Bioequivalence and Bioavailability Forum

Dear Detlew and Jay,

❝ ❝ If CV of one parameter such as AUC5-t is observed more than 100% while for other parameter such as Cmax, Auc0-5 or AUCinf is within 20-30%. So should one go for full replicate design and sample size estimation based on highest CV observed as 114%.

IMHO it is rather unusual for MR-products that the late partial AUC is more variable than the early one. Was this behavior due to an “outlying” subject? If yes, which CV do you get after exclusion? I would be cautious to draw premature conclusions.

❝ But that's in Europe a no go for AUC values. Here scaled ABE (via widened acceptance limits, ABEL) is only allowed for Cmax, […]

Disagree. The MR-GL (Section 6.8.2.2.) allows ABEL for partial AUCs. Hence,

library(PowerTOST)
sampleN.scABEL(CV=1.14, theta0=0.9, design="2x2x4")

+++++++++++ scaled (widened) ABEL +++++++++++
            Sample size estimation
---------------------------------------------
Study design:  2x2x4 (full replicate)
log-transformed data (multiplicative model)
1e+05 studies for each step simulated.

alpha  = 0.05, target power = 0.8
CVw(T) = 1.14; CVw(R) = 1.14
Null (true) ratio = 0.9
ABE limits / PE constraints = 0.8 ... 1.25
Regulatory settings: EMA
- CVswitch =  0.3, cap on scABEL if CVw(R) > 0.5
- Regulatory constant = 0.76

Sample size search
 n     power
80   0.7954
82   0.8049