Bioequivalence and Bioavailability Forum

Hello all!

Lately I have been reading about Two-Stage Sequential (Potvin method B) Designs and I have some questions.

1. If we dont pass BE in the first stage, why do we have to assume a fixed GMR (i.e. 95% - same as before the 1st stage) when doing sample size estimation for the 2nd stage? Why dont we just use the observed GMR from the 1st stage? Because TIE would increase?
Has anyone ever gone into the 2nd stage with sample size estimation based on observed GMR from the 1st stage and the agency accepted it without any objections?
Additionally, if we use fixed GMR for both stages, can we also use GMR for example 92% from the beginning (not exactly GMR=95%)?

2. I understand the difference between Group Sequential Designs and Adaptive Two-Stage Sequential Designs, but I have troubles understanding what exactly are Add-On Designs. Here Add-On Designs are defined as "Sample sizes of both groups have a lower limit." Could anyone please explain what this exactly means?

3. And the last question, according to this slide there are currently no Two Stage Sequential methods for replicate designs and designs with 2 formulations.
a) why cant we use Two-Stage Sequential design for replicate designs (for example 2x2x3)? I assume you have to use the same design in both stages (in 1st and 2nd), but other than that, why cant we use it (using adjusted alpha of course)?
b) regarding 2 formulations, so there is no way to go into the study with 2 test formulations and then choose the best one to go into the 2nd stage if we dont pass the BE in the 1st stage? Of course alpha should be adjusted both for 2 test formulations and one interim analysis - so I would say Bonferroni (most conservative) alpha correction with alpha 1.667% (3 hypotheses) or alpha 1.25% (4 hypotheses) should be used?

Thank you and best regards
BEQool