Study Design Considerations for Trials to Evaluate Multi-Cancer Early Detection Assays for Clinical Utility

Blood-based assays using various technologies and biomarkers are in commercial development for the purpose of detecting multiple cancer types concurrently at an early-stage of disease. These multi-cancer early detection (M.C.E.D) assays have the potential to improve the detection of cancers, particularly those for which no current screening modality exists. However, the unknown clinical benefits and harms of using M.C.E.D assays for cancer screening necessitate the development and implementation of a randomized controlled trial (RCT) to ascertain their clinical effectiveness. This was the consensus of experts at a National Cancer Institute-hosted workshop to discuss initial design concepts for such a trial. Using these assays to screen simultaneously for multiple cancers poses novel uncertainties for patient care compared to conventional screening tests for single cancers, such as: establishing the diagnostic work-up to confirm the presence of cancer at any organ site; clarifying appropriate follow-up for a positive assay for which there is no definitive diagnosis; identifying potential harms such as overdiagnosis of indolent disease; determining clinically effective and efficient strategies for disseminating M.C.E.D. screening in real-world practice; and understanding the ethical implications, such as potentially alleviating or exacerbating existing health disparities. These assays present new and complex challenges for designing an RCT. Issues that emerged from the meeting centered around the need for a flexibly designed, clinical utility RCT to rigorously capture the evidence required to fully understand the net benefit of this promising technology. Specific topic areas were endpoints, screening protocols, recruitment, diagnostic pathway, pilot phase, data elements, specimen collection, and ethical considerations.