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Reporting of Drug Trial Funding Sources and Author Financial Conflicts of Interest in Cochrane and non- Cochrane Meta-analyses: A Cross-sectional Study ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-035633

Article Type: Original research

Date Submitted by the 08-Nov-2019 Author:

Complete List of Authors: Turner, Kimberly; Jewish General Hospital and McGill University Carboni-Jiménez, Andrea; McGill University Benea, Carla; Jewish General Hospital Elder, Katharine; Jewish General Hospital Levis, Brooke; McGill University, Epidemiology, Biostatistics and Occupational Health Boruff, Jill; McGill University, Schulich Library of Physical Sciences, Life Sciences, and Engineering Roseman, Michelle; McGill University Bero, Lisa; University of Sydney, Charles Perkins Centre / Pharmacy Lexchin, Joel; York University, School of Health Policy and Management

Turner, Erick; Portland VA Medical Center, ; Oregon Health & Science http://bmjopen.bmj.com/ University, Psychiatry Benedetti, Andrea; McGill University Thombs, Brett; Jewish General Hospital and McGill University

Keywords: EPIDEMIOLOGY, STATISTICS & RESEARCH METHODS, MEDICAL ETHICS

on September 24, 2021 by guest. Protected copyright.

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4 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35

36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

44 on September 24, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 1 Reporting of Drug Trial Funding Sources and Author Financial Conflicts of Interest in 4 5 6 2 Cochrane and non-Cochrane Meta-analyses: A Cross-sectional Study 7 8 3 9 10 4 Kimberly A Turner, Andrea Carboni-Jiménez, Carla Benea, Katharine 11 12 5 Elder, Brooke Levis, Jill Boruff, Michelle Roseman, Lisa A Bero, 13 14

15 6 Joel Lexchin, Erick H Turner, Andrea Benedetti, Brett D Thombs 16 For peer review only 17 7 18 19 8 Affiliations: 20 21 22 9 Lady Davis Institute for Medical Research, Jewish General Hospital and McGill University, 23 24 10 Montreal, Quebec, Canada 25 26 11 Kimberly A Turner (masters student) 27 28 12 Andrea Carboni-Jiménez (research assistant) 29 30 31 13 Carla Benea (undergraduate student)

32 http://bmjopen.bmj.com/ 33 14 Katharine Elder (research assistant) 34 35 15 Brooke Levis (doctoral student) 36 37 38 16 Brett D Thombs (professor) 39

40 17 on September 24, 2021 by guest. Protected copyright. 41 42 18 Schulich Library of Physical Sciences, Life Sciences, and Engineering, McGill University, 43 44 19 Montreal, Quebec, Canada 45 46 47 20 Jill Boruff (associate librarian) 48 49 21 50 51 22 Kingsway Medical Centre Family Health Organization, Toronto, 52 53 54 23 Ontario, Canada 55 56 57 1 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 24 Michelle Roseman (family physician) 4 5 25 6 7 8 26 Charles Perkins Centre, and Faculty of Medicine and Health, and School of Pharmacy, The 9 10 27 University of Sydney, Sydney, Australia 11 12 28 Lisa A Bero (professor) 13 14 15 29 16 For peer review only 17 30 School of Health Policy and Management, Faculty of Health, York University, Toronto, Ontario, 18 19 31 Canada 20 21 22 32 Joel Lexchin (professor emeritus) 23 24 33 25 26 34 Department of Psychiatry and Department of Pharmacology, Oregon Health and Science 27 28 29 35 University, Portland, Oregon, USA 30 31 36 Erick H Turner (associate professor)

32 http://bmjopen.bmj.com/ 33 37 34 35 38 Department of Epidemiology, Biostatistics and Occupational Health, McGill University, 36 37 38 39 Montreal, Quebec, Canada 39

40 40 Andrea Benedetti (associate professor) on September 24, 2021 by guest. Protected copyright. 41 42 41 43 44 45 42 Correspondence to: Brett D. Thombs, PhD; Jewish General Hospital; 4333 Cote Ste. Catherine 46 47 43 Road; Montreal, Quebec, Canada H3T 1E4; Tel (514) 340-8222 ext. 25112; E-mail: 48 49 44 [email protected]; ORCID: 0000-0002-5644-8432 50 51 52 45 53 54 46 Word count: 4,048 55 56 57 2 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 47 ABSTRACT 4 5 6 48 Objective: To (1) investigate the extent to which recently published meta-analyses report trial 7 8 49 funding, author-industry financial ties, and author-industry employment from included RCTs, 9 10 50 comparing Cochrane and non-Cochrane meta-analyses; (2) examine characteristics of meta- 11 12 51 analyses independently associated with reporting funding sources of included RCTs; and (3) 13 14 15 52 compare reporting among recently published Cochrane meta-analyses to Cochrane reviews 16 For peer review only 17 53 published in 2010. 18 19 54 Design: Review of consecutive sample of recently published meta-analyses. 20 21 22 55 Data sources: MEDLINE database via PubMed searched on October 19, 2018. 23 24 56 Eligibility criteria for selecting articles: We selected the 250 most recent meta-analyses listed 25 26 57 in PubMed that included a documented search of at least one database, statistically combined 27 28 29 58 results from ≥ 2 RCTs, and evaluated the effects of a drug or class of drugs. 30 31 59 Results: 90 of 107 (84%) Cochrane meta-analyses reported funding sources for some or all

32 http://bmjopen.bmj.com/ 33 60 included trials compared with 21 of 143 (15%) non-Cochrane meta-analyses, a difference of 69% 34 35 61 (95% confidence interval [CI], 59% to 77%). Percent reporting was also higher for Cochrane 36 37 38 62 meta-analyses compared with non-Cochrane meta-analyses for trial author-industry financial ties 39

40 63 (44% versus 1%; 95% CI for difference, 33% to 52%) and employment (17% versus 1%; 95% on September 24, 2021 by guest. Protected copyright. 41 42 64 CI for difference, 9% to 24%). In multivariable analysis, compared with Cochrane meta- 43 44 45 65 analyses, the odds ratio for reporting trial funding was ≤ 0.11 for all other journal category and 46 47 66 impact factor combinations. Compared with Cochrane reviews from 2010, reporting of funding 48 49 67 sources of included RCTs among recently published Cochrane meta-analyses improved by 54% 50 51 52 68 (95% CI, 42% to 63%), and reporting of trial author-industry financial ties and employment 53 54 69 improved by 37% (95% CI, 26% to 47%) and 10% (95% CI, 2% to 19%). 55 56 57 3 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 70 Conclusions: Reporting of trial funding sources, trial author-industry financial ties, and trial 4 5 6 71 author-industry employment in Cochrane meta-analyses has improved since 2010 and is higher 7 8 72 than in non-Cochrane meta-analyses. 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 4 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 73 Strengths and limitations of this study 4 5 6 74  We assessed reporting in 250 recently published meta-analyses, including 107 7 8 75 Cochrane meta-analyses. 9 10 76  The meta-analyses selected for inclusion in our study were representative of the 11 12 13 77 spectrum of meta-analyses of drug interventions and the journals where they were 14 15 78 published in 2016-2018. 16 For peer review only 17 79  We compared reporting practices among Cochrane and non-Cochrane meta- 18 19 20 80 analyses and recent Cochrane meta-analyses with Cochrane systematic reviews 21 22 81 from 2010. 23 24 82  Most meta-analyses of drug trials are published as Cochrane reviews or in 25 26 27 83 relatively low-impact specialty medicine journals. Thus, we were unable to 28 29 84 examine whether meta-analyses published in different types of journals or 30 31 85 journals with different impact factors are more or less likely to report on financial

32 http://bmjopen.bmj.com/ 33 86 conflicts of interest from included trials. 34 35 36 87  Our study examined only disclosed financial conflicts of interest and did not 37 38 88 attempt to identify non-disclosed conflicts. 39

40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 5 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 89 Financial conflicts of interest (FCOIs) can introduce bias in drug trials by influencing 4 5 6 90 how a trial is designed, inclusion and exclusion criteria, choice of drug dosages and comparators, 7 8 91 selection of trial outcomes, how analyses are conducted, interpretation of findings, which 9 10 92 outcomes are reported, and whether trial results are published.1-9 Drug trials funded by industry 11 12 93 are approximately 30% more likely to report favourable efficacy findings than non-industry 13 14 15 94 trials,8 and drug trials with principal investigators with FCOIs have higher odds of reporting 16 For peer review only 17 95 favourable outcomes than those led by principal investigators without FCOIs, even after 18 19 96 controlling for trial funding sources.7 20 21 22 97 Previous studies that have examined meta-analyses of drug trials published in high- 23 24 98 impact journals and Cochrane systematic reviews of drug trials have found that funding sources 25 26 99 and author FCOIs of included randomized controlled trials (RCTs) were rarely reported.10, 11 A 27 28 29 100 2011 study found that only 2 of a sample of 29 (7%) meta-analyses on the effects of drug 30 31 101 interventions published in high-impact journals in 2009 reported the funding sources of included

32 http://bmjopen.bmj.com/ 33 102 drug trials and that none reported trial author-industry financial ties or author-industry 34 35 103 employment.10 A second study, published in 2012, examined Cochrane systematic reviews of 36 37 38 104 drug trials and found that only 46 of 151 (30%) eligible reviews published in 2010 reported 39

40 105 information on the funding source of some or all included trials, 11 (7%) provided any on September 24, 2021 by guest. Protected copyright. 41 42 106 information on author-industry financial ties, and 10 (7%) provided any information on author- 43 44 11 45 107 industry employment from included trials. 46 47 108 In 2012, the Cochrane Collaboration began to require that Cochrane reviews report trial 48 49 109 funding sources and FCOIs of the primary researchers of all included trials in the characteristics 50 51 52 110 of included studies table (Methodolgical Expectations of Cochrane Intervention Reviews 53 54 111 (MECIR), standards R69 and R70) .12-13 The Preferred Reporting Items for Systematic Reviews 55 56 57 6 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 112 and Meta-analyses (PRISMA) statement, however, has not been updated since its publication in 4 5 14, 15 6 113 2009 and does not address the reporting of trial funding or author FCOIs of trials included in 7 8 114 systematic reviews and meta-analyses. 9 10 115 We do not know of any studies that have compared reporting among Cochrane meta- 11 12 116 analyses with meta-analyses published in other journals or examined whether reporting in 13 14 15 117 Cochrane reviews has improved since Cochrane implemented its reporting policy. The objectives 16 For peer review only 17 118 of the present study were to (1) investigate the extent to which Cochrane and non-Cochrane 18 19 119 meta-analyses of drug trials report trial funding sources, author-industry financial ties, and 20 21 22 120 author-industry employment; (2) examine characteristics of meta-analyses that are independently 23 24 121 associated with reporting funding sources of included RCTs; and (3) compare reporting among 25 26 122 recently published Cochrane meta-analyses to reporting from Cochrane systematic reviews 27 28 11 29 123 published in 2010, prior to implementation of Cochrane’s reporting policy. 30 31 124 METHODS

32 http://bmjopen.bmj.com/ 33 125 The methods for the present study were based on our previous study of reporting of 34 35 126 funding sources, author-industry financial ties, and author-industry employment from trials 36 37 38 127 included in Cochrane systematic reviews published in 2010; however in the present study, we 39

40 128 included only Cochrane reviews that contained a meta-analysis, whereas in the previous study all on September 24, 2021 by guest. Protected copyright. 41 42 129 Cochrane reviews that included results from at least one RCT were eligible.11 Because of this 43 44 45 130 difference, in our comparison, in addition to main analyses, we conducted sensitivity analyses 46 47 131 that only included systematic reviews with meta-analyses from the previous study. A study 48 49 132 protocol was developed prior to initiating the present study and was posted on the Open Science 50 51 52 133 Framework (https://osf.io/njk5w/). 53 54 134 Selection of meta-analyses 55 56 57 7 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 135 Meta-analyses in any language were eligible if they (1) included a documented search for 4 5 6 136 eligible RCTs using at least one database, (2) statistically combined results from ≥ 2 RCTs, and 7 8 137 (3) evaluated the efficacy/effectiveness or harm of a drug or class of drugs against an alternative 9 10 138 treatment (e.g., placebo, alternative drug, non-pharmacological treatment) or no treatment. Meta- 11 12 139 analyses that only assessed different methods of administration, dosages, or dosage schedules of 13 14 15 140 the same drug were excluded. Drugs were defined broadly to include biologics and vaccines, but 16 For peer review only 17 141 not nutritional supplements or medical devices without a drug component. Meta-analyses that 18 19 142 investigated a combination of pharmacological and non-pharmacological interventions or 20 21 22 143 interventions which may or may not involve a drug (e.g., amnioinfusion) were included if a study 23 24 144 group was exclusively given a drug intervention or if the meta-analysis assessed the addition of a 25 26 145 drug to a treatment received by both intervention and control groups. Interventions were 27 28 29 146 classified as having a drug component if any form of the active ingredient (e.g., dosage, route, 30 31 147 strength, compound) was listed as an approved or discontinued brand name, generic drug or

