Phase I-II clinical trial design: a state-of-the-art paradigm for dose finding

Area of Science:

• Clinical trial design
• Pharmacology
• Biostatistics

Background:

• Conventional phase I trials for dose-finding are limited as they focus solely on toxicity, not the optimal risk-benefit balance.
• The maximum tolerated dose (MTD) is often used for expansion cohorts, which may not be the most beneficial dose for patients.

Purpose of the Study:

• To introduce and evaluate the EffTox design, a novel phase I-II approach for determining the optimal dose.
• To compare the EffTox design's performance against traditional methods like the 3+3 design and the continuous reassessment method.

Main Methods:

• The study reviews the phase I-II paradigm and the EffTox design.
• A computer simulation study was conducted to compare EffTox with the 3+3 design and continuous reassessment method.

Main Results:

• The EffTox design demonstrated a higher probability of identifying the optimal dose.
• Simulations indicated that the EffTox design treats more patients at the optimal dose compared to conventional methods.

Conclusions:

• The EffTox design offers a superior approach to finding the optimal phase-2 recommended dose (P2RD) by integrating efficacy and toxicity.
• This design provides a more coherent and efficient method for clinical decision-making in early-phase drug development.