What a mess! [Regulatives / Guidelines]
❝ ❝ 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 .
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
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?

I expect that the FDA’s guidance for yet another NOAC (apixaban) will be revised as well.
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png)
Helmut Schütz
![[image]](https://static.bebac.at/img/CC by.png)
The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Complete thread:
- New D. Guidance – Dabigatran jag009 2015-09-21 23:19 [Regulatives / Guidelines]
- New D. Guidance – Dabigatran nobody 2015-09-22 11:04
- The FDA’s fourth BE approach! Helmut 2015-09-22 11:43
- The FDA’s fourth BE approach! nobody 2015-09-22 13:06
- The FDA’s fourth BE approach! Helmut 2015-09-22 13:25
- The FDA’s fourth BE approach! Yada Yada Yada jag009 2015-09-23 20:29
- Yucky… Helmut 2015-09-23 22:06
- The FDA’s fourth BE approach! Yada Yada Yada jag009 2015-09-23 20:29
- The FDA’s fourth BE approach! Helmut 2015-09-22 13:25
- The FDA’s fourth BE approach! d_labes 2015-09-22 14:08
- New PowerTOST function(s) Helmut 2015-09-22 14:27
- New PowerTOST function(s) d_labes 2015-09-22 14:59
- Pradaxa = HVDP (dabigatran = HVD?) Helmut 2015-09-22 15:16
- Pradaxa = HVDP (dabigatran = HVD?) Shuanghe 2015-09-22 16:53
- Highly variable NTID d_labes 2015-09-23 08:23
- What a mess!Helmut 2015-09-23 13:20
- Messy numbers - PowerTOST V1.3-01 preview d_labes 2015-09-24 09:18
- What a mess! Shuanghe 2015-09-25 16:32
- What a mess!Helmut 2015-09-23 13:20
- Pradaxa = HVDP (dabigatran = HVD?) Helmut 2015-09-22 15:16
- New PowerTOST function(s) d_labes 2015-09-22 14:59
- OT: power.NTIDFDA() Helmut 2015-09-23 00:10
- OT: power.NTIDFDA() d_labes 2015-09-23 09:37
- New PowerTOST function(s) Helmut 2015-09-22 14:27
- The FDA’s fourth BE approach! nobody 2015-09-22 13:06
- The FDA’s fourth BE approach! Helmut 2015-09-22 11:43
- New D. Guidance – Dabigatran nobody 2015-09-22 11:04