The i3+3 Design for Phase I Clinical Trials

TL;DR

The paper introduces the i3+3 design, a simple, rule-based method for phase I clinical trials that improves safety and accuracy in identifying the maximum tolerated dose, matching the performance of more complex model-based designs.

Contribution

The i3+3 design offers a new rule-based approach that enhances safety and reliability in dose-finding trials without requiring complex statistical modeling.

Findings

i3+3 outperforms 3+3 in safety and MTD identification

i3+3 has comparable performance to model-based designs

The design is simple, transparent, and easy to implement

Abstract

Purpose: The 3+3 design has been shown to be less likely to achieve the objectives of phase I dose-finding trials when compared with more advanced model-based designs. One major criticism of the 3+3 design is that it is based on simple rules, does not depend on statistical models for inference, and leads to unsafe and unreliable operating characteristics. On the other hand, being rule-based allows 3+3 to be easily understood and implemented in practice, making it the first choice among clinicians. Is it possible to have a rule-based design with great performance? Methods: We propose a new rule-based design called i3+3, where the letter "i" represents the word "interval". The i3+3 design is based on simple but more advanced rules that account for the variabilities in the observed data. We compare the operating characteristics for the proposed i3+3 design with other popular phase I designs by simulation. Results: The i3+3 design is far superior than the 3+3 design in trial safety and the ability to identify the true MTD. Compared with model-based phase I designs, i3+3 also demonstrates comparable performances. In other words, the i3+3 design possesses both the simplicity and transparency of the rule-based approaches, and the superior operating characteristics seen in model-based approaches. An online R Shiny tool (https://i3design.shinyapps.io/i3plus3/) is provided to illustrate the i3+3 design, although in practice it requires no software to design or conduct a dose-finding trial. Conclusion: The i3+3 design could be a practice-altering method for the clinical community.