EMA: Full replicate study [Regulatives / Guidelines]
❝ Question: To address the challenges related to recruitment of cancer patients in PK BE study, we want to plan a full replicate design study. Will the EMA agency accept this approach even if we are not suspecting the drug to be highly variable?
❝ As per EMA guidance, “If an applicant suspects that a drug product can be considered as highly variable in its rate and/or extent of absorption, a replicate cross-over design study can be carried out.”
Standard design
If two formulations are compared, a randomised, two-period, two-sequence single dose crossover design is recommended.
Alternative designs
Under certain circumstances, provided the study design and the statistical analyses are scientifically sound, alternative well-established designs could be considered such as […] replicate designs e.g. for substances with highly variable pharmacokinetic characteristics.
❝ As per USFDA guidance “A replicate crossover study design (either partial or fully replicate) is appropriate for drugs whether the reference product is a highly variable drug or not. A replicate design can have the advantage of using fewer subjects compared to a non-replicate design, although each subject in a replicate design study would receive more treatments”.
PowerTOST
:library(PowerTOST)
CV <- 0.25 # assumed within-subject CV
theta0 <- 0.95 # assumed T/R-ratio
target <- 0.80 # target (desired) power
design <- c("2x2x2", "2x2x4", "2x3x3") # guess…
n.per <- as.integer(substr(design, 5, 5))
expl <- data.frame(design = design, n = NA, treatments = NA)
for (j in seq_along(design)) {
expl[j, 2] <- sampleN.TOST(CV = CV, theta0 = theta0, design = design[j],
targetpower = target, print = FALSE)[["Sample size"]]
expl[j, 3] <- sprintf("%.0f ", expl[j, 2] * n.per[j])
}
fmt <- paste0("Sample sizes and number of treatments for assumed CV = %.3g ",
"and T/R-ratio = %.3g,\npowered for at least %.0f%% ",
"and evaluation for Average Bioequivalence (ABE).\n")
cat(sprintf(fmt, CV, theta0, 100 * target)); print(expl, row.names = FALSE)
Sample sizes and number of treatments for assumed CV = 0.25 and T/R-ratio = 0.95,
powered for at least 80% and evaluation for Average Bioequivalence (ABE).
design n treatments
2x2x2 28 56
2x2x4 14 56
2x3x3 21 63
❝ We understand that widening criteria will be applied only to Cmax if we observe Swr > 0.294 or else conventional BE criteria will be applied.
- If > 30%:
- Reference-scaling by Average Bioequivalence with Expanding Limits (ABEL)
- Upper cap of scaling at \(\small{CV_\text{wR}=50\%}\) (maximum expansion 69.84–143.19%)
- 90% CI within expanded limits \(\small{\left\{L,U\right\}=\exp(\mp 0.76\cdot s_\text{wR})}\)
- Point estimate within 80.00–125.00%
- Reference-scaling by Average Bioequivalence with Expanding Limits (ABEL)
- If ≤ 30%:
- ABE
- 90% CI within 80.00–125.00%
- ABE
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Helmut Schütz
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Science Quotes
Complete thread:
- full replicate study for drug not highly variable - EMA perspective Ankit Parikh 2024-07-11 04:40 [Regulatives / Guidelines]
- EMA: Full replicate studyHelmut 2024-07-15 09:13