Master protocols are a powerful but under-utilized option for complex clinical development programs. Our Greg Licholai, MD, explores:
Master protocols are an example of how clinical research is changing and moving in exciting directions. Yet these innovations can be misunderstood or under-appreciated by the people who need such tools in their clinical design offerings. Master protocols include platform, umbrella and basket trial designs. These approaches are used most often in oncology, however other diseases states should be considered.
Master protocols were developed to more efficiently address the clinical development challenge of determining which therapy or combinations could get the most robust response in diseases that have heterogeneous patient populations or where multiple therapeutic approaches exist. They offer unique and flexible designs and can incorporate biomarker development, genetic subtyping and therapies with different mechanisms of action.
Master protocols can provide opportunities for flexibility and creativity in the regulated industry of clinical development which needs to operate with a high degree of safety. Some examples of individuals who should consider master protocol options:
- Decision makers at sponsors who are managing complex drug or device portfolios such as an antibody that could be useful in multiple disease states;
- Academic consortium leaders who are bringing together multiple stakeholders to explore how to address complicated disease states such as how to best evaluate different drugs for epilepsy;
- Patient advocacy groups that are trying to assemble various solutions for difficult disorders such as determining which combination of drug could be most effective in rare genetic conditions.
Recently the Clinical Trial Transformation Initiative (CTTI) brought together leaders from industry, academic, government, and other areas to discuss how to best educate and provide resources to expand the use of master protocols in clinical development. By way of background, CTTI is public/private partnership co-founded by the FDA and Duke University. Its mission is “to develop and drive adoption of practices that will increase the quality and efficiency of clinical trials.” The organization comprises more than 80 organizations from across the clinical trial enterprise. Members include representatives of government agencies, industry representatives, patient advocacy groups, professional societies, investigator groups, academic institutions, and other interested parties.
I am a CTTI member and have joined various meetings. This article is a reflection of my thoughts having attended the 2-day master protocol advisory meeting; it’s a starting point for definitions, some examples and where to go to find more information.
What’s in a name: master protocol nomenclature. One of the basic issues where interested parties can run into trouble is the various terms used to describe subtypes of master protocol designs. We recommend that the industry use definitions put forth by the Food and Drug Administration (FDA). According to Nicholas Richardson, reviewer at the Center for Drug Evaluation and Research (CEDR) at the FDA, we need to standardize terms to describe master protocol and subtypes. The FDA guidance document describes such considerations in Efficient Clinical Trial Design Strategies To Expedite Development of Oncology Drugs and Biologics.
Master protocol is the general term that describes a trial design with multiple sub-studies which may have different objectives and evaluates one or more drugs or one or more diseases. Under the master protocol heading there are three different types of trial designs: basket, umbrella and platform.
Basket Design is a type of trial that tests one drug in different diseases. These are usually exploratory and come early in the development process. By definition the trial is disease (or genetic biomarker) agnostic and its objective is to determine the efficacy of a single compound or device against one or more different disease types. The basket design frequently shows up in oncology. For example it could include patients with a certain genetic mutation in common regardless of the site or origin of cancer in the body. When is used in oncology, these are often considered exploratory or “signal-finding” trials. They could be phase II proof-of-concept (POC) trials in an early stage of development with individual sub-studies 20 and 50 subjects. An example of drug that benefited from a more flexible study design is vemurafenib, which was originally approved for the treatment of melanoma with BRAF V600E genetic mutation. A basket study was conducted to show that vemurafenib was also effective in treating a rare blood cancer known as Erdheim-Chester Disease (ECD) and helped lead to approval for the new indication.
Umbrella Design is a trial that evaluates multiple therapies for one disease. They can also evaluate different therapies for multiple diseases if there is sufficient expectations that patients would respond to investigations drugs based on case reports or pre-clinical data. In oncology, one tumor type might be considered the “umbrella” and sub-studies are used to evaluate different therapies against different molecular or genetic markers. An example would be the NCI-Match trial, which is a phase II, multicenter, uncontrolled trial that is evaluating 30 approved and unapproved treatments targeting genetic mutations in cancers including advanced solid tumors, lymphomas, myelomas. The umbrella design as also been used in other trials for advanced non-small cell lung cancer (NSCLC) and colorectal cancer.
Platform Design is a trial that is used to perpetually evaluate several targeted for one or more diseases. This type of design allows for the addition or exclusion of new therapies or even different patient groups during the trial. Researcher employ the use of interim analyses at pre-specified points to determine efficacy or futility so that selected therapies can be halted while others added. The flexibility of the platform design could facilitate the transition to an approval or confirmatory trial.
