In September 2018, the FDA provided a draft guidance on master protocols reflecting an increased interest in these designs by industry. This came after a 2017 editorial published by the Drs. Woodcock and LaVange from the FDA in the New England Journal of Medicine. In this guidance master protocol is defined as a protocol designed with multiple substudies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure. As the adoption of these innovative trial methods is on the rise, we speak with Jay Park, Director, Cytel, about the concept of master protocols, their importance and future growth potential. We take a closer look at their use in oncology trials where the increase in biomarker driven enrichment and stratification designs, as well as the use of companion diagnostics, ensures that master protocols are often adopted by trial investigators.
Cytel: Can you define master protocols and biomarker-guided trials, for us?
Jay Park (JP): Master protocols refer to a single overarching protocol developed to evaluate multiple hypotheses and the general goals are improving efficiency and establishing uniformity through standardization of procedures in the development and evaluation of different interventions. They are often classified as basket trials, umbrella trials and platform trials. The interest in these designs has increased in the industry, but there are several inconsistencies in the nomenclature. We also conducted a systematic review last year to describe master protocol reporting with the goal of facilitating the further development and spread of these innovative trial designs [Reporting of master protocols towards a standardized approach: A systematic review].
Cytel: Why are they becoming increasingly important in Oncology?
JP: I think we are heading towards precision medicine and precision in oncology has now become more of a reality. Over the last few years, we have seen immense advancements in genomics and other omics technology. The list of potential biomarkers that can be used to improve patient outcomes, especially in oncology, has grown considerably. Instead of just relying on histopathology information alone, we can use information on biomarkers in order to come up with ‘targeted therapies’ that can specifically target cancers based on their genetic mutations. Master protocols, especially umbrella and basket trials, are becoming very important to further make precision oncology a reality.
Also, oncology tends to have historical trends of methodological innovations. I am excited about how at Cytel we actively research precision medicine and help our clients and partners with it.
Cytel: Despite the popularity, why are they infrequently used?
JP: They are increasing vastly, in numbers. I believe this will change the future of clinical trial research, particularly drug development. With the approval process getting more difficult, different companies, patient advocacy groups, and other stakeholders are recognizing the need for collaboration. My colleagues and I have been a part of this discussion with the Clinical Trials Transformation Initiative (CTTI). It is a Duke and FDA initiative, and their objective is to improve the adoption of master protocols. In my experience, there is high interest in master protocols, but we need a culture shift. If you are a small biotech, then undertaking large-scale trials can be difficult unless you collaborate with other organizations that have similar interests.
Cytel: What role has the FDA and other regulatory bodies played in supporting a wider dissemination of master protocols?
JP: The FDA has played a very important role. In addition to their draft guidance on master protocols and the hallmark NEJM paper by Dr. Woodcock, in September 2019, the FDA has released a draft guidance on Complex Innovative Trial Designs (CID) for industry sponsors to have more effective interactions with the FDA regarding CID proposals that include master protocols. The European groups too have played an important role. The National Institute for Health Research (NIHR), Cancer Research UK (CRUK) and the Health Boards of Wales, Northern Ireland and Scotland have funded the Experimental Cancer Medicine Centres (ECMC) network to support wider dissemination of master protocols and other CIDs. They published their European consensus statement on CID cancer trials in January of this year.
We also cannot forget about global health. Few weeks ago (Feb 24, 2020), the World Health Organization (WHO) released their master protocol for Covid-19. While it does not have any basket and umbrella trial design components, it is nice to see the gaining momentum for master protocols in other research areas that are outside of oncology.
Cytel: What is the growth potential of master protocols over the coming years?
JP: The growth potential of master protocols is immense. Now is the time when number of master protocols will increase, and it will become the future norm of clinical trial research. Our group at Cytel is particularly interested in sorting the health inequities in the low- and middle-income group of countries. We are trying to not only describe the concept of master protocols but also increase its adoption among the researchers in these geographic regions.
Cytel: Do you see these trials going outside of oncology?
JP: Certainly, yes. But, not many. There is an example of an umbrella trial being conducted in an African country where they are using the patients’ history and their HIV resistance levels in separate therapies to come up with different risk stratification. Here, you are just using biomarkers or any other patient characteristics to determine which one has higher, lower or moderate risks.
The development is exciting but the areas outside of oncology have a lot more to catch up. This is largely because there is a better understanding of the molecular and biological mechanisms in cancer as compared to all other clinical areas. More efforts to improve awareness and training will be required to apply these innovative trial design methods to fields outside of oncology.
Join Cytel for a complimentary webinar on master protocols! Jay Park, Director, Cytel will introduce basket and umbrella trials and explore their extension to design in various contexts from the HIV epidemic in global health to expedited oncology trials.
About Jay Park
Jay is a Director for Cytel based in Vancouver, BC. He recently joined the company in December 2019 when MTEK Sciences was acquired by Cytel. His research interests include application of master protocols, adaptive trial designs, and real-world analytics to global health. He currently teaches a course on adaptive trial designs and master protocols at McMaster University and is working on a book, “Introduction to Adaptive Trial Designs and Master Protocols” that will be published by Cambridge University Press in 2021.