32 http://bmjopen.bmj.com/ 33 148 therapeutic biological product by the US Food and Drug Administration (FDA) as listed in the 34 35 149 Drugs@FDA database at the time of review.16 If an agent was not listed in the Drugs@FDA 36 37 38 150 database and was classified by the FDA as a non-drug (e.g., food additive, supplement), then it 39

40 151 was not considered a drug. If an agent was not regulated as a drug and was not listed as a non- on September 24, 2021 by guest. Protected copyright. 41 42 152 drug by the FDA, drug status was determined based on consensus among investigators using 43 44 45 153 publicly available sources that provided information on the agent. 46 47 154 We searched the MEDLINE database via PubMed on October 19, 2018 using a search 48 49 155 developed by a medical librarian (see eMethods1 for strategy). Citations were uploaded into the 50 51 52 156 systematic review software DistillerSR (Evidence Partners, Ottawa, Canada), which was used to 53 54 157 code and track results. Two investigators independently evaluated titles and abstracts for 55 56 57 8 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 158 potential eligibility. Full texts of titles and abstracts deemed potentially eligible by either 4 5 6 159 investigator were then reviewed by two investigators independently. Disagreements at the full- 7 8 160 text level were resolved through consensus with a third investigator consulted as necessary. 9 10 161 Because we sought to include the most recently published meta-analyses that met eligibility 11 12 162 criteria, prior to reviewing, citations were organized by PubMed reference identification numbers 13 14 15 163 with the most recent first. Title and abstract and full-text reviews were conducted sequentially 16 For peer review only 17 164 until we obtained our desired number of included meta-analyses based on our power analysis. 18 19 165 Data extraction 20 21 22 166 For each eligible meta-analysis, one reviewer initially extracted all data into a pre-defined 23 24 167 form in DistillerSR, and a second reviewer validated all extracted data using the DistillerSR 25 26 168 Quality Control function. Discrepancies were resolved by consensus and consultation with a 27 28 29 169 third investigator, if needed. For each included meta-analysis, reviewers extracted first author 30 31 170 last name; year of publication; journal name; Clarivate Analytics 2017 journal impact factor;

32 http://bmjopen.bmj.com/ 33 171 journal speciality area based on Clarivate Analytics classification; whether it was a Cochrane 34 35 172 meta-analysis published in the Cochrane Database of Systematic Reviews or elsewhere; funding 36 37 38 173 source for the meta-analysis and author-industry financial ties and employment; reporting in the 39

40 174 meta-analysis of trial funding sources, trial author-industry financial ties, and trial author- on September 24, 2021 by guest. Protected copyright. 41 42 175 industry employment; and whether the meta-analysis referenced a published protocol or 43 44 45 176 contained a PROSPERO registration number. If a registration number was not provided, we 46 47 177 searched the PROSPERO website (https://www.crd.york.ac.uk/PROSPERO/) using key terms 48 49 178 from the published article, then attempted to match the principal investigator, funding source, 50 51 52 179 intervention, non-intervention comparator group, and design from the article to registrations 53 54 180 obtained in the search. 55 56 57 9 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 181 To extract information on meta-analysis funding source, meta-analysis author-industry 4 5 6 182 financial ties, and meta-analysis author-industry employment and to determine whether or not 7 8 183 trial funding sources, trial author-industry financial ties, and trial author-industry employment 9 10 184 were reported in the meta-analysis, for each included meta-analysis, reviewers examined all text, 11 12 185 tables, figures, appendices, disclosure statements, acknowledgements and any online 13 14 15 186 supplemental material, published with the manuscript or linked to the manuscript. Funding 16 For peer review only 17 187 sources for meta-analyses were classified as (1) non-industry (e.g., public granting agency, 18 19 188 private not-for-profit granting agency), (2) pharmaceutical industry, (3) combined 20 21 22 189 pharmaceutical industry and non-industry, (4) no funding or (5) not reported. Financial ties of 23 24 190 meta-analysis authors to industry were defined per the International Committee of Medical 25 26 191 Journal Editors Uniform Disclosure Form for Potential Conflicts of Interest17 and included 27 28 29 192 current or former board membership, current or former consultancy, current or former industry 30 31 193 employment, expert testimony, industry grants (issued or pending), payment for lectures

32 http://bmjopen.bmj.com/ 33 194 including service on speakers bureaus, payment for manuscript preparation, patents (planned, 34 35 195 pending, or issued), royalties, payment for development of educational presentations, stock or 36 37 38 196 stock options, travel reimbursement, or other relationships with industry, as disclosed in the 39

40 197 review. Of these, we specifically coded if industry employees were part of the author group. If a on September 24, 2021 by guest. Protected copyright. 41 42 198 meta-analysis did not contain a disclosure statement, meta-analysis author-industry financial ties 43 44 45 199 were coded as not reported. 46 47 200 For reporting of (1) trial funding sources, (2) trial author-industry financial ties, and (3) 48 49 201 trial author-industry employment, meta-analyses were coded as (1) reporting for all included 50 51 52 202 trials; (2) reporting for some, but not all, included trials; or (3) not reporting. Meta-analyses that 53 54 203 included data from a pharmaceutical industry database or noted that trial drugs were supplied by 55 56 57 10 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 204 the manufacturers for certain trials, but that did not make any explicit statement of trial funding 4 5 6 205 sources, were coded as not reporting. For meta-analyses that reported information on funding 7 8 206 sources or author FCOIs from included trials, either fully or partially, we recorded where in the 9 10 207 meta-analysis the information was reported. Specifically, we recorded whether the information 11 12 208 was reported in the abstract, lay summary, risk of bias material (text, figure or table, both), main 13 14 15 209 text other than risk of bias, elsewhere in the main document (e.g., characteristics of included 16 For peer review only 17 210 studies table, other table, footnote of a table), or in an online appendix. See eMethods2. 18 19 211 Power analysis 20 21 22 212 To determine the number of meta-analyses to target, we first calculated the number of 23 24 213 included meta-analyses that would be needed for 80% power to find a statistically significant 25 26 214 difference if there were a 20% difference in reporting trial funding sources based on meta- 27 28 29 215 analysis characteristics, with  = 0.05. We varied the rates of reporting from 10% versus 30% to 30 31 216 70% versus 90% and considered scenarios where the proportion of reporting meta-analyses with

32 http://bmjopen.bmj.com/ 33 217 each characteristic (e.g., high-impact journals versus low-impact journals) was 50% versus 50% 34 35 36 218 and 30% versus 70%. For a two-tailed binomial test with  = 0.05, the maximum number of 37 38 219 included meta-analyses needed in any scenario was 239. Because the consequence of 39

40 220 overpowering the study was additional labour and not risk to human participants, we rounded on September 24, 2021 by guest. Protected copyright. 41 42 43 221 this number up to 250 meta-analyses. See eMethods3. 44 45 222 Statistical analyses 46 47 223 We presented characteristics of included meta-analyses descriptively, including funding 48 49 50 224 sources and FCOIs. We determined the proportion of meta-analyses that reported trial funding 51 52 225 source, author-industry financial ties, and author-industry employment of included trials for (1) 53 54 226 all included trials, (2) some, but not all, included trials, and (3) no included trials, along with 55 56 57 11 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 227 95% confidence intervals (CIs). We compared the difference between the proportion of recently 4 5 6 228 published Cochrane meta-analyses that reported study funding, author-industry financial ties, and 7 8 229 author-industry employment from included RCTs with recently published non-Cochrane meta- 9 10 230 analyses and with Cochrane systematic reviews published in 2010. Because the present study 11 12 231 included meta-analyses only, but the previous study of Cochrane reviews included systematic 13 14 15 232 reviews with or without meta-analyses,11 we conducted a sensitivity analysis in which we 16 For peer review only 17 233 excluded Cochrane systematic reviews from 2010 that did not include a meta-analysis and would 18 19 234 not have been eligible for inclusion in the present study. We calculated 95% CIs for all 20 21 18 22 235 differences. 23 24 236 To assess the relationship between meta-analysis characteristics and reporting of funding 25 26 237 sources for some or all included trials, versus not reporting, we fit unadjusted (bivariate) and 27 28 29 238 adjusted (multivariate) logistic regression models with all predictors using the glm function in R 30 31 239 (R version 3.2.3; RStudio Version 1.0.136).19,20 The predictor variables that were considered in

32 http://bmjopen.bmj.com/ 33 240 bivariate and. adjusted analyses were: (1) combined category (Cochrane, specialty medicine, 34 35 241 general medicine, multidisciplinary) and impact factor of the journal in which the meta-analysis 36 37 38 242 was published; and (2) whether there was industry funding for the meta-analysis or any FCOI 39

40 243 disclosed by meta-analysis authors. We combined journal category and impact factor because of on September 24, 2021 by guest. Protected copyright. 41 42 244 the small number of journals in some categories and the small number of journals with impact 43 44 45 245 factor greater than that of Cochrane. Thus, meta-analyses were categorized as (1) low-impact ( 46 47 246 3.0) specialty medicine journals, (2) low-impact ( 3.0) general medicine or multidisciplinary 48 49 50 247 journals, (3) medium-impact (3.1 - 6.7) specialty medicine journals, (4) high-impact (> 6.8) 51 52 248 specialty medicine or general medicine journals, and (5) Cochrane meta-analyses (impact factor 53 54 249 = 6.8; reference category). Because 28 of 33 meta-analyses in general medicine journals were 55 56 57 12 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 250 from a single journal (Medicine) and not necessarily representative of general medicine as a 4 5 6 251 category, and because 9 of the 10 meta-analyses published in multidisciplinary science journals 7 8 252 were published in a single journal (PLOS ONE), we combined general medicine and 9 10 253 multidisciplinary journals. 11 12 254 Our initial protocol indicated that, if possible, we would include in the logistic regression 13 14 15 255 model the year of publication of the meta-analysis and whether there was meta-analysis funding 16 For peer review only 17 256 by industry, meta-analysis author-industry financial ties, and meta-analysis author-industry 18 19 257 employment, separately. However, 246 of 250 included meta-analyses were published in 2017- 20 21 22 258 2018, and only 3 meta-analyses had industry funding; thus, we did not include year of 23 24 259 publication, and we grouped meta-analysis funding source and author FCOIs into a single 25 26 260 variable (No FCOIs including funding source versus any FCOI). Additionally, we only 27 28 29 261 conducted a multivariable analysis for the reporting of funding sources of included RCTs and not 30 31 262 for reporting of author-industry financial ties and author-industry employment, because there

32 http://bmjopen.bmj.com/ 33 263 were not enough examples of meta-analyses that reported author-industry financial ties and 34 35 264 author-industry employment. 36 37 38 265 Patient and Public Involvement 39

40 266 Patients and members of the public were not involved in the on September 24, 2021 by guest. Protected copyright. 41 42 267 design, conduct, reporting, or plan for dissemination of our 43 44 45 268 research. 46 47 269 RESULTS 48 49 270 Selection of eligible meta-analyses 50 51 52 271 Our initial search of PubMed without date restrictions retrieved 9,725 unique citations. 53 54 272 To select 250 eligible meta-analyses, working backwards from the most recent, a total of 401 55 56 57 13 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 273 citations were screened for eligibility; 64 were excluded at the title and abstract level and 76 at 4 5 6 274 the full-text level. See Figure1. 7 8 275 As shown in Table 1, of the 250 included meta-analyses, 107 (43%) were Cochrane 9 10 276 reviews, all of which were published in the Cochrane Database of Systematic Reviews. Among 11 12 277 the 143 non-Cochrane meta-analyses, 33 (23%) were published in general medicine journals 13 14 15 278 (including 28 in the journal Medicine), 100 (70%) in specialty medicine journals, and 10 (7%) in 16 For peer review only 17 279 multidisciplinary journals (including 9 in PLOS ONE). The mean number of included RCTs for 18 19 280 both Cochrane and non-Cochrane meta-analyses was approximately 20. Among the 143 non- 20 21 22 281 Cochrane meta-analyses, 25 (17%) referenced a published protocol or were registered in 23 24 282 PROSPERO, and 106 (74%) were published in a journal with impact factor ≤ 3. 25 26 283 Of the 250 meta-analyses, 3 (1%) reported being funded by industry, 148 (59%) reported 27 28 29 284 funding from non-industry sources, 56 (22%) reported no funding, and 43 (17%) did not report 30 31 285 funding source; 3 (1%) had at least 1 author who reported current industry employment, 51

32 http://bmjopen.bmj.com/ 33 286 (20%) had at least 1 author that reported other financial ties with industry, 187 (75%) reported 34 35 36 287 that there were no authors with FCOIs, and 12 (5%) did not report any information about author 37 38 288 FCOIs. Characteristics of each of the 250 included meta-analyses are shown in eTable1. 39

