Flexible two-stage design with sample size reassessment for survival trials

Area of Science:

• Clinical Trials Methodology
• Biostatistics
• Survival Analysis

Background:

• Traditional fixed-design clinical trials are sensitive to pre-specified parameters like treatment effect and event rates.
• Misspecification of these parameters can lead to underpowered or overpowered trials, compromising study integrity.
• Flexible trial designs offer adaptive modification capabilities at interim analyses to address these limitations.

Purpose of the Study:

• To introduce and evaluate a flexible, adaptive trial design with sample size re-evaluation for survival trials.
• To assess the performance of this design, particularly when initial key parameters are misspecified.
• To provide practical guidance for selecting trial parameters in flexible designs.

Main Methods:

• Development of a flexible trial design incorporating sample size re-evaluation at interim analyses.
• Simulation studies and analysis of properties in practical settings to evaluate the design's performance.
• Focus on preserving initially specified global error rates despite design modifications.

Main Results:

• The proposed flexible design demonstrates improved power control when initial parameters are misspecified.
• The method results in a reasonable increase in sample size, if any, mitigating risks of underpowering.
• The study provides practical guidelines for parameter selection in flexible survival trial designs.

Conclusions:

• Flexible trial designs with adaptive sample size re-evaluation are effective for survival trials.
• This approach enhances statistical power and maintains trial integrity when faced with parameter uncertainty.
• The findings support the adoption of adaptive designs for more robust clinical trial planning and execution.