Contributed Commentary by Kathy Giusti, Richard Hamermesh, and Bradley Smith

June 4, 2019 | Healthcare research often gets caught up in conflicting priorities among drug makers, research institutions, patient organizations, and regulators—and nowhere is this more prevalent than in clinical research.

Both pharma and nonprofits want to take advantage of the speed and flexibility of master protocols for research in precision medicine. However, nonprofits prioritize data-sharing, and look to find the best drugs for patients, while manufacturers are concerned with data quality and trial infrastructure, and look to provide the widest patient access. At the end of the day, though, we all share the same goal: bringing new, safe, effective drugs to save and improve lives.

Master protocols for clinical trials offer the potential of efficient, broad, flexible hypotheses-testing. As noted by Janet Woodcock, Director for the FDA’s Center of Drug Evaluation and Research, they present two types of innovation: first, a streamlined logistical infrastructure that can improve the data output; and second, innovative statistical approaches that allow more objectives to be met. However, master protocols can be challenging as they require a significant investment of time and resources to get off the ground and face the above-mentioned conflicting priorities.

While many have discussed pros and cons of master protocols, we believed it was time to go further: to define exactly why and how to employ a master protocol. And so, we convened experts on some of the highest-profile master protocols in oncology, and set them an unprecedented challenge: not only to speak bluntly about challenges they’ve faced, but to help define the “sweet spot”—the best circumstances for master protocols—and how to mitigate the risks inherent in their development and execution.

Unusually, our participants included life-sciences executives as well as leaders of nonprofit organizations leading master protocol trials: Beat AML, MyDRUG, GBM Agile, and Precision Promise. At this unique gathering, we agreed on a set of conditions wherein industry and nonprofit organizations can work together on master protocols most fruitfully, and on a set of preventative actions to de-risk them.

We defined the “sweet spot” as situations in which one or more of the following conditions exist:

• Therapeutic categories that combine an unmet clinical need with opportunity in the appropriate stage of pharmaceutical development. Often, these areas are “graveyards”—areas that have seen many prior investigational drugs fail.
• Therapeutics that are being investigated for secondary, or niche, indications, rather than core or first indications for the pharma or biotech partner.
• Studies to investigate complex combination therapies, especially in immuno-oncology, or indication expansions.

An additional “sweet spot” for biotech is the employment of simple or modular master protocols that can help organizations advance more rapidly to proof-of-concept and further funding.

After defining where and when to use a master protocol, we discussed the specifics of how to ensure its success. We agreed that risk mitigation should focus on four areas: legal, fundraising, business development, and execution.

• Legal issues, including questions of liability, as well as ownership of intellectual property and patient samples, require dedicated legal expertise familiar with these issues, and strong templates and relationships across legal and contracting staff.
• Fundraising is an everyday reality for nonprofit organizations, and gathering support for a new master protocol can be difficult. Taking advantage of an existing donor network can be the solution, but building a trustworthy clinical and business infrastructure is necessary. Royalty agreements and other models of revenue-stream development are beneficial.
• Business development—obtaining the best assets for a master protocol—requires dedicated staff focused on and experienced in building industry partnerships. This often entails patience and persistence in maintaining pipeline visibility and pharma relationships, to obtain access to drugs at the suitable time. 
• The last area of risk lies in execution, due to the complexity of master protocols. This risk may be addressed by strong study management by a small, dedicated, experienced staff within the nonprofit organization.

Our experts agreed that partners must be willing to take the time to build and demonstrate confidence in each other’s expertise and infrastructure. That thoughtfully built trust can be assisted by proceeding with agility. For example, a successful master protocol project can begin with a small number of different hypotheses, expanding after the study has begun to produce results.

Our candid discussion and findings are steps toward more fruitful master-protocol partnerships between nonprofits and life-sciences companies—partnerships driven by appreciation of what both sides bring toward our mutual goal of discovering new treatments better and faster. Master protocols aren’t a panacea, but done right, they can be an exciting way to improve research and save lives.

Kathy Giusti, a multiple myeloma patient, is the Co-Chair of the Harvard Business School Kraft Precision Medicine Accelerator and the Founder and Chief Mission Officer of the Multiple Myeloma Research Foundation (MMRF) and the Multiple Myeloma Research Consortium (MMRC). Kathy has more than two decades of experience in the pharmaceutical industry, previously holding senior positions at G.D. Searle and Merck. She’s been named on TIME 100 Most Influential People for her disruptive approach to fighting cancer and accelerating treatments. She can be reached at kgiusti@hbs.edu.

Richard G. Hamermesh is a senior fellow at Harvard Business School and the Co-Chair of the Harvard Business School Kraft Precision Medicine Accelerator. Richard has been instrumental in expanding the role of healthcare in MBA education and faculty research. He has taught multiple courses at the Harvard Business School, including creating and teaching the second-year MBA elective, Building Life Science Businesses, served on numerous boards, and has participated in the early stages in over 20 organizations. He can be reached at rhamermesh@hbs.edu.

Brad Smith is the Vice President of Translational Research at IQVIA, the leading human data sciences company. He has worked with biopharma and non-profit organizations to design clinical studies and advance precision medicine for over 15 years. Brad also leads the Clinical Team at the Harvard Business School Kraft Precision Medicine Accelerator, bringing together leaders of current master protocols to better understand successful innovation in clinical research. He can be reached at Brad.Smith@iqvia.com.