Bioequivalence and Bioavailability Forum

Dear Detlew,

❝ this is a very eminent important post .

THX. Was mainly a kind of self-defense. If such an idea pops up in the future, I would just link to this post.

❝ ❝ […] we still need 10⁵ simulations within every simulated study. This leads to ~10¹⁴ (110,000,000,000,000‼) simulations overall.

❝

❝ This is an optimistic (sic!) estimation […]

❝

❝ So let us estimate more pessimistically (but may be too optimistically) an additional factor of 4 (one for the power monitoring step + 3 for the sample size estimation) within each of the simulations […]

At least for “Type 1” designs, you need only one step – as you ingeniously have implemented it in Power2Stage. An estimated total sample size ≤ n₁ implies power ≥ target.

❝ Just to make your message crystal clear!

Yep. Whether it takes five or fifty years makes no difference in practice. It simply takes too long.

❝ If this all is necessary to be really done for a certain regulatory body (which one remains my secret ) remains an open question. As elsewhere said: Regulators are a bunch of strange people.

I think that it is justified if regulators ask for demonstration that the TIE is maintained. That’s their job.
Sponsors should learn that Two-Stage Design are not the jack of all trades device (<span lang="de"> „eier­le­gen­de Woll­milch­sau” </span>) as they inadvertently believe. TSDs are fine in ABE to deal with an uncertain CV. This is not necessary if we apply scaling – which inherently takes care of higher than expected variability. If a study is powered for ABE, everything should be OK (well, cough, inflation in ABEL/RSABE – another story).
Like in ABE the nasty thing is the ratio…