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THE CHANGING FACE OF CLINICAL TRIALS
Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both
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Janet Woodcock, M.D., and Lisa M. LaVange, P…
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July 6, 2017
N Engl J Med 2017; 377:62-70
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Comments open through August 2, 2017
Available on the NEJM.org full site.
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Trial Innovations
Two types of innovation are hallmarks of master protocols: the use of a trial network with infrastructure in place to streamline trial logistics, improve data quality, and facilitate data collection and sharing; and the use of a common protocol that incorporates innovative statistical approaches to study design and data analysis, enabling a broader set of objectives to be met more effectively than would be possible in independent trials (Figure 3
Figure 3
Areas of Innovation in Master Protocols.
).30,31 Since medicine is taught by example, we outline a few innovations below.
Trial Network and Infrastructure
Common Screening Platform
Under the paradigm of conducting independent trials for each therapy, patients may be recruited and screened for one protocol, not meet the inclusion criteria, and either get screened for another trial or miss the opportunity to participate altogether. For each separate trial, the process of data collection and testing is repeated, with overlapping information gathered for multiple trials but not shared among them. The master-protocol counterpart is the use of a common screening platform to identify all trials for which a patient is eligible. This coordinated screening is at the heart of a master protocol and represents one of its chief advantages — more efficient use of patients and resources. Sponsors and research investigators benefit from a streamlined recruitment process, often of higher quality and yielding fewer screening failures and shorter recruitment times. Patients benefit through more opportunities to participate in investigational research and earlier access to potentially beneficial therapies.
Centralization and Shared Governance
The use of centralized shared governance for all trials that are conducted under the master protocol represents another major advantage. Single governing bodies such as the steering committee, institutional review board, and data monitoring committee can be established and assigned oversight for all trials or substudies in a master protocol. 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. Decisions about discontinuing or adding therapies in both of our examples depend on such centralization. Central laboratories, reading centers (e.g., imaging center and spirometry center), adjudication committees, and other central facilities enhance data quality through coordinated training efforts and quality-control oversight. Quality improvements that are identified for one trial are applied to all.
Study Sites and Systems
The use of a common trial network and associated infrastructure affords considerable advantages in both efficiency and quality. 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. The use of a single system for clinical data management will enable shorter start-up times as the protocol is expanded to incorporate new investigations. The use of a single central randomization system facilitates the addition of new therapies with minimal disruption. Real-time access to the genomic, proteomic, pathological, and imaging data streams is requisite for the adaptive features of I-SPY 2.
Common Protocol and Design Elements
Protocol Elements
Trials that are conducted under a master protocol have similar study designs and protocol elements, with differences dictated only by peculiarities of the individual therapies under investigation. The schedule of visits, clinical examination components, measurement procedures, outcome definitions, and ascertainment procedures are shared across trials, allowing for reuse of study materials. Even though Lung-MAP consists of individual substudies for each biomarker–therapy combination, protocol elements such as visit schedules and imaging protocols are shared as much as possible.
Innovative Designs
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.32-35 The flexibility to allow promising new therapies to enter and poor-performing therapies to discontinue usually requires some form of adaptive design, but the level of complexity of those adaptations can vary according to the objectives of the master protocol. For example, I-SPY 2 incorporates both Bayesian adaptation algorithms for basing trial decisions on estimated posterior probabilities that are computed at frequent interim-analysis points and response-adaptive randomization. Although the use of response-adaptive randomization (i.e., purposefully assigning patients to more promising treatments on the basis of accruing data) has been the subject of much discussion in single-purpose clinical trials,36 the I-SPY 2 investigators argue that its use is consistent with the objectives of the trial on statistical, ethical, scientific, economic, and logistic grounds.37 In contrast, the individual substudies of Lung-MAP, which are designed to evaluate biomarker-matched therapies in parallel and independently of each other, do not involve any trial adaptations, beyond the ability to start and stop the substudies themselves.
One innovative design feature unique to the master-protocol setting is the shared use of control patients among trials of the same biomarker or disease. In a simple case, a trial of two therapies that target the same biomarker signature can share control patients, even if the drugs enter and exit the master protocol at different times, under the assumption that there have not been substantial ecologic changes in care that could alter the outcome in the control group. Comparative analyses of each drug versus control take advantage of shared control patients, reducing the overall sample size, and correlations between the analyses are not an issue, provided the test drugs are not compared with each other. If the recruitment periods overlap but are not identical, the randomization algorithm can switch between a two-group and three-group scheme. In this case, shared control patients may be limited to those assigned concurrently to each drug (i.e., in the overlapping recruitment period) or expanded to include nonconcurrent control patients, provided the potential for ecologic changes to confound treatment effects is addressed. In Lung-MAP, for example, only a single treatment is being investigated for each biomarker profile to date, but if a second treatment is identified, the potential to share control patients with the same biomarker profile is available.
Support for Other Research
By taking advantage of coordinated data collection across multiple trials, master protocols can enhance other research initiatives. For example, having a master protocol in place for a rare disease can facilitate the collection of case histories of patients seen in the participating clinical practices, providing a data source for future externally controlled trials that may be more relevant than other historical data sources.
Similarly, activities that are needed to evaluate the performance of new biomarkers that are not linked to a target therapy can be conducted within a master protocol. Typically, extensive studies relating biomarker results to clinical outcomes are needed to understand biomarker performance characteristics and set cutoff values. These data are difficult to gather and may come from retrospective samples with incomplete or inadequate outcome data. Ongoing master protocols constitute an ideal means of collecting such information.
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