Comparing methods for (S)ABE [RSABE / ABEL]

posted by Helmut Homepage – Vienna, Austria, 2018-03-01 13:32 (1335 d 14:13 ago) – Posting: # 18489
Views: 8,535

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 Cmax, 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 swR <0.294, mixed effects model irrespective of the design.
  2. EEA, Russia, EEU, Egypt, ANVISA
    ABEL for Cmax (MR products additionally: Cmin, pAUCs), upper cap on scaling at CVwR 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 swT with swR (though no conditions for passing given so far).
  4. Health Canada
    ABEL for AUC, upper cap on scaling at CVwR 57.4%, clinical justification required, mixed effects model. GMR restriction 80.0–125.0%.
    GMR of Cmax within 80.0–125.0% (no CI needed).
  5. GCC member states
    Widening of the acceptance limits for Cmax only (fixed and pre-specified to 75–133%), clinical justification required, CVwR >30% demonstrated in a full replicate design, GMR restriction 80.00–125.00%.
In all methods (except #4: Cmax and #5: assessed by ABE) inflation of the Type I Error is possible.

At the 2nd 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 11
1.41

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

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