Bioequivalence and Bioavailability Forum

Hi ElMaestro,

❝ FDA updated the canonical BE guideline for ANDAs.

THX, had a quick look.

❝ Draft.

What else…

Main difference is that reference-scaling is detailed and not just mentioning the progesterone guidance in a footnote – like in the  draft of 2013. Interesting difference:

Progesterone guidance

\(\small{\text{a. the 95% upper confidence bound for }\left(\widehat{Y}_T-\widehat{Y}_R\right)^2-\theta s_{wR}^2\text{ must be}\leq 0}\)

New ANDA draft

\(\small{\text{a. The 95% upper confidence bound for }\left(\widehat{Y}_T-\widehat{Y}_R\right)^2-\theta s_{wR}^2\text{ must be}\leq 0}\)
\(\small{\;\;\;\;\text{(numbers should be kept to a minimum of four significant figures for comparison).}}\)

(my emphasis)
We had a few discussions about rounding in RSABE in the past (here and there).

In both guidances the formula is confusing. The regulatory limit \(\small{\sigma_\textrm{w0}=0.25}\) leads to the regulatory constant $$\small{\theta_\textrm{s}=\frac{\log_{e}1.25}{\sigma_\textrm{w0}}=0.89257\ldots}$$Furthermore, we need the standard error \(\small{s_\textrm{d}}\) of the point estimate \(\small{PE=\widehat{Y}_\textrm{T}-\widehat{Y}_\textrm{R}}\) given by $$\small{s_\textrm{d}=\sqrt{\frac{MSE}{seq^2}\sum{\frac{1}{n_i}}},}$$ where \(\small{MSE}\) is the residual Mean Squares Error, \(\small{seq}\) the number of sequences, and \(\small{n_i}\) are the number of subjects in sequence \(\small{i}\). According to the SAS-code (without an explanation) \(\small{s_\textrm{d}}\) acts as a bias correction and therefore,$$\small{crit=PE^2-s_\textrm{d}^2-\theta_\textrm{s}^2\cdot s_\textrm{wR}^2.}$$ Reference-scaling for NTIDs is also outlined. Again, a statement about rounding (contrary to the warfarin guidance).