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Stopping a trial early - and then what?
1Statistics Collaborative, Inc., Washington, DC, USA. janet@statcollab.com
Clinical Trials (London, England)
|August 11, 2012
Summary
Early stopping in clinical trials can bias results. This study discusses bias correction methods for effect sizes and p-values, finding corrections were negligible in the RALES trial.
Area of Science:
- Biostatistics
- Clinical Trial Design
- Medical Research Methodology
Background:
- Early stopping of clinical trials due to strong evidence of benefit can introduce bias.
- Observed effect sizes, confidence intervals, and p-values are biased in frequentist group sequential trials.
- Bias leads to overestimation of treatment effects and narrower confidence intervals.
Purpose of the Study:
- To present methods for correcting bias in effect sizes, confidence intervals, and p-values for early-stopped trials.
- To evaluate the impact of bias correction on the conclusions of the Randomized Aldactone Evaluation Study (RALES).
Main Methods:
- Discussion of bias correction techniques for early-stopped group sequential trials.
- Application of correction methods to data from the RALES trial.
Main Results:
- The impact of bias on the RALES trial results was found to be negligible.
- Corrections to estimated values in the RALES trial were small, even when stopped at 50% information.
Conclusions:
- No single method for p-value correction is universally applicable.
- Recommends stagewise ordering for interpreting evidence from early stopping, preserving Type I error rates.
- Associated methods for calculating effect size and confidence intervals are proposed.
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