Bioequivalence and Bioavailability Forum

Dear Mittiry,

The results of both compounds are certainly not fully independent, but considering them as such allows to remain on the most conservative side for the sake of sample size estimation.

Most of the time, the counterpart to pay (additional subjects to include to account for duplicity) is not so high.

Taking the post-hoc estimates of the Irbesartan/Hydrochlorothiazide example you shared, the sample size is driven by irbesartan (higher variability and ratio more deviating from unity than hydrochlorothiazide):

Ratio=1.0793, GCV=0.2013, (25 =>) 26 subjects to reach a power of 80%: actual power = 82.6%.

For hydrochlorothiazide (ratio=0.9534 and GCV=0.1531), power = 99.2% with 26 subjects.

So assuming independence, the combined power with N=26 = 0.826 * 0.992 = 81.9%
=> no need to include any additional subject to adjust for the multiplicity issue.

The impact would become more relevant if both compounds have a ratio far from unity and/or high variability.
For instance, for a ratio of 0.85 and a GCV of 0.3, you would need 292 subjects to reach a power of 80% to demonstrate the classical (single-compound) bioequivalence, but (395 =>) 396 subjects (104 additional subjects) for the combined bioequivalence.
Anyway, we are here quite far away from realistic BE scenarios