Translation of Innovative Dose-Finding Designs Into Practical Phase I Trials

• Activity Number: 226
• Type: Topic Contributed
• Date/Time: Monday, August 5, 2013 : 2:00 PM to 3:50 PM
• Sponsor: Biometrics Section
• Author(s): Yuan Ji*+ and Sue-Jane Wang
• Companies: NorthShore Univ. HealthSystem Research Institute and Food and Drug Administration
• Keywords: Phase I ; Dose finding ; Toxicity probability interval ; MTD ; Adaptive designs ; Practical designs

Abstract

The 3+3 design is the most common choice by clinicians for phase I dose-escalation oncology trials. In recent reviews, more than 95% of phase I trials are based on the 3+3 design. However, the performance of 3+3 has rarely been compared to model-based designs under simulation studies with matched sample sizes. In the vast majority of statistical literature, 3+3 has been shown to be inferior in identifying the true MTD, although the sample size required by 3+3 is often orders of magnitude smaller than model-based designs. Through comparative simulation studies with matched sample sizes, we demonstrate that the 3+3 design has higher risks of exposing patients to toxic doses above the MTD than the mTPI design (Ji et al., 2010), a newly developed adaptive method. In addition, compared to mTPI, 3+3 does not yield higher probabilities in identifying the correct MTD even when the sample size is matched. Given that the mTPI design is equally as transparent, costless to implement with free software, and more flexible in practical situations, we highly encourage its adoption in early dose-escalation studies whenever the 3+3 design is also considered.