Bioequivalence and Bioavailability Forum

Hi Hiren!

❝ […] appropriate sample size for a drug […] having T/R = 0.90 and % CVintra = 60 for a Reference Replicated Pivotal BE study (3 period)? We opt for 80% power...!!!

Which regulation: FDA or EMA?

• FDA
  sampleN.RSABE(theta0=0.9, CV=0.6, design="2x3x3", details=FALSE)
++++++++ Reference scaled ABE crit. +++++++++
           Sample size estimation
---------------------------------------------
Study design:  2x3x3
log-transformed data (multiplicative model)
1e+05 studies simulated.

alpha  = 0.05, target power = 0.8
CVw(T) = 0.6; CVw(R) = 0.6
Null (true) ratio = 0.9
ABE limits / PE constraints = 0.8 ... 1.25

Sample size
 n     power
33   0.817090
  
  
• EMA
  require(PowerTOST)
sampleN.scABEL(theta0=0.9, CV=0.6, design="2x3x3", details=FALSE)
+++++++++++ scaled (widened) ABEL +++++++++++
            Sample size estimation
---------------------------------------------
Study design:  2x3x3
log-transformed data (multiplicative model)
1e+05 studies simulated.

alpha  = 0.05, target power = 0.8
CVw(T) = 0.6; CVw(R) = 0.6
Null (true) ratio = 0.9
ABE limits / PE constraints = 0.8 ... 1.25
Regulatory body: EMA
- CVswitch =  0.3, cap on ABEL if CV > 0.5
- Regulatory constant = 0.76

Sample size search
 n     power
48   0.814780

Note that FDA’s method (function sampleN.RSABE) is not available in the current official release of PowerTOST (v1.1-00). I used a private copy of 1.1-01 provided by Detlew. I guess he will upload it to CRAN returning from his vacation in two weeks. In the meantime see the approximation in v1.1-00:

require(PowerTOST)
sampleN.scABEL(theta0=0.9, CV=0.6, design="2x3x3", regulator="FDA", details=FALSE)
+++++++++++ scaled (widened) ABEL +++++++++++
            Sample size estimation
---------------------------------------------
Study design:  2x3x3
log-transformed data (multiplicative model)
1e+05 studies simulated.

alpha  = 0.05, target power = 0.8
CVw(T) = 0.6; CVw(R) = 0.6
Null (true) ratio = 0.9
ABE limits / PE constraints = 0.8 ... 1.25
Regulatory body: FDA

Sample size
 n     power
30   0.800130

See also Tóthfalusi and Endrényi (2011)* – Tables A1 and A3 for GMR 0.9, CV 60%, 80% power:
EMA: 46 (round up to the next multiple of three: 48)
FDA: 31 (round up to the next multiple of three: 33)

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• Tóthfalusi L and L Endrényi
  Sample Sizes for Designing Bioequivalence Studies for Highly Variable Drugs
  J Pharm Pharmaceut Sci 15(1), 73–84 (2011)
  online