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With technology’s increasing ability to gather and analyze previously unmanageable data sets, and medicine’s forays into genomics and targeted therapies, the time of the master protocol may be at hand.
The innovative form of trial design known as a master protocol is gaining attention, particularly in oncology. “The widespread availability of next-generation genomic sequencing has opened the door to the development of precision oncology,” as experts have noted. With technology’s increasing ability to gather and analyze previously unmanageable data sets, and medicine’s forays into genomics and targeted therapies, the time of the master protocol may be at hand.
But what will it take to make the master protocol a standard in oncology research? When and under what circumstances is a master protocol appropriate and how can its use be optimized to drive patient impact?
Well-known past, ongoing, and planned master protocol studies suggested that significant progress has been made in the field establishing design and operational practices. The Harvard Business School (HBS) Kraft Precision Medicine Accelerator (referred to as “the Accelerator” throughout) saw the immense potential of the master protocol model and evidence of substantial progress. To better understand the landscape, the Accelerator brought on QuintilesIMS to conduct a review, based on primary and secondary research.
The Accelerator, with the help of QuintilesIMS, has taken on this rapidly evolving area of research-investigating past, current, and planned trials and interviewing experts from all facets of research, to understand current approaches and work with leaders to increase collaboration and patient impact across a range of cancers.
Master protocols in oncology research
Master protocols in oncology research are designed, as Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), puts it simply, “to answer more questions more efficiently and in less time.”
Various terms are currently used to describe study designs that differ from a traditional interventional Phase I, II, or III design, including adaptive, platform, or innovative design. Each of these terms have either specific meanings (adaptive) or are general (innovative). However, the term master protocol is well accepted to represent an ongoing trial intended for the addition or removal of drugs, arms, and study hypotheses.
Master protocols may or may not be adaptive, umbrella, or basket studies. They may be a collection of sub-studies or a complex statistical design or platform for rapid learning and decision-making. Whether umbrella, basket, or platform, a master protocol seeks to update the randomized clinical trial model for the genomic age.
Because of their ability to combine a variety of logistical, innovative, and correlative elements, while making it possible to learn more from smaller patient populations, many master protocols investigate targeted therapies, personalized medicine, and immune responses-frequently in oncology. Their ability to speed and streamline the trial process holds the promise for new, more targeted anti-cancer agents that can help more patients sooner.
The Accelerator Clinical Trials work stream
The Accelerator’s Clinical Trials work stream seeks to help advance trial design across cancers by:
The Accelerator partnered with QuintilesIMS to assess the landscape of master protocols, in order to understand and identify common challenges and best practices. This research was accomplished through interviews with external study leaders, statistical-design experts, and FDA staff, as well as literature research. Although this was a thorough effort, in practice, each of the studies continue to evolve quite rapidly. Thus, while the lessons persist in importance, the studies continue to change to meet their individual challenges and opportunities to further develop the master protocol model.
The QuintilesIMS project for the Accelerator began with an investigation into a range of master protocol trials, both ongoing and in development.
Well-known studies, started some years ago, have paved the way for a new model to conduct clinical research using master protocols: BATTLE and I-SPY 2, for lung and breast cancer, respectively, established the feasibility of a new paradigm for oncology trials, with a comprehensive approach to drugs and outcomes, supporting a collaborative research community. More recent ongoing examples include NCI-MATCH and newer trials as part of I-SPY 2. These significantly expand the scope of a master protocol study by either greatly expanding the collaborative organization and breadth of research within a master protocol study or increasing the number of drugs, arms, and partnerships to rapidly advance clinical research.
The QuintilesIMS review of current and planned master-protocol trials included the following:
Ongoing master protocols
Master protocols In preparation/planning
From the sources analyzed and experts consulted, it is possible to identify a variety of ways in which new and future trials can be improved by learning from the challenges met by past and current trials. The QuintilesIMS study found a set of general learnings, as well as two sets of more specific challenges to be met: those related to the study design, and those related to the operating model that a master protocol uses.
Design considerations vary, depending upon the strategic goal of the study, and result in varying levels of complexity (see Table 1).
Operating model learnings
Several operational factors can make it possible to develop an ecosystem that is collaborative while maintaining defined roles and responsibilities. Some of the critical elements that can ensure success are presented in Table 2.
Master protocol studies offer innovative potential to create a metamorphosis in oncology, offering new hope to patients and guidance to clinicians. Through this review with QuintilesIMS and based upon its breadth of work, the Accelerator seeks to help stakeholders across all cancers collaborate and learn, with the mission of bringing better drugs to patients faster. This landscape analysis has presented several sets of common challenges to master protocol trials-particularly related to study design and operations. The hope is that considering and addressing these research challenges can improve ongoing and future trials.
Based upon its research to date, the Accelerator hopes to hone its role in improving trial design, execution, and accrual across all cancers. To this end, the Accelerator will seek all opportunities for collaboration and guidance from many experts, including those from FDA.
The Accelerator seeks to find answers to additional questions through those collaborations. Those include, but are not limited to:
From involving stakeholders in new ways, to addressing financial concerns, to designing studies in new ways, there are a variety of ways to help the potential promise of master protocols be fulfilled. The Accelerator believes that the most powerful way to achieve this is to help participants across the healthcare industry collaborate in ever deeper and more innovative ways.
Bradley Smith, PhD, is Vice President, Translational Medicine, IQVIA; Kathy Giusti, MBA, is Founder, Multiple Myeloma Research Foundation, and Senior Fellow & Faculty Co-Chair, Kraft Precision Medicine Accelerator, Harvard Business School; Richard Hamermesh, DBA, Senior Fellow & Faculty Co-Chair, Kraft Precision Medicine Accelerator, Harvard Business School; Dixie-Lee W. Esseltine, MD, FRCPC, is Consultant and Clinical Trials Workstream Lead, Kraft Precision Medicine Accelerator, Harvard Business School