Bioequivalence and Bioavailability Forum

Dear ElMag!

❝ As per the EMA Bioequivalence guideline, under section 4.1.10 on Highly Variable Drugs, it is depicted that the applicant should justify that the calculated intra-subject variability for the Cmax of the reference product is a reliable estimate and that it is not the result of outliers.

❝ What we would therefore like to enquire is what statistical test could be used (and is perhaps accepted from the authorities as per your experience?) in order to demonstrate that the calculation of the intra-subject variability is in fact a reliable estimate and that outliers have not been included in the aforementioned calculation.

EMA was asked this question last June to no avail. We are still waiting for the clarification document. I spoke to members of the PK-group last week in Barcelona: The document is already finalized and has to go through the mills of EMA's bureaucracy in order to get published.

❝ Would it be possible to use WinNonlin for this purpose?

WinNonlin (up to the last version 5.3) - no.
In Phoenix/WinNonlin 6.1 at least you get the model's studentized residuals. But actually we are interested in the intra-subject residuals, which are not available.
Let's see what the next release (6.2) announced by the end of March will have to offer…

❝ Or perhaps SPSS or SAS?

SPSS no idea. For SAS see the reference in this post. For a reference about outliers in 2×2 cross-overs see this post. Hotelling's T² is implemented in package bear for R.