Bioequivalence and Bioavailability Forum

Hi Shuanghe,

❝ In the "additional comments" of the same FDA guidance, they tell us in order to apply the scaled method the criterion is "within-subject variability ≥ 30%)", so clearly here the variability is not equal to variance since you need to do sqrt(exp(s2w) - 1) to get it.

Yep, sloppy as usual.

[…] please provide evidence of high variability […] (i.e., within-subject variability ≥ 30%).
If s_wR ≥ 0.294, use the reference-scaled procedure to determine BE for the individual PK parameter(s)

\(\sqrt{\log(0.294^2) + 1} = 0.2935604 \ldots {\color{Red} \neq} 0.294\)
\(100\sqrt{e^{0.294^2}-1} = 30.04689\ldots\% {\color{Red} \neq} 30\%\)
Who cares about the fourth significant digit…

Regulators love simple numbers.
What does the EMA tell us? The switching variability is clearly defined as CV_wR 30% (based on the paper of the two Lászlós). That would translate into a regulatory σ₀ of 0.29356… and a switching condition \(\theta_s = \log(1.25)/\sigma_0 \equiv -\log(0.80)/\sigma_0 = 0.760128 \ldots\) Well, what do we have to use? 0.760. IIRC, Panos Macheras complained about it in one his papers about reference-scaling.

Picky: In code assessing ABEL (SAS, Phoenix/WinNonlin) only the 90% CI should be rounded to two digits, not the expanded limits themselves. Otherwise a discontinuity will appear close to CV_wR 50%: