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Pink Sheet – Master Protocols Are Both Welcome And Inevitable – US FDA's Woodcock

Pink Sheet – Master Protocols Are Both Welcome And Inevitable – US FDA's Woodcock

Executive Summary


Center for Drug Evaluation and Research Director Janet Woodcock continues to promote innovation in clinical trial design with a review of master protocols in the New England Journal of Medicine.

FDA trumpeted its support for novel clinical trial designs using master protocols with a review article in the New England Journal of Medicine authored by top drug review officials.


“As the targets for new drugs become more and more precise, there is no alternative but to move forward with these coordinated research efforts,” Center for Drug Evaluation and Research Director Janet Woodcock and Office of Biostatistics Director Lisa LaVange conclude in the July 6 NEJM.


Woodcock and LaVange reflect on experience with the first generation of master protocols, especially the I-SPY 2 and Lung-MAP trials, to make the case that such studies can meet the fast-growing demands of precision medicine.


“The common denominator is a need to answer more questions, more efficiently and in less time,” they said. Master protocols, which can encompass multiple substudies and adaptive statistics, are “a methodologic innovation responsive to this need.”


A common protocol enables “a broader set of objectives to be met more effectively than would be possible in independent trials,” the article states.


Woodcock and LaVange’s review article is part of the New England Journal of Medicine’s series “The Changing Face of Clinical Trials.” The series, which reviews issues in clinical trial design and conduct, kicked off a year ago with Woodcock as lead editor. (Also see “A Cautious Guide To The Interpretation Of Clinical Trials From NEJM” – Pink Sheet, 3 Oct, 2016.)


CDER has embraced innovation in trial design, with Woodcock in particular making the case for master protocols. (Also see “Rethinking Oncology Development: Master Protocols May Shorten Time To Approval” – Pink Sheet, 4 May, 2016.)


The agency’s welcoming stance on new types of clinical trials looks set to continue under new FDA Commissioner Scott Gottlieb’s “medical innovation development plan,” which includes a forthcoming guidance on clinical evaluation of targeted therapies for rare disease subsets. (Also see “US FDA ‘Medical Innovation Development Plan’ Outlined By Gottlieb” – Pink Sheet, 20 Jun, 2017.)

The Importance Of Infrastructure

The extensive trial infrastructure and complex co-ordination required by master protocols is both a strength and weakness of the innovative methodology.


“Taken together, stakeholder coordination, infrastructure requirements, and complex trial-design elements can extend the start-up time for a master protocol considerably as compared with that for a single-purpose trial,” the article states.


Nonetheless, “the infrastructure required for implementation increases data quality and trial efficiencies,” the article states. “If designed correctly, master protocols can last many years, even decades, with innovations from the laboratory translating quickly to clinical evaluation.”


Coordinated patient screening is “at the heart of a master protocol and represents one of its chief advantages – more efficient use of patients and resources,” the articles notes. “Having a network of experienced clinical centers to serve as study sites for multiple trials under a master protocol makes sense as compared with establishing study centers one trial at a time.”


A trial network also provides “infrastructure in place to streamline trial logistics, improve data quality, and facilitate data collection and sharing,” the article adds. Another “major advantage” comes from centralized facilities and governance. “In addition to using fewer resources, centralized governance enables uniform decisions to be made about various aspects of all the trials being conducted under the protocol.”


Master protocol trials can “share control patients among trials of the same biomarker or disease,” Woodcock and LaVange point out.

Adapting To Change

“With multiple questions to address under a single protocol, usually in an area of unmet need, and an extensive infrastructure in place to handle data flow, master protocols are a natural environment for considering innovative trial designs,” Woodcock and LaVange observe.


The broad master protocol concept can incorporate a range of design elements, including Bayesian adaptation algorithms and response-adaptive randomization, but the complexity of the statistics can vary depending on trial objectives. “Exploratory protocols such as I-SPY 2 may identify therapies for further study, whereas master protocols such as Lung-MAP may be evaluating therapies in parallel,” they pointed out.


I-SPY 2, an adaptive Phase II platform trial looking at neoadjuvant breast cancer therapy in biomarker-identified subgroups, has evaluated 12 therapies from nine sponsors in eight genetically defined subgroups, the article reports. Five therapies have advanced for further study. (See sidebar for more of our coverage of master protocols trials in practice.)


Lung-MAP, which is studying biomarker-matched therapies in rare squamous-cell subsets of non-small cell lung cancer (NSCLC), started with four molecular targets and four investigational drugs; now three of each remain.


Both trials have had to change in response to changes in clinical practice. I-SPY 2 originally included pertuzumab as a test drug, but when it was approved as Genentech’s Perjeta the I-SPY trial was altered, with pertuzumab replacing trastuzumab as the standard of care for HER2-positive breast cancer.


The approval of Bristol’s Opdivo (nivolumab) changed the squamous NSCLC landscape for Lung-MAP. Opdivo demonstrated superiority to docetaxel, the chemotherapy Lung-MAP used as the standard of care for biomarker-matched substudies. Opdivo prompted redesign in Lung-MAP, the NEJM article reports. The substudies originally compared a targeted therapy with standard of care with progression-free survival or overall survival as the endpoint, but after approval of Opdivo they were redesigned as single-group studies with a primary endpoint of overall response rate. If a therapy meets success criteria, a Phase III trial will be planned with the then-prevalent standard of care for the control.

Looking Past Cancer

Cancer has been the subject of most master protocol trials to date, “owing the advances made in identifying tumor subtypes or mutations for targeting” in oncology. However, Woodcock and LaVange note, interest in outside of oncology is growing. The authors point to:


  • The Antibiotic Resistance Leadership Group’s ADAPT trial, a master protocol that is testing “therapies targeted to resistant pathogens at multiple sites of infection.” ADAPT uses “adaptive methods and technology similar to those in I-SPY 2,” they note.
  • The Dominantly Inherited Alzheimer Network Trial (DIAN-TU), a “study of potentially disease-modifying treatments in persons at risk for or with a type of early-onset Alzheimer’s disease caused by a genetic mutation.” DIAN-TU currently has two therapies under study.
  • PREVAIL II, a single protocol that aimed to evaluate multiple therapies for Ebola virus disease using “a flexible Bayesian adaptive design with the potential to add new therapies and update the standard of care as experimental therapies became available for testing,” the authors state. However, the trial was stopped early when the subsiding Ebola epidemic reduced enrollment, and only one treatment was evaluated.

Looking Past Phase II

Master protocol trials have so far demonstrated the most utility in identifying promising agents for further (and more conventional) clinical study. But plans are being developed to extend master protocols into the Phase III setting, Woodcock and LaVange report.


“Discussion is under way for an I-SPY 3 master protocol that would be designed to provide evidence of effectiveness for agents successfully completing I-SPY 2,” the article states.


The non-profit QuantumLeap Healthcare Collaborative, which oversees the I-SPY program, describes I-SPY 3 as a “standing trial consisting of a master protocol and IND with shared control arms aimed to reduce time and costs.” A “novel IT infrastructure” is in development.


I-SPY 3 will include “targeted eligibility criteria for subtypes of breast cancer most likely to respond” with serial interim analysis supporting an adaptive design, QuantumLeap materials state.


Lung-MAP was designed as Phase II/III trial, but only the Phase II portion is active. The NEJM article reports that 40 patients have been enrolled out of a planned 100-170 in Phase II. Phase III plans call for 300 to 400 patients.…