Bioequivalence and Bioavailability Forum

Hi Pjs,

your considerations are essentially correct. OK, a little bit theoretical because in all jurisdictions we need the respective region’s reference product. But yes, if we consider the same data set, the conclusions might differ if we apply different reference-scaling methods – especially in borderline cases.

What do we have now?

1. US-FDA, CFDA
   RSABE for both AUC and C_max, no clinical justification required, fixed effects model for the partial replicate design and mixed effects model for full replicate design. GMR restriction 80.00–125.00%. If s_wR <0.294, mixed effects model irrespective of the design.
   
2. EEA, Russia, EEU, Egypt, ANVISA
   ABEL for C_max (MR products additionally: C_min, _pAUCs), upper cap on scaling at CV_wR 50%, clinical justification required, fixed effects model. GMR restriction 80.00–125.00%.
   
3. WHO
   Like #3. Pilot phase for AUC. 4-period full replicate design man­datory, comparison of s_wT with s_wR (though no conditions for passing given so far).
   
4. Health Canada
   ABEL for AUC, upper cap on scaling at CV_wR 57.4%, clinical justification required, mixed effects model. GMR restriction 80.0–125.0%.
   GMR of C_max within 80.0–125.0% (no CI needed).
   
5. GCC member states
   Widening of the acceptance limits for C_max only (fixed and pre-specified to 75–133%), clinical justification required, CV_wR >30% demonstrated in a full replicate design, GMR restriction 80.00–125.00%.

In all methods (except #4: C_max and #5: assessed by ABE) inflation of the Type I Error is possible.

At the 2^nd International Conference of the Global Bioequivalence Harmonization Initiative (Rockville, Sep 2016) an entire session was devoted to reference-scaling. No consensus reached. On the contrary. Each agency defended its concept as if it is an eternal truth. Disappointing.

BTW, we have lacking harmonization even in ABE. For NTIDs the EMA’s acceptance range is 90.00–111.11%, whereas for Health Canada it is 90.0–112.0%.

library(PowerTOST)
round(100*CI.BE(pe=1.05, CV=0.12, n=24), 2)
 lower  upper
 98.96 111.41

The same study would fail for the EMA but pass for HC.