Bioequivalence and Bioavailability Forum

❝ How can we find outlier? which one will be appropriate scenario for any regulatory point of view?

• EMA and others following its ABEL method:
  An outlier test is not acceptable. Have to justify that the estimated CV_wR (driving the expanded limits) is not caused by outliers. Aha. Can be explored by box plots of studentized residuals of the EMA’s model. Some people set the limits to 2×IQR. If outliers are detected, remove them and recalculate CV_wR. However, the analysis has still to be done with the complete data set (the outlier is not removed). Since the expanded limits will be narrower you shoot yourself in the foot.
  
• FDA:
  No way.
  
• Health Canada:
  See the guidance (Sections 2.3.5 and 2.7.4.1). Outliers can be completely removed from the data set if
  • identification is performed before the BE assessment (i.e., no CIs calculated already),
    
  • the studentized model residual is outside {–3, +3} (irrespective whether T or R),
    
  • identified for all PK metrics (that’s a big obstacle, especially if one has to deal with partial AUCs of multiphasic products),
    
  • not more than 5% of subjects (or only one subject if the sample size is 20 or lower),
    
  • the procedure is stated unambiguously in the protocol.