Bioequivalence and Bioavailability Forum

Dear all,

Long time lurker, first time questioner here! Hi everybody!

A regulatory-reception question rather than a statistical one, but I hope it would still be welcome.

The convention is to drive the BE sample size with an assumed T/R-ratio of 0.95 (lower side, since 1/1.05 = 0.9524 ofc). My read of ICH M13A is that no particular value of theta0 is prescribed, only that the assumption be justified.

The adjacent thread already covers most of the statistical ground, with ElMaestro's view that one simply plugs in the GMR considered realistic plus a worst-case buffer, and d_labes' observation that he has never met a sponsor-desired sample size which failed to find a 'scientific' justification (Armani suit optional). Helmut's own articles default to theta0 = 0.90 for RSABE/ABEL without apology (reminiscent of the two Lászlós recommendations). Among practitioners the matter seems quite settled.

The question is the assessors' side. Has anyone here run into pushback from EU agencies — EMA via DCP/MRP, or national authorities — when an ABE protocol used an assumed deviation larger than 5%, say theta0 = 0.90, outside the HVD/NTID setting? Statistically that is the conservative direction (n inflated, power preserved against a less flattering outcome), and a deficiency on principle would be hard to justify. But principle and practice may differ.

The context, and the reason I am asking: some Central European authorities I deal with routinely question the sample size assumptions in ways that suggest they are overly strict in analysing the a priori assumptions post hoc (regardless of outcome). Rounded ISCVs are contested, back-calculated ISCVs are contested, occasionally one wonders whether anything would not be contested (dropout rate anyone?) We had a recent pivotal that failed with an observed GMR around 0.88, and we are now wondering whether reaching for theta0 = 0.90 in the repeat study is a sensible pre-emptive move or merely an invitation to a different flavour of a deficiency letter. EAEU experience also welcome, though I suspect the relevant adjective there is 'creative' rather than 'consistent'.

Thanks,
Marty