Bioequivalence and Bioavailability Forum

Sorry for my late response.

❝ Oh dear! EMA region, really‽ Outright bizarre.

No no, EMA has not asked this question (yet ). I just wanted to make a hypothetical example and mentioned EMA in order to use ABEL and not RSABE (it is probably not even relevant but anyway).

❝ 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.

Yes it could also be any replicate design (2-sequence 3-period full replicate design or 2-sequence 4-period full replicate designs), 3-sequence 3-period partial replicate design here was just an example.
Nevertheless, a deficiency letter regarding 2-sequence 3-period full replicate design from an European agency was already received (it was answered successfully) so 3-sequence 3-period partial replicate design is now used sometimes instead.

❝ 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.

My bad, I meant a pivotal study. I wanted to ask if agencies can ask you to justify using any replicate design when the drug's CVw in the study is for example around 20% - but you already answered that below.

❝ 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.

Thank you for the answers, everything is clear now.

BEQool