A National Strategy to Develop Pragmatic Clinical Trials Infrastructure Thomas W. Concannon, Ph.D.1,2, Jeanne-Marie Guise, M.D., M.P.H.3, Rowena J. Dolor, M.D., M.H.S.4, Paul Meissner, M.S.P.H.5, Sean Tunis, M.D., M.P.H.6, Jerry A. Krishnan, M.D., Ph.D.7,8, Wilson D. Pace, M.D.9, Joel Saltz, M.D., Ph.D.10, William R. Hersh, M.D.3, Lloyd Michener, M.D.4, and Timothy S. Carey, M.D., M.P.H.11 Abstract An important challenge in comparative effectiveness research is the lack of infrastructure to support pragmatic clinical trials, which com- pare interventions in usual practice settings and subjects. These trials present challenges that differ from those of classical efficacy trials, which are conducted under ideal circumstances, in patients selected for their suitability, and with highly controlled protocols. In 2012, we launched a 1-year learning network to identify high-priority pragmatic clinical trials and to deploy research infrastructure through the NIH Clinical and Translational Science Awards Consortium that could be used to launch and sustain them. The network and infrastructure were initiated as a learning ground and shared resource for investigators and communities interested in developing pragmatic clinical trials. We followed a three-stage process of developing the network, prioritizing proposed trials, and implementing learning exercises that culminated in a 1-day network meeting at the end of the year. The year-long project resulted in five recommendations related to developing the network, enhancing community engagement, addressing regulatory challenges, advancing information technology, and developing research methods. The recommendations can be implemented within 24 months and are designed to lead toward a sustained national infrastructure for pragmatic trials. Clin Trans Sci 2014; Volume 7: 164–171 Keywords: trials, translational research, ethics, methodology Background An important methodological focus in comparative effectiveness planning committee (Table 1) drew representatives from 17 research (CER) is the advancement of pragmatic clinical trials CTSAs and other organizations with expertise in stakeholder (PCTs),1 which overlap conceptually with practical trials,2 large and community engagement (Supplement: Community simple trials,3 and effectiveness trials. The approach strives to and Stakeholder Engagement Experience of Coauthors), generate results that are relevant to patients and clinicians by quantitative and qualitative research methods, informatics, comparing interventions in participants and settings representative CER, dissemination and implementation research, and a range of usual care. Pragmatic trials and trial infrastructure have been of clinical and health systems topics relevant to developing a supported through initiatives at NIH,4,5 the Centers for Medicare strategic plan for development of PCT research infrastructure. & Medicaid Services,6 the Agency for Healthcare Research and The planning committee began by reviewing existing definitions Quality (AHRQ),7 the Patient-Centered Outcomes Research of PCTs.11,12 These definitions place PCTs on a continuum with Institute (PCORI),8 Practice-Based Research Networks (PBRNs),9 explanatory trials but with a focus on comparisons of clinical, and community-based participatory research initiatives across community and health systems interventions. This led to the the Federal government.10 following definitions: A challenge for these initiatives has been the lack of sustained • A pragmatic clinical trial is a prospective comparison of a research infrastructure to support them. For this reason, the NIH community-, clinical-, or system-level intervention and a Clinical and Translational Science Awards (CTSA) Consortium relevant comparator in participants who are similar to those launched an effort in 2012 to advance such an infrastructure. affected by the condition(s) under study and in settings The proposed PCT infrastructure (PCTi) would attempt to align that are similar to those in which the condition is typically CTSA and other research institutions, their partners, and the treated. NIH National Center for Advancing Translational Sciences on a • A pragmatic clinical trial infrastructure includes the resources, common goal of developing and deploying an infrastructure to systems, and processes needed to prioritize, conduct, and use support high-priority PCTs. Such an infrastructure might also the results of PCTs. serve as a learning ground and shared resource for investigators Three goals that emerged were to: (1) generate a set of and communities interested in developing PCTs. recommendations for building a PCTi; (2) catalyze PCT research projects within CTSA-affiliated research consortia; and (3) Approach evaluate the performance of this