Journal
BIOMETRICAL JOURNAL
Volume 55, Issue 4, Pages 617-633Publisher
WILEY
DOI: 10.1002/bimj.201200189
Keywords
Adaptive design; Blinded procedure; Clinical trials; Sample size reestimation; Unblinded procedure
Funding
- Deutsche Forschungsgemeinschaft (DFG) [FR 3070/1-1]
Ask authors/readers for more resources
Internal pilot studies are a popular design feature to address uncertainties in the sample size calculations caused by vague information on nuisance parameters. Despite their popularity, only very recently blinded sample size reestimation procedures for trials with count data were proposed and their properties systematically investigated. Although blinded procedures are favored by regulatory authorities, practical application is somewhat limited by fears that blinded procedures are prone to bias if the treatment effect was misspecified in the planning. Here, we compare unblinded and blinded procedures with respect to bias, error rates, and sample size distribution. We find that both procedures maintain the desired power and that the unblinded procedure is slightly liberal whereas the actual significance level of the blinded procedure is close to the nominal level. Furthermore, we show that in situations where uncertainty about the assumed treatment effect exists, the blinded estimator of the control event rate is biased in contrast to the unblinded estimator, which results in differences in mean sample sizes in favor of the unblinded procedure. However, these differences are rather small compared to the deviations of the mean sample sizes from the sample size required to detect the true, but unknown effect. We demonstrate that the variation of the sample size resulting from the blinded procedure is in many practically relevant situations considerably smaller than the one of the unblinded procedures. The methods are extended to overdispersed counts using a quasi-likelihood approach and are illustrated by trials in relapsing multiple sclerosis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available