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Low risk pragmatic trials do not always require participants’ informed consent

BMJ 2019; 364 doi: (Published 27 March 2019) Cite this as: BMJ 2019;364:l1092

This article has a correction. Please see:

  1. Rafael Dal-Ré, senior investigator1,
  2. Cristina Avendaño-Solà, head2,
  3. Brigitte Bloechl-Daum, professor3,
  4. Anthonius de Boer, professor4,
  5. Stefan Eriksson, associate professor5,
  6. Uwe Fuhr, professor6,
  7. Søren Holm, professor7,
  8. Stefan K James, professor8,
  9. Robert J Mentz, investigator9,
  10. Emilio Perucca, professor10,
  11. Frits R Rosendaal, professor11,
  12. Shaun Treweek, professor12
  1. 1Epidemiology Unit, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid, Avda Reyes Católicos 2, E-28040 Madrid, Spain
  2. 2Clinical Pharmacology Service, Puerta de Hierro University Hospital, Majadahonda, Madrid, Spain
  3. 3Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
  4. 4Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
  5. 5Centre for Research Ethics and Bioethics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
  6. 6Universityof Cologne Faculty of Medicine and University Hospital Cologne Centre of Pharmacology,Department I of Pharmacology, Clinical Pharmacology Unit, Cologne, Germany
  7. 7Centre for Social Ethics and Policy, School of Law, University of Manchester, Manchester, UK
  8. 8Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
  9. 9Department of Medicine, Duke University Medical Centre and Clinical Research Institute, Durham, NC, USA
  10. 10Department of Internal Medicine, University of Pavia, Pavia, Italy
  11. 11Department of Clinical Epidemiology C7-P, Leiden University Medical Center, Leiden, The Netherlands.
  12. 12Health Services Research Unit, University of Aberdeen, Aberdeen , UK
  1. Correspondence to: R Dal-Ré rafael.dalre{at}

Clinical trial regulations should remove unnecessary obstacles for the conduct of pragmatic trials assessing the comparative effectiveness of medicines posing no or minimal risk to participants, say Rafael Dal-Ré and colleagues

Key messages

  • Randomised controlled trials do not always inform daily clinical practice because of limited generalisability

  • Low risk pragmatic randomised controlled trials can assess comparative effectiveness of interventions with no or only minimal incremental risk

  • Obtaining written informed consent for these trials can hamper recruitment and reduce the generalisability of results

  • Council for International Organizations of Medical Sciences guidelines state that written informed consent can be waived if the research would be impractical if consent was required, has important social value, poses no more than minimal risk to participants, and is approved by a research ethics committee

  • EU clinical trial regulations should be revised to allow the waiver or modification of informed consent in low risk pragmatic trials

Real world comparative effectiveness research is an important component of evidence-based medicine. Observational data can be collected in routine clinical practice but often have poor procedural quality and are prone to confounding, leading to overestimation of treatment effects.1 Randomised controlled trials (RCTs) are the gold standard for determining a causal effect of interventions, but they can have a critical limitation: the results may not be applicable to other settings.2 Two factors that prevent generalisability of RCT results are strict participant selection criteria and the informed consent process—both can lead to a patient group that bears little resemblance to the population the treatment will be used in. Moreover, RCTs are susceptible to the Hawthorne effect, whereby participants may change their behaviour when they are aware of taking part in research.

RCTs may create an artificial world—for example, 79% of RCTs assessing interventions for chronic conditions exclude patients with concomitant chronic conditions.3 …

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