Randomized Clinical Trials With Biomarkers: Design Issues

TLDR

Biomarker tests that inform treatment decisions are essential for personalized cancer care, yet their clinical utility can only be definitively assessed through large randomized clinical trials, making efficient trial design critical for timely implementation. The authors aim to guide the design and interpretation of such trials by providing an in‑depth comparison of the advantages and disadvantages of commonly used designs. Their discussion focuses on efficiency comparisons, special interim monitoring challenges inherent to these complex trials, and illustrates key points with examples from ongoing and completed studies. They conclude that, in most circumstances, randomized biomarker‑stratified designs—using the biomarker to guide analysis but not treatment assignment—offer the most rigorous assessment of biomarker clinical utility.

Abstract

Clinical biomarker tests that aid in making treatment decisions will play an important role in achieving personalized medicine for cancer patients. Definitive evaluation of the clinical utility of these biomarkers requires conducting large randomized clinical trials (RCTs). Efficient RCT design is therefore crucial for timely introduction of these medical advances into clinical practice, and a variety of designs have been proposed for this purpose. To guide design and interpretation of RCTs evaluating biomarkers, we present an in-depth comparison of advantages and disadvantages of the commonly used designs. Key aspects of the discussion include efficiency comparisons and special interim monitoring issues that arise because of the complexity of these RCTs. Important ongoing and completed trials are used as examples. We conclude that, in most settings, randomized biomarker-stratified designs (ie, designs that use the biomarker to guide analysis but not treatment assignment) should be used to obtain a rigorous assessment of biomarker clinical utility.