Background An extensive literature has covered the statistical properties of the
Continual Reassessment Method (CRM) and the modifications of this method. While there
are some applications of CRM designs in recent Phase I trials, the standard method
(SM) of escalating doses after three patients with an option for an additional three
patients SM remains very popular, mainly due to its simplicity. From a practical
perspective, clinicians are interested in designs that can estimate the MTD using
fewer patients for a fixed number of doses, or can test more dose levels for a given
sample size.
Purpose This article compares CRM-based methods with the SM in terms of the number of
patients needed to reach the MTD, total sample size required, and trial duration.
Methods The comparisons are performed under two alternative schemes: a fixed or a
varying sample approach with the implementation of a stopping rule. The stopping rule
halts the trial if the confidence interval around the MTD is within a pre-specified
bound. Our simulations evaluated several CRM-based methods under different scenarios
by varying the number of dose levels from five to eight and the location of the true
MTD.
Results CRM and SM are comparable in terms of how fast they reach the MTD and the
total sample size required when testing a limited number of dose levels (≤5), but as
the number of dose levels increases, CRM reaches the MTD in fewer patients when used
with a fixed sample of 20 patients. However, a sample size of 20—25 patients is not
sufficient to achieve a narrow precision around the estimated toxicity rate at the
MTD.
Limitations We focused on methods with practical design features that are of interest to
clinicians. However, there are several alternative CRM-based designs that are not
investigated in this manuscript, and hence our results are not generalizable to other
designs.
Conclusions We show that CRM-based methods are an improvement over the SM in terms of
accuracy and optimal dose allocation in almost all cases, except when the true dose
is among the lower levels. Clinical Trials 2008; 5: 465—477.
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