Bioequivalence and Bioavailability Forum

Hi Silva,

THX for the !

❝ A question that I've been tried to understand is that in a partial replicate design (for EU Scaled Average BE), is it possible to use 2 sequence (RTR and TRR, for example)

Well, that’s the so-called “extra-reference design” (a conventional 2×2 cross-over with an additional period where only R is administered). There are some publications (dealing with PBE/IBE) and it is covered in Chow/Liu – I guess. See also this post. I don’t like it because T is never administered in period 3; personally I haven’t seen one in the context of RSABE yet. If you want to opt for three periods, I would suggest a fully replicated design instead: RTR|TRT (we get not only CV_WR, but CV_WT as well – nice to know).

❝ or the study has to be design in a 3 sequence (RTR, TRR and RRT, according to FDA's progesterone example or according to data set on EMA Q&A document)?

EMA doesn’t recommend a specific design in the GL (3- or 4-period replicates are acceptable). IMHO, the codes in the Q&A are just examples.

❝ Does Phoenix enable a correct estimation of within subject variability and the calculation of the 90% CIs with this study design, or only SAS is possible to be used?

We have cross-validated RTRT|TRTR and RTR|TRR|RRT in Phoenix/WinNonlin against SAS. See my whitepaper. Recently we showed how to use templates, which is much more comfortable.* Download the examples for PHX/WNL v6.3 here (sorry, 20.9MB…).
When it comes to RTR|TRR: Like the partial replicate it might be problematic, since T is not replicated. However, since EMA’s model is “crippled” you would not face problems like with FDA’s mixed-effects model (if CV_WR <30%). You can use the code in the Q&A document without modifications (both in SAS and PHX).

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• Henry A, Schütz H, Hughes L, Davis S. Performing Reference-Scaled Average Bioequivalence (RSABE) in Phoenix^® WinNonlin^®. AAPS Annual Meeting (November 12, 2013), Poster: T2350.
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