Bioequivalence and Bioavailability Forum

Dear Andrew!

❝ My data manager tells me that SAS will not allow sequence to be dropped from the regression (mixed effects?) model.

❝

❝ We've thus fallen at the first hurdle...

No, your horse refused to jump the first fence, unseating the rider.

Try a conventional 2×2 without sequence: The CI (T/R) should be exactly the same.
In a 2×4 replicate I get differences in the 6^th significant figure.
In the EU you have to stick with EMA's crippled model anyhow.

BTW, you are not the first asking this question.
What you can do, is start with EMA's suggestion (throw away all test data), and recode periods to "occasion":
In sequence RTRT period 1 => occasion 1, period 3 => occasion 2
In sequence TRTR period 2 => occasion 1, period 4 => occasion 2
Set up a model with fixed effects occasion+subject, estimate "occasion 2-1"
With EMA's dataset I get (back-transformed):
Occasion 1: 2032, Occasion 2: 2249
Occasion 2/1: 110.64% (90% CI: 97.74 - 125.24%), CV 47.32% (which is identical to FDA's - referred by EMA as Method C).