40 289 Reporting in meta-analyses of funding sources and author FCOIs from included drug trials on September 24, 2021 by guest. Protected copyright. 41 42 290 As shown in Table 2, 111 of the 250 (44%) included meta-analyses reported the funding 43 44 45 291 sources for some or all included trials, 49 (20%) reported author-industry financial ties for some 46 47 292 or all included trials, and 19 (8%) reported author-industry employment for some or all included 48 49 293 trials. Of the 107 Cochrane meta-analyses, 90 (84%) reported funding sources for some or all 50 51 52 294 included trials compared with 21 of 143 (15%) non-Cochrane meta-analyses, a difference of 69% 53 54 295 (95% CI, 59% to 77%); 47 (44%) Cochrane meta-analyses reported author-industry financial ties 55 56 57 14 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 296 for some or all included trials compared with 2 (1%) non-Cochrane meta-analyses, a difference 4 5 6 297 of 43% (95% CI, 33% to 52%); 18 (17%) Cochrane meta-analyses reported, fully or partially, 7 8 298 author-industry employment compared with 1 (1%) non-Cochrane meta-analysis, a difference of 9 10 299 16% (95% CI, 9% to 24%). 11 12 300 Among the 90 Cochrane meta-analyses that reported funding sources for some or all 13 14 15 301 included trials, 77 (86%) provided this information in the characteristics of included studies 16 For peer review only 17 302 table, including 23 (26%) that also included it in the assessment of risk of bias of included trials; 18 19 303 7 (8%) included it in the risk of bias assessment and at least one other place, but not the 20 21 22 304 characteristics of included studies table, and 6 (7%) reported only as part of the risk of bias 23 24 305 assessment. In total, 36 (40%) reported in the context of the risk of bias assessment. See eTable2 25 26 306 for reporting for all 250 included meta-analyses. 27 28 29 307 Factors associated with reporting FCOIs from included trials in multivariable analysis 30 31 308 As shown in Table 3, the odds ratio for reporting funding sources for some or all included

32 http://bmjopen.bmj.com/ 33 309 RCTs among non-Cochrane meta-analyses was  0.11 compared with Cochrane meta-analyses 34 35 36 310 for all journal category and impact factor combinations. Meta-analyses with any declared FCOI 37 38 311 (OR 1.29, 95% CI 0.53 to 3.19) and meta-analyses for which the presence of FCOIs was not 39

40 312 reported (OR 1.18, 95% CI 0.40 to 3.44) did not differ significantly in reporting compared with on September 24, 2021 by guest. Protected copyright. 41 42 43 313 those with no declared FCOIs. 44 45 314 Comparison of recent Cochrane meta-analyses versus Cochrane reviews published in 2010 46 47 315 Reporting of funding sources for some or all included trials improved from 30% in 48 49 316 Cochrane reviews of drug trials published in 2010 to 84% in recently published Cochrane meta- 50 51 52 317 analyses, an improvement of 54% (95% CI, 42% to 63%). Reporting of author-industry financial 53 54 318 ties for some or all included trials improved from 7% in 2010 to 44% in recent meta-analyses, a 55 56 57 15 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 319 37% change (95% CI, 26% to 47%). Reporting of author-industry employment for some or all 4 5 6 320 included trials improved from 7% in 2010 to 17% in recent meta-analyses (10%; 95% CI, 2% to 7 8 321 19%). Results did not change when the comparison was restricted to Cochrane reviews published 9 10 322 in 2010 that included a meta-analysis. See Table 2. Figure 2 summarizes reporting among 11 12 323 recently published Cochrane and non-Cochrane meta-analyses and Cochrane reviews from 2010. 13 14 15 324 DISCUSSION 16 For peer review only 17 325 Principal findings 18 19 326 We reviewed the 250 most recent meta-analyses of drug treatments listed in PubMed at 20 21 22 327 the time of our search. Of these, 107 (43%) were Cochrane reviews, 100 (40%) were published 23 24 328 in specialty medicine journals, and 43 (17%) were published in general medicine or 25 26 329 multidisciplinary journals, including 28 in Medicine and 9 in PLOS ONE. Of the 143 non- 27 28 29 330 Cochrane meta-analyses, 106 (74%) were published in journals with impact factor  3. 30 31 331 Among Cochrane meta-analyses, 84% reported funding sources for some or all included

32 http://bmjopen.bmj.com/ 33 332 RCTs compared with 15% of non-Cochrane meta-analyses. Cochrane meta-analyses were also 34 35 36 333 more likely than non-Cochrane meta-analyses to report author-industry financial ties (44% 37 38 334 versus 1%) and author-industry employment (17% versus 1%). 39

40 335 In 2010, only 30% of 151 Cochrane systematic reviews of drug treatments reported trial on September 24, 2021 by guest. Protected copyright. 41 42 11 43 336 funding sources. This improved to 84% among recent Cochrane meta-analyses. Cochrane 44 45 337 reviews also improved reporting of author-industry financial ties and author-industry 46 47 338 employment of included RCTs from 7% to 44% and from 7% to 17%. It is possible that the 48 49 339 reason that few meta-analyses reported author-industry employment is because some may have 50 51 52 340 assumed that author-industry employment would be considered a type of author-industry 53 54 55 56 57 16 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 341 financial tie and did not report employment separately, whereas we considered author-industry 4 5 6 342 financial ties and employment separately. 7 8 343 Among the 90 Cochrane meta-analyses that reported funding sources of included trials in 9 10 344 the present study, 86% included the information in the characteristics of included studies table, 11 12 345 as required by Cochrane, and 40% included the information in the risk of bias assessment. 13 14 15 346 Findings in context 16 For peer review only 17 347 In 2012, soon after our previous results showed that few Cochrane systematic reviews of 18 19 348 drug trials reported funding sources and author FCOIs of included trials,11 the Cochrane 20 21 22 349 Collaboration began to require that trial funding sources and FCOIs be reported for every 23 24 350 included RCT in the characteristics of included studies table.12-13 Reporting of trial funding 25 26 351 sources among recent Cochrane meta-analyses has not reached 100%, and work is needed to 27 28 29 352 improve the reporting of other types of author FCOIs, which was under 50% despite being 30 31 353 required by Cochrane. Nonetheless, the improvements documented in the present study are

32 http://bmjopen.bmj.com/ 33 354 substantial, both compared with previous Cochrane reviews and with contemporary non- 34 35 355 Cochrane meta-analyses. Cochrane is a global organization consisting of a large number of 36 37 38 356 different review and methods groups that span numerous fields of health research. This diversity 39

40 357 suggests that changes that have occurred likely resulted from change in the mandatory reporting on September 24, 2021 by guest. Protected copyright. 41 42 358 requirements for Cochrane reviews and widespread adoption by the organization. It also suggests 43 44 45 359 the possibility that other journals could improve the transparency of reporting of trial funding 46 47 360 and trial author FCOI in evidence syntheses by adopting similar reporting requirements. The 48 49 361 current version of the PRISMA statement does not address reporting of 50 51 52 362 trial funding sources and FCOIs of trial authors by investigators who publish systematic reviews 53 54 363 and meta-analyses.15,16 The forthcoming updated PRISMA statement, however, will require that 55 56 57 17 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 364 trial funding, although not trial author FCOIs, be reported (personal communication, David 4 5 6 365 Moher, May 22, 2019). 7 8 366 Members of our research team have previously recommended that risk of bias from trial 9 10 367 funding and trial author FCOIs be included in the Cochrane Risk of Bias Tool based on evidence 11 12 368 that links trial sponsorship and trial author FCOIs to outcomes.10 This recommendation was 13 14 15 369 debated at a Cochrane Methods Symposium in 2013, but consensus was not reached for 16 For peer review only 17 370 inclusion.12,21 The present study found that 40% of Cochrane meta- 18 19 371 analyses that reported on FCOIs from included trials included 20 21 22 372 this as part of a risk of bias assessment, even though this has 23 24 373 not been recommended by Cochrane. Currently, a new tool, the Tool 25 26 374 for Addressing Conflicts of Interest in Trials (TACIT),22 which specifically addresses risk of bias 27 28 29 375 from industry sponsorship of trials and author-industry financial ties and employment, is being 30 31 376 developed for inclusion in Cochrane reviews. Once the TACIT tool is completed, risk of bias

32 http://bmjopen.bmj.com/ 33 377 from trial funding and trial author FCOIs will be explicitly considered in Cochrane reviews and, 34 35 36 378 potentially, in non-Cochrane reviews, as well. Meanwhile, authors should, at a minimum, 37 38 379 describe FCOIs and discuss the degree to which they may influence confidence in findings. 39

40 380 Strengths and limitations on September 24, 2021 by guest. Protected copyright. 41 42 381 A strength of the present study is that we assessed reporting in a large number of recently 43 44 45 382 published meta-analyses, including 107 Cochrane meta-analyses, which allowed us to compare 46 47 383 reporting practices among Cochrane and non-Cochrane meta-analyses and recent Cochrane 48 49 384 meta-analyses with Cochrane systematic reviews from 2010. However, there are limitations that 50 51 52 385 should be considered. First, since most meta-analyses of drug trials are published as Cochrane 53 54 386 reviews or in relatively low-impact specialty medicine journals, we were not able to conduct 55 56 57 18 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 387 robust assessments of whether meta-analyses published in different types of journals or journals 4 5 6 388 with different impact factors are more or less likely to report on trial funding and trial author 7 8 389 FCOIs for included drug trials. The vast majority of meta-analyses published in general medicine 9 10 390 journals were from a single journal (Medicine), which further limited our ability to examine this 11 12 391 factor. On the other hand, the meta-analyses selected for inclusion in our study constituted a 13 14 15 392 consecutive sample of the most recent meta-analyses listed in PubMed and, thus, were 16 For peer review only 17 393 representative of the spectrum of meta-analyses of drug interventions and the journals where 18 19 394 they were published in 2016-2018. Second, our study examined only disclosed FCOIs. A 20 21 22 395 surprising finding was that a higher proportion of Cochrane meta-analysis authors indicated that 23 24 396 they had FCOIs compared with non-Cochrane authors; it is not known if this reflects greater 25 26 397 industry involvement among Cochrane authors or a higher propensity to report transparently and 27 28 29 398 completely among this group of authors. Third, information about FCOIs from included RCTs 30 31 399 was not extracted from the RCT publications. Finally, our previous study of Cochrane reviews

32 http://bmjopen.bmj.com/ 33 400 from 2010 included all systematic reviews, whereas the present study was restricted to reviews 34 35 401 with meta-analyses. However, a sensitivity analysis showed that results did not change when we 36 37 38 402 compared recent results to those from 2010 that were restricted to reviews with a meta-analysis. 39

40 403 Conclusions and policy implications on September 24, 2021 by guest. Protected copyright. 41 42 404 In summary, the percentage of recent Cochrane meta-analyses 43 44 45 405 on the effects of drug interventions that transparently reported 46 47 406 funding sources and trial author-industry financial ties and 48 49 407 employment for included trials far exceeds reporting in other 50 51 408 52 journals. It also far exceeds reporting in Cochrane systematic 53 54 409 reviews published in 2010, before the implementation by Cochrane of its policy 55 56 57 19 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 410 requiring the reporting of trial funding sources and author-industry FCOIs. These results suggest 4 5 6 411 that it is possible to achieve more transparent reporting of FCOIs from trials included in meta- 7 8 412 analyses. We encourage the uptake and enforcement of reporting requirements in the 9 10 413 forthcoming updated PRISMA statement.23 We also encourage the adoption of Cochrane’s new 11 12 414 TACIT tool22 by journals and authors in order to assess trial funding sources and author FCOIs 13 14 15 415 as risks of bias. Continued non-disclosure of FCOIs when evidence is synthesized in meta- 16 For peer review only 17 416 analyses misleads readers of medical journals into believing that there is not risk of bias from 18 19 417 FCOIs to be considered, even though an increasingly robust evidence base tells us that this is 20 21 7,8 22 418 often not the case. 23 24 25 26 27 28 29 30 31

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40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 20 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 419 Acknowledgement: The authors thank Drs. Ian Shrier and Jonathan Kimmelman for providing 4 5 6 420 helpful comments on an earlier version of the manuscript. They were not compensated for their 7 8 421 contribution. 9 10 422 Contributors: KAT, MR, JB, LAB, JL, EHT, AB, and BDT were responsible for the study 11 12 423 conception and design. KAT, ACJ, CB, and KE were responsible for title and abstract and full- 13 14 15 424 text review. KAT and ACJ were responsible for data extraction and validation. KAT, BL, AB, 16 For peer review only 17 425 and BDT analysed and interpreted results. KAT and BDT drafted the 18 19 426 manuscript. All authors provided a critical review and approved 20 21 22 427 the final manuscript. BDT is the guarantor. 23 24 428 Copyright for authors: The Corresponding Author has the right to 25 26 429 grant on behalf of all authors and does grant on behalf of all 27 28 430 29 authors, a worldwide licence 30 31 431 (http://www.bmj.com/sites/default/files/BMJ%20Author%20Licence%2

32 http://bmjopen.bmj.com/ 33 432 0March%202013.doc) to the Publishers and its licensees in 34 35 433 perpetuity, in all forms, formats and media (whether known now 36 37 38 434 or created in the future), to i) publish, reproduce, distribute, 39

40 435 display and store the Contribution, ii) translate the on September 24, 2021 by guest. Protected copyright. 41 42 436 Contribution into other languages, create adaptations, reprints, 43 44 437 include within collections and create summaries, extracts 45 46 47 438 and/or, abstracts of the Contribution and convert or allow 48 49 439 conversion into any format including without limitation audio, 50 51 440 iii) create any other derivative work(s) based in whole or part 52 53 441 on the on the Contribution, iv) to exploit all subsidiary rights 54 55 56 442 to exploit all subsidiary rights that currently exist or as may 57 21 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 443 exist in the future in the Contribution, v) the inclusion of 4 5 444 6 electronic links from the Contribution to third party material 7 8 445 where-ever it may be located; and, vi) licence any third party 9 10 446 to do any or all of the above. All research articles will be 11 12 447 made available on an open access basis (with authors being asked 13 14 15 448 to pay an open access fee—seehttp://www.bmj.com/about- 16 For peer review only 17 449 bmj/resources-authors/forms-policies-and-checklists/copyright- 18 19 450 open-access-and-permission-reuse). The terms of such open access 20 21 451 shall be governed by a Creative Commons licence—details as to 22 23 24 452 which Creative Commons licence will apply to the research 25 26 453 article are set out in our worldwide licence referred to above. 27 28 454 Funding: Ms. Turner was supported by a Fonds de Recherche Québec - Santé 29 30 31 455 (FRQ-S) masters training award, Ms. Levis was supported by a Canadian Institutes of Health

32 http://bmjopen.bmj.com/ 33 456 Research doctoral research award, and Drs. Benedetti and Thombs were supported by FRQ-S 34 35 457 researcher awards, all outside of the submitted work. 36 37 38 458 Declaration of Competing Interests: All authors have completed the ICMJE uniform 39

40 459 disclosure form at www.icmje.org/coi_disclosure.pdf. Dr. Bero disclosed that she on September 24, 2021 by guest. Protected copyright. 41 42 460 is Senior Editor, Cochrane Public Health and Health Systems, for 43 44 461 which the University of Sydney receives remuneration. Dr. Thombs 45 46 47 462 disclosed that he is a content editor with the Cochrane Common 48 49 463 Mental Disorders review group (no remuneration received). All 50 51 464 other authors declared: no support from any organisation for the submitted work; no 52 53 54 465 financial relationships with any organisations that might have an interest in the submitted work 55 56 57 22 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 466 in the previous three years; no other relationships or activities that could appear to have 4 5 6 467 influenced the submitted work. 7 8 468 Ethics Statement: As this study involved only the review of published articles, research ethics 9 10 469 approval was not required. 11 12 470 Transparency Declaration: The manuscript’s guarantor affirms that this manuscript is an 13 14 15 471 honest, accurate, and transparent account of the study being reported; that no important aspects 16 For peer review only 17 472 of the study have been omitted; and that any discrepancies from the study as planned (and, if 18 19 473 relevant, registered) have been explained. 20 21 22 474 Data Sharing: All extracted data are available in the main tables or in eTable1 and eTable2. No 23 24 475 additional data were extracted. 25 26 27 28 29 30 31

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40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 23 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 476 REFERENCES 4 5 6 7 477 1. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and 8 9 478 research outcome and quality: systematic review. BMJ. 2003;326(7400):1167-70. 10 11 479 2. Bero LA, Rennie D. Influences on the quality of published drug studies. Int J Technol Assess 12 13 480 Health Care. 1996;12(2):209-37. 14 15 16 481 3. Melander H, Ahlqvist-RastadFor peer J, Meijer review G, Beermann B. Evidenceonly b (i) ased medicine— 17 18 482 selective reporting from studies sponsored by pharmaceutical industry: review of studies in 19 20 483 new drug applications. BMJ. 2003;326(7400):1171-3. 21 22 23 484 4. Rising K, Bacchetti P, Bero L. Reporting bias in drug trials submitted to the Food and Drug 24 25 485 Administration: review of publication and presentation. PLoS Med. 2008;5(11):e217.4. 26 27 486 5. Sismondo S. How pharmaceutical industry funding affects trial outcomes: causal structures 28 29 30 487 and responses. Soc Sci Med. 2008;66(9):1909-14. 31

32 488 6. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of http://bmjopen.bmj.com/ 33 34 489 antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358(3):252- 35 36 490 60. 37 38 39 491 7. Ahn R, Woodbridge A, Abraham A, Saba S, Korenstein D, Madden E, et al. Financial ties of

40 on September 24, 2021 by guest. Protected copyright. 41 492 principal investigators and randomized controlled trial outcomes: cross sectional study. BMJ 42 43 493 2017;356:i6770. 44 45 46 494 8. Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsorship and research 47 48 495 outcome. Cochrane Database of Syst Rev. 2017;2:MR000033. 49 50 496 9. Lexchin J. Those who have the gold make the evidence: how the pharmaceutical industry 51 52 53 497 biases the outcomes of clinical trials of medications. Sci Eng Ethics. 2012;18(2):247-61. 54 55 56 57 24 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 498 10. Roseman M, Milette K, Bero LA, Coyne JC, Lexchin J, Turner EH, et al. Reporting of 4 5 6 499 conflicts of interest in meta-analyses of trials of pharmacological treatments. JAMA. 7 8 500 2011;305(10):1008-17. 9 10 501 11. Roseman M, Turner EH, Lexchin J, Coyne JC, Bero LA, Thombs BD. Reporting of conflicts 11 12 502 of interest from drug trials in Cochrane reviews: cross sectional study. BMJ. 13 14 15 503 2012;345:e5155. 16 For peer review only 17 504 12. Bero LA. Why the Cochrane risk of bias tool should include funding source as a standard 18 19 505 item. Cochrane Database of Syst Rev. 2013;12:ED000075. 20 21 22 506 13. Higgins J, Lasserson T, Chandler J, Tovey D, Churchill R. Methodological expectatinos of 23 24 507 Cochrane intervention reviews (MECIR). Version July 2019. Available from: 25 26 508 https://community.cochrane.org/mecir-manual. Accessed August 22, 2019. 27 28 29 509 14. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic 30 31 510 reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.

32 http://bmjopen.bmj.com/ 33 511 15. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The 34 35 512 PRISMA statement for reporting systematic reviews and meta-analyses of studies that 36 37 38 513 evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. 39

40 514 16. Administration USFaD. Drugs@FDA: FDA Approved Drug Products Database. Available on September 24, 2021 by guest. Protected copyright. 41 42 515 from: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed August 22, 2019. 43 44 45 516 17. Drazen JM, Van Der Weyden MB, Sahni P, Rosenberg J, Marusic A, Laine C, et al. 46 47 517 Uniform format for disclosure of competing interests in ICMJE journals. JAMA. 48 49 518 2010;303(1):75-6. 50 51 52 519 18. Newcombe RG. Interval estimation for the difference between independent proportions: 53 54 520 comparison of eleven methods. Stat Med. 1998;17(8):873-90. 55 56 57 25 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 521 19. R Core Team. R: A language and environment for statistical computing. R Foundation for 4 5 6 522 Statistical Computing; 2018. 7 8 523 20. RStudio Team. RStudio: Integrated development for R. Boston, MA: RStudio, Inc.; 2015. 9 10 524 21. Sterne JA. Why the Cochrane risk of bias tool should not include funding source as a 11 12 525 standard item. Cochrane Database Syst Rev. 2013(12). 13 14 15 526 22. Lundh A. Tool for Addressing Conflicts of Interest in Trials (TACIT) in Cochrane Reviews 16 For peer review only 17 527 [PowerPoint slides]. 2018. 18 19 20 528 23. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann T, Mulrow CD, Shamseer L, 21 22 23 529 Moher, D. Updating the PRISMA reporting guideline for systematic reviews and meta - 24 25 530 analyses: study protocol. 2018. Available from: https://osf.io/xwcv5/. Accessed August 22, 26 27 531 2019. 28 29 30 31 532

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40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 26 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 533 FIGURES 4 5 6 7 534 Figure 1. Flow diagram of selection of eligible meta-analyses. 8 9 10 535 Figure 2. Percentage of recently published Cochrane and non-Cochrane meta-analyses and 2010 11 12 536 Cochrane systematic reviews that reported included trial funding source, author-industry 13 14 537 financial ties, and author-industry employment for some or all included trials. 15 16 For peer review only 17 18 538 19 20 21 22 23 24 25 26 27 28 29 30 31

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40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 27 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 Table 1. Characteristics of included meta-analyses 4 5 6 Cochrane Non-Cochrane 7 8 Meta-Analyses Meta-Analyses 9 10 (N = 107) (N = 143) 11 12 Year of publication 13 14 2016, N (%) 0 4 (3%) 15 16 For peer review only 17 2017, N (%) 22 (21%) 31 (22%) 18 19 2018, N (%) 85 (79%) 108 (76%) 20 21 Number of Included RCTs, mean ± SD 21.4 ± 24.4 19.6 ± 46.4 22 23 Registered in PROSPERO or Published Protocol, N 107 (100%) 25 (17%)a 24 25 (%) 26 27 Impact Factor, mean ± SD 6.8 ± 0 3.6 ± 5.4 28 29 ≤ 3 0 106 (74%) 30 31 3.1-6.7 0 27 (19%)

32 http://bmjopen.bmj.com/ 33 6.8 107 (100%) 0 34 35 36 > 6.8 0 10 (7.0%) 37 38 Meta-Analysis Funding Sources 39 b

40 Not reported 4 (4%) 39 (27%) on September 24, 2021 by guest. Protected copyright. 41 42 Industry 0 3 (2%) 43 44 Non-Industry 93 (87%) 55 (38%) 45 46 No funding 10 (9%) 46 (32%) 47 48 Meta-Analysis Author Financial Ties to Industry 49 50 (Including Employment)c 51 52 Not reported, N (%) 1 (1%) 11 (8%) 53 54 55 No authors with reported financial ties, N (%) 70 (65%) 117 (81%) 56 57 28 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3  1 author with reported financial ties, N (%) 36 (34%) 15 (10%) 4 5 Proportion of authors with financial ties, 11% ± 17% 4% ± 15% 6

7 d 8 mean ± SD 9 10 Journal Category 11 12 Cochrane review, N (%) 107 (100%) 0 13 14 Specialty medicine N (%) 0 100 (70%) 15 16 General medicineFor (non-Cochrane), peer freview N (%) only0 33 (23%) 17 18 Multidisciplinary,g N (%) 0 10 (7%) 19 20 539 aOne meta-analysis reported that they registered in PROSPERO but did not provide a registration number and one 21 540 could not be found. We contacted the authors and they did not provide us with further information; thus this was 22 541 coded as not registered. bOnly 3 included meta-analyses reported author-industry employment and these were 23 542 grouped with author-industry financial ties for this table cCochrane reviews typically have a “Sources of Support” 24 543 section with funding information. These reviews did not include that section. dProportion of authors with financial 25 544 ties or employment of those that reported. eClassifications for specialty medicine journals (note that some journals 26 545 had more than one classification): Anesthesiology, N = 3; Biochemistry & Molecular Biology, N =1; Biotechnology 27 546 & Applied Microbiology, N =2; Cardiac & Cardiovascular Systems, N = 7; Cell Biology, N = 1; Chemistry, 28 547 Medicinal, N = 4; Chemistry, Multidisciplinary, N =2; Clinical Neurology, N = 6; Critical Care Medicine, N =2; 29 548 Dermatology, N = 3; Emergency Medicine, N = 2; Endocrinology & Metabolism, N = 2; Gastroenterology & 30 549 Hepatology, N = 6; Genetics & Heredity, N = 1; Hematology, N = 2; Immunology, N = 6; Infectious Diseases, N 31 550 =3; Integrative & Complementary Medicine, N =1; Medicine, Research & Experimental, N = 3; Microbiology, N =

32 551 2; Neurosciences, N =3; No classification, N = 2; Obstetrics & Gynecology, N = 4; Oncology, N = 11; http://bmjopen.bmj.com/ 33 552 Ophthalmology, N = 3; Orthopedics, N = 6; Parasitology, N = 1; Peripheral Vascular Disease, N =5; Pharmacology 34 553 & Pharmacy, N = 13; Physiology, N =1; Psychiatry, N = 4; Psychology, N = 1; Reproductive Biology, N = 1; 35 554 Respiratory System, N = 6; Rheumatology, N = 3; Sport Sciences, N = 1; Surgery, N =11; Toxicology, N = 2; f 36 555 Tropical Medicine, N = 1; Urology & Nephrology, N =1. Of the 33 included general medicine journals, 28 were g 37 556 published in the journal “Medicine”. Of the 10 journals classified as multidisciplinary, 9 were published in the 38 557 journal “PLOS ONE”. 39

40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 29 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 4 Table 2. Summary of reporting patterns of disclosed funding source and author-industry FCOI from included RCTs 5 6 Number of Meta-analyses Reporting 7 Number of Meta-analyses Reporting Funding Number of Meta-analyses Reporting Author Author-Industry Employment of Included 8 Sources of Included RCTs Financial Ties of Included RCTs 9 RCTs 10 11 Full or Full or 12 Full Partial Full or Partial Full Partial Full Partial For peer review onlyPartial Partial 13 14 Recently Published Meta-analyses: 15 16 Cochrane (N = 107), N (%) 70 (65%) 20 (19%) 90 (84%) 24 (22%) 23 (21%) 47 (44%) 1 (1%) 17 (16%) 18 (17%)

