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RegisterSurprise? [Two-Stage / GS Designs]
Dear Helmut, dear GSD!
This is not a surprise if you think twice.
Compare GSD's values with figure 4 from the paper of the two Laszlos
Tothfalusi, Endrenyi
"Limits for the scaled average bioequivalence of highly variable drugs and drug products"
Pharm. Res. Vol.20, 382-389 (2003)
![[image]](img/uploaded/image35.jpg)
Open symbols are the scaled ABE simulations.
Despite the fact that they have simulated 2x2 cross-over studies and used sigma0 = 0.2 the qualitative behaviour resembles the numbers given by GSD.
To have an empirical alpha IMHO it is indeed necessary to simulate studies at an GMR which is identical with the widened acceptance limits dependent on the CV used for the simulation.
This is irrespective of the fact that we use the sample CV for widening the BE limits in the evaluation of each study. In simulating with a certain CV we know it and therefore we know also the inequivalence margins that would apply for the population.
We act the same way in case of normal ABE simulating with an GMR at the BE limit 1.25 (or 0.8) but use the sample point estimate in evaluation of each simulated study.
❝ ❝ Let’s just start with the usual 1-stage design with a full replicate model and consider EMA scaling. If I simulate as above, I get an empirical type I error of 5.1%, 8.5% 25.4%, 36.9%, 47.1% and 49.8% for CVs of 10%, 30%, 35%, 40%, 50% and 70% respectively. (The sample size that I used in each case was powered at 80%).
❝
❝ Terrible – and surprising.
This is not a surprise if you think twice.
Compare GSD's values with figure 4 from the paper of the two Laszlos
Tothfalusi, Endrenyi
"Limits for the scaled average bioequivalence of highly variable drugs and drug products"
Pharm. Res. Vol.20, 382-389 (2003)
Open symbols are the scaled ABE simulations.
Despite the fact that they have simulated 2x2 cross-over studies and used sigma0 = 0.2 the qualitative behaviour resembles the numbers given by GSD.
To have an empirical alpha IMHO it is indeed necessary to simulate studies at an GMR which is identical with the widened acceptance limits dependent on the CV used for the simulation.
This is irrespective of the fact that we use the sample CV for widening the BE limits in the evaluation of each study. In simulating with a certain CV we know it and therefore we know also the inequivalence margins that would apply for the population.
We act the same way in case of normal ABE simulating with an GMR at the BE limit 1.25 (or 0.8) but use the sample point estimate in evaluation of each simulated study.
—
Regards,
Detlew
Regards,
Detlew
Complete thread:
- Potvin’s 2-stage adaptive design GSD 2012-08-17 20:56 [Two-Stage / GS Designs]
![[Mix]](https://static.bebac.at/img/mix.png "open in Mix view")
- Potvin’s 2-stage adaptive design + RSABE/ABEL Helmut 2012-08-18 00:39
- Potvin’s 2-stage adaptive design + RSABE/ABEL GSD 2012-08-31 16:30
- Tough job Helmut 2012-08-31 18:37
- Tough job GSD 2012-08-31 19:23
- C/D for EMA? Good luck! Helmut 2012-09-01 15:09
- Surprise?d_labes 2012-09-05 12:57
- Got it. Ages for sims to complete Helmut 2012-09-05 13:35
- Tough job GSD 2012-08-31 19:23
- Tough job Helmut 2012-08-31 18:37
- Power for Two stage Design K2K 2013-10-07 14:43
- Power for Two stage Design Helmut 2013-10-07 14:59
- Power for Two stage Design K2K 2013-10-08 14:35
- “Interim power” Helmut 2013-10-08 14:58
- “Interim power” K2K 2013-10-09 12:39
- Validation of PowerTOST Helmut 2013-10-09 14:10
- Phoenix/WinNonlin - power d_labes 2013-10-09 16:11
- Phoenix/WinNonlin - power Helmut 2013-10-09 18:19
- power K2K 2013-10-10 08:36
- Phoenix/WinNonlin - power Helmut 2013-10-09 18:19
- “Interim power” K2K 2013-10-09 12:39
- “Interim power” Helmut 2013-10-08 14:58
- Power for Two stage Design K2K 2013-10-08 14:35
- Power for Two stage Design Helmut 2013-10-07 14:59
- Potvin’s 2-stage adaptive design + RSABE/ABEL GSD 2012-08-31 16:30
- Potvin’s 2-stage adaptive design + RSABE/ABEL Helmut 2012-08-18 00:39
Ing. Helmut Schütz