Bioequivalence and Bioavailability Forum

Hi ElMaestro,

❝ It gets a little tricky if applicants specify that a successful pilot must be accepted as a pivotal, which happens and is ok with some authorities.

Haven’t thought about that! Definitely OK for the FDA (even mentioned in the guidance). Was OK in some European countries (esp. Scandinavia, Germany, Austria). Assessors of a certain southwestern peninsula essentially said:

“Thanks for showing us the GMR and CV. Nice to see such a narrow CI, although that wasn’t the purpose of the study. Now please go ahead and perform the pivotal study based on an appropriate sample size estimation.”

No idea about the current practice.*

❝ Success at the pilot sage is in itself rare though.

Not that rare. For 0.943 ≤ T/R ≤ 1.06 and CV 15% a study with n=12 likely will pass (power 80.2%).

❝ In such a situation alpha speculation may be relevant due to type I errors.

Still I don’t get it. If a pilot “passes” BE I think it should be possible to state in the protocol the intention to submit the study as pivotal evidence. Would make sense if the CV is already expected to be low and/or the GMR close to 1. No adjustment necessary, IMHO. Whether peninsulists would accept that is another story.

❝ I am fairly sure a reviewer would raise the point if a paper is submitted. Especially if it ends up in hands of people who have reviewed Potvin's paper and the sequelae.

If you have Method C in mind, yes.

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• Might well be that the sample size estimation based on the pilot’s CV will suggest us to run the pivotal study in less subjects than the pilot.