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Comparison of Isotonic Designs for Dose-Finding
Anastasia Ivanova1, Nancy Flournoy
1Associate Professor, Department of Biostatistics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7420.
Statistics in Biopharmaceutical Research
|February 17, 2010
Summary
The cumulative cohort design is the best method for assigning patients to drug doses based on toxicity estimates. This sequential design adjusts future doses based on toxicity levels compared to a target rate.
Area of Science:
- Clinical Trials
- Biostatistics
- Pharmacology
Background:
- Sequential dose-finding studies are crucial for determining optimal drug dosages.
- Estimating monotone dose-toxicity relationships is essential for patient safety.
- Existing decision rules for dose allocation require rigorous comparison.
Purpose of the Study:
- To compare the performance of various decision rules for subject allocation in dose-finding studies.
- To identify the most effective sequential decision rule for estimating monotone dose-toxicity curves.
- To evaluate rules based on isotonic estimates and target toxicity probabilities.
Main Methods:
- Comparison of multiple sequential decision rules for dose allocation.
- Utilized sequential isotonic estimates of a monotone dose-toxicity curve.
- Evaluated a rule based on proximity to target toxicity probability.
- Assessed the cumulative cohort design for dose assignment.
Main Results:
- The decision rule prioritizing the dose with the closest toxicity probability to the target performed poorly.
- The cumulative cohort design demonstrated superior performance in dose allocation.
- This design adaptively adjusts the next subject's dose (decrease, increase, or repeat) based on estimated toxicity relative to the target quantile.
Conclusions:
- The cumulative cohort design is recommended as the optimal rule for sequential dose-finding studies.
- Adaptive dose adjustments based on estimated toxicity and target quantiles improve trial efficiency and safety.
- The tested proximity-based rule is not suitable for effective dose allocation in these settings.
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