of 25-35%) and if we get a drug's CVw of 22% from our pilot study, can we then do a regular study with design 2x3x3 (in case we get CVw for Cmax 35% so then we could widen the limits and use ABEL)?

Yes, if you state it in the protocol. In general I would trust a – reasonable large! – pilot study more than the literature. The reference may have changed in the meantime, different sampling, bioanalytical method, etc.
BTW, why do you want to use a partial replicate design and not one of the 2-sequence 3-period full replicate designs (TRT|RTR or TRR|RTT)? Acceptable for the EMA (see the Q&A document and this post for examples). Same degrees of freedom and similar sample sizes. More informative because you can also estimate CV_wT, which is useful in designing other studies (quite often CV_wT < CV_wR and you need a smaller sample size). In the partial replicate you have to assume CV_wT = CV_wR, which is often wrong.

❝ And if then our drug's CVw from this regular study is lets say 21%, can agencies ask us to justify replicate 2x3x3 design as if why didnt we use conventional 2x2x2 design if we got CVw=22% in our pilot study?

By ‘regular study’ are you meaning a simple crossover? Even if you observed CV_w ≥30% I would be cautious. That’s only a hint of a highly variable reference. See this article for details.
There is nothing to justify. Any study in a replicate design can also be assessed for ABE. My – former – best enemy once said »From a purely statistical perspective, all studies should be performed in a replicate design.« One of the rare occasions I agree with him.