title: Pragmatic trial design elements showed a different impact on trial interpretation and feasibility than explanatory elements.
abstract: To illustrate how pragmatic trial design elements or inserting explanatory trial elements in pragmatic trials affect validity, generalizability, precision, and operational feasibility.
  
  
  
  From illustrative examples identified through the IMI Get Real Consortium, we selected randomized drug trials with a pragmatic design feature. We searched all publications on these trials for information on how pragmatic trial design features affect validity, generalizability, precision, or feasibility.
  
  
  
  We present examples from the Salford lung study, International Suicide Prevention Trial, Sequenced Treatment Alternatives to Relieve Depression, and Cluster Randomized Usual care vs. Caduet Investigation Assessing Long-term-risk trial. These examples show that incorporating pragmatic trial design elements in trials may affect generalizability, precision and validity and may lead to operational challenges different from traditional explanatory trials. Inserting explanatory trial elements into pragmatic trials may also affect validity, generalizability, and operational feasibility, especially when these trial elements are incorporated in one arm of the trial only. Design choices that positively affect one of these domains (e.g., generalizability) may negatively affect others (e.g., feasibility).
  
  
  
  Consequences of incorporating pragmatic or explanatory trial design elements in pragmatic trials should be explicitly considered and balanced for all relevant domains, including validity, generalizability, precision, and operational feasibility. Tools are needed to make these consequences more transparent.
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, the Netherlands.
authors.forename: Joost B
authors.initials: JB
authors.lastname: Nieuwenhuis
authors.affiliation: RWE Study Delivery, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Elaine
authors.initials: E
authors.lastname: Irving
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, the Netherlands.
authors.forename: Katrien
authors.initials: K
authors.lastname: Oude Rengerink
authors.affiliation: RWE Study Delivery, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Lloyd
authors.affiliation: Eli Lilly and Company Ltd., Er Wood Manor, Sunninghill Road, Windlesham, Surrey GU206PH, United Kingdom.
authors.forename: Iris
authors.initials: I
authors.lastname: Goetz
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, the Netherlands.
authors.forename: Diederick E
authors.initials: DE
authors.lastname: Grobbee
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, the Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Stolk
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, the Netherlands.
authors.forename: Rolf H H
authors.initials: RH
authors.lastname: Groenwold
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, the Netherlands. Electronic address: m.g.p.zuidgeest@umcutrecht.nl.
authors.forename: Mira G P
authors.initials: MG
authors.lastname: Zuidgeest
mesh_terms: D016021:Epidemiologic Studies; D005240:Feasibility Studies; D006801:Humans; D012107:Research Design
keywords: Explanatory trial; Generalizability; Operational feasibility; Pragmatic clinical trials; Precision; Real-world evidence; Trial design; Validity