Statistical controversies in clinical research: requiem for the 3 + 3 design for phase I trials

Background: More than 95% of published phase I trials have used the 3 + 3 design to identify the dose to be recommended for phase II trials. However, the statistical community agrees on the limitations of the 3 + 3 design compared with model-based approaches. Moreover, the mechanisms of action of targeted agents strongly challenge the hypothesis that the maximum tolerated dose constitutes the optimal dose, and more outcomes including clinical and biological activity increasingly need to be taken into account to identify the optimal dose.

Patients and methods: We review key elements from clinical publications and from the statistical literature to show that the 3 + 3 design lacks the necessary flexibility to address the challenges of targeted agents.

Results: The design issues raised by expansion cohorts, new definitions of dose-limiting toxicity and trials of combinations are not easily addressed by the 3 + 3 design or its extensions.

Conclusions: Alternative statistical proposals have been developed to make a better use of the complex data generated by phase I trials. Their applications require a close collaboration between all actors of early phase clinical trials.