Bioequivalence and Bioavailability Forum

Dear all,

something is rotten in the state of Denmark…
For the test case you need the script of the previous post and the library PowerTOST.

adj  <- 0.0294
n1   <- 24
CVwR <- 0.25 # mostly no scaling
GMR  <- 0.88 # a bad one

First the functions of PowerTOST:

power.RSABE(alpha = adj, CV = CVwR, theta0 = GMR, design = "2x2x4", n = n1)
[1] 0.49905
sampleN.RSABE(alpha = adj, CV = CVwR, theta0 = GMR, design = "2x2x4", details = FALSE)
++++++++ Reference scaled ABE crit. +++++++++
           Sample size estimation
---------------------------------------------
Study design: 2x2x4 (4 period full replicate)
log-transformed data (multiplicative model)
1e+05 studies for each step simulated.

alpha  = 0.0294, target power = 0.8
CVw(T) = 0.25; CVw(R) = 0.25
True ratio = 0.88
ABE limits / PE constraints = 0.8 ... 1.25
Regulatory settings: FDA

Sample size
 n    power
52   0.80636

Since power in the first stage <0.8, we would initiate a second stage with 52 – 24 = 28 subjects.

Now the function with its defaults. Additionally I set details = FALSE to return the data.frame of results, inter = TRUE to show the intermediate stage 2 sample sizes, and increased the number of calls for the workaround to a crazy number:

RSS(n1 = n1, CVwR = CVwR, GMR = GMR, calls = 2500, details = FALSE, inter = TRUE)
 n2 times
 22     1
 24    24
 26   699
 76  1776

  alpha.adj n1 CVwR  GMR target n2   N futile
1    0.0294 24 0.25 0.88    0.8 76 100   TRUE

What’s going on here – where does the discontinuity in estimated stage 2 sample sizes come from? The study would stop for futility in the first stage!
Another try with a higher nmax:

RSS(n1 = n1, CVwR = CVwR, GMR = GMR, calls = 50, nmax = 250, details = FALSE, inter = TRUE)
 n2 times
 24     1
 26    16
 28    26
 30     7

  alpha.adj n1 CVwR  GMR target n2  N futile
1    0.0294 24 0.25 0.88    0.8 30 54  FALSE

Now the study would proceed to the second stage but with 30 subjects instead of the 28 estimated by sampleN.RSABE().