Bioequivalence and Bioavailability Forum

Dear HS,

❝ Yes; see this post for TRT/RTR (75% of TR/RT) and TRRT/RTTR (50% of TR/RT).

❝ No idea about TRR/RTT...

as I have understood until now all 3 period and all 4 period replicate designs, regardless of which sequences are used, have the same variance of the treatment effect namely
   3 period : 3/8*s2/N
   4 period : 1/8*s2/N

if no carry-over term is incorporated in the model.

Compared to the common 2x2 design with variance
   1/2*s2/N
you get your mentioned 75% or 50% respectively.

See for that
Jones and Kenward
Design and Analsis of Cross-over Trials
Chapter 3

Only if a carry-over term (as simple carry over in different flavors) or other interaction terms are introduced in the model different variances arose for the different designs.

Regarding the carry-over (and the model for simple carry-over) I adopt SENN's position: With an adequate wash-out period an standardization of the study it is futile in BE studies.
Interesting enough there is no teensy-weensy attempt of incorporation of carry-over in the FDA code for analysing average BE in replicate designs.

Thus IMHO we have always the same sample size estimation formula for 3 or 4 period replicate designs.