17 Non-Cochrane (N = 143), N (%) 14 (10%) 7 (5%) 21 (15%) 1 (1%) 1 (1%) 2 (1%) 0 http://bmjopen.bmj.com/ 1 (1%) 1 (1%) 18 19 20 Difference in Reporting Between 56% 14% 69% 22% 21% 43% 1% 15% 16% 21 22 Cochrane and Non-Cochrane Meta- (44% to 65%) (6% to 23%) (59% to 77%) (14% to 31%) (13% to 30%) (33% to 52 %) (-2% to 5%) (9% to 23%) (9% to 24%) 23 analyses, % (95% CI) 24 2010: 25 on September 24, 2021 by guest. Protected copyright. 26 All Cochrane Systematic Reviews 30 (20%) 16 (11%) 46 (30%) 2 (1%) 9 (6%) 11 (7%) 0 10 (7%) 10 (7%) 27 28 (N = 151), N (%)a 29 30 Difference in Reporting Between 46% 8% 54% 21% 16% 37% 1% 9% 10% 31 Recently Published Cochrane Meta- (34% to 56%) (-1% to 18%) (42% to 63%) (13% to 30%) (7% to 25%) (26% to 47%) (-2% to 5%) (2% to 18%) (2% to 19%) 32 33 analyses versus Cochrane 34 Systematic Reviews Published in 35 36 2010, % (95% CI) 37 2010: 38 39 Cochrane Meta-analyses (N =119), 21 (19%) 15 (13%) 36 (30%) 0 (0%) 7 (6%) 7 (6%) 0 (0%) 7 (6%) 7 (6%) 40 41 42 30 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 N (%) 4 5 Difference in Reporting Between 48% 6% 54% 22% 16% 38% 1% 10% 11% 6 Recently Published Cochrane Meta- (36% to 58%) (-3% to 16%) (42% to 63%) (15% to 31%) (7% to 25%) (27% to 48%) (-2% to 5%0 (2% to 19%) (3% to 20%) 7 8 analyses versus Cochrane Meta- 9 analyses Published in 2010, % (95% 10 11 CI) 12 558 a Results from Roseman et al., 2012. For peer review only 13 14 15 16

17 http://bmjopen.bmj.com/ 18 19 20 21 22 23 24

25 on September 24, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 31 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 33 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 Table 3. Factors associated with reporting funding sources of included RCTs 4 5 6 Proportion that Unadjusted odds Adjusted odds ratio 7 8 reported some or ratio (95% CI) (95% CI) 9 10 all declared 11 12 funding sources 13 14 from included 15 16 For peer RCTsreview only 17 18 19 FCOI of meta-analysis 20 21 (including meta-analysis 22 23 funding) 24 25 reference = no FCOI 67/151 (44%) 26 27 Any disclosed FCOI 35/51 (69%) 2.74 (1.42 to 5.49) 1.29 (0.53 to 3.19) 28 29 Not reported 9/48 (19%) 0.29 (0.12 to 0.62) 1.18 (0.40 to 3.44) 30 31

32 http://bmjopen.bmj.com/ 33 Impact Factor and Journal 34 35 Type 36 37 reference = Cochrane 90/107 (84%) 38 39 Specialty impact factor ≤ 3b 4/65 (6%) 0.01 (< 0.01 to 0.03) 0.01 (< 0.01 to 0.04) 40 on September 24, 2021 by guest. Protected copyright. 41 42 General (N=31) or 4/41 (10%) 0.02 (< 0.01 to 0.06) 0.02 (< 0.01to 0.06) 43 44 Multidisciplinary (N=10) 45 46 impact factor ≤ 3 47 48 Specialty impact factor 3.1 - 10/27 (37%) 0.11 (0.04 to 0.28) 0.11 (0.04 to 0.28) 49 50 6.7c 51 52 Specialty (N=8) or General 3/10 (30%) 0.08 (0.02 to 0.32) 0.08 (0.02 to 0.32) 53 54 (N=2) impact factor > 6.8 55 56 57 32 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 34 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 559 aNot reported included meta-analyses for which the presence of FCOI could not be determined 4 560 because either meta-anlaysis funding, meta-analysis author FCOI, or both were not reported. 561 b Two meta-analyses were from journals that did not have an impact factor, and these were coded as having an impact factor of 0.5 for our 5 562 analyses. 6 563 c There were no multidisciplinary or general medicine journals with an impact factor of 3.1-6.7. 7 564 FCOI = financial conflicts of interest 8 9 565 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 33 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 Records screened, beginning with most 3 recently published 4 5 N = 401 6 7 Records excluded 8 For peer review Nonly = 64 9 •Not a systematic review and 10 11 meta-analysis (N = 35)

12 •Not a drug treatment (N = 29) http://bmjopen.bmj.com/ 13 14 15 Full-text records assessed 16 for eligibility 17 18 N = 327 19

20 Records excluded on September 24, 2021 by guest. Protected copyright. 21 N = 76 22 •Not a systematic review and 23 24 meta-analysis (N = 31) 25 •Not a drug treatment (N = 45) 26 27 28 29 30 Meta-analyses included in 31 study 32 N = 250 33 34 35 36 37 38 39 40 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from Page 36 of 107 BMJ Open http://bmjopen.bmj.com/ on September 24, 2021 by guest. Protected copyright.

For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 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 37 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 Supplementary Material 4 5 6 7 8 eMethods1. Search strategy 9 10 eMethods2. Data extraction form 11 12 eMethods3. Power analysis 13 14 15 eTable1. Detailed characteristics of included meta-analyses 16 For peer review only 17 eTable2. Detailed reporting of study funding source, author-industry financial ties, and author- 18 19 industry employment from included RCTs 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 eMethods1. Search strategy 4 5 6 To obtain our sample, we searched the MEDLINE database via PubMed on October 19, 7 2018 using the following search strategy: 8 9 10 11 (((("Randomized Controlled Trials as Topic"[Mesh] or randomized control trial 12 [tiab] or randomized controled trial [tiab] OR randomized controlled trial [tiab] or 13 14 randomized control trials [tiab] OR randomized controled trials [tiab] OR 15 16 Randomized controlledFor peertrials [tiab] orreview randomised control only trial [tiab] or randomised 17 18 controled trial [tiab] OR randomised controlled trial [tiab] or randomised control 19 trials [tiab] OR randomised controled trials [tiab] OR Randomised controlled trials 20 21 [tiab]) AND ("Therapeutic Uses"[Mesh] OR "Vaccines"[Mesh]) AND ("Meta- 22 23 Analysis" [Publication Type] or meta analysis [tiab]) AND (systematic review 24 25 [tiab] OR search [tiab] or searched [tiab] or MEDLINE [tiab] OR PubMed [tiab])))) 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 eMethods 2. Data extraction form 4 5 6 7 8 First Author, last name: Last name of first author of meta-analysis 9 10 11 Year of publication (or in press): Year of publication of meta-analysis 12 13 14 15 Journal: Name of journal in which meta-analysis was published 16 For peer review only 17 18 Journal Impact factor: Where meta-analysis published (low-high split or continuous based on 19 20 data distribution) 21 22 23 Specialty area of Journal: Where meta-analysis published (per Thomson Reuters Journal 24 25 Science Citation Index - Expanded categories) 26 27 28 29 Cochrane Review (Y/N): Is the meta-analysis a Cochrane Review? Select "Yes" even if the 30 Cochrane Review is being published in another journal 31

32 Response from radio options: http://bmjopen.bmj.com/ 33 34 - Y (Yes) 35 - N (No) 36 37 38 39 Journal policies for reporting COI of Included Trials: Presence or absence of instructions for

40 on September 24, 2021 by guest. Protected copyright. 41 reporting in the author instructions 42 - Y (Yes) 43 44 - N (No) 45 46 47 48 # of RCTs synthesized in Meta-Analysis (total RCTs in included meta-analysis related to 49 drugs) 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 Date Range of Included Trials: Date range in years of publication of studies (RCTs) included 4 5 related to drugs in the meta-analysis (XXXX - XXXX). Use "In press" for end date if there are in 6 7 press trials. Use “Unpublished” if a trial is in progress or has never been published. 8 9 10 Study population: Characteristics of study population of included trials (e.g. condition/disorder, 11 12 adult/child) 13 14 15 Pharmacological agent: Pharmacologic treatment evaluated in the meta-analysis 16 For peer review only 17 - Name(s) of treatment if specific drug(s) investigated 18 19 - Class of treatment if broader category of drugs investigated, and number of drugs 20 21 evaluated (e.g. SSRIs – 5 included) 22 23 24 Control/comparison arms: Other treatment arms (control/comparison) included in the meta- 25 26 analysis (e.g. placebo, name of comparison pharmacologic treatment, name of behavioral 27 intervention) 28 29 30 31 Meta-Analysis Author Financial Ties / Funding Sources Reported: Does the meta-analysis

40 on September 24, 2021 by guest. Protected copyright. 41 - Both financial ties and funding sources 42 43 - Neither reported 44 45 46 Funding Source of Meta-Analysis (if applicable – only shown if above item indicates meta- 47 48 analysis funding sources reported or both financial ties and meta-analysis funding sources 49 50 reported) Source of financial support for the meta-analysis: 51 52 Response from radio options: 53 - Industry 54 55 - Combined industry and non-industry 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 - Non-industry (e.g. public granting agency, private not-for-profit granting agency) 4 5 - No study funding 6 7 8 Type of Industry Funding (if applicable – only shown if above item indicates industry 9 10 funding or combined industry and non-industry present): If the meta-analysis is industry 11 12 funded, what is the type of support provided by industry? Response from radio options: 13 14 - Financial support 15 - Resources (e.g. statistical analyses) 16 For peer review only 17 - Both financial support and resources 18 19 20 21 # of Meta-Analysis Authors: Number of authors of the meta-analysis (count authors named in 22 byline or in an author group) 23 24 25 26 # of Meta-Analysis Authors with Financial Ties to Industry (if applicable – only shown if 27 meta-analysis author financial ties or both financial ties and meta-analysis funding sources 28 29 are reported): Number of authors of the meta-analysis who have financial ties such as industry 30 31 board member, consultant, investments, patents, research funding, royalties (including former,

40 on September 24, 2021 by guest. Protected copyright. 41 are reported): Number of authors of the meta-analysis who are current industry employees. 42 43 Response from radio options: 44 45 Numbers 0 - ≥10 46 47 48 Quality or Risk Assessment of Included RCTs (Y/N): Was quality or risk assessment of 49 50 included RCTs, by methods from Cochrane, Jadad, etc., reported in the meta-analysis. 51 52 Response from radio options: 53 - Y (Yes) 54 55 - N (No) 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 4 5 Quality or Risk Assessment Method of Included RCTs (if applicable – only shown if 6 7 answer to previous item is yes- quality or risk assessment of included RCTs is reported): If 8 the meta-analysis authors report a quality or risk assessment method of included RCTs, what is 9 10 the reported method of quality assessment? 11 12 13 14 Meta-analysis Authors Report Funding Sources of Included Studies: Response from radio 15 options: 16 For peer review only 17 - Reported for each included study 18 19 - Reported in summary statement or for some, but not all, trials 20 21 - Included study funding sources not reported 22 23 24 Placement in publication of Included RCTs’ Funding Source (if applicable – only shown if 25 26 the response to Meta-analysis Authors Report Funding Sources of Included Studies is (1) 27 Reported for Each included Study or (2) Reported in summary statement or for some, but not all, 28 29 trials): 30 31 - Abstract

40 on September 24, 2021 by guest. Protected copyright. 41 - Lay Summary 42 43 44 45 Placement in risk of bias or quality assessment of Included RCTs’ Funding Source (if 46 applicable – only shown if placement in publication of included RCT’s Funding Source is risk of 47 48 bias or quality assessment): 49 50 - Text 51 52 - Figure/table 53 - Both text and figure/table 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 Meta-analysis Authors Report Author Financial Ties of Included Studies: Response from 4 5 radio options: 6 7 - Reported for each included study 8 - Reported in summary statement or for some, but not all, trials 9 10 - Included study author financial ties not reported 11 12 13 14 Placement in publication of Included RCTs’ Author Financial Ties (if applicable – only 15 shown if the response Meta-analysis Authors Report Author Financial Ties of Included Studies is 16 For peer review only 17 (1) Reported for Each included Study or (2) Reported in summary statement or for some, but not 18 19 all, trials): 20 21 - Abstract 22 - Main text, other than risk of bias or quality section 23 24 - In risk of bias or quality assessment 25 26 - Other in main document (e.g., a characteristics of studies table, other table, in a 27 footnote of a table 28 29 - Online appendix 30 31 - Lay Summary

