Bioequivalence and Bioavailability Forum

Hi John,

❝ Can someone educate me on how FDA chose a value of 0.10 to sigma w0 as the regulatory constant for the scaled reference BE analysis for an NTI drug (see warfarin BE guidance)? I kind of understand why they chose 0.25 for sigma w0 for HVDs but I don't get the reason for NTI.

To harmonize with the EMA’s (fixed) acceptance range for NTIDs of 90.00–111.11%? There is some empiric evidence that it “worked” on this side of the pond.
Guidelines of 1992 and 2001:

“In specific cases of a narrow therapeutic range the acceptance interval may need to be tightened.”
(No numbers, but case by case; 90.00–111.11% was commonly applied.)

2010:

“In specific cases of products with a narrow therapeutic index, the acceptance interval for AUC should be tightened to 90.00-111.11%. Where C_max is of particular importance for safety, efficacy or drug level monitoring the 90.00-111.11% acceptance interval should also be applied for this parameter.”

Don’t forget HC’s 90.0–112.0% for AUC (since 2006).

❝ According to the presntation and literature from FDA, 0.1 represents a CV of ~10%.

Yep.

\(\sigma_0 = 0.1 (CV \sim 10.03\%)\)
\(\theta_s = \log{(1.11111)}/\sigma{_{0}}^{2} = 1.11006\ldots\)
\(\sigma_{wR} = \sqrt{\log{(CV_{wR}^{2}+1)}}\)
\([L, U] = e^{\mp \log{(1.11111))\cdot \sigma_{wR} / \sigma_0}}\)

Therefore, at CV_wR 10.03% the scaled AR is 90.00–111.11%. Since this scaling will result in limits wider than the conventional 80–125% for CV_wR >21.42% the additional criterion “must pass 80–125%” is part of the method. See also this presentation.