Exclusion of subjects [Design Issues]
![[image]](img/uploaded/image77.jpg)
❝ Does FDA raise any concern …
I don’t have a crystal ball. Substitute “does the FDA” by “will the FDA likely”.
❝ … if we get around 20 to 25% positive pre-dose concentration in subsequent period of the study?
I don’t think so. See the current NDA-draft (Section Subjects with predose plasma drug concentrations):
If the predose concentration is ≤ 5 percent of Cmax 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 Cmax, you drop the subject from all BE study evaluations.
If you exclude subjects you decrease the chance to demonstrate BE (= increase the producer’s risk). The patient’s risk (Type I Error) is of regulatory concern – not the Type II Error (β = 1 – π). If you are able to show BE despite the lower sample size, fine.The loss in power is not substantial in most cases:
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.
In the worst case the FDA might ask why you didn’t perform a pilot study.
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.
But that’s not mandatory. A depot injection, well… IMHO, the reference product’s data are sufficient to justify the chosen design.Dif-tor heh smusma 🖖🏼 Довге життя Україна!
![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png)
Helmut Schütz
![[image]](https://static.bebac.at/img/CC by.png)
The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Complete thread:
- Positive Pre-dose in subsequent period of long acting depot injection Compliance 2015-10-14 12:54 [Design Issues]
- Exclusion of subjectsHelmut 2015-10-14 14:44
- Positive Pre-dose in subsequent period of long acting depot injection ElMaestro 2015-10-14 22:37
- Positive Pre-dose in subsequent period of long acting depot injection Compliance 2015-10-15 07:36
- Expected loss in power Helmut 2015-10-15 13:45
- Positive Pre-dose in subsequent period of long acting depot injection Compliance 2015-10-15 07:36