40 on September 24, 2021 by guest. Protected copyright. 41 - Figure/table 42 43 - Both text and figure/table 44 45 46 Meta-analysis Authors Report Author Industry Employment of Included Studies: Do the 47 48 authors of the meta-analysis report current author industry affiliation (employment) for the 49 50 included studies? Response from radio options: 51 52 - Reported for each included study 53 - Reported in summary statement or for some, but not all, trials 54 55 - Included study author industry employment not reported 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 44 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 4 5 Placement in publication of Included RCTs’ Author Industry Employment (if applicable – 6 7 only shown if the response to Meta-analysis Authors Report Author Industry Affiliation 8 (Employment) of Included Studies is (1) Reported for Each included Study or (2) Reported in 9 10 summary statement or for some, but not all, trials): 11 12 - Abstract 13 14 - Main text, other than risk of bias or quality section 15 - In risk of bias or quality assessment 16 For peer review only 17 - Other in main document (e.g., a characteristics of studies table, other table, in a 18 19 footnote of a table) 20 21 - Online appendix 22 - Lay Summary 23 24 25 26 Placement in risk of bias or quality assessment of Included RCTs’ Author Industry 27 Employment (only shown if placement in publication of included RCT’s Author Industry 28 29 Affiliation is risk of bias or quality assessment): 30 31 - Text

32 http://bmjopen.bmj.com/ 33 - Figure/table 34 - Both text and figure/table 35 36 37 38 Do the authors report a PROSPERO registration number in the text? 39 - Yes

40 on September 24, 2021 by guest. Protected copyright. 41 - No 42 43 What is the registration number (e.g., CRD42017062454)? (if applicable – only shown if the 44 45 response to Do the authors report a PROSPERO registration number in the text? Is yes) 46 47 48 What stages were completed (ignore started) at the time of registration. Make sure to select 49 50 the earliest registration version at the bottom of the page. Please check all stages that were 51 52 completed. (if applicable – only shown if the response to Do the authors report a PROSPERO 53 registration number in the text? Is yes) 54 55 - Preliminary searches 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 45 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 - Piloting of the study selection process 4 5 - Formal screening of search results against eligibility criteria 6 7 - Data extraction 8 - Risk of bias (quality) assessment 9 10 - Data analysis 11 12 - None completed 13 14 15 Was a registration found in PROSPERO? (if applicable – only shown if the response to Do 16 For peer review only 17 the authors report a PROSPERO registration number in the text? Is no) 18 19 20 21 What is the registration number (e.g., CRD42017062454)? (if applicable – only shown if the 22 response to Was a registration found in PROSPERO? Is yes) 23 24 25 26 What stages were completed (ignore started) at the time of registration. Make sure to select 27 the earliest registration version at the bottom of the page. Please check all stages that were 28 29 completed. (if applicable – only shown if the response to Was a registration found in 30 31 PROSPERO? Is yes)

40 on September 24, 2021 by guest. Protected copyright. 41 - Data analysis 42 43 - None completed 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 46 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 eMethods3. Power analysis 4 5 6 7 Allocation ratio: 50% and 50% (1:1) 8 20% difference 9 Proportion reporting Sample size Sample size Sample size Actual power Actual alpha 10 COI group 1 group 2 total 11 Low impact High 12 impact 13 10% 30% 69 69 138 .807 .033 14 20% 40% 90 90 180 .802 .037 15 30% 50% 102 102 204 .806 .042 16 40% For60% peer102 review102 only204 .801 .038 17 50% 70% 102 102 204 .806 .036 18 60% 80% 90 90 180 .802 .032 19 70% 90% 69 69 138 .807 .025 20 21 22 23 Allocation ratio: 30% and 70% (3:7) 24 25 20% difference 26 Proportion reporting Sample size Sample size Sample size Actual power Actual alpha 27 COI group 1 group 2 total 28 Low impact High 29 impact 30 10% 30% 105 44 149 .815 .038 31 20% 40% 141 59 200 .807 .040 30% 50% 165 69 234 .801 .045 32 http://bmjopen.bmj.com/ 33 40% 60% 168 71 239 .805 .043 34 50% 70% 166 70 236 .864 .042 35 60% 80% 148 62 210 .802 .040 36 70% 90% 133 47 160 .802 .035 37 38 39

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1 2 3 4 eTable1. Detailed characteristics of included meta-analyses 5 6 eTable1. Detailed characteristics of included meta-analyses 7 First Author Year Journal 2017 Specialty Area Meta- Number of Number Publicatio Population Drug Intervention(s) Comparison Arm(s) 8 Impact analysis Meta- of drug n Dates of 9 Factor Funding analysis RCTs included 10 source(s) Authors Included drug RCTs with 11 Industry 12 For peerFinancial review only 13 Ties / Number of 14 Meta- 15 analysis 16 Authorsa

