What a mess! [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2015-09-23 15:20 (3432 d 13:49 ago) – Posting: # 15460
Views: 17,000

Dear Detlew,

❝ ❝ This is the first example I’m aware of were the observation “HVDs/HVDPs are safe drugs since they have a flat dose/response-curve” seemingly does not hold.

❝ ❝ A dirty story? Wikipedia ...


❝ A really dirty story :vomit:.


Indeed! On another note I don’t understand why the FDA came up with their “BE approach #4”. It would have been sufficient to state “apply the NTID-approach given in the Warfarin guidance”. With the reported CVs (@Shuanghe: Did you ever observe one <21.42%?) downscaling would be unlikely. The sample size would be driven by part of the requirement “must pass 80.00–125.00%”. Sample sizes (80% power, 4-period full rep­li­cate, CVT=CVR):

      expected GMR
 CV    0.90  0.95
0.25    32    18
0.30    40    22
0.35    54    28
0.40    68    34
0.45    84    42
0.50   102    50
0.55   120    60
0.60   140    68

However; I guess the FDA wanted to play it ”safe”. But: Given that for dabigatran no dose-titration and TDM – as for Warfarin – is (falsely?) suggested by Boehringer (despite the observed bleeding-rates!) I would classify it as a NTID and ask even for the EMA’s more strict limits of 90.00–111.11% regardless the variability. Sample sizes (80% power, GMR 0.95, CVT=CVR):

          design
 CV   2×2×2   2×2×4
0.25   258     130
0.30   366     184
0.35   492     246
0.40   630     316
0.45   782     392
0.50   946     474
0.55  1120     560
0.60  1302     652


In this post I linked to Boehringer’s ‘world record’ study. Incidentally it was dabigatran… Unfortunatelly the pranial state was not given (fasting?). Did not pass FDA’s RSABE for total dabi­ga­tran (primary) and conventional ABE for free dabi­ga­tran (secondary).
  Total dabigatran
metric  upper 95% lin. crit.   PE
AUCt     -0.082 (pass; ≤0)   1.2633 (fail; outside 0.8000–1.2500)
Cmax     -0.085 (pass)       1.2549 (fail)

No RSABE-analysis was presented for AUC; failed ABE (90% 118.32–131.51).
  Free dabigatran
metric    PE       90% CI
AUCt    126.22  119.36–133.47 (fail)
AUC∞    124.49  118.11–131.21 (fail)
Cmax    125.30  118.42–132.59 (fail)

The FDA’s 2012 guidance recommended RSABE for free dabigatran only – which was not pre­sented by Boehringer on ClinTrials.gov. Nevertheless, given the PEs of AUCt and Cmax the study would have failed to show RSABE. The highest ISCV was observed for Cmax of free dabigatran with ~48%. Were the primary and secondary targets switched by Boeh­ringer in May 2012 (from free to total dabi­ga­tran)?

My question from above

❝ ❝ How did Boehringer’s formulation “survive” phase III and/or bridging from the formulation used in phase III to the marketed formulation?

still holds. :angry:

I expect that the FDA’s guidance for yet another NOAC (apixaban) will be revised as well.

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