Bioequivalence and Bioavailability Forum

Dear Nav,

I’m not in my office, so be a little patient to get a thorough response – first I have to read your 66 pages of statistics.

Just for completeness (because you sent me the paper by private mail):

Julious SA. TUTORIAL IN BIOSTATISTICS. Sample sizes for clinical trials with Normal data.
Stat Med. 2004;23(12):1921–86. doi:10.1002/sim.1783.

❝ Well, I am not sure how to estimate the sample size for a parallel design?

We’ll handle that…

❝ Re: 60% of inter to estimate the intra: I am a statistician and I routinely see the PK individuals taking 60% of inter to be the intra for estimating sample size for a crossover design and always wondered about the validity of the approach.

Hey, that’s black magick!
Examples

1. Imagine two studies; one with very tight inclusion criteria with respect to anthrompometric covariates (sex, BMI, age, …), the other one very ‘liberal’. CV_inter (but not CV_intra!) will be higher in the first one; just my 2 ¢.
   
2. If I remember it correctly, diltiazem is a compound with low to moderate intra-subject CV (about 15%), but much higher CV_inter.
   
3. Extreme examples are all studies employing different phenotypes. Whereas the phenotype is time-invariant – we don’t change our genotype in the washout – the intra-subject variability may be horrible (20fold differences in C_max are not uncommon).

Lessons from the examples:

1. Although you may have established some kind of intra-/inter-CV ratio, this most likely is not – only – a property of the compound / formulation(s), but also of the study’s design/performance.
   
2. No, not 60%, rather 25%…
   
3. Again from my aging memory: buspirone CV_intra ~15%, CV_inter >80%?

Therefore I would consider

❝ 60% of inter to estimate the intra

again as black magick.