17 http://bmjopen.bmj.com/ 18 Cochrane Reviews (n = 107) Gemcitabine, vandetanib, 19 Cochrane Adults (19 years and S-1 (tegafur + gimeracil + Best supportive care, 20 Database of over) with advanced oteracil), gemcitabine + 5-fluorouracil + 21 Systematic Medicine, General Non- biliary tract oxaliplatin, 5-fluorouracil cisplatin + 1 22 Abdel-Rahman 2018 Reviews 6.8 & Internal industry 0/3 7 2004-2016 carcinomas + folinic acid, capecitabine radiotherapy Cochrane Participants with or 23 Database of without evidence of 24 Systematic Medicine, General Non- cardiovascular Adams2 2018 Reviews 6.8 & Internal industry 0/4 36 1994-2012 disease Fluvastatin Placebo 25 on September 24, 2021 by guest. Protected copyright. Cochrane People with co- 26 Database of occurring depression 27 Systematic Medicine, General Non- and alcohol Antidepressants - 16 types, Placebo, 28 Agabio3 2018 Reviews 6.8 & Internal industry 0/3 27 1969-2015 dependence diazepam, memantine psychotherapy Adults (16 years and 29 Cochrane over) with acute 30 Database of spontaneous 31 Al-Shahi Systematic Medicine, General Not intracerebral Blood clotting factors, Placebo, open control, Salman4 2018 Reviews 6.8 & Internal reported 0/5 11b 1999-2015 haemorrhage antifibrinolytic drugs fresh frozen plasma 32 Cochrane Patients with 33 Database of antipsychotic- 34 Systematic Medicine, General Non- induced tardive Gamma-aminobutyric acid 5 35 Alabed 2018 Reviews 6.8 & Internal industry 0/4 11 1976-2008 dyskinesia (TD) agonists - 6 types Placebo Cochrane 36 Database of Patients with 37 Systematic Medicine, General No hepatorenal Terlipressin, terlipressin + Placebo, no 38 Allegretti6 2017 Reviews 6.8 & Internal funding 3/8 8 1998-2016 syndrome albumin intervention, albumin Cochrane Patients undergoing Antibiotic antimicrobial 39 Database of haemodialysis using lock solutions - 11 types, 40 Systematic Medicine, General Non- a central venous non-antibiotic 41 Arechabala7 2018 Reviews 6.8 & Internal industry 0/7 37 1998-2017 catheter antimicrobial lock Heparin, saline 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 solutions - 10 types, 4 antibiotic + non-antibiotic antimicrobial lock 5 solutions - 3 types 6 Valproate, carbamazepine, 7 lithium, pregabalin, 8 captodiame, paroxetine, tricyclic antidepressants - 4 9 types, alpidem, buspirone, 10 flumazenil, propranolol, 11 Cochrane Adult (18 years and progesterone, magnesium Database of over) chronic aspartate, bromazepam, 12 Systematic Medicine, General No benzodiazepine cyamemazine, zopiclone, Placebo, no 8 For peer reviewc only 13 Baandrup 2018 Reviews 6.8 & Internal funding 1/6 33 1981-2016 users flunitrazepam intervention 14 Individuals with Cochrane antiphospholipid 15 Database of antibodies and no Aspirin + anticoagulants, Placebo, 16 Systematic Medicine, General Non- history of aspirin, aspirin + low immunoglobulin, Bala9 2018 Reviews 6.8 & Internal industry 3/6 9 1997-2016 thrombosis molecular weight heparin unfractionated heparin 17 http://bmjopen.bmj.com/ Heterosexual adult 18 couples (18 years or 19 Cochrane more) with a partner 20 Database of having a clinical 21 Systematic Medicine, General Non- diagnosis of Barbato10 2018 Reviews 6.8 & Internal industry 0/3 4d 2000-2012 depressive disorder Antidepressants - 9 types Couples therapy 22 Cochrane Psychiatric patients 23 Database of with antipsychotic- 24 Systematic Medicine, General Non- induced tardive Bergman11 2018 Reviews 6.8 & Internal industry 0/3 4 1981-1997 dyskinesia Benzodiazepines - 3 types Placebo, usual care 25 Tricyclic on September 24, 2021 by guest. Protected copyright. antidepressants 26 (TCAs), selective serotonin 27 reuptake inhibitors (SSRIs), monoamine 28 oxidase inhibitors 29 (MAOIs), serotonin– 30 norepinephrine reuptake 31 Cochrane inhibitors (SNRIs), Database of Adults (18 years and norepinephrine reuptake 32 Systematic Medicine, General Non- over) with panic inhibitors (NRIs), 33 Bighelli12 2018 Reviews 6.8 & Internal industry 2/9 41 1989-2011 disorder nefazodone, ritanserin Placebo 34 Cochrane Database of 35 Systematic Medicine, General Non- People with 36 Birks13 2018 Reviews 6.8 & Internal industry 0/2 30 1996-2017 Alzheimer’s disease Donepezil Placebo 37 Cochrane Database of Adults (18 years and No treatment, usual 38 Systematic Medicine, General Non- over) with quiescent care (azathioprine + 39 Boyapati14 2018 Reviews 6.8 & Internal industry 3/8 6 1978-2017 Crohn’s disease Azathioprine, infliximab infliximab) 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane 4 Database of Women of Systematic Medicine, General Non- reproductive age Combined oral contractive Placebo, leuprolide, 5 Brown15 2018 Reviews 6.8 & Internal industry 0/4 5 1993-2017 with endometriosis pill - 3 types goserelin 6 Cochrane 7 Database of 8 Systematic Medicine, General Non- Adults with atrial Factor Xa inhibitors - 7 Bruins Slot16 2018 Reviews 6.8 & Internal industry 1/2e 13 2008-2014 fibrillation types Warfarin 9 People with 10 schizophrenia and 11 schizophrenia-like disorders such as 12 For peer review onlyschizophreniform 13 Cochrane disorder, delusional 14 Database of disorder, or Systematic Medicine, General No schizoaffective Zuclopenthixol Placebo, other drugs - 15 Bryan17 2017 Reviews 6.8 & Internal funding 0/3 20 1968-2007 disorder dihydrochloride 11 types 16 Antifibrinolytic agents - 2 Cochrane Women of types, non-steroidal anti- Placebo, herbal 17 http://bmjopen.bmj.com/ Database of reproductive age inflammatory drugs medicines, 18 Systematic Medicine, General No with heavy (NSAIDs), progestogens, levonorgestrel 19 Bryant-Smith18 2018 Reviews 6.8 & Internal funding 1/4 13 1970-2016 menstrual bleeding ethamsylate intrauterine system 20 Adults (17 years and 21 Cochrane over) in non-ICU Database of acute care settings 22 Systematic Medicine, General Non- diagnosed with Nonantipsychotics, 23 Burry19 2018 Reviews 6.8 & Internal industry 0/9 9 1996-2016 delirium Antipsychotics - 5 types placebo 24 Cochrane Adult patients (18 Database of years and older) 25 Systematic Medicine, General Non- with ureteral stone on September 24, 2021 by guest. Protected copyright. 26 Campschroer20 2018 Reviews 6.8 & Internal industry 0/4 67 2002-2017 disease Alpha-blockers - 6 types Placebo, usual care 27 Adults with cancer Cochrane and adults receiving 28 Database of palliative care with 29 Systematic Medicine, General Non- opioid-induced Mu-opioid antagonists - 3 30 Candy21 2018 Reviews 6.8 & Internal industry 0/5 8 1996-2017 bowel dysfunction types Placebo 31 Cochrane Patients with Database of paracetamol 32 Systematic Medicine, General Non- (acetaminophen) Methionine, cysteamine, 33 Chiew22 2018 Reviews 6.8 & Internal industry 0/4 9f 1976-2014 overdose dimercaprol, acetylcysteine Placebo, no treatment 34 Children aged up to Cochrane five years with a 35 Database of clinical diagnosis of 36 Systematic Medicine, General Not community-acquired Placebo, antibiotics 37 Das23 2018 Reviews 6.8 & Internal reported 0/3 7 2010-2017 pneumonia (CAP) Vitamin D alone Cochrane Healthy individuals 38 Database of (16 to 65 years) and 39 Systematic Medicine, General Non- pregnant women and Inactivated parenteral 40 Demicheli24 2018 Reviews 6.8 & Internal industry 1/5 71g 1969-2014 their newborns influenza vaccine Placebo, no treatment 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane 4 Database of Systematic Medicine, General Non- Elderly participants 5 Demicheli25 2018 Reviews 6.8 & Internal industry 1/7 8 1969-2004 (65 years and over) Influenza vaccines Placebo 6 Fondaparinux, 7 rivaroxaban, low molecular 8 weight heparin, nonsteroidal anti-inflammatory 9 drugs, vasotonin, 10 Patients with sulodexide, 11 superficial heparansulphate, vitamin K Cochrane thrombophlebitis of antagonists, enzyme 12 Database of For peer review onlythe leg or diagnosis therapy, unfractionated 13 Systematic Medicine, General Non- of a thrombus in a heparin, heparin calcium, Placebo, elastic 14 Di Nisio26 2018 Reviews 6.8 & Internal industry 2/3 32 1970-2017 superficial vein defibrotide stockings Cochrane Patients with 15 Database of antipsychotic- Noradrenergic drugs - 2 16 Systematic Medicine, General Non- induced tardive types, dopaminergic drugs El-Sayeh27 2018 Reviews 6.8 & Internal industry 0/4 10 1973-2010 dyskinesia - 7 types Placebo 17 http://bmjopen.bmj.com/ People of all ages on 18 continuous vitamin 19 K antagonist (VKA) 20 or direct oral 21 Cochrane anticoagulant Usual care (surgical Database of (DOAC) treatment treatment), usual care 22 Systematic Medicine, General Non- undergoing an oral Antifibrinolytic agents - 2 (surgical treatment) + 23 Engelen28 2018 Reviews 6.8 & Internal industry 0/5 3 1989-2015 or dental procedure types placebo 24 Selective serotonin Cochrane reuptake inhibitors (SSRIs) 25 Database of Adults (18 years and - 4 types, on September 24, 2021 by guest. Protected copyright. tricyclic 26 Systematic Medicine, General Non- over) living with antidepressants (TCAs) - 2 27 Eshun-Wilson29 2018 Reviews 6.8 & Internal industry 1/6 10 1994-2014 HIV and depression types Placebo, mirtazapine Cochrane People with 28 Database of antipsychotic- 29 Systematic Medicine, General Non- induced tardive Calcium channel blockers - 30 Essali30 2018 Reviews 6.8 & Internal industry 0/4 3 1992-1997 dyskinesia 3 types Placebo 31 Selective serotonin reuptake inhibitors - 4 32 Cochrane types; tricyclic 33 Database of antidepressants - 3 types; 34 Systematic Medicine, General Non- Adults (18 years and other antidepressants - 6 Placebo, insomnia Everitt31 2018 Reviews 6.8 & Internal industry 3/8 23 1978-2013 over) with insomnia types medication - 2 types 35 Cochrane 36 Database of Regular tobacco 37 Systematic Medicine, General Non- smokers (20 years Nicotine replacement Fanshawe32 2017 Reviews 6.8 & Internal industry 0/6 4 2004-2014 and under) therapy, bupropion Placebo 38 Cochrane Subfertile women of Placebo, selective 39 Database of reproductive age estrogen receptor 40 Systematic Medicine, General Non- with polycystic modulators, 33 41 Franik 2018 Reviews 6.8 & Internal industry 0/5 42 2004-2017 ovary syndrome Letrozole clomiphene citrate 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 followed by 4 intrauterine insemination, 5 laparoscopic ovarian 6 drilling, follicle- 7 stimulating hormone, 8 anastrozole Cochrane Sulfadoxine- 9 Database of Pregnant women pyrimethamine, 10 Systematic Medicine, General Non- living in malaria- cotrimoxazole, 11 González34 2018 Reviews 6.8 & Internal industry 0/6 6 1994-2014 endemic areas Mefloquine placebo Adult women with 12 Cochrane For peer review onlymoderate or severe 13 Database of cervical Non-steroidal anti- 14 Systematic Medicine, General Non- intraepithelial inflammatory agents Grabosch35 2018 Reviews 6.8 & Internal industry 0/3 3 2006-2017 neoplasia (CIN) (NSAIDs) - 2 types Placebo 15 Cochrane 16 Database of Adults and children Systematic Medicine, General Non- being treated for Usual treatment, 17 http://bmjopen.bmj.com/ Graves36 2018 Reviews 6.8 & Internal industry 0/4 24h 1981-2017 falciparum malaria Primaquine bulaquine 18 Cochrane Pregnant women 19 Database of who were about to 20 Systematic Medicine, General Non- receive a cesarean Antiseptic solutions - 3 37 21 Haas 2018 Reviews 6.8 & Internal industry 0/4 11 1997-2017 delivery types Placebo, no treatment Cochrane 22 Database of People with cancer Low molecular weight 23 Systematic Medicine, General Non- and venous heparin, unfractioned 24 Hakoum38 2018 Reviews 6.8 & Internal industry 0/10 15 1991-2009 thromboembolism heparin Fondaparinux Placebo, no treatment, 25 Immunocompetent on September 24, 2021 by guest. Protected copyright. alternative therapies - 26 Cochrane patients with 7 types, other drug 27 Database of localised Old World comparators - 6 types, Heras- Systematic Medicine, General Non- cutaneous Antimonials – 2 types, other non-drug 28 Mosteiro39 2017 Reviews 6.8 & Internal industry 0/10 89 1990-2015 leishmaniasis non-antimonials – 22 types comparators - 4 types 29 Cochrane People with Chemotherapy, targeted 30 Database of esophageal or therapy, EGFR-targeting 31 Systematic Medicine, General Non- gastroesophageal agents, cetuximab, Best supportive care, Janmaat40 2017 Reviews 6.8 & Internal industry 0/8 41 1980-2015 junction cancer ramucirumab unspecified control 32 Cochrane 33 Database of 34 Systematic Medicine, General Non- Healthy children (15 Placebo, no Jefferson41 2018 Reviews 6.8 & Internal industry 1/4 41 1971-2016 years and under) Influenza vaccine - 2 types intervention 35 Middle-aged and 36 older men (40 or 37 over) with lower Cochrane urinary tract 38 Database of 2006- symptoms as a result 39 Systematic Medicine, General Non- Unpublishe of benign prostatic Silodosin, tamsulosin, 40 Jung42 2017 Reviews 6.8 & Internal industry 0/6 19 d hyperplasia naftopidil, and alfuzosin Placebo 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane 4 Database of Systematic Medicine, General Non- 5 Kaempfen43 2018 Reviews 6.8 & Internal industry 0/4 3 2013-2017 Preterm infants Propranolol Placebo, no treatment 6 Cochrane 7 Database of 8 Systematic Medicine, General Non- Ambulatory people Kahale44 2017 Reviews 6.8 & Internal industry 0/10 7 1979-2012 with cancer Warfarin, apixaban Placebo, no treatment 9 Cochrane 10 Database of People with cancer 11 Systematic Medicine, General Non- and central venous Kahale45 2018 Reviews 6.8 & Internal industry 0/10 13 1990-2013 catheters Anticoagulant - 6 types Placebo, no treatment 12 For peer review only Vitamin K antagonist - 2 13 Cochrane types, direct oral 14 Database of People with cancer anticoagulant - 4 types; Systematic Medicine, General Non- and venous low molecular weight 15 Kahale46 2018 Reviews 6.8 & Internal industry 0/11 16 2001-2018 thromboembolism heparin - 4 types Anticoagulants 16 Cochrane Database of 17 http://bmjopen.bmj.com/ Systematic Medicine, General Non- Children and adults 18 Kapur47 2018 Reviews 6.8 & Internal industry 3/5 7 1992-2012 with bronchiectasis Corticosteroids - 3 types Placebo, no treatment 19 Cochrane 20 Database of 21 Systematic Medicine, General Non- Adults and children Macrolide antibiotics - 4 Placebo, no Kelly48 2018 Reviews 6.8 & Internal industry 2/8 15 1997-2014 with bronchiectasis types intervention 22 Cochrane Adults and children 23 Database of with acute β2 -agonist, β2 - 24 Systematic Medicine, General Non- exacerbation of agonist + ipratropium, Knightly49 2017 Reviews 6.8 & Internal industry 0/7 25 1996-2017 asthma Magnesium sulfate placebo 25 Cochrane on September 24, 2021 by guest. Protected copyright. 