Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding

Area of Science:

• Oncology
• Clinical Trial Design
• Biostatistics

Background:

• The modified Fibonacci up-and-down (MF-UD) method is the most common design for dose-finding in cancer trials.
• MF-UD designs often result in suboptimal patient dosing and are less effective than alternative methods.
• The US FDA's 2012 decision favoring accelerated titration (AT) over Escalation with Overdose Control (EWOC) prompted this comparative study.

Purpose of the Study:

• To compare the operating characteristics of the accelerated titration (AT) design and three versions of the Escalation with Overdose Control (EWOC) design.
• To evaluate the performance of AT and EWOC in dose-finding cancer trials.
• To assess the safety and efficacy of AT versus EWOC from both clinical investigator and patient perspectives.

Main Methods:

• An extensive simulation study was conducted to compare AT and EWOC designs.
• Operating characteristics of each design were evaluated under various practical scenarios.
• Performance metrics included bias, mean square error, and the proportion of patients treated at optimal doses.

Main Results:

• The AT design demonstrated poorer operating characteristics compared to all three EWOC versions.
• EWOC designs showed uniformly higher proportions of patients receiving doses within the optimal range of the maximum tolerated dose (MTD).
• EWOC designs exhibited lower bias and mean square error, indicating improved performance over AT.

Conclusions:

• EWOC designs are preferable to AT designs for dose-finding cancer trials due to superior operating characteristics.
• EWOC designs enhance patient safety and ensure a higher proportion of patients receive optimal therapeutic doses.
• The findings suggest a re-evaluation of FDA's stance on EWOC for first-in-human trials is warranted.