Two-stage design and 'forced bioequivalence' [Two-Stage / GS Designs]

posted by ElMaestro  – Denmark, 2018-06-06 12:53 (2236 d 02:41 ago) – Posting: # 18855
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Hi Mikalai,

❝ We plan to conduct a sequential (two stage) BE study, and I am concerned with "forced bioequivalence". Specifically, if we obtain non-equivalent results in the first stage with very low power and should recruit more volunteers, how can we protect ourselves from getting into "forced bioequivalence"? In other words, how can we differentiate between underpowered trials and non-equivalent results in the sequential BE? And how can we put this (protection against "forced bioequivalence") in the protocol not to raise many questions from regulators?

If you use one of the Potvin variants (and you will do that, no discussion:-D) then forced bioequivalence is not your biggest issue.
Bear in mind that your "very low power" is still based on a fixed GMR of e.g. 0.95, not on the observed GMR. I don't think it is a good idea to fiddle with the Potvin-like decision trees. I mean, if you do a little, minor, innocent modification without running a series of tests for power, sample size and type I error, then all manners of hell can break loose on you. I have seen it several times now.
Forced BE is not a term that is widely adopted from the regulatory side. If the (true) GMR is within 80.00-125.00 then in principle you have a product for which you can one way or another show BE and which can be approvable. Obviously you will never know the true GMR, only you can estimate it through observations which have a variance, hence the need for a CI.
Your two-stage approach is great if you are certain about the GMR (close to 100%) and uncertain about the CV. If you are not convinced that you have a good GMR, then lay your hands off the two-stage approach. Run like hell. It will 'on average' not work well for you. :-)

Pass or fail!

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