BMJ Confidential: For Review Only Opening the blinds and shedding light on the risks and problems of blinding in clinical trials Journal: BMJ Manuscript ID BMJ-2019-050313 Article Type: Analysis BMJ Journal: BMJ Date Submitted by the 18-Apr-2019 Author: Complete List of Authors: Anand, Rohan; Queen's University Belfast, Wellcome-Wolfson Institute for Experimental Medicine Norrie, John; University of Edinburgh, Usher Institute of Population Health Sciences and Informatics Bradley, Judy; Queen's University Belfast, Wellcome-Wolfson Institute for Experimental Medicine McAuley, Daniel; Queen's University Belfast, Wellcome-Wolfson Institute for Experimental Medicine Clarke, Mike; Queen's University Belfast, Northern Ireland Methodology Hub blinding, placebos, clinical trials, pragmatic trials, clinical trial Keywords: methodology, RCT, PROBE, bias https://mc.manuscriptcentral.com/bmj Page 1 of 25 BMJ 1 2 3 1 Full Title: 4 5 6 7 2 Opening the blinds and shedding light on the risks and problems of blinding 8 9 3 10 in clinical trials 11 12 Confidential: For Review Only 13 4 Standfast: Blinding can have negative implications for a clinical trial. 14 15 16 5 Author Positions, Names and Emails: 17 18 19 6 Rohan Anand1, [email protected], (ORCiD: 0000-0002-1957-5336); 20 21 7 Professor John Norrie2, [email protected], 22 23 24 8 Professor Judy M Bradley3, [email protected], (ORCiD: 0000-0002-7423-135X) 25 26 9 Professor Danny F McAuley4, [email protected], (ORCiD: 0000-0002-3283-1947) 27 28 29 10 Professor Mike Clarke5, [email protected], (ORCiD: 0000-0002-2926-7257) 30 31 11 32 33 34 12 Author Affiliations and Addresses: 35 36 13 1 Doctoral Research Student in Clinical Trial Methodology; Wellcome-Wolfson Institute for 37 38 39 14 Experimental Medicine; School of Medicine, Dentistry and Biomedical Sciences; Queen's 40 41 15 University Belfast; Belfast; BT9 7BL; United Kingdom. 42 43 16 44 45 46 17 2 Professor of Medical Statistics and Trial Methodology; Usher Institute of Population Health 47 48 18 Sciences and Informatics; The University of Edinburgh; Edinburgh; EH16 4UX; United 49 50 51 19 Kingdom. 52 53 20 54 55 56 57 58 59 60 Page 1 of 25 18APR2019 https://mc.manuscriptcentral.com/bmj BMJ Page 2 of 25 1 2 3 21 3 Director of the Wellcome Trust-Wolfson Northern Ireland Clinical Research Facility; 4 5 6 22 Wellcome-Wolfson Institute for Experimental Medicine; School of Medicine, Dentistry and 7 8 23 Biomedical Sciences; Queen's University Belfast; Belfast; BT9 7BL; United Kingdom. 9 10 11 24 12 Confidential: For Review Only 13 25 4 Clinical Professor and Consultant in Intensive Care Medicine; Wellcome-Wolfson Institute 14 15 16 26 for Experimental Medicine; School of Medicine, Dentistry and Biomedical Sciences; Queen's 17 18 27 University Belfast; Belfast; BT9 7BL; United Kingdom. 19 20 28 21 22 23 29 5 Director of the Northern Ireland Clinical Trials Unit and the Northern Ireland Methodology 24 25 30 Hub; Centre for Public Health; School of Medicine, Dentistry and Biomedical Sciences; 26 27 28 31 Queen's University Belfast; Belfast; BT12 6BJ; United Kingdom. 29 30 32 31 32 33 33 Correspondence to [email protected] (ORCiD: 0000-0002-2926-7257) 34 35 34 36 37 38 35 Contributors and sources: 39 40 41 36 The objective of this paper is to highlight the potential harm of blinding and placebos when 42 43 37 used in clinical trials. As blinding is such an established and prominent feature of past and 44 45 46 38 current trials, there is a need for a comprehensive paper that describes the potential 47 48 39 negative consequences of using it in some trials. The authors have combined extensive 49 50 40 51 experience in the design, conduct, management and analysis of clinical trials both from a 52 53 41 clinical and methodological aspect. Professor Mike Clarke is the Director of the Northern 54 55 42 Ireland Clinical Trials Unit and the Northern Ireland Methodology Hub, and Co-ordinating 56 57 58 43 Editor of the Cochrane Methodology Review Group, and has over 30 years’ experience in 59 60 44 trials and systematic reviews. John Norrie is Professor of Medical Statistics and Trial Page 2 of 25 18APR2019 https://mc.manuscriptcentral.com/bmj Page 3 of 25 BMJ 1 2 3 45 Methodology and is Director of Edinburgh Clinical Trials Unit. Professor Judy Bradley is a 4 5 6 46 physiotherapist and Director of the Wellcome Trust-Wolfson Northern Ireland Clinical 7 8 47 Research Facility and Co-Lead of the Northern Ireland Clinical Research Network for 9 10 11 48 Respiratory Health. Professor Danny McAuley is a Consultant in Intensive Care Medicine at 12 Confidential: For Review Only 13 49 the Royal Victoria Hospital Belfast, Director of the MRC/NIHR Efficacy and Mechanism 14 15 16 50 Evaluation (EME) Programme and Co-Director of Research for the Intensive Care Society. 