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Multiple testing of noninferiority hypotheses in active controlled trials
H M James Hung1, Sue-Jane Wang
1Division of Biometrics I, Food and Drug Administration, Rockville, Maryland 20852, USA. hung@cder.fda.gov
Journal of Biopharmaceutical Statistics
|June 23, 2004
Summary
Prespecifying the maximum noninferiority margin allows valid statistical testing for multiple hypotheses at the same alpha level. This approach avoids multiplicity issues and ensures robust noninferiority trial analysis.
Area of Science:
- Biostatistics
- Clinical Trials
Background:
- Noninferiority trials aim to demonstrate that a new treatment is not unacceptably worse than a standard treatment.
- Statistical methods are crucial for establishing noninferiority while managing potential biases and multiplicity.
Purpose of the Study:
- To outline a valid statistical approach for multiple noninferiority hypotheses when a maximum noninferiority margin is prespecified.
- To address the complexities of multiplicity when using different confidence intervals for superiority and noninferiority testing.
Main Methods:
- Utilizing a single, prespecified maximum noninferiority margin for hypothesis testing.
- Performing statistical testing at a consistent alpha level across multiple noninferiority hypotheses.
- Highlighting the importance of fixing margin elements in advance, independent of trial data analysis.
Main Results:
- Valid statistical testing is achievable for multiple noninferiority hypotheses using a single alpha level when the maximum margin is prespecified.
- Using different confidence intervals (e.g., intent-to-treat vs. per-protocol) can introduce multiplicity issues requiring alpha adjustment.
- Pre-specifying margin elements prevents data-driven influence, ensuring the integrity of noninferiority analysis.
Conclusions:
- A prespecified maximum noninferiority margin simplifies multiple hypothesis testing and maintains statistical validity.
- Careful consideration of confidence intervals and pre-specification of margins are essential for robust noninferiority trial design and analysis.
- Adherence to pre-specified parameters is critical to avoid invalidating noninferiority trial results.
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