Bioequivalence and Bioavailability Forum

Hi Brus,

❝ In a partial replicated design (3-periods, 3 sequences), only reference is replicated, with a sample size of 45, CRO sent to me the following with proc GLM for ANOVA for the R/R comparison:

❝ …

❝ Least Squares Means:

❝ R1: 2.522

❝ R2: 2.419

❝

❝ Also they sent to me the following 90% CI for the comparative R1/R2:

❝

❝ Ratio = 110.79

❝ 90% Confidence Interval = 87.31 - 140.57

❝ Intra-subject CV% = 21.18

I guess, your problems started already at the beginning.

There can be only one.

There is no ‘R₁’ and ‘R₂’, only one R repeatedly administered in the sequences in different periods. Say, the sequences are TRR | RTR | RRT. Did the CRO call the first administration in each sequence R₁ and the second R₂ (while dropping T)?
This gives after recoding:   ░R1R2 | R1░R2 | R1R2░

❝ But I have several doubts:

❝ - It surprises me a 90% CI so wide for a relatively low, at least not high, ISCV.

As said above, such a ‘comparison’ will not work.

❝ - If I back-calculated the CV from this 90% CI with “CVfromCI” of PowerTOST, I obtain a CV of around 70%. Why?

You tried CI2CV(lower=0.8731, upper=1.4057, design="2x2x2", n=40), right? That’s not what you have. After recoding (wild guess) you have an Incomplete Block Design. Other degrees of freedom, 

❝ - In addition, I have tried to calculate the ratio and 90% CI with MSE and LSM according to the Helmut example from Pamplona lecture on 2018 "Basic Statistic on BE", slide 16 and 17:

❝ …

❝ I obtained a ratio of 110,8 but a 90% CI of 102,44 – 119,94. Same ratio as CRO but different 90 % CI. This is strange although it is in line with the ISCV presented by the CRO.

These formulas are for a 2×2×2 crossover and are also implemented in CI2CV(). But again, there is only one R. A ‘PE’ and ‘CI’ doesn’t make sense.

❝ Furthermore, doing various tests, … why?

No idea.

❝ So, what is the correct 90% CI?

There is none. You can only calculate the CV_wR according to the EMA’s or the FDA’s models. The results will be similar, though quite often the one of the FDA is a bit smaller.

If you want, send me the raw data off-list.