Sequential designs for phase I clinical trials with late-onset toxicities

Biometrics. 2000 Dec;56(4):1177-82. doi: 10.1111/j.0006-341x.2000.01177.x.


Traditional designs for phase I clinical trials require each patient (or small group of patients) to be completely followed before the next patient or group is assigned. In situations such as when evaluating late-onset effects of radiation or toxicities from chemopreventive agents, this may result in trials of impractically long duration. We propose a new method, called the time-to-event continual reassessment method (TITE-CRM), that allows patients to be entered in a staggered fashion. It is an extension of the continual reassessment method (CRM; O'Quigley, Pepe, and Fisher, 1990, Biometrics 46, 33-48). We also note that this time-to-toxicity approach can be applied to extend other designs for studies of short-term toxicities. We prove that the recommended dose given by the TITE-CRM converges to the correct level under certain conditions. A simulation study shows our method's accuracy and safety are comparable with CRM's while the former takes a much shorter trial duration: a trial that would take up to 12 years to complete by the CRM could be reduced to 2-4 years by our method.

MeSH terms

  • Anticarcinogenic Agents / toxicity
  • Antineoplastic Agents / toxicity
  • Clinical Trials, Phase I as Topic / methods*
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Follow-Up Studies
  • Humans
  • Neoplasms / drug therapy
  • Neoplasms / prevention & control
  • Neoplasms / radiotherapy
  • Radiotherapy / adverse effects
  • Reproducibility of Results
  • Research Design*
  • Safety
  • Time Factors
  • Treatment Failure


  • Anticarcinogenic Agents
  • Antineoplastic Agents