Bioequivalence and Bioavailability Forum

Hi Helmut,

❝ This proposed final sample size should be

❝ recruited if the estimation obtained from the

❝ interim analysis were lower than the one predefined

❝ in the protocol in order to keep the

❝ consumer risk.

❝ What puzzles me here is the “proposed final sample size”. I don’t understand why performing the stage in a smaller sample size should violate the consumer’s risk. The contrary was already demonstrated by Potvin et al. with Method B.

You're completely right. In addition, if one follows the Potvin method with good result and gets RMS support then I think it will be very, very difficult for another EU regulator to defend a PSRtPH at CMDh or CHMP on basis of something like the above idea when nothing about it has been published. I am saying this not on basis of regulations (there aren't any due to EU's national sovereignty preservation) but on basis of practical experience.
Potvin showed that under her framework type I errors are preserved at 5% when the final sample size floats freely. If we tamper with final sample size like proposed above, the average sample size will inevitably go up as may power consequently. This means that we may be exposing more volunteers to IMPs than we would have done under Potvin even with preserved type I error rates. This can certainly be argued to be unethical. And due to the literal quote above it is not readily easy for a regulator to argue that it is the extra little power that is the true advantage.
I'll be happy to take the challenge

Now back to the compiler. I need to recharge my dilithium crystals.