Bioequivalence and Bioavailability Forum

Dear BEman,

❝ according to the new EMA-Guideline we want to perform a study in 2-Stage Design. But we want to do it in an 'extreme' way, which is not explicitly forbidden in the Guideline.

Not only not forbidden but explicitly allowed. Just to cite:
"For example, using 94.12% confidence intervals for both the analysis of stage 1 and the combined data from stage 1 and stage 2 would be acceptable, but there are many acceptable alternatives and the choice of how much alpha to spend at the interim analysis is at the company’s discretion."

❝ What do you think about such an approach?

Many sponsors seem to favourite such extreme settings. Seems the provision of practical "no penalty" is very attractive for them .

❝ Do you have any experience with authority concerning this issue?

None up to now.

❝ Does the penalty assignment to the stages keeps the 'overall' type 1 error of the study under control?

See comments of EM and Helmut. Simulations necessary!
Potvin et.al. mention in their introductory text a paper of Hauck et.al. (see below) in which for the O'Brian-Fleming nominal alphas an overall alpha inflation (up to 6%) was supposedly observed. I don't have that paper so I can't check the truth and what they have done exactly.

❝ Do you know literature about an alpha-spending function, which i can use to calculate such extrem alpha spending described above ?

Your settings are comparable to the Haybittle-Peto nominal alphas (0.001 stage 1, 0.049 stage 2) or the O'Brian-Fleming nominal alphas (0.005 stage 1, 0.048 in stage 2).
But remember these alphas are derived for superiority trials with a parallel-group design and mid-course interim evaluation.

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Hauck WW, Preston PE, Bois FY.
A group sequential approach to crossover trials for average bioequivalence.
Journal of Biopharmaceutical Statistics 1997; 7:87–96.