initiative through an iterative We undertook a three-stage process to build infrastructure that learning network approach. Thereby, the intent was tolearn by could support PCTs within the CTSA Consortium: developing a doing; to learn how to build infrastructure from the experience researcher network; prioritizing proposed trials; and implementing of launching actual trials. learning exercises that would culminate in a 1-day workshop. Prioritizing proposed trials Developing the network To accomplish these goals, the planning committee solicited We held a 1-day meeting to launch a national network of PCT proposals to serve as illustrative “use cases” for a learning thought leaders on infrastructure for PCTs. A 32-member network of CTSA members and partners. A solicitation was 1The RAND Corporation, Boston, Massachusetts, USA; 2Tufts University, Boston, Massachusetts, USA; 3Oregon Health & Science University, Portland, Oregon, USA; 4Duke University School of Medicine, Durham, North Carolina, USA; 5Montefiore Medical Center & Albert Einstein College of Medicine, New York, New York, USA;6 Center for Medical Technology Policy, Baltimore, Maryland, USA; 7University of Illinois, Chicago, Illinois, USA; 8University of Illinois Hospital & Health Sciences System, Chicago, Illinois, USA; 9University of Colorado, Denver, Colorado, USA; 10Emory School of Medicine, Atlanta, Georgia, USA; 11University of North Carolina, Chapel Hill, North Carolina, USA. Correspondence: Thomas W. Concannon ([email protected]) D O I : 10 .1111/c t s .12143 164 VOLUME 7 • ISSUE 2 WWW.CTSJOURNAL.COM Concannon et al. n Pragmatic Clinical Trials Infrastructure Name Affiliation Sergio Aguilar-Gaxiola University of California, Davis, California Syed Ahmed Medical College of Wisconsin, Milwaukee, Wisconsin Arthur Blank Albert Einstein College of Medicine, New York, New York Kathleen Brady Medical University of South Carolina, Charleston, South Carolina Tim Carey The University of North Carolina, Chapel Hill, North Carolina Thomas Concannon Tufts Clinical and Translational Science Institute, Tufts University, Boston, Massachusetts Linda Cottler University of Florida, Gainesville, Florida Rowena Dolor Duke University, Durham, North Carolina Milton Eder University of Chicago, Chicago, Illinois Alecia Fair Clinical and Translational Science Awards Consortium Coordinating Center, Vanderbilt University, Nashville, Tennessee Carol Ferrans University of Illinois, Chicago, Illinois Rosemarie Filart National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland Dan Ford Johns Hopkins University, Baltimore, Maryland Mark Helfand Oregon Health & Science University, Portland, Oregon William Hersh Oregon Health & Science University, Portland, Oregon Larry Kessler University of Washington, Seattle, Washington Jerry Krishnan University of Illinois, Chicago, Illinois Colleen Lawrence Clinical and Translational Science Awards Consortium Coordinating Center, Vanderbilt University, Nashville, Tennessee Paul Meissner Albert Einstein College of Medicine, New York, New York Lloyd Michener Duke University, Durham, North Carolina Peter Neumann Tufts University, Boston, Massachusetts Iris Obrams National Center for Advancing Translational Science, NIH, Bethesda, Maryland Wilson Pace University of Colorado, Denver, Colorado Harold Pincus Columbia University, New York, New York Al Richmond The University of North Carolina, Chapel Hill, North Carolina Gary Rosenthal University of Iowa, Iowa City, Iowa Joel Saltz Emory University, Atlanta, Georgia Andrea Sawczuk National Center for Advancing Translational Science, NIH, Bethesda, Maryland Harry Selker Tufts University, Boston, Massachusetts Jodi Segal Johns Hopkins University, Baltimore, Maryland Jonathan Tobin The Rockefeller University, New York, New York Sean Tunis Center for Medical Technology Policy, Baltimore, Maryland Table 1. PCTi workshop planning committee. issued to members of the CTSA community in July 2012; 19 The nicotine replacement for hospitalized smokers (NICHOLS) proposals were submitted by investigators and reviewed by a study subgroup of the planning committee by early September. The The objectives of the proposed research are to compare the proposals were reviewed on eight primary and five secondary effectiveness and cost-effectiveness of counseling plus nicotine criteria (Figure 1). Primary review criteria were considered replacement therapy (NRT) versus counseling alone in hospitalized “must-have” features of each use case. Secondary criteria were smokers. The investigators propose a cluster-randomized design, considered “desired” features. Five illustrative use cases were using hospitals (N = 50) as the unit of randomization. The selected (Table 2), representing a range of interventions in investigators