## Replicate vs. 2×2×2 (ethics?) [Regulatives / Guidelines]

Hi M.tareq,

» first case:
» the published data suggest slightly boarder line CV% of 29-31%
» my question about the ethical view of such approach vs sponsor risk due to inadequate design?

For ABE I don’t see a general advantage of replicate designs, except if one expects low droput-rates. When the dropout-rate exceeds ~5% the loss in power (more periods) might be substantial. Try this one:

```library(PowerTOST) CV     <- 0.31 # assume CV theta0 <- 0.95 # assumed GMR target <- 0.80 # desired power dor    <- seq(0, 15, by=0.1) # expected droput-rates (%) ######################################################## des    <- c("2x2x4", "2x2x3", "2x3x3", "2x2x2") col    <- c("red", "magenta", "blue", "darkgreen") op     <- par(no.readonly=TRUE) # safe graphic defaults par(pty="s")                    # square plotting region for (j in seq_along(des)) {     # loop over designs   # calculate number of washout periods   wo  <- as.integer(substr(des[j], nchar(des[j]), nchar(des[j]))) - 1   # sample size at start   N   <- sampleN.TOST(CV=CV, design=des[j], targetpower=target,                       print=FALSE)[["Sample size"]]   pwr <- numeric() # vector of final powers   for (k in seq_along(dor)) { # loop over dropout-rates     el <- N # eligible subjects at the end of the study     for (l in 1:wo) { # loop over washout periods       el     <- el*(1-dor[k]/100) # reduce sample sizes       pwr[k] <- 100*suppressMessages(power.TOST(CV=CV, design=des[j],                                      n=floor(el))) # final powers     }   }   if (j == 1) {     plot(dor, pwr, type="s", main=sprintf("CV %.1f%%", 100*CV),          cex.main=0.9, cex.axis=0.85, lwd=2, col=col[j], las=1,          xlab="dropout-rate (%)", ylab="final power (%)")     grid()   } else {     lines(dor, pwr, type="s", lwd=2, col=col[j])   } } legend("bottomleft", legend=des, col=col, lwd=rep(2, length(des)),        bg="white", cex=0.8, title="design") par(op) # restore defaults```

There is an exception: If you suspect an HVD(P) you should perform the pilot study in a replicate design to get an estimate of CVwR (and CVwT in the full replicates) which is needed for estimating the sample size of the pivotal study. If the pilot study was a simple crossover you have to assume that CVw = CVwR = CVwT, which might be false.
For borderline cases (no reference-scaling intended but one suspects that the CV might be higher than assumed) a Two-Stage Design can be a good alternative. A while ago I reviewed a manuscript exploring the pros and cons of TSDs vs. ABEL. Was very interesting and I hope that the authors submit a revised MS soon.

» 2nd case
» regarding drugs which aren't stated to be HVDP (from previous studies or assessment reports)
» suppose the CV was found to be around 20% and the sponsor or cro wishes to go for replicate design for safe planning that the drug might shows high CV just in case or so

“Just in case” never works.

» […] in EMA guidelines regarding replicate design and widening of acceptance range for cmax it stated that the drug known to be HVPD CV > 30 …

Exactly. You have to state in the protocol that you intend reference-scaling. Furthermore, you have to give a justification that the widened acceptance range for Cmax is of no clinical relevance. IMHO, that’s bizarre (the FDA for good reasons doesn’t require it). HVD(P)s are safe and efficacious despite their high variability since their dose-response curves are flat. The fact that the originator’s drug was approved (no problems in phase III) and is on the market for years demonstrates that there are no safety/efficacy issues.

» … and not as a result of outliers

Nobody knows how to deal with this story. Regulations  science. Not required by the FDA…

» so from ethical point of view, given the drug isn't HVPD and it's stated in the protocol if the drug CV% was less than 30% the normal acceptance criteria will be applied, …

It doesn’t work that way. State in the protocol that you intent to scale and follow the EMA’s conditions. If CVwR ≤30% don’t scale or apply ABEL otherwise.

» why the need for the extra periods/dosing of volunteers from ethical/scientific view?

For the decision (ABE or ABEL) based on CVwR a replicate design is required.

Cheers,
Helmut Schütz

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