Novel Statistical Designs for Phase I/II and Phase II Clinical Trials With Dose-Finding Objectives

Abstract

In modern drug development, there has been an increasing interest in adaptive clinical trials—research designs that allow judicious modification of certain aspects of an ongoing clinical trial based on prespecified criteria according to accumulating data to achieve predetermined experimental objectives. A particularly important application of adaptive designs is in phase I and II stages of drug development. Many novel adaptive designs have been proposed in the context of phase I oncology trials of cytotoxic agents where acceptable toxicity frequently translates into therapeutic response. However, an assessment of efficacy measurements based on biomarkers in early development is also very important. The current paper gives an overview of adaptive designs for early development studies that utilize efficacy measurements in design adaptation rules. These include seamless phase I/II designs, where efficacy and safety considerations are both incorporated in dose-finding objectives, and phase II dose-response studies, which typically aim at establishing a dose-response relationship with respect to some efficacy outcome and at identifying the most promising doses to be tested in subsequent confirmatory trials. The authors discuss statistical, logistical, and regulatory aspects of these designs and provide perspectives on their applications in modern clinical trials.