Methodology and Application of Adaptive and Sequential Approaches in Contemporary Clinical Trials

Table 1

Summary of main Phase I clinical trial designs.

Designs	Advantages	Disadvantages
Standard 3 + 3 design	Robust.; Simple.; Easy to carry out.	MTD is not a dose with any particular probability of DLT, but in the range from 20% to 25% DLT.; Can not estimate MTD with target probability of DLT <20% or >33%.; Not all toxicity data of all patients are used to determine the MTD.; Many patients are likely to be treated at low doses.
ID isotonic design	Only assumes a monotonically increasing relationship between dose and toxicity.; Semiparametric.; Can estimate MTD with different TTL (0~100%).; Robust and easy to use.; Good for combination of multiple drugs and treatments.	The accuracy of MTD may not be as good as CRM or EWOC.; The trial efficiency may not be as good as CRM or EWOC.
CRM continual reassessment method	Fit parametric model for dose toxicity relationship.; Adaptive optimal design.; Accurate estimation of MTD.; Improved trial efficiency.; Allow flexible MTD with different TTL.	High risk of patients being treated with over toxic dosages.; If the parametric model is not reliable, the result could be questionable.; May fail to find MTD.
EWOC escalation with overdose control	Includes all advantages of CRM.; Controls the overdosing probability.; Further improves MTD accuracy and trial efficiency.	If the parametric model is not reliable, the result could be questionable.; May fail to find MTD.