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STOPPING RULES FOR LONG TERM CLINICAL TRIALS BASED ON TWO CONSECUTIVE: REJECTIONS OF THE NULL HYPOTHESIS
Mohamed Mubasher1, Howard E Rockette2
1Jaeb Center for Health Research.
Communications in Statistics: Theory and Methods
|May 20, 2025
Summary
This study introduces a new method for stopping long-term clinical trials using time-to-event data. It ensures trial validity by requiring multiple rejections, offering a realistic approach for large studies.
Area of Science:
- Biostatistics
- Clinical Trial Design
- Statistical Methods
Background:
- Long-term randomized clinical trials (RCTs) with time-to-event outcomes require robust stopping rules.
- Existing methods may not adequately control Type I error rates during interim analyses.
- Early termination without sustained evidence can lead to unreliable conclusions.
Purpose of the Study:
- To develop and evaluate a strategy for stopping long-term RCTs based on multiple consecutive rejections.
- To control the experiment-wise error rate while maintaining statistical integrity.
- To provide a more realistic and reliable stopping rule for large multi-center trials.
Main Methods:
- The proposed strategy utilizes criteria requiring multiple consecutive or non-consecutive rejections at a specified alpha-level.
- Interim test alpha-levels were determined based on an overall pre-specified test size.
- Boundary cutoff values were calculated using multi-dimensional integration and/or simulation methods.
Main Results:
- The study presents a procedure using two consecutive rejections with corresponding alpha-levels for interim tests.
- The required reduction in interim alpha-levels to maintain the experiment-wise error rate was found to be modest.
- The power of the test was evaluated under various alternative accrual and hazard patterns.
Conclusions:
- The developed stopping strategy offers a more realistic approach for terminating long-term clinical trials.
- It ensures that trials are only stopped when a sustained effect is demonstrated, enhancing reliability.
- This method is particularly beneficial for large, multi-center trials where early termination is undesirable without strong evidence.
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