An Evaluation of Phase I Clinical Trial Designs in the Continuous Dose-Response Setting

Stat Med. 2001 Aug 30;20(16):2399-408. doi: 10.1002/sim.903.


Both traditional phase I designs and the increasingly popular continual reassessment method (CRM) designs select an estimate of maximum tolerable dose (MTD) from among a set of prespecified dose levels. Although CRM designs use an implied dose-response model to select the next dose level, in general it is neither assumed nor necessary that this model be tied to the actual dose of a drug. In contrast, in our two-stage design the fitting of a dose-response model after data have been collected is a necessary feature of the design, and the MTD is not constrained to be one of the prespecified dose levels. We conducted a simulation study to evaluate the performance of the two-stage design, two likelihood-based CRM designs, and two traditional designs in estimating the MTD in situations where one assumes that an explicit dose-response model exists. Under a wide variety of dose-response settings, we examined the bias and precision of estimates, and the fraction of estimates that were extremely high or low. We also studied the effect of adding a model fitting step at the end of a traditional design or a CRM design. The best performance was achieved using the two-stage and CRM designs. Although the CRM designs generally had smaller bias, the two-stage design yielded equal or somewhat smaller precision in some cases. The addition of a model-fitting step slightly improved the precision of the CRM estimates and decreased the percentage of extreme estimates. Allowing interpolation between doses for updating during CRM did not improve overall performance.

Publication types

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

MeSH terms

  • Bias
  • Clinical Trials, Phase I as Topic / standards*
  • Data Interpretation, Statistical*
  • Dose-Response Relationship, Drug*
  • Drug Monitoring / methods
  • Humans
  • Likelihood Functions*
  • Research Design / standards*
  • Sensitivity and Specificity