Bioequivalence and Bioavailability Forum

Hi Achievwin,

❝ 1) is there a precedence of conducting two stage study for 4-period full replicate design? (four periods in stage 1 and stage 2)

I have seen one since 2010. Not for RSABE but for the EMA’s ABEL. Asymmetric alphas – don’t remember which approach: Haybittle-Peto (0.001/0.049) or O’Brien/Fleming (0.005/0.048). Even in a 2×2×2 crossover TSD there is an inflated Type I Error. This study ended in a – vested – deficiency letter of the MHRA.

“The applicant has to demonstrate that the patient’s risk is controlled.”

Oops!

❝ 2) what kind of penalty we can factor in?

That’s not the point and should be the least of your worries. Unless you have a magic wand providing you with a suitable adjusted α, no way.
Did you bother to read that (already linked in my previous post)?