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Back to the forum  Query: 2017-11-22 17:36 CET (UTC+1h)
 
nobody
Senior

2017-07-13 15:13

Posting: # 17537
Views: 945
 

 FDA BE Guide Warfarin – never used? [Regulatives / Guidelines]

Hy again!

Wanted to have a look on some real-life data re. FDA Warfarin BE Guidance - and found no MA later than 2011 and nothing with PAR published on FDA homepage. Surprise!

Does anyone have a list of other FDA individual BE guides on hand referring to the methods specified in the warfarin guideline? (Google didn't find anything for me...).

Many thanks in advance

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2017-07-13 16:53

@ nobody
Posting: # 17538
Views: 835
 

 FDA BE Guide Warfarin – never used?

Hi nobody,

» […] a list of other FDA individual BE guides on hand referring to the methods specified in the warfarin guideline? (Google didn't find anything for me...).

:google: ⇐ click!

Not a list but have a look at tacrolimus, sirolimus, levothyroxine, valproic acid, carbamazepine, and two other anticoagulants, rivaroxaban and dabigatran.
For dabigatran I expect never ever a “level 3 change” or any generic, since this stuff is highly variable. THX to Boeh­ringer to have this crap on the market.

[image]Regards,
Helmut Schütz 
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The quality of responses received is directly proportional to the quality of the question asked. ☼
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nobody
Senior

2017-07-13 19:00

@ Helmut
Posting: # 17540
Views: 814
 

 FDA BE Guide Warfarin – never used?

Hi Vienna!

Thanks a lot for making it googlable for me! :-)

Unfortunately even for this broader range of compounds I couldn't find any data at the FDA. Maybe it's tooooo new after all.

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2017-07-13 19:54

@ nobody
Posting: # 17541
Views: 810
 

 Sample sizes are not prohibitive

Hi to the North!

» […] Maybe it's tooooo new after all.

Maybe. Sample sizes are not that bad. The FDA requires tighter release spec’s. Hence, we implemented 0.975 as the default in PowerTOST.

library(PowerTOST)
CVwR <- 0.1 # e.g., Cmax of valproic acid (AUC has ~0.05).
s.r  <- 1   # ratio of swT/swR
CVwT <- mse2CV(CV2mse(CVwR)*s.r)
sampleN.NTIDFDA(CV=c(CVwT, CVwR), details=FALSE)

+++++++++++ FDA method for NTID's +++++++++++
           Sample size estimation
---------------------------------------------
Study design:  2x2x4
log-transformed data (multiplicative model)
1e+05 studies for each step simulated.

alpha  = 0.05, target power = 0.8
CVw(T) = 0.1, CVw(R) = 0.1
True ratio     = 0.975
ABE limits     = 0.8 ... 1.25
Regulatory settings: FDA

Sample size
 n     power
18   0.841790

No problem.

Now swT∕swR 2.

s.r  <- 2
CVwT <- mse2CV(CV2mse(CVwR)*s.r)
sampleN.NTIDFDA(CV=c(CVwT, CVwR), details=FALSE)

+++++++++++ FDA method for NTID's +++++++++++
           Sample size estimation
---------------------------------------------
Study design:  2x2x4
log-transformed data (multiplicative model)
1e+05 studies for each step simulated.

alpha  = 0.05, target power = 0.8
CVw(T) = 0.1417745, CVw(R) = 0.1
True ratio     = 0.975
ABE limits     = 0.8 ... 1.25
Regulatory settings: FDA

Sample size
 n     power
28   0.817760

Still easy.

Boehringer’s formulation change. The family’s slaves planned for T/R 0.85 (tried at lot, couldn’t do better), a CVwR of 80%, and RSABE (old guidance). That’s the infamous 4-period full replicate study in 180 subjects on ClinicalTrials.gov.
Nowadays:

sampleN.NTIDFDA(CV=0.8, theta0=0.85, details=FALSE)

+++++++++++ FDA method for NTID's +++++++++++
           Sample size estimation
---------------------------------------------
Study design:  2x2x4
log-transformed data (multiplicative model)
1e+05 studies for each step simulated.

alpha  = 0.05, target power = 0.8
CVw(T) = 0.8, CVw(R) = 0.8
True ratio     = 0.85
ABE limits     = 0.8 ... 1.25
Regulatory settings: FDA

Sample size

   power
836  0.800870

Oops.

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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nobody
Senior

2017-07-13 20:12

@ Helmut
Posting: # 17542
Views: 800
 

 Sample sizes are not prohibitive

» ...planned for T/R 0.85 (tried at lot, couldn’t do better), a CVwR of 80%,...

Picked from the PAR? :-)

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2017-07-13 20:36

@ nobody
Posting: # 17544
Views: 793
 

 Sample sizes are not prohibitive

Hi nobody,

» ...planned for T/R 0.85 (tried at lot, couldn’t do better), a CVwR of 80%,...
»
» Picked from the PAR? :-)

No. Heard from the poor guy who planned the study. :-D

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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