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An adaptive hierarchical test procedure for selecting safe and efficient treatments.
Franz König1, Peter Bauer, Werner Brannath
1Section of Medical Statistics, Medical University of Vienna, Spitalgasse 23, A-1090 Vienna, Austria. franz.koenig@meduniwien.ac.at
Biometrical Journal. Biometrische Zeitschrift
|September 16, 2006
Summary
Truncating high-dose treatments due to safety concerns and low-dose treatments due to lack of efficacy does not inflate type I error rates. Simulation studies explore hierarchical testing and sample size reallocation for improved power in dose-control comparisons.
Area of Science:
- Clinical Trials
- Biostatistics
- Pharmacology
Background:
- Multiple dose-controlled trials often face early termination of high doses due to safety concerns and low doses due to lack of efficacy.
- Data safety monitoring committees frequently make these decisions during interim analyses.
Purpose of the Study:
- To investigate the properties of a hierarchical testing procedure for efficacy outcomes in dose-control comparisons where some doses are truncated.
- To assess the impact of dose truncation on type I error rates and statistical power.
- To explore methods for improving power, such as sample size reallocation.
Main Methods:
- The study proposes a hierarchical test procedure, starting with the highest selected dose group compared to placebo at full alpha level.
- Properties were investigated through simulations, considering left and right truncation scenarios.
- The impact of positive correlation between efficacy and toxicity, and dose selection based on monotone safety functions were examined.
- A sample size reallocation procedure was also investigated to enhance power.
Main Results:
- Left truncation (dropping low doses) does not inflate the type I error rate.
- Right truncation (dropping high doses) does not inflate the type I error rate if efficacy and toxicity are positively related and dose selection is based on monotone safety functions.
- Simulations revealed a conflict between minimizing the number of unsafely treated patients and maximizing the power to detect safe and effective doses.
- Sample size reallocation can potentially increase power.
Conclusions:
- Hierarchical testing procedures with dose truncation can be employed without inflating type I error rates under specific conditions (positive efficacy-toxicity relationship).
- There is an inherent trade-off between patient safety and statistical power in dose-finding studies with truncation.
- Sample size reallocation is a viable strategy to potentially improve the power of detecting efficacious doses in truncated trials.
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