Model Based vs. Rule Based Designs in Phase I Dose Finding Clinical Trials

Abstract

A phase I clinical trial is needed when a new drug or treatment is first used in human
subjects. For ethnic reason, in such a trial, we have to carefully balance the possible benefit and
harm so that the benefit is maximized and harm is minimized, which deems that the design is
adaptive with small sample size, and is primarily focusing on safety end-points with efficacy
end-points as secondary ones.Various adaptive designs have been developed to find a Maximum Tolerant Dose
(MTD) with acceptable Dose Limiting Toxicity (DLT) rate pre-defined by investigators. Such
designs can be grouped into rule-based designs and model-based designs. The widely used
rule-based design is the 3+3 design1 whereas the most referenced model based design is Continuous
Reassessment Method (CRM).2 In a 3+3 design, dose escalation or de-escalation depends
on the toxicity of current dose through assigning group of 3 patients to a dose. It follows
an up and down algorithm or a random walk rule according to which we choose dose adaptively
based on toxicity.