Bioequivalence and Bioavailability Forum

Hi Dan,

❝ My question for today: is this still the case/state of science that you can not combine 2-stage and replicate designs?

Yes.

❝ A short update would be very much apreciated. In case that there is new literature available I would love if you could give references.

Though I’m deeply involved in this kind of stuff I even don’t know anybody working on it.

If we take the GL literally

“The plan to use a two-stage approach must be pre-specified in the protocol along with the adjusted significance levels to be used for each of the analyses.”

the blue part is the show-stopper.
It’s even worse than a year ago. Do you remember this post? Since many decisions have to be taken into account in the EMA’s ABEL (CV_wR >30%? CV_wR >50%? GMR within 80.00–125.00?) this method itself may lead to an inflation of the type I error. The latest release of PowerTOST contains two functions which iteratively adjust α in such a way that the TIE is preserved: scABEL.ad() for the adjustment and sampleN.scABEL.ad() for the sample size. With this algo on the average you need four iterations to get the adjusted α. Hence, multiply the runtimes given at the end of this post by four…

If (‼) you succeed in convincing regulators that a pre-specified α is not necessary (te-hee) but can be estimated based on stage 1 data, it should be doable (runtime a couple of minutes at the most). Given the EMA’s skepticism concerning TSDs in general (see this post) IMHO, chances are close to nil.