Potvin method B subtleties [Two-Stage / GS Designs]

posted by d_labes  – Berlin, Germany, 2011-02-02 10:15 (5254 d 11:45 ago) – Posting: # 6537
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Dear J. Detlor,

❝ ❝ Q2: If yes in Q1: It may happen that in the sample size ...

❝ The determination of alpha relates to the allocation of subjects between stages. What complicates the above with respect to Potvin et al. is the ratio of subjects is not known for the final analysis, and thus the impact on the choice of alpha would need to be evaluated through simulation.


The ratio of subjects between both stages is always not known at the planning stage in methods with interim sample size adaption. Therefore this is also true for the Potvin et.al. methods.
Using any scheme of nominal alpha values from the classical group-sequential designs is therefore not exactly correct because they rely on same number of subjects in each stage and the impact on the overall alpha has to be shown.

❝ ❝ Q3: Do you think that the power calculation makes sense if executed with the point estimate from stage 1 instead of GMR=0.95?

To express my question more precisely: The power calculation in Method B is done in case of non-BE evaluated at alpha=0.0294. Eventually this is superfluous because if using the point estimate will result always in a power below that desired?

❝ Potvin et al. does mention this. I believe they reference Cui et al.2 who determine that if this approach is applied naively, it can inflate the type I error rate up to 30%.


Needs to be shown if this is true also for cross-over designs aimed to evaluate equivalence.
Do you know any 'non-naive' application?

❝ ❝ Q4: Do you think Method B is nearer then Method C to the sentence ...

❝ They both have interim analyses; method B evaluates BE initially, whereas method C evaluates the power, then BE. I don't know if you could say that one is closer than the other.


My concern was that Method C has the possibility to evaluate the data at stage 1 with alpha=0.05 if the power was great enough, i.e. without paying any penalty.
I know Helmut prefers Method C and has already convinced the German BfARM :cool:.
This would also my preferred choice according to the reasoning of Potvin et.al. in their recommendations "Another advantage of method C is that it is designed so that if the study were found to have adequate power at the first stage, the alpha for that study would be the same as if it were designed to be single-stage". Why to pay a penalty for repeated testing, if no repeated tests are applied?
But ... see the comments paper and remember the London EGA symposium (2010) discussion.
Eventually we have to take Guidances here literally to make our sponsors happy? Any experience other then Helmut's?
—
Regards,

Detlew

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