Bioequivalence and Bioavailability Forum

Dear Dan,

Thanks for the response - it's really appreciated.

The client in this matter has requested me to come up with an idea on the design as well as the sample size for a Phase-I study, so proof-of-concept. The medication concerns Orlistat, which is known as highly variable on PK. I am not sure for PD (fat excretion in this case), but from literature search this seems to have a CV of around 35%. Ofcourse most interest is in T vs R1 and T vs R2. From guideline perspective, FDA recommends a bootstrapping method for the analysis, EMA advices either Schuirmann or the dose-scale method (using a Emax model). I dit not find anything on design nor on sample size or power calculations. For design, I was quite confident that 6x3 would be best, although your point of dropout would be a concern (not to mention the costs for the client ). Another possibility would be to have the design similar to:

          Gr1  Gr2   Gr3
period 1: T    R1    R1
period 2: R1   T     R2
period 3: R2   R2    T

for testing T vs R1 in crossover for period 1/2, Gr1/2, and for testing T vs R2 in crossover for period 2/3, Gr2/3. But I suppose there are a lot of snags involved in a design like this.

My current view would be to calculate the sample size based on the ratio of ED50's for test and reference which should fall within the 80-125% range of bioequivalence, but then I only have it for the 2x2 case of test versus reference. I suppose this is in line with the dose-scale method of EMA, however the study to be performed is going to be FDA-submitted.

Note: in the clinical literature found sofar on this matter, no one bothers with a proper sample size calculation - most are based upon 'empirical considerations'. The used sample sizes vary between 18 and 48...

Any alternative views or ideas on the above are highly appreciated.

Best regards from sunny Netherlands.