Bioequivalence and Bioavailability Forum

❝ Does FDA raise any concern …

❝ … if we get around 20 to 25% positive pre-dose concentration in subsequent period of the study?

If the predose concentration is ≤ 5 per­cent of C_max value in a subject with predose plasma con­cen­tra­tion, you can include the subject’s data without any adjustments in all pharmacokinetic measure­ments and calculations. We recommend that if the predose value is greater than 5 per­cent of C_max, you drop the subject from all BE study evaluations.

library(PowerTOST)
CV     <- seq(0.2, 0.6, 0.1)
GMR    <- 0.95
pi     <- 0.85
design <- "2x2x2"
pct.do <- c(0, 20, 25)
min    <- 12
n      <- vector("integer", length(CV))
for (j in seq_along(CV)) {
  n[j] <- sampleN.TOST(CV=CV[j], theta0=GMR, targetpower=pi,
            design=design, print=FALSE)[["Sample size"]]
  if (n[j] < 12) n[j] <- 12
}
res    <- matrix(nrow=length(CV)*length(pct.do), ncol=6, byrow=TRUE,
            dimnames=list(NULL,
              c("pct.CV", "pct.do", "n", "power",
                "loss.abs", "loss.rel.pct")))
r <- 0
for (j in seq_along(CV)) {
  for (k in seq_along(pct.do)) {
    r         <- r+1
    res[r, 1] <- 100*CV[j]
    res[r, 2] <- pct.do[k]
    res[r, 3] <- trunc(n[j]*(100-pct.do[k])/100)
    res[r, 4] <- power.TOST(CV=CV[j], theta0=GMR,
                   n=res[r, 3], design=design)
    if (res[r, 3] == n[j]) {
      pwr.max <- res[r, 4]
    } else {
      res[r, 5] <- round(pwr.max - res[r, 4], 5)
      res[r, 6] <- round(100*(1-res[r, 4]/pwr.max), 3)
    }
  }
}
res    <- data.frame(res)
print(res, row.names=FALSE)

 pct.CV pct.do   n   power loss.abs loss.rel.pct
     20      0  22 0.86889       NA           NA
     20     20  17 0.76365  0.10524       12.112
     20     25  16 0.73541  0.13347       15.361
     30      0  44 0.85076       NA           NA
     30     20  35 0.75955  0.09121       10.721
     30     25  33 0.73220  0.11855       13.935
     40      0  76 0.85644       NA           NA
     40     20  60 0.76574  0.09070       10.590
     40     25  57 0.74270  0.11374       13.281
     50      0 112 0.85187       NA           NA
     50     20  89 0.76333  0.08854       10.394
     50     25  84 0.73758  0.11429       13.416
     60      0 154 0.85229       NA           NA
     60     20 123 0.76649  0.08580       10.067
     60     25 115 0.73669  0.11561       13.564


❝ […] wash out duration fixed based on the data available on FDA site under SBOA for reference product.

If the applicant chooses, a pilot study in a small number of subjects can be carried out before pro­ceed­ing with a full BE study. This pilot study can be used to validate analytical methodology, assess vari­abi­lity, optimize sample collection time intervals, and provide other information.

❝ Does FDA raise any concern if we get around 20 to 25% positive pre-dose concentration in subsequent period of the study? Please note that the product is long acting depot injection and wash out duration fixed based on the data available on FDA site under SBOA for reference product.