Proceedings: DIA 2019 Global Annual Meeting

DIA GAM 2019
Master Protocol Trials:
From Innovation to Operationalization

Debra Michaels
DIA

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lthough only few people in the research and development enterprise have had the opportunity to work with a master protocol trial, it is difficult not to be aware of the excitement surrounding these innovative trials. “Innovative” in this case does not mean new: the I-SPY 2 trial was launched in 2010 as an evolution of the I-SPY1 trial that began in 2006. The LUNG-MAP trial of the National Cancer Institute was launched in 2014, and the EPAD (European Prevention of Alzheimer’s Dementia) study in 2016. Since then, new master protocol trials either have been launched (the MyDRUG trial of the Multiple Myeloma Research Foundation in 2018, and the GBM AGILE trial of the Global Coalition for Adaptive Research in June, 2019) or are in active start-up mode (such as the Precision Promise of the Pancreatic Cancer Action Network, set to launch in 2019).

Despite some confusion around the lexicon of master protocols, their benefits and promise are clear. These overarching trial structures, with key design components and operational aspects shared across multiple trials or substudies, can be used to assess one or more interventions in multiple diseases or disease subtypes. Speaking at the recent DIA Global Annual Meeting, Meredith Buxton, Chief Operating Officer of the Global Coalition for Adaptive Research, said “Drug development is (currently) a long and costly process that impedes the timely delivery of newly approved agents and devices. There is an opportunity for master protocols and platform trials, with their advanced designs and process-oriented infrastructures, to overcome these challenges.”

Key Takeaways

  • Master protocol trials, whether basket, umbrella, or platform trials, are collaborative endeavors with the ultimate goal of speeding the discovery and development of cures for patients with deadly diseases. Additionally, all collaborating stakeholders realize benefits from master protocol trials.
  • The design, start-up, and operational aspects of master protocol trials can be complex, but these trials face the same challenges as traditional clinical trials. With appropriate planning, challenges can be overcome, and unique benefits can be realized.
  • Open communication about uncertainties around master protocols and traditional change management efforts have lessened hesitation about collaboration, especially cross-industry, and resistance to new approaches within organizations.
Among master protocol designs, the Adaptive Platform Trial (APT) is discussed most frequently because its structure can support the evaluation of multiple treatments for several subgroups simultaneously, under a single master protocol. A trial network is formed and utilizes a shared infrastructure, with common design and protocol elements, control arm sharing, and coordinated data collection. Once set up, the shared infrastructure and processes increase efficiency and reduce the need to “reinvent the wheel” when new drugs move into the study. The shared control arm reduces the number of patients exposed to placebo and maximizes the number who can potentially benefit from treatment arms. Non-responding patients in a treatment arm spend less time exposed to drugs that are ineffective for them and, depending on the design, can be re-randomized to another arm, increasing the probability of finding effective, safe medications for more patients. Data sharing across compounds and indications enhances the use of historical data and speeds the learning process for the trial. Operational efficiencies extend to the clinical trial investigation sites, and an added benefit is that one site may participate in multiple arms of the trial, thus offering its patients a wider portfolio of treatment options.

FDA has shown a strong commitment to master protocols. Last fall, the FDA issued a draft guidance on the use of master protocols to expedite the development of oncology drugs and biologics. Applications of master protocol design need not be restricted to oncology, and trial sponsors are encouraged to begin discussion with FDA staff early in the planning stages of these trials.

SPEAKERS AND PANELISTS

MaryAnn Morgan-Cox, Senior Director, Immunology Design Hub, Eli Lilly and Company (Chair)

Meredith Buxton, Chief Operating Officer, Global Coalition For Adaptive Research

Mitzi Allred, Director Clinical Operations; Head, Clinical Content Standards, Merck & Co., Inc.

Karen Lynn Price, Senior Research Advisor, Statistical Innovation Center, Eli Lilly and Company

“Operationally, master protocol trials are perceived as complex—and they are. The additional planning required increases start-up time, but the efficiencies gained outweigh the extra effort as the trial continues,” says Buxton. Adaptive platform trials are long-running, sometimes designed as perpetual trials, and the upfront investment of effort is repaid over and over through the years. The growing experience with ongoing master protocol studies has highlighted key areas for operational consideration. To preserve the key tenets of these trials, including flexible but structured and uniform processes, focus, efficiency, and adaptability, particular care must be taken with the planning of key aspects of the trial. These include trial site selection, staff training, data management (data collection, cost, and sharing), and safety management, among others. As with all trials, it is critical to establish and actively monitor metrics to ensure GCP compliance and data integrity, and especially to anticipate operational hurdles and devise prospective methods to catch them early. Tools such as the TransCelerate Common Protocol Template (CPT) may be helpful in creating a basic framework for the governance of the master protocol trial and in guiding the development of uniform processes, according to Mitzi Allred, Director, Head Clinical Content Standards, at Merck Sharp & Dohme Corp. In multi-party collaborations, companies using the CPT can better prepare to “plug in” to new arms of the study.
As a new paradigm for clinical research, master protocol trials may encounter resistance to adoption. Within organizations, the identification of champions to advocate and to help work through complex issues is important. MaryAnn Morgan-Cox, Senior Director at the Immunology Design Hub, and Karen Price, Senior Research Advisor at the Statistical Innovation Center, Eli Lilly and Company, point out that a cross-disciplinary team of clinical development, statistics, and clinical operations champions, for example, can be particularly effective. They emphasize that open-mindedness, honest communication about uncertainties versus true risks, and solution-focused discussions are key to getting staff on board and contributing to forward movement in implementing master protocol trials. Sometimes a formal change management process may be necessary, but, says Morgan-Cox, “The ecosystem is ready for a change.”
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