Bioequivalence and Bioavailability Forum

❝ We have been doing patient PK study for USFDA submission and […] 36 should complete both periods.

❝ So far we have enrolled 37 subjects since pre-valence of diseases covered in study is rare and limitations of site selection. […] only 31 subjects will be considered for stat. analysis.

❝ Now, situation is Reference product got expired and if we want to procure another lot of reference product for remaining 03 subjects then the cost would be 10 million.

❝ 1. Can we stop the study with 37 subjects and perform stat. analysis with 31 subjects?

❝ 2. Does FDA accept this type of study if we perform analysis with 31 subjects and file pre-plan deviation.

library(PowerTOST)
# change the values below to yours
CV     <- 0.24
theta0 <- 0.95
target <- 0.90
design <- "2x2"
plan   <- sampleN.TOST(CV = CV, theta0 = theta0, targetpower = target, design = design)

You get:
+++++++++++ Equivalence test - TOST +++++++++++
            Sample size estimation
-----------------------------------------------
Study design: 2x2 crossover
log-transformed data (multiplicative model)

alpha = 0.05, target power = 0.9
BE margins = 0.8 ... 1.25
True ratio = 0.95,  CV = 0.24

Sample size (total)
 n     power
36   0.914510

What will happen if you have just 31 eligible subjects?
elig  <- 31
power <- suppressMessages(power.TOST(CV = CV, theta0 = theta0, design = design, n = elig))
fmt1  <- "%5.2f%%"
fmt2  <- "(n = %.0f)"
cat("Planned power:", sprintf(fmt1, 100 * plan[["Achieved power"]]),
    sprintf(fmt2, plan[["Sample size"]]),
    "\nActual power :", sprintf(fmt1, 100 * power), sprintf(fmt2, elig),
    "\nRelative loss:",
    sprintf(fmt1, 100 * (1 - power / plan[["Achieved power"]])), "\n")

You get:
Planned power: 91.45% (n = 36)
Actual power : 87.14% (n = 31)
Relative loss:  4.71%

Would such a relative loss in power really hurt?
Recall that the CV and the T/-ratio were assumptions as well. Power is much more sensitive to deviations of these parameters than the sample size. See also this article.

❝ 3. If we procure another lot of reference product then should we keep retention samples 30 capsules?

❝ 4. What will be the anticipated challenges w.r.t. stat. analysis or regulatory acceptance?