Safety Concerns of the 3+3 Design: A Comparison to the mTPI Design

Conference paper
Part of the Springer Proceedings in Mathematics & Statistics book series (PROMS, volume 55)


The 3 + 3 design is the most common choice by clinicians for phase I dose-escalation oncology trials. In recent reviews, more than 90 % of phase I trials are based on the 3 + 3 design (Rogatko et al., Journal of Clinical Oncology 25:4982–4986, 2007). The simplicity and transparency of 3 + 3 allows clinicians to conduct dose escalations in practice with virtually no logistic cost, and trial protocols based on 3 + 3 pass IRB and biostatistics reviews briskly. However, the performance of 3 + 3 has never 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 magnitude smaller than model-based designs. In this paper, 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., Clinical Trials 7:653–663, 2010), a newly developed adaptive method. In addition, compared to mTPI, 3 + 3 does not provide higher probabilities in identifying the correct MTD even when the sample size is matched. Given the fact that the mTPI design is equally transparent, simple and costless to implement with free software, and more flexible in practical situations, we highly encourage more adoptions of the mTPI design in early dose-escalation studies whenever the 3 + 3 design is also considered. We provide a free software to allow direct comparisons of the 3 + 3 design to other model-based designs in simulation studies with matched sample sizes.


Maximum Tolerate Dose Adaptive Design Simulated Trial Average Sample Size Maximum Sample Size 
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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Center for Clinical and Research Informatics, NorthShoreUniversity HealthSystemEvanstonUSA
  2. 2.Office of Biostatistics/Office of Translational Sciences, Center for Drug Evaluation and ResearchU.S. Food and Drug AdministrationSilver SpringUSA

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