An example of platform design to determine the best approach for early stage high-risk breast cancer are the I-SPY trials. These evaluate pathological response rate of multiple drug mechanisms such as immunotherapy, checkpoint, tyrosine kinase or HER2 inhibitors. The trials are sponsored by the not-for-profit Quantum Leap Healthcare which started as a collaboration between University of California, San Francisco and Silicon Valley entrepreneurs.
Master protocol benefits include the ability to evaluate heterogeneous populations within one trial. Due to the ability to have patients in multiple arms under the same protocol design, there are several benefits from the master trial approach. Since standard randomized controlled trials are designed to measure for effects in the treatment versus placebo group, it is challenging to evaluate differences based on inter-patient and intra-patient heterogeneity. In fact, many drug developers try to limit variability in order to measure the strongest effect in a population, which means reducing patient heterogeneity as much as possible. Master protocols, on the other hand, allow patients with different disease types, or different genetic markers, to enroll in separate arms, thus facilitating the ability to evaluate how patient subtypes respond. This allows findings researchers to make conclusions regarding different genetic pathways and disease progression. Additionally, allowing the combinations of drugs or targeted therapies means the ability to increase the number of genetic mutations being studied.
Research should be aware that master protocols may limit the ability to use certain endpoints and could have operational complexities. To reliably evaluate heterogeneous populations some cancer basket trial may use the endpoint of overall response rate. However, this could result in difficulty determining progression-free survival or overall survival, which are often needed for approval. The absence of control groups and small sample sizes could also limit the ability to evaluate therapeutic effect. Other endpoint challenges could be the need to rely on histology for predictive response and feasibility. In some cases, there would be reduced ability to compare trial arms to each other and require further clinical research. Patient enrollment may be slowed due to small populations and the need to separate groups by markers in the case of rare cancers. Longer trials could mean that standards-of-care may change during the trial course, which could lead to difficulty determine clinical significance. The scale and time commitment could be associated higher cost for governance and operations, which could limit the ability of sponsors or advocacy groups to effectively execute.
In summary, master protocols are a power clinical development design element, and could be used to evaluate complex programs that include multiple disease states or multiple therapeutic option. These flexible trials should be considered when working with heterogeneous patient populations and clinical scientists should be aware of their potential as well as some of the operational challenges.
Key Publications and Selected References
(Thanks to Daniel Millar, Senior Director of Strategic Business Transformation at Janssen R&D, Johnson & Johnson, for compiling this list of where to go for further reading.)
Berry SM, Conner J, Lewis RJ. The Platform Trial: An Efficient Strategy for Evaluating Multiple Treatments. JAMA April 28, 2015;Volume 313, Number 16, page 1619. Core concept of platform trials/master protocols.
Park, JJH, et. al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials volume 20, Article number: 572 (2019). Overview of Master Protocols.
Stern and Mehta, “Adaptive Platform Trials: The Clinical Trial of the Future?” Harvard Business School Publishing accessed at: https://store.hbr.org/product/adaptive-platform-trials-the-clinical-trial-of-the-future/618025?sku=618025-PDF-ENG. Harvard Business School case elucidates case for change, opportunity and challenges to be address.
Woodcock J, GBM AGILE Trial Launch, YouTube video (2015): accessed at: https://www.youtube.com/watch?v=nHqUil9P32E&t=1151s. Perspective of Dr. Janet Woodcock, Director of CDER, US FDA.
Lesser and Naaz, “Master Protocols: Shifting the drug development paradigm” Deloitte Insights (2018) accessed at: https://www2.deloitte.com/us/en/insights/industry/life-sciences/master-protocol-clinical-trial-drug-development-process.html Perspective on potential efficiencies in drug development through application of platform trials.
Woodcock J, LaVange, L.M. Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both. New England Journal of Medicine. 2017;377. US FDA Perspective.
Sudhop, et. al., Master protocols in clinical trials: a universal Swiss Army knife? Lancet Oncol. 2019 Jun;20(6):e336-e342. doi: 10.1016/S1470-2045(19)30271-2
Landscape Analysis & Case Studies. European Regulatory Perspective.
Woodcock J, LaVange, L.M. Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both. New England Journal of Medicine. 2017;377.
Transformational Opportunity and Efficiencies. US FDA Perspective – this seminal article catalyzed international interest.
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