Simple benchmark for complex dose finding studies

Biometrics. 2014 Jun;70(2):389-97. doi: 10.1111/biom.12158. Epub 2014 Feb 25.


While a general goal of early phase clinical studies is to identify an acceptable dose for further investigation, modern dose finding studies and designs are highly specific to individual clinical settings. In addition, as outcome-adaptive dose finding methods often involve complex algorithms, it is crucial to have diagnostic tools to evaluate the plausibility of a method's simulated performance and the adequacy of the algorithm. In this article, we propose a simple technique that provides an upper limit, or a benchmark, of accuracy for dose finding methods for a given design objective. The proposed benchmark is nonparametric optimal in the sense of O'Quigley et al. (2002, Biostatistics 3, 51-56), and is demonstrated by examples to be a practical accuracy upper bound for model-based dose finding methods. We illustrate the implementation of the technique in the context of phase I trials that consider multiple toxicities and phase I/II trials where dosing decisions are based on both toxicity and efficacy, and apply the benchmark to several clinical examples considered in the literature. By comparing the operating characteristics of a dose finding method to that of the benchmark, we can form quick initial assessments of whether the method is adequately calibrated and evaluate its sensitivity to the dose-outcome relationships.

Keywords: Combination therapy; Efficacy-toxicity tradeoff; Multiple toxicities; Phase I trials; Phase I/II trials; Utility scores.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Algorithms
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / toxicity
  • Bayes Theorem
  • Benchmarking / statistics & numerical data
  • Biometry / methods*
  • Boronic Acids / administration & dosage
  • Boronic Acids / toxicity
  • Bortezomib
  • Clinical Trials, Phase I as Topic / statistics & numerical data*
  • Clinical Trials, Phase II as Topic / statistics & numerical data
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / toxicity
  • Humans
  • Lymphoma / drug therapy
  • Models, Statistical
  • Pyrazines / administration & dosage
  • Pyrazines / toxicity
  • Stroke / drug therapy
  • Urinary Bladder Neoplasms / drug therapy


  • Antineoplastic Agents
  • Boronic Acids
  • Fibrinolytic Agents
  • Pyrazines
  • Bortezomib