title: Statistical lessons learned for designing cluster randomized pragmatic clinical trials from the NIH Health Care Systems Collaboratory Biostatistics and Design Core.
abstract: Pragmatic clinical trials embedded within health care systems provide an important opportunity to evaluate new interventions and treatments. Networks have recently been developed to support practical and efficient studies. Pragmatic trials will lead to improvements in how we deliver health care and promise to more rapidly translate research findings into practice.
  
  
  
  The National Institutes of Health (NIH) Health Care Systems Collaboratory was formed to conduct pragmatic clinical trials and to cultivate collaboration across research areas and disciplines to develop best practices for future studies. Through a two-stage grant process including a pilot phase (UH2) and a main trial phase (UH3), investigators across the Collaboratory had the opportunity to work together to improve all aspects of these trials before they were launched and to address new issues that arose during implementation. Seven Cores were created to address the various considerations, including Electronic Health Records; Phenotypes, Data Standards, and Data Quality; Biostatistics and Design Core; Patient-Reported Outcomes; Health Care Systems Interactions; Regulatory/Ethics; and Stakeholder Engagement. The goal of this article is to summarize the Biostatistics and Design Core's lessons learned during the initial pilot phase with seven pragmatic clinical trials conducted between 2012 and 2014.
  
  
  
  Methodological issues arose from the five cluster-randomized trials, also called group-randomized trials, including consideration of crossover and stepped wedge designs. We outlined general themes and challenges and proposed solutions from the pilot phase including topics such as study design, unit of randomization, sample size, and statistical analysis. Our findings are applicable to other pragmatic clinical trials conducted within health care systems.
  
  
  
  Pragmatic clinical trials using the UH2/UH3 funding mechanism provide an opportunity to ensure that all relevant design issues have been fully considered in order to reliably and efficiently evaluate new interventions and treatments. The integrity and generalizability of trial results can only be ensured if rigorous designs and appropriate analysis choices are an essential part of their research protocols.
authors.affiliation: Biostatistics Unit, Group Health Research Institute, Seattle, WA, USA Department of Biostatistics, University of Washington, Seattle, WA, USA cook.aj@ghc.org.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Cook
authors.affiliation: Department of Biostatistics & Bioinformatics, Duke University School of Medicine, Durham, NC, USA Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Delong
authors.affiliation: Office of Disease Prevention, Division of Program Coordination Planning and Strategic Initiatives, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Murray
authors.affiliation: Kaiser Permanente Center for Health Research, Portland, OR, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Vollmer
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Heagerty
mesh_terms: D056808:Biostatistics; D057286:Electronic Health Records / Q000706:statistics & numerical data*; D017408:Guidelines as Topic; D006801:Humans; D009316:National Institutes of Health (U.S.); D016032:Randomized Controlled Trials as Topic / Q000592:standards*; D012107:Research Design / Q000592:standards*; D014481:United States
keywords: NIH Collaboratory; Pragmatic clinical trials; cluster-randomized; electronic health record; group randomized