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Summary

This study introduces a robust continual reassessment method (CRM) using the expectation-maximization (EM) algorithm to address limitations in phase I clinical trial dose finding. The new design improves efficiency and robustness in determining maximum tolerated dose (MTD).

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Area of Science:

Biostatistics
Clinical Trials
Pharmacometrics

Background:

The continual reassessment method (CRM) is standard for phase I clinical trials but faces limitations.
These include delayed toxicity observation and sensitivity to initial toxicity probability settings.

Purpose of the Study:

To develop a robust CRM design overcoming current limitations for accurate dose finding.
To enhance the efficiency and reliability of maximum tolerated dose (MTD) determination in early-phase trials.

Main Methods:

Utilized the expectation-maximization (EM) algorithm to handle unobserved toxicity outcomes as missing data.
Proposed parallel execution of multiple CRM models with model selection and averaging for robustness.
Employed simulation studies to evaluate the operating characteristics of the proposed EM-CRM designs.

Main Results:

The robust EM-CRM designs effectively addressed the limitations of delayed toxicity observation and sensitivity to prespecified probabilities.
Demonstrated improved maximum tolerated dose (MTD) selection accuracy.
Significantly shortened trial duration compared to traditional CRM methods.

Conclusions:

The proposed robust EM-CRM approach offers a more efficient and reliable method for dose-finding in phase I clinical trials.
This methodology enhances robustness and reduces trial time, making it a valuable advancement in clinical trial design.