Toxicity equivalence range design (TEQR): a practical Phase I design.

Area of Science:

• Biostatistics
• Clinical Trial Design
• Pharmacometrics

Background:

• The standard 3+3 design is widely used in Phase I trials for dose escalation.
• However, the 3+3 design has limitations in accurately estimating toxicity at the maximum tolerated dose (MTD).
• The continual reassessment method (CRM) offers an alternative but faces challenges in statistical and implementation complexity.

Purpose of the Study:

• Introduce the target equivalence range (TEQR) design as a frequentist implementation of the modified toxicity probability interval (mTPI) design.
• Compare the TEQR design against the standard 3+3 design and other competitors (mTPI, CRM).
• Evaluate operating characteristics and ease of implementation for dose escalation designs.

Main Methods:

• Describe four competing designs: 3+3, mTPI, CRM, and TEQR.
• Utilize simulated trials to compare operating characteristics.
• Assess the ease of implementation for each design.

Main Results:

• The TEQR design demonstrates superior performance over the 3+3 design in several key areas.
• Specifically, TEQR shows improvements in selecting the MTD near the target toxicity level, patient allocation to MTD levels, and overall toxicity rates.
• TEQR also offers enhanced accuracy and precision in estimating toxicity rates at the MTD, performing comparably to CRM and mTPI.

Conclusions:

• The TEQR design presents a viable alternative to the 3+3 design for Phase I trials.
• It offers improved operating characteristics and ease of implementation.
• The TEQR design provides insights into potential anti-cancer activity at the MTD, with a supporting R package available.