Bioequivalence and Bioavailability Forum

Dear Helmut / All,

❝ I agree that the frameworks of Potvin etc. are purely empirical. To show whether a given α maintains the TIE for a desired range of n₁/CV and target power takes 30 minutes in Power2Stage.

Well, yes, but this is again only empirical.

❝ I’m not sure whether the two lines in Kieser/Rauch fulfill the requirements of a formal proof.

I actually meant the dicsussion on the decision scheme and the properties from Potvin et al (not mathematical theorems and proofs - there are in fact none).

❝ What I don’t understand in GSDs (lacking experience): How do you arrive at N? Is Detlew right when he said that this is the expected sample size?

You can use the sample size from a fixed design and adapt it based on an inflation factor. Addplan for example provides such values (one should however keep in mind that everything in Addplan is based on the Normal approximation). Of course, no one keeps you from further playing around and checking some design properties (as for example the resulting average sample size). A good idea may be to focus on a realistic best guess for the interim CV and so determine n1, and to cover a bad CV scenario via the second stage n2.

❝ Your example would translate to a fixed sample design with GMR 0.95, CV ~44%, and target power 0.8. So the only purpose of the interim is hoping for a lucky punch (i.e., ASN 64)? If the CV is just a little bit higher (50%), power is unacceptable.

In your case the CV is already pretty high and maybe the design properties do not behave so well in those regions? I have not investigated this thoroughly...

❝ If (if!) you have some clue about the variability.

Yes, but when is this not the case? You would not conduct a confirmatory BE study without having performed other PK studies with that substance, would you? You will always have a first in man trial and some bioavailability trials (or historical trials from a comparator).

Regarding the boundaries that Detlew mentioned: It should be based on one-sided bounds. Using directly two-sided can mess things up.

Best regards,
Ben