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Research

Outcomes for patients with the same disease treated inside and outside of randomized trials: a systematic review and meta-analysis

Natasha Fernandes, Dianne Bryant, Lauren Griffith, Mohamed El-Rabbany, Nisha M. Fernandes, Crystal Kean, Jacquelyn Marsh, Siddhi Mathur, Rebecca Moyer, Clare J. Reade, John J. Riva, Lyndsay Somerville and Neera Bhatnagar
CMAJ November 04, 2014 186 (16) E596-E609; DOI: https://doi.org/10.1503/cmaj.131693
Natasha Fernandes
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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  • For correspondence: natasha.fernandes31@gmail.com
Dianne Bryant
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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Lauren Griffith
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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Mohamed El-Rabbany
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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Nisha M. Fernandes
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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Crystal Kean
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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Jacquelyn Marsh
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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Siddhi Mathur
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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Rebecca Moyer
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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Clare J. Reade
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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John J. Riva
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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Lyndsay Somerville
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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Neera Bhatnagar
Faculty of Medicine (Natasha Fernandes, Mathur), University of Ottawa, Ottawa, Ont.; Faculty of Health Sciences (Bryant, Marsh, Moyer) and Schulich School of Medicine and Dentistry (Bryant), The University of Western Ontario, London, Ont.; Department of Clinical Epidemiology and Biostatistics (Bryant, Griffith), Department of Medicine (Nisha Fernandes), Health Sciences Library (Bhatnagar), Department of Family Medicine (Riva) and Division of Gynecologic Oncology (Reade), McMaster University, Hamilton, Ont.; Faculty of Dentistry (El-Rabbany), University of Toronto, Toronto, Ont.; School of Medical and Applied Sciences (Kean), Central Queensland University, Rockhampton, Australia; Department of Orthopaedic Surgery (Somerville), London Health Sciences Centre, London, Ont.
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Abstract

Background: It is unclear whether participation in a randomized controlled trial (RCT), irrespective of assigned treatment, is harmful or beneficial to participants. We compared outcomes for patients with the same diagnoses who did (“insiders”) and did not (“outsiders”) enter RCTs, without regard to the specific therapies received for their respective diagnoses.

Methods: By searching the MEDLINE (1966–2010), Embase (1980–2010), CENTRAL (1960–2010) and PsycINFO (1880–2010) databases, we identified 147 studies that reported the health outcomes of “insiders” and a group of parallel or consecutive “outsiders” within the same time period. We prepared a narrative review and, as appropriate, meta-analyses of patients’ outcomes.

Results: We found no clinically or statistically significant differences in outcomes between “insiders” and “outsiders” in the 23 studies in which the experimental intervention was ineffective (standard mean difference in continuous outcomes −0.03, 95% confidence interval [CI] −0.1 to 0.04) or in the 7 studies in which the experimental intervention was effective and was received by both “insiders” and “outsiders” (mean difference 0.04, 95% CI −0.04 to 0.13). However, in 9 studies in which an effective intervention was received only by “insiders,” the “outsiders” experienced significantly worse health outcomes (mean difference −0.36, 95% CI −0.61 to −0.12).

Interpretation: We found no evidence to support clinically important overall harm or benefit arising from participation in RCTs. This conclusion refutes earlier claims that trial participants are at increased risk of harm.

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Canadian Medical Association Journal: 186 (16)
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Vol. 186, Issue 16
4 Nov 2014
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Outcomes for patients with the same disease treated inside and outside of randomized trials: a systematic review and meta-analysis
Natasha Fernandes, Dianne Bryant, Lauren Griffith, Mohamed El-Rabbany, Nisha M. Fernandes, Crystal Kean, Jacquelyn Marsh, Siddhi Mathur, Rebecca Moyer, Clare J. Reade, John J. Riva, Lyndsay Somerville, Neera Bhatnagar
CMAJ Nov 2014, 186 (16) E596-E609; DOI: 10.1503/cmaj.131693

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Outcomes for patients with the same disease treated inside and outside of randomized trials: a systematic review and meta-analysis
Natasha Fernandes, Dianne Bryant, Lauren Griffith, Mohamed El-Rabbany, Nisha M. Fernandes, Crystal Kean, Jacquelyn Marsh, Siddhi Mathur, Rebecca Moyer, Clare J. Reade, John J. Riva, Lyndsay Somerville, Neera Bhatnagar
CMAJ Nov 2014, 186 (16) E596-E609; DOI: 10.1503/cmaj.131693
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