Bioequivalence and Bioavailability Forum

Thank you both for wise counsel!

To add some spice to the situation, this failed pivotal came after a pitch-perfect pilot with GMR ~1, ISCV ~18% (same as in the literature) on a BCS III molecule (although with a nice 2-compartmental kinetics).

The failed pivotal reported a ~27% ISCV, with this bad GMR of ~0.88. You can show outliers with Cook's distance, DFFITS, QQplot etc., but in my practice you can show these things in most studies (even ones which pass) and they should be accepted rather than relied upon in any meaningful way unless you have something damning on the subjects themselves.

The CMC people of course swear that the products from the pilot and the pivotal are practically the same.

My thought is that there is a kind of survival bias at play here. The study was powered at 80%, and we wouldn't be discussing it if it passed. If the study fails, the reported GMR and/or ISCV tends to be bad. Sorry because this may slightly muddle the frequentist and baysean realms

The Armani-pressure is in the other way in this case… and if I take the ISCV and the GMR as read from the failed study I'm looking at 100+ subjects for said molecule and even I start to get nervous

I intend to take the orig. reported ISCVs, treat the failed ISCV as an outlier and dismiss it (I guess Helmut would advise me to pool them based on the chi-sq. distribution), power the new study at 90% with standard 95% theta0 and show the GMR sensitivity plot to the Armani people.

Thanks again, didn't want to leave you guys without an update!