Master Protocol Trial Design for Efficient and Rational Evaluation of Novel Therapeutic Oncology Devices

Abstract

Historically, the gold standard for evaluation of cancer therapeutics, including medical devices, has been the randomized clinical trial. Although high-quality clinical data are essential for safe and judicious use of therapeutic oncology devices, class II devices require only preclinical data for US Food and Drug Administration approval and are often not rigorously evaluated prior to widespread uptake. Herein, we review master protocol design in medical oncology and its application to therapeutic oncology devices, using examples from radiation oncology. Unique challenges of clinical testing of radiation oncology devices (RODs) include patient and treatment heterogeneity, lack of funding for trials by industry and health-care payers, and operator dependence. To address these challenges, we propose the use of master protocols to optimize regulatory, financial, administrative, quality assurance, and statistical efficiency of trials evaluating RODs. These device-specific master protocols can be extrapolated to other devices and encompass multiple substudies with the same design, statistical considerations, logistics, and infrastructure. As a practical example, we outline our phase I and II master protocol trial of stereotactic magnetic resonance imaging-guided adaptive radiotherapy, which to the best of our knowledge is the first master protocol trial to test a ROD. Development of more efficient clinical trials is needed to promote thorough evaluation of therapeutic oncology devices, including RODs, in a resource-limited environment, allowing more practical and rapid identification of the most valuable advances in our field.

Figure 1.

Schema for phase I and II master protocol evaluating magnetic resonance imaging–guided linear accelerator (MR-Linac) for online-adaptive stereotactic body radiotherapy (SBRT) in several disease sites. Feasibility outcomes are pooled for the phase I study, allowing more rapid determination of this outcome. For the phase II study, cancer type–agnostic outcomes will be pooled across disease sites that share similar technical and toxicity consideration (eg, fatigue among all substudies and acute gastrointestinal toxicity among the pancreatic cancer and renal tumor SBRT substudies). The master protocol is written to allow seamless addition and removal of substudies via amendment. MRI = magnetic resonance imaging.