Bioequivalence and Bioavailability Forum

Hi Elena,

❝ To be in compliance with method C of Potvin, we re-calculate CI for Cmax with α=0,0294. Let`s assume that BE criterion for Cmax is met after this step. […] Otherwise, finally we will have the following in a CSR: BE criterion was met for AUC using α=0,05 (90%CI) and BE criterion was met for Cmax using α=0,0294 (94,12% CI). Does it look OK?

Absolutely. The ideas behind the different alphas in Potvin C are:

1. If interim power is ≥80%, essentially your assumptions about the CV were correct. Assess the study like a fixed sample design with α 0.05. You stop anyway (pass/fail).
   
2. If interim power is <80%, your assumptions about the CV were not correct. Assess the study with the adjusted α 0.0294.
   1. If you pass, stop.
      
   2. If you fail, initiate the second stage.

Hence, in your example you are for C_max in the branch 2.a. and for AUC in branch 1. All is good.

❝ Should we also re-calculate CI for AUC with α=0,0294?

You could but please only “at home”. That’s against the method and what you should have laid down in the protocol. See the end of this post. My study would have passed with the adjusted α as well.
But what if not? See this bizarre case study. If the sponsor would have known before that the agency will not accept Method C, they would have planned for Method B, initiated a second stage with 6 (six!) subjects and happily walked away. Stupid.

What will you do with your ”homework”?

• If the adjusted α passes as well, you sleep well and are prepared to answer a deficiency letter.
  
• If you fail, I’ll promise you sleepless nights. What can you do? Nothing. Confess that you cherry-picked and think about coming up with an amendment switching from C to B? Too late. If you are religious, pray. If not, get drunk.

That’s why in my personal ranking Potvin C is just № 6.
I recommended it for years. Well, no more.
IMHO, the small gain in power claimed by the authors is not worth the troubles:

library(PowerTOST)
library(Power2Stage)
CV  <- seq(0.15, 0.4, 0.05)
res <- data.frame(CV = CV, fixed = NA, n1 = NA,
                  B = NA, C = NA, C.B = NA)
n1  <- n <- numeric()
for (j in seq_along(CV)) {
  res$fixed[j]  <- sampleN.TOST(CV = CV[j],
                                print = FALSE)[["Sample size"]]
  res$n1[j]     <- 0.8 * res$fixed[j] # my recommendation
  res$n1[j]     <- ceiling(res$n1[j] + ceiling(res$n1[j]) %% 2)
  if (res$n1[j] < 12) res$n1[j] <- 12
  res$B[j]      <- power.tsd(method = "B", CV = CV[j],
                             n1 = res$n1[j])[["pBE"]]
  res$C[j]      <- power.tsd(method = "C", CV = CV[j],
                             n1 = res$n1[j])[["pBE"]]
  res$C.B[j]    <- 100 * (res$C[j] - res$B[j]) / res$B[j]
}
res[, 4:6] <- signif(res[, 4:6], 4)
names(res)[4:6] <- c("Method B", "Method C", "C/B (%)")
cat("Power in the final analysis\n"); print(res, row.names = FALSE)

Power in the final analysis
   CV fixed n1 Method B Method C C/B (%)
 0.15    12 12   0.8830   0.8994  1.8580
 0.20    20 16   0.8521   0.8624  1.2120
 0.25    28 24   0.8424   0.8508  0.9924
 0.30    40 32   0.8343   0.8411  0.8163
 0.35    52 42   0.8315   0.8350  0.4245
 0.40    66 54   0.8287   0.8321  0.4067