Bioequivalence and Bioavailability Forum

Dear Ben!

❝ I have another question regarding your slides (Moscow). On slide 72 you write "Don’t jeopardize! Smaller sample sizes in the first stage than in a fixed design don’t pay off. Total sample sizes are ~10–20% higher."

A direct comparison of a particular fixed design (assuming a CV) and sequential design (sample size re-estimation) is somewhat delusionary. The sample size penalty in Method C (taboo in the EU…) is negligible if the study is powered like a fixed sample design (no α-adjustment in stage 1). For Method B you have a penalty even if passing in stage 1. Only if I have reliable CV data (previous studies of known quality) I go with a fixed design myself.

❝ If the sample size from the first stage is chosen to be equal to the fixed design, then why performing a sequential design at all? Then the only chance of concluding BE (if not after stage 1) after all is to have a greater sample size than a fixed design; but this means that one always has a sample size greater or equal to fixed design - no possibility for having less any more…

If we want to compare the performance in terms of total sample sizes we would have to look at a number of fixed design studies (including failed ones due to higher than expected CVs) and sequential designs. I guess that the disadvantage of adaptive designs would disappear. Personally I see two-stage designs as a second chance to show BE if the assumptions about the CV turn out to be wrong. Tell your boss that he/she paid for failed/repeated studies in the past as well – or overpowering them “just to be sure”.

Example (Method B, Potvin Table II): You think that the CV is 20%, but it may be as low as 10%. You perform the study with 12 subjects (reasonable if the CV is 10%). If the CV turns out to be 10% the chance to proceed to stage 2 is only 0.6%. But: If the CV is 20% (your primary assumption!) chances to proceed to the second stage are 56.4%. You loose a lot of time. On the other hand if you perform the study in 24 subjects chances for a second stage are only 8.6%. If the CV is 10% you pass in the first stage anyway. If the CV is higher (e.g., 30%) chance to proceed to stage 2 is 58.3%. In the fixed design you simply fail and run another study – this is what I call a sample size penalty! Up to you.