The continual reassessment method: comparison of Bayesian stopping rules for dose-ranging studies

S Zohar, S Chevret
Statistics in Medicine 2001 October 15, 20 (19): 2827-43
The continual reassessment method (CRM) provides a Bayesian estimation of the maximum tolerated dose (MTD) in phase I clinical trials and is also used to estimate the minimal efficacy dose (MED) in phase II clinical trials. In this paper we propose Bayesian stopping rules for the CRM, based on either posterior or predictive probability distributions that can be applied sequentially during the trial. These rules aim at early detection of either the mis-choice of dose range or a prefixed gain in the point estimate or accuracy of estimated probability of response associated with the MTD (or MED). They were compared through a simulation study under six situations that could represent the underlying unknown dose-response (either toxicity or failure) relationship, in terms of sample size, probability of correct selection and bias of the response probability associated to the MTD (or MED). Our results show that the stopping rules act correctly, with early stopping by using the two first rules based on the posterior distribution when the actual underlying dose-response relationship is far from that initially supposed, while the rules based on predictive gain functions provide a discontinuation of inclusions whatever the actual dose-response curve after 20 patients on average, that is, depending mostly on the accumulated data. The stopping rules were then applied to a data set from a dose-ranging phase II clinical trial aiming at estimating the MED dose of midazolam in the sedation of infants during cardiac catheterization. All these findings suggest the early use of the two first rules to detect a mis-choice of dose range, while they confirm the requirement of including at least 20 patients at the same dose to reach an accurate estimate of MTD (MED). A two-stage design is under study.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Trending Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"