Original Article| Volume 62, ISSUE 5, P479-484, May 2009

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A new 'Mechanistic-Practical” Framework for designing and interpreting randomized trials

  • Paul J. Karanicolas
    Corresponding author. Department of Clinical Epidemiology and Biostatistics, McMaster University Medical Center, 1200 Main St. W., Room 2C12, Hamilton, Ontario, L8N 3Z5, Canada. Tel.: +905-525-9140, ext.44648; fax: +905-523-8781.
    Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

    Department of Surgery, University of Western Ontario, London, Ontario, Canada
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  • Victor M. Montori
    Knowledge & Encounter Research Unit, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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  • P.J. Devereaux
    Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

    Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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  • Holger Schünemann
    Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

    Italian National Cancer Institute, Rome/Istituto Regina Elena, Italy
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  • Gordon H. Guyatt
    Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

    Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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      Methodologists have traditionally categorized randomized controlled trials (RCTs) as explanatory (representing the ideal setting) and pragmatic (representing the real-world setting). Although this framework has greatly advanced the design and interpretation of RCTs, current interpretations of the explanatory-pragmatic framework suffer from two major limitations. First, they confound purpose with structure. Second, they ignore the varying perspective of those using RCT results to make clinical and policy decisions in the real world. The purpose of a trial should determine researchers' choices regarding the trial's structure and the structure of a trial determines the extent to which a decision maker will find the results useful. In this article, we introduce two terms that refer explicitly to the purpose of a trial: A trial is mechanistic to the extent that it addresses a biological relationship. In contrast, a trial is practical to the extent that it provides comprehensive information that bears directly on specific health care decisions. This revised framework facilitates investigators' choice of optimal trial design, and clinicians' optimal interpretation of RCT results. If our goal is clinical trials most relevant to individual patient decision making, we will eschew the use of trials that enroll patients unlikely to benefit (e.g., those with uncertain diagnosis); those likely to be noncompliant; treated by practitioners whose differing expertise is likely to result in differing outcomes; and permitting cointerventions that are likely to influence treatment effectiveness—i.e., the conventional pragmatic trial. Instead we will design, implement, and apply the results of practical trials to our patients.


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        • Schwartz D.
        • Lellouch J.
        Explanatory and pragmatic attitudes in therapeutical trials.
        J Chron Dis. 1967; 20: 637-648
        • Barreto M.L.
        Efficacy, effectiveness, and the evaluation of public health interventions.
        J Epidemiol Community Health. 2005; 59: 345-346
        • Haynes B.
        Can it work? Does it work? Is it worth it?.
        BMJ. 1999; 319: 652-653
        • Laporte J.R.
        From clinical trials to usual practice: efficacy and effectiveness in clinical pharmacology.
        Methods Find Exp Clin Pharmacol. 1999; 21: 17
        • Mukherjee D.
        • Eagle K.A.
        Improving quality of care in the real world: efficacy versus effectiveness?.
        Am Heart J. 2003; 146 ([comment]): 946-947
        • Cochrane A.L.
        Effectiveness and efficiency: random reflection on health services.
        Nuffield Provincial Hospitals Trust, London1972
        • Sackett D.L.
        • Gent M.
        Controversy in counting and attributing events in clinical trials.
        NEJM. 1979; 301: 1410-1412
        • Hallfors D.
        • Cho H.
        • Sanchez V.
        • Khatapoush S.
        • Kim H.M.
        • Bauer D.
        Efficacy vs effectiveness trial results of an indicated “model” substance abuse program: implications for public health.
        Am J Public Health. 2006; 96: 2254-2259
        • Bauer M.S.
        • Williford W.O.
        • Dawson E.E.
        • et al.
        Principles of effectiveness trials and their implementation in VA Cooperative Study #430: ‘Reducing the efficacy-effectiveness gap in bipolar disorder’.
        J Affect Disord. 2001; 67: 61-78
        • Flay B.R.
        • Biglan A.
        • Boruch R.F.
        • et al.
        Standards of evidence: criteria for efficacy, effectiveness and dissemination.
        Prev Sci. 2005; 6: 151-175
        • Gartlehner G.
        • Hansen R.A.
        • Nissman D.
        • Lohr K.N.
        • Carey T.S.
        A simple and valid tool distinguished efficacy from effectiveness studies.
        J Clin Epidemiol. 2006; 59: 1040-1048
        • Kraemer H.C.
        “Rules” of evidence in assessing the efficacy and effectiveness of treatments.
        Dev Neuropsychol. 2003; 24: 705-718
        • McMahon A.D.
        Study control, violators, inclusion criteria and defining explanatory and pragmatic trials.
        Stat Med. 2002; 21: 1365-1376
        • Santaguida P.L.
        • Helfand M.
        • Raina P.
        Challenges in systematic reviews that evaluate drug efficacy or effectiveness.
        Ann Intern Med. 2005; 142: 1066-1072
        • Streiner D.L.
        The 2 “Es” of research: efficacy and effectiveness trials.
        Can J Psychiatry—Revue Canadienne de Psychiatrie. 2002; 47: 552-556
        • Sackett D.L.
        Explanatory versus management trials.
        in: Haynes R.B. Sackett D.L. Guyatt G.H. Tugwell P. Clinical epidemiology: How to do clinical practice research. 3rd edition. Lippincott, Williams and Wilkins, Philadelphia2005: 183-188
        • Birkmeyer J.D.
        • Sun Y.
        • Wong S.L.
        • Stukel T.A.
        Hospital volume and late survival after cancer surgery.
        Ann Surg. 2007; 245: 777-783
        • Hannan E.L.
        • Radzyner M.
        • Rubin D.
        • Dougherty J.
        • Brennan M.F.
        The influence of hospital and surgeon volume on in-hospital mortality for colectomy, gastrectomy, and lung lobectomy in patients with cancer.
        Surgery. 2002; 131: 6-15
        • Holt J.D.
        • Poloniecki J.D.
        • Gerrard D.
        • Loftus I.M.
        • Thompson M.M.
        Meta-analysis and systematic review of the relationship betwen volume and outcome in abdominal aortic aneurysm surgery.
        Brit J Surg. 2007; 94: 395-403
        • Shervin N.
        • Rubash H.E.
        • Katz J.N.
        Orthopaedic procedure volume and patient outcomes: a systematic review.
        Clin Orthop Relat Res. 2007; 457: 35-41
        • Kroenke K.
        • West S.L.
        • Swindle R.
        • et al.
        Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial.
        JAMA. 2001; 286: 2947-2955
        • Kraemer H.C.
        Pitfalls of multisite randomized clinical trials of efficacy and effectiveness.
        Schizophr Bull. 2000; 26: 533-541
        • Montori V.M.
        • Isley W.L.
        • Guyatt G.H.
        Waking up from the DREAM of preventing diabetes with drugs.
        BMJ. 2007; 334: 882-884
        • Schunemann H.J.
        • Guyatt G.H.
        Hello MID, where do you come from?.
        Health Serv Res. 2005; 40: 593-597
        • Glasziou P.P.
        • Irwig L.M.
        An evidence based approach to individualising treatment.
        BMJ. 1995; 311: 1356-1359