Reference-scaling: Don’t use FARTSSIE! [Power / Sample Size]
❝ What BE limits should be taken into consideration while estimating sample size for replicate design studies for USFDA & EMA.
If you want to go with reference-scaling, none! The limits depend on the CVwR and are estimated in the actual study. Hence, you need simulations, where your assumed CVwR is the average. Either use the tables provided by the two Lászlós* or package
PowerTOST
for R. The software is open source and comes free of costs. 
❝ Should it be 80-125% ?
No (see above). Only if you don’t want reference-scaling (i.e., conventional ABE). Actually reference-scaling was introduced to avoid the extreme sample sizes required for ABE.
❝ We normally use FARTSSIE
FARTSSIE cannot perform the necessary simulations and therefore, is not suitable for any of the reference-scaling methods.
❝ For a product with 51% ISCV (from a completed partial replicate study UKMHRA) by using FARTSSIE we arrived at different sample size for EMA
❝
❝ - Sample size estimated = 27 (80% Power, 95-105% T/R, Method C1, BE Limits 69.84 to 143.19%)
❝ - Sample size estimated = 76 (80% Power, 95-105% T/R, No reference Scaled BE Limits-80-125%)
- Do not assume a T/R of 95% for HVDP(s). The two Lászlós recommend a 10% difference and for good reasons. Therefore, 90% is the default in
PowerTOST
’s reference-scaling functions.
- If ever possible avoid the partial replicate design. Though the evaluation works for the EMA’s methods, sometimes no convergence is achieved for the FDA’s mixed effects model (if CVwR <30%) – independent from the software. Study done, no result, you are fired.
Better to opt for full replicate 2-sequence designs: 4-periods (TRTR|RTRT) or – if you are afraid of dropouts and/or want to avoid large sampling volumes – 3-periods (TRT|RTR). In the latter one you need at least twelve eligible subjects in sequence RTR according to the EMA’s Q&A-document (not relevant in practice).
PowerTOST
, start the R-console, and type library(PowerTOST)
. If you want to make yourself familiar with PowerTOST
, type help(package=PowerTOST)
.Try these examples, where
"2x2x4"
denotes the 4-perod full replicate, "2x2x3"
the 3-period full replicate, and "2x3x3"
the 3-sequence 3-period (partial) replicate.- The EMA’s ABEL
sampleN.scABEL(CV=0.51, design="2x2x4")
sampleN.scABEL(CV=0.51, design="2x2x3")
sampleN.scABEL(CV=0.51, design="2x3x3")
- Health Canada’s ABEL
sampleN.scABEL(CV=0.51, design="2x2x4", regulator="HC")
sampleN.scABEL(CV=0.51, design="2x2x3", regulator="HC")
sampleN.scABEL(CV=0.51, design="2x3x3", regulator="HC")
- The FDA’s RSABE
sampleN.RSABE(CV=0.51, design="2x2x4")
sampleN.RSABE(CV=0.51, design="2x2x3")
sampleN.RSABE(CV=0.51, design="2x3x3")
theta0=0.95
to the function calls but don’t blame me if the study fails. If you want 90% power instead of the default 80%, add the argument targetpower=0.90
.I suggest to perform a power analysis (recommended by ICH E9) assessing the influence of deviations from assumptions (lower/higher CVwR, T/R deviating more than expected from 100%, less eligible subjects due to dropouts). Try (with the default partial replicate):
pa.scABE(CV=0.51, regulator="EMA")
pa.scABE(CV=0.51, regulator="HC")
pa.scABE(CV=0.51, regulator="FDA")
- Endrényi L, Tóthfalusi L. Sample Sizes for Designing Bioequivalence Studies for Highly Variable Drugs. J Pharm Pharmaceut Sci. 2011;15(1):73–84.
free resource.
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:
- Sample Size Estimation -Replicate design- BE limits cakhatri 2017-11-30 09:44 [Power / Sample Size]
- Reference-scaling: Don’t use FARTSSIE!Helmut 2017-11-30 10:58
- Reference-scaling: Don’t use FARTSSIE? Astea 2017-11-30 22:50
- Reference-scaling: Don’t use FARTSSIE! Helmut 2017-12-01 11:42
- Reference-scaling: USE PowerTOST Astea 2017-12-01 14:16
- Reference-scaling: USE PowerTOST cakhatri 2017-12-04 06:00
- Reference-scaling: USE PowerTOST Helmut 2017-12-04 15:07
- Reference-scaling: USE PowerTOST cakhatri 2017-12-05 05:33
- Reference-scaling: USE PowerTOST Helmut 2017-12-04 15:07
- Use PowerTOST d_labes 2017-12-06 09:52
- Use PowerTOST, not Endrényi L, Tóthfalusi L tables mittyri 2017-12-07 16:03
- Precision in Endrényi L, Tóthfalusi L tables d_labes 2017-12-07 18:21
- Precision of PowerTOST mittyri 2017-12-08 22:56
- Precision of PowerTOST Helmut 2017-12-09 17:00
- Precision of PowerTOST mittyri 2017-12-09 21:05
- Precision of PowerTOST Astea 2017-12-10 00:10
- Precision of PowerTOST Helmut 2017-12-10 20:27
- Precision of PowerTOST Astea 2017-12-10 21:13
- Precision of PowerTOST Helmut 2017-12-10 20:27
- Precision of PowerTOST Astea 2017-12-10 00:10
- Precision of PowerTOST mittyri 2017-12-09 21:05
- Precision of PowerTOST Helmut 2017-12-09 17:00
- Precision of PowerTOST mittyri 2017-12-08 22:56
- Precision in Endrényi L, Tóthfalusi L tables d_labes 2017-12-07 18:21
- Use PowerTOST, not Endrényi L, Tóthfalusi L tables mittyri 2017-12-07 16:03
- Reference-scaling: USE PowerTOST cakhatri 2017-12-04 06:00
- Reference-scaling: USE PowerTOST Astea 2017-12-01 14:16
- Reference-scaling: Don’t use FARTSSIE! Helmut 2017-12-01 11:42
- Reference-scaling: Don’t use FARTSSIE! pjs 2018-02-09 13:08
- Reference-scaling: Don’t use FARTSSIE! Helmut 2018-02-09 20:15
- Reference-scaling: Don’t use FARTSSIE? Astea 2017-11-30 22:50
- Reference-scaling: Don’t use FARTSSIE!Helmut 2017-11-30 10:58