The i3+3 design for phase I clinical trials.

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 (this https URL) 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.