Bioequivalence and Bioavailability Forum

Hi bebacrk,

❝ But in full replicate design if subject found outlier in particular period for Cmax and AUC parameters of Swr calculation, shall we remove that particular period data from PK & Statistical analysis or from entire study periods?

❝ can you please mention what are the scenarios we can fallow for Canada full replicate design to exclude the subject from pharmacokinetic and statistical analysis.

The Guidance Document: Conduct and Analysis of Comparative Bioavailability Studies of 2018 contains Section 2.3.5 about outliers. However, I was wrong above, saying

❝ ❝ […] Section 2.3.5 of Health Canada’s guidance is still applicable

because in the Notice to stakeholders – Implementation of ICH M13A: Bioequivalence for immediate release solid oral dosage forms of 2025 we find:

All sections of this guidance remain applicable […] with the exception of Section 2.3.5. In order to harmonise ap­proach­es, Sec­tion 2.3.5 is superseded by the ICH M13A guideline.

(my emphasis)
IMHO, that’s ambiguous at least. ICH M13A (no outlier assessment) deals only with 2×2 cross-over and parallel designs, whereas HC’s 2018 guidance also with replicate designs and reference-scaling for AUC.
So does that mean that outlier assessment is not applicable for these studies (covered in the upcoming ICH M13C) as well? 

Nothing is stated about outliers in the Supplement to the Concept Paper to ICH M13C of 2025. I don’t know whether the M13 EWG will discuss it at all. Currently in jurisdictions applying ABEL – except Chile and Brazil – it has to be demon­strat­ed that the high variability of the reference is not caused by outliers. No outlier assessment has to be performed for RSABE (US FDA and China’s CDE).