A Phase II Design with Direct Assignment Option in Stage II for Initial Marker Validation

• Activity Number: 300
• Type: Contributed
• Date/Time: Tuesday, July 31, 2012 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Ming-Wen An*+ and Sumithra J. Mandrekar and Daniel J. Sargent
• Companies: Vassar College and Mayo Clinic and Mayo Clinic
• Keywords: clinical trials design ; direct assignment ; biomarkers ; simulation

Abstract

Biomarkers are critical to targeted therapies as they can identify patients who are more likely to benefit from a given treatment. Several clinical trial designs for biomarker directed therapy have been proposed including marker-stratified, sequential testing strategy, adaptive, and enrichment. These differ primarily in study population and randomization scheme. Recognizing the need for randomization yet acknowledging the possibility of promising but inconclusive results at interim, we propose a 2-stage marker+ Phase II design where Stage I randomizes patients equally to targeted therapy or control, while Stage II has the option to adopt direct assignment (DA; all patients receive targeted therapy). Simulations suggest relatively minimal loss in power (< 2%) and increase in Type I error rate (< 1%) for our design vs. a balanced randomized 2-stage design. We also explore effects of interim analysis timing and population shifts. Our design has potential appeal due to its DA option, while maintaining relatively desirable statistical properties. The DA, if adopted, provides an extended confirmation phase as an alternative to stopping the trial early for efficacy after Stage I.