Dose-finding based on efficacy-toxicity trade-offs

Biometrics. 2004 Sep;60(3):684-93. doi: 10.1111/j.0006-341X.2004.00218.x.


We present an adaptive Bayesian method for dose-finding in phase I/II clinical trials based on trade-offs between the probabilities of treatment efficacy and toxicity. The method accommodates either trinary or bivariate binary outcomes, as well as efficacy probabilities that possibly are nonmonotone in dose. Doses are selected for successive patient cohorts based on a set of efficacy-toxicity trade-off contours that partition the two-dimensional outcome probability domain. Priors are established by solving for hyperparameters that optimize the fit of the model to elicited mean outcome probabilities. For trinary outcomes, the new algorithm is compared to the method of Thall and Russell (1998, Biometrics 54, 251-264) by application to a trial of rapid treatment for ischemic stroke. The bivariate binary outcome case is illustrated by a trial of graft-versus-host disease treatment in allogeneic bone marrow transplantation. Computer simulations show that, under a wide rage of dose-outcome scenarios, the new method has high probabilities of making correct decisions and treats most patients at doses with desirable efficacy-toxicity trade-offs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abciximab
  • Algorithms
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / toxicity
  • Bayes Theorem
  • Biometry
  • Clinical Trials, Phase I as Topic / statistics & numerical data*
  • Clinical Trials, Phase II as Topic / statistics & numerical data*
  • Dose-Response Relationship, Drug
  • Graft vs Host Disease / drug therapy
  • Humans
  • Immunoglobulin Fab Fragments / administration & dosage
  • Immunoglobulin Fab Fragments / toxicity
  • Models, Statistical
  • Pentostatin / administration & dosage
  • Pentostatin / toxicity
  • Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / toxicity
  • Stroke / drug therapy
  • Tissue Plasminogen Activator / administration & dosage
  • Tissue Plasminogen Activator / toxicity


  • Antibodies, Monoclonal
  • Immunoglobulin Fab Fragments
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Recombinant Proteins
  • Pentostatin
  • reteplase
  • Tissue Plasminogen Activator
  • Abciximab