17 18 51 Rohan Anand is a PhD candidate exploring how trial methods, such as the use of placebos, 19 20 52 can affect the outcomes. 21 22 23 53 24 25 54 26 27 28 55 Contributor and guarantor information: 29 30 56 The corresponding author attests that all listed authors meet authorship criteria and that no 31 32 33 57 others meeting the criteria have been omitted. All authors contributed to conceptualisation 34 35 58 and writing of the paper. Rohan Anand prepared the original draft. Mike Clarke is guarantor. 36 37 38 59 39 40 60 The Corresponding Author has the right to grant on behalf of all authors and does grant on 41 42 61 behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in 43 44 45 62 all forms, formats and media (whether known now or created in the future), to i) publish, 46 47 63 reproduce, distribute, display and store the Contribution, ii) translate the Contribution into 48 49 50 64 other languages, create adaptations, reprints, include within collections and create 51 52 65 summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative 53 54 55 66 work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) 56 57 67 the inclusion of electronic links from the Contribution to third party material where-ever it 58 59 68 60 may be located; and, vi) licence any third party to do any or all of the above. Page 3 of 25 18APR2019 https://mc.manuscriptcentral.com/bmj BMJ Page 4 of 25 1 2 3 69 4 5 6 70 7 8 71 Competing interests declaration: 9 10 11 72 All authors have read and understood the BMJ Group policy on declaration of interests and 12 Confidential: For Review Only 13 73 declare no conflicts of interest. 14 15 16 74 17 18 75 Patient and Public Involvement: 19 20 76 It was not appropriate or possible to involve patients or the public in this work 21 22 23 77 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 4 of 25 18APR2019 https://mc.manuscriptcentral.com/bmj Page 5 of 25 BMJ 1 2 3 4 5 78 ABSTRACT 6 7 8 79 Controlled trials with blinding of patients and researchers to interventions are complex to 9 10 80 implement. There is debate about the actual impact that blinding and the commonly 11 12 Confidential: For Review Only 13 81 associated placebo can have on the results of trials. Blinding is not always possible or may 14 15 82 be challenging to setup and implement. Here, we highlight problems associated with the 16 17 18 83 practicality, the potential harm to patients and the applicability of a trial’s results, using 19 20 84 both real world and hypothetical examples. There are many instances where blinding might 21 22 23 85 actually damage the quality and reliability of a study, which is especially true in 24 25 86 effectiveness trials. Adequate randomisation, blinding of outcome assessment and use of 26 27 28 87 objective outcomes should reduce the main causes of bias which blinding of patients and 29 30 88 practitioners is intended to limit. This, coupled with doubts about whether the results 31 32 89 obtained when blinding is used are a good estimate of what will happen in routine practice, 33 34 35 90 suggests that it might be better to reduce the emphasis on patient and participant blinding, 36 37 91 especially in pragmatic randomised trials exploring effectiveness. 38 39 40 92 41 42 93 43 44 45 94 46 47 48 49 95 INTRODUCTION 50 51 52 96 Blinding (also referred to as masking) in clinical trials is used with the intention of reducing 53 54 97 various forms of bias, in the hope that this will increase the reliability of the trial’s results. 55 56 th 57 98 First documented in the 18 century (1), the process of blinding is essentially the 58 59 99 withholding of information from people involved in the trial relating to the interventions 60 Page 5 of 25 18APR2019 https://mc.manuscriptcentral.com/bmj BMJ Page 6 of 25 1 2 3 100 that are being compared. Double or triple blind trials are usually regarded as the “gold 4 5 6 101 standard” of clinical research and evidence (2, 3).