26 Database of People with chronic 27 Systematic Medicine, General Non- obstructive Inactivated influenza Kopsaftis50 2018 Reviews 6.8 & Internal industry 0/3 11 1961-2004 pulmonary disease vaccine Placebo 28 Aminosalicylates - 4 types, 29 corticosteroids, superoxide 30 dismutase, amifostine, bile 31 acid sequestrants, magnesium oxide, 32 misoprostol, octreotide, 33 Cochrane Adults (18 years and selenium, sodium butyrate, 34 Database of over) undergoing sucralfate, ibuprofen, Systematic Medicine, General Non- radiotherapy for famotidine, smectite, 35 Lawrie51 2018 Reviews 6.8 & Internal industry 0/9 38 1978-2016 pelvic cancers simethicone, tropisetron Placebo, no treatment 36 Cochrane 37 Database of Usual care, emergency Systematic Medicine, General Non- Women with signs delivery, cessation of 38 Leathersich52 2018 Reviews 6.8 & Internal industry 0/4 8 1987-2007 of fetal distress Tocolytic agents – 7 types oxytocic infusion 39 Cochrane Medicine, General Non- Women with uterine Gonadotropin-hormone 40 Lethaby53 2017 Database of 6.8 & Internal industry 1/3 38 1989-2012 fibroids releasing analogue, Placebo, no treatment 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Systematic selective progesterone- 4 Reviews receptor modulators Cochrane 5 Database of 0.9% sodium chloride 6 Systematic Medicine, General Non- Adults with central (normal saline 7 López-Briz54 2018 Reviews 6.8 & Internal industry 0/6 11 2002-2015 venous catheters Heparin solution) 8 Children (18 years Cochrane and under) with 9 Database of prolonged wet 10 Systematic Medicine, General Non- cough (longer than 11 Marchant55 2018 Reviews 6.8 & Internal industry 2/4 3 1993-2012 10 days) Antibiotics - 2 types Placebo, no treatment Cochrane 12 Database of For peer review only 13 Systematic Medicine, General Non- Patients with 14 Matar56 2018 Reviews 6.8 & Internal industry 0/3 7 1963-1999 schizophrenia Fluphenazine Placebo Cochrane 15 Database of People with solid or Low-molecular weight 16 Systematic Medicine, General Non- hematologic cancer heparin (LMWH) - 10 Unfractionated heparin Matar57 2018 Reviews 6.8 & Internal industry 0/11 20 1986-2018 undergoing surgery types (UFH), fondaparinux 17 http://bmjopen.bmj.com/ Cochrane 18 Database of Postoperative 19 Systematic Medicine, General Non- paediatric patients 20 McNicol58 2018 Reviews 6.8 & Internal industry 1/3 13 1992-2016 (17 years and under) Ketorolac Placebo, opioid 21 Children (16 years and under) 22 presenting to a 23 hospital or 24 Cochrane emergency Diazepam + Database of department in an phenytoin, diazepam, 25 Systematic Medicine, General Non- acute tonic-clonic on September 24, 2021 by guest. Protected copyright. paraldehyde, 26 McTague59 2018 Reviews 6.8 & Internal industry 0/3 18 1995-2014 convulsion Lorazepam midazolam 27 Cochrane Database of Patients with 28 Systematic Medicine, General Non- multiple myeloma Placebo, no treatment - 29 Mhaskar60 2017 Reviews 6.8 & Internal industry 0/4 24 1982-2015 (MM) Bisphosphonates - 5 types Network meta-analysis 30 Cochrane 31 Database of No treatment, placebo, Systematic Medicine, General Non- Typhoid fever vaccines - 4 typhoid-inactive 32 Milligan61 2018 Reviews 6.8 & Internal industry 0/4 18 1980-2016 Adults and children types agents 33 Cochrane Tramadol, non-steroidal 34 Database of People undergoing anti-inflammatory drugs, Systematic Medicine, General Non- orthodontic paracetamol, local 35 Monk62 2017 Reviews 6.8 & Internal industry 0/4 32 1993-2016 treatment anaesthetic Placebo, no treatment 36 Cochrane Patients with 37 Database of hepatitis C virus- Rituximab, interferon, Usual care, Systematic Medicine, General No associated mixed immunosuppressive drug immunoadsorption 38 Montero63 2018 Reviews 6.8 & Internal fundingi 1/7 10 1991-2012 cryoglobulinaemia therapy apheresis 39 Adults (18 years and 40 Cochrane Medicine, General Non- over) with chronic Cannabis-based medicines Placebo, 64 41 Mücke 2018 Database of 6.8 & Internal industry 2/5 16 2004-2017 neuropathic pain - 5 types dihydrocodeine 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Systematic 4 Reviews Cochrane 5 Database of 6 Systematic Medicine, General Non- Adults and children 7 Narula65 2018 Reviews 6.8 & Internal industry 3/7 10j 1990-2014 with Crohn's disease Corticosteroids - 5 types Enteral nutrition 8 Adults or children Cochrane with partial onset 9 Database of seizures or 10 Systematic Medicine, General Non- generalised onset Antiepileptic drugs - 10 11 Nevitt66 2017 Reviews 6.8 & Internal industry 1/5 76 1981-2015 tonic-clonic seizures types Network meta-analysis Cochrane Adults and children 12 Database of For peer review onlywith focal onset or 13 Systematic Medicine, General Non- generalised onset 14 Nevitt67 2018 Reviews 6.8 & Internal industry 1/4 14 1995-2015 seizures Lamotrigine Carbamazepine Cochrane 15 Database of Adults (18 years and 16 Systematic Medicine, General Non- over) with venous Dressings - 12 types; Norman68 2018 Reviews 6.8 & Internal industry 1/6 78 1985-2016 leg ulcers Topical agents - 10 types Network meta-analysis 17 http://bmjopen.bmj.com/ Cochrane 18 Database of Children and adults 19 Systematic Medicine, General Non- with acute asthma 20 Normansell69 2018 Reviews 6.8 & Internal industry 0/6 6 1974-2016 exacerbation Antibiotics - 4 types Placebo 21 Propranolol, timolol maleate, bleomycin, 22 Children (17 years atenolol, prednisolone, 23 Cochrane and under) with captopril, ibuprofen + 24 Database of single or multiple paracetamol, methylene Systematic Medicine, General Non- haemangiomas blue, triamcinolone, Placebo, radiation, 25 Novoa70 2018 Reviews 6.8 & Internal industry 1/7 24 1977-2016 located on the skin methylprednisolone on September 24, 2021 by guest. Protected copyright. lasers 26 Preterm (< 37 27 weeks’ gestation) Cochrane and low birth weight 28 Database of (< 2500 grams) 29 Systematic Medicine, General No infants less than Erythropoiesis-stimulating 30 Ohlsson71 2017 Reviews 6.8 & Internal funding 0/2 34 1991-2017 eight days of age agents (ESAs) - 2 types Placebo, no treatment 31 Cochrane Adults exhibiting Database of aggression or Placebo, other anti- 32 Systematic Medicine, General No agitation (or both) psychotic medications 33 Ostinelli72 2018 Reviews 6.8 & Internal funding 1/5 3 2005-2016 due to psychosis Aripiprazole - 2 types 34 Cochrane Patients with Haloperidol, Database of psychosis-induced olanzapine, quetiapine, 35 Systematic Medicine, General Non- aggression or oxcarbazepine, 36 Ostinelli73 2018 Reviews 6.8 & Internal industry 0/6 9 2010-2014 agitation Risperidone valproic acid 37 Cochrane Database of 1985- Adults (18 years and 38 Systematic Medicine, General Non- Unpublishe over) with cancer 39 Ostuzzi74 2018 Reviews 6.8 & Internal industry 1/5 7 d and depression Antidepressants - 6 types Placebo 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane 4 Database of Children and adults Systematic Medicine, General Non- with active Crohn’s 5 Parker75 2018 Reviews 6.8 & Internal industry 2/5 2 2011-2013 disease Naltrexone Placebo 6 Tamoxifen, interferon- 7 alpha, interleukin-2, 8 interferon-alpha + interleukin-2, Bacille 9 Single agent Calmette-Guérin 10 chemotherapy, (BCG), 11 Patients with polychemotherapy, corynebacterium unresectable lymph temozolomide, parvum, anti-PD1 12 Cochrane For peer review onlynode metastasis and dacarbazine, anti-CTLA4 monoclonal 13 Database of distant metastatic monoclonal antibodies, antibodies, sorafenib, 14 Systematic Medicine, General Non- cutaneous other immunostimulating elesclomo, anti- Pasquali76 2018 Reviews 6.8 & Internal industry 0/5 122 1972-2015 melanoma agents, MEK inhibitors angiogenic drugs 15 Cochrane 16 Database of Children (18 years Omalizumab, leukotriene Systematic Medicine, General Non- and under) with receptor antagonists - 2 17 http://bmjopen.bmj.com/ Pike77 2018 Reviews 6.8 & Internal industry 0/4 4 2007-2017 asthma types, corticosteroids Placebo 18 Cochrane 19 Database of Patients with 20 Systematic Medicine, General Not Not Raynaud’s 78 21 Rirash 2017 Reviews 6.8 & Internal reported reported/8 38 1982-2000 phenomenon Calcium channel blockers Placebo Cochrane Adults (18 years and 22 Database of over) with 23 Systematic Medicine, General Non- unprovoked venous Warfarin, aspirin, 24 Robertson79 2017 Reviews 6.8 & Internal industry 0/3 6 1995-2016 thromboembolism rivaroxaban Placebo Sexually active 25 Cochrane adults (16 years and on September 24, 2021 by guest. Protected copyright. 26 Database of over) with genital 27 Systematic Medicine, General Non- ulcers compatible Macrolide antibiotics - 3 Other antibiotics - 4 Romero80 2017 Reviews 6.8 & Internal industry 0/3 7 1983-1999 with chancroid types types 28 Cochrane 29 Database of People with scabies 30 Systematic Medicine, General Non- of all ages and either 81 31 Rosumeck 2018 Reviews 6.8 & Internal industry 0/3 15 1996-2016 sex Ivermectin Permethrin Cochrane 32 Database of Adults (18 years and Local anaesthetic 33 Systematic Medicine, General Non- over) undergoing mixture (standard 34 Rüschen82 2018 Reviews 6.8 & Internal industry 0/4 7 1995-2012 intraocular surgery Hyaluronidase treatment) Methylphenidate, 35 modafinil, cholinesterase 36 inhibitors (ChEIs), atypical 37 Cochrane antipsychotics, Database of antidepressants, 38 Systematic Medicine, General Non- People with mibampator, valproate, 39 Ruthirakuhan83 2018 Reviews 6.8 & Internal industry 2/5 21 1998-2017 Alzheimer's Disease semagacestat Placebo 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane 4 Database of Anti-vascular endothelial Systematic Medicine, General No Preterm infants with growth factor agents - 2 5 Sankar84 2018 Reviews 6.8 & Internal funding 0/3 6 2011-2016 retinopathy types Cryo/laser therapy 6 Levosimendan, 7 dobutamine, enoximone, 8 Adults (18 years and epinephrine, Cochrane over) with norepinephrine- 9 Database of cardiogenic shock or dobutamine, amrinone, 10 Systematic Medicine, General Non- acute low cardiac dopexamine, dopamine, 11 Schumann85 2018 Reviews 6.8 & Internal industry 3/9 13 1990-2013 output syndrome nitric oxid Placebo, no treatment Acetazolamide, ibuprofen, 12 Cochrane For peer review only dexamethasone, oxygen, 13 Database of People suffering nitric oxide, gabapentin, Placebo, normal air, 14 Simancas- Systematic Medicine, General Non- from high altitude magnesium sulphate, unspecified control, Racines86 2018 Reviews 6.8 & Internal industry 0/6 13k 1992-1994 illness sumatriptan paracetamol 15 Cochrane 16 Database of Systematic Medicine, General Non- Adults and children 17 http://bmjopen.bmj.com/ Smith87 2017 Reviews 6.8 & Internal industry 0/2 4 1998-2015 with cystic fibrosis Salmeterol, tiotropium No treatment, placebo 18 Cochrane Placebo, no treatment, 19 Database of Intramuscular or intramuscular or 20 Systematic Medicine, General Non- intravenous opioids - 16 intravenous opioids - 88 21 Smith 2018 Reviews 6.8 & Internal industry 0/3 70 1958-2017 Women in labour types 16 types Alkaloids - 3 types, 22 antidepressants - 3 types, 23 levetiracetam, 24 cyproheptadin, promethazine, buspiron, 25 cognitive on September 24, 2021 by guest. Protected copyright. enhancers - 2 26 Cochrane types, VMAT2 inhibitors, 27 Database of ethyleicosapentaenoic acid Systematic Medicine, General Non- Adults with chronic (ethyl-EPA), hormones - 3 28 Soares-Weiser89 2018 Reviews 6.8 & Internal industry 0/5l 24m 1971-2014 psychiatric disorders types, lithium, ceruletide Placebo 29 People with 30 coronary disease, 31 ischaemic cerebrovascular 32 disease, peripheral 33 Cochrane arterial disease, or at 34 Database of high risk of Systematic Medicine, General Non- atherothrombotic Placebo, usual care 35 Squizzato90 2017 Reviews 6.8 & Internal industry 2/5 15 2001-2017 disease Clopidrogel (aspirin) 36 Articaine, articaine + 37 Individuals epinephrine, lidocaine + undergoing dental epinephrine, bupivacaine + 38 Cochrane procedures and epinephrine, mepivacaine 39 Database of volunteers who took + epinephrine, 40 Systematic Medicine, General Non- part in simulated mepivacaine + 91 41 St George 2018 Reviews 6.8 & Internal industry 1/7 123 1954-2017 scenario studies levonordefrin, Local anaesthetics 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 mepivacaine, prilocaine, 4 prilocaine + felypressin, prilocaine + epinephrine 5 Cochrane 6 Database of 7 Systematic Medicine, General Non- Adults and children 92 8 Stern 2017 Reviews 6.8 & Internal industry 0/6 17 1972-2015 with pneumonia Corticosteroids - 7 types Placebo, usual care Children and 9 adolescents (18 10 years or under) with 11 autism spectrum Cochrane disorder (ASD) or 12 Database of For peer review onlypervasive 13 Systematic Medicine, General No developmental 14 Sturman93 2017 Reviews 6.8 & Internal funding 0/3 4 1995-2013 disorder (PDD) Methylphenidate Placebo Cochrane Psychiatric patients 15 Database of with antipsychotic- 16 Tammenmaa- Systematic Medicine, General Non- induced tardive Aho94 2018 Reviews 6.8 & Internal industry 0/4 14 1976-2014 dyskinesia Cholinergic drugs - 6 types Placebo 17 http://bmjopen.bmj.com/ Adults (17 years and 18 over) with severe 19 Cochrane mental illness and 20 Database of co-occurring 21 Systematic Medicine, General Non- substance use Other antipsychotics - Temmingh95 2018 Reviews 6.8 & Internal industry 2/4 8 2006-2014 disorder Risperidone 5 types 22 Cochrane Adults with HIV- 23 Database of associated 24 Systematic Medicine, General Non- cryptococcal Antifungal induction Tenforde96 2018 Reviews 6.8 & Internal industry 1/7 13 1997-2018 meningitis therapies - 6 types Network meta-analysis 25 on September 24, 2021 by guest. Protected copyright. H2 receptor 26 antagonists, proton 27 pump inhibitors, prostaglandin 28 analogues, 29 anticholinergics, 30 H2 receptor antagonists, antacids, sucralfate, 31 proton pump inhibitors, teprenone, naloxone, Cochrane prostaglandin analogues, bioflavonoids, 32 Database of anticholinergics, antacids, placebo, no treatment, 33 Systematic Medicine, General Non- People admitted to sucralfate, teprenone, other medication (not 34 Toews97 2018 Reviews 6.8 & Internal industry 0/7 103n 1977-2016 intensive care units naloxone, bioflavonoids defined) Cochrane Children (16 years 35 Database of and under) with 36 Systematic Medicine, General Non- recurrent acute otitis 37 Venekamp98 2018 Reviews 6.8 & Internal industry 1/4 3o 1992-1996 media Antibiotics - 3 types Grommets Cochrane 38 Database of Individuals who had 39 Systematic Medicine, General Non- an ischemic or 40 Vermeij99 2018 Reviews 6.8 & Internal industry 0/6 8 1998-2016 hemorrhagic stroke Preventive antibiotics Placebo, standard care 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Patients with critical 4 Cochrane limb ischaemia Database of 1983- unsuitable for rescue 5 Systematic Medicine, General Non- Unpublishe or reconstructive Placebo, other active 6 Vietto100 2018 Reviews 6.8 & Internal industry 0/6 33 d intervention Prostanoids - 7 types drugs - 4 types 7 Cochrane 8 Database of Systematic Medicine, General Non- Patients with acute 9 Wall101 2018 Reviews 6.8 & Internal industry 0/5 5 1995-2014 bacterial meningitis Glycerol Treatment as usual 10 Adult patients (over 11 18 years) undergoing any 12 Cochrane For peer review onlyelective or urgent 13 Database of surgical procedure Placebo, no treatment, 14 Systematic Medicine, General Non- under general thoracic epidural Weibel102 2018 Reviews 6.8 & Internal industry 3/10 68 1985-2017 anaesthesia Lidocaine analgesia - 3 types 15 Cochrane Thiazides, beta-blockers, 16 Database of Adult patients with angiotensin-converting- Systematic Medicine, General Non- primary enzyme inhibitors, calcium 17 http://bmjopen.bmj.com/ Wright103 2018 Reviews 6.8 & Internal industry 0/3 24 1966-2008 hypertension channel blockers Placebo 18 Patients with focal 19 Cochrane epilepsy that failed 20 Database of to respond to one or 21 Systematic Medicine, General Non- more antiepileptic Xiao104 2018 Reviews 6.8 & Internal industry 0/4 2 2001-2003 drugs Losigamone Placebo 22 Cochrane 23 Database of Adult and elder 24 Systematic Medicine, General No patients with solid Thrombopoietin receptor Zhang105 2017 Reviews 6.8 & Internal funding 0/5 3 2009-2015 tumours agonists (TPO-RAs) Placebo 25 Cochrane on September 24, 2021 by guest. Protected copyright. 26 Database of Adults (18 years and 27 Systematic Medicine, General Non- over) with Zhou106 2017 Reviews 6.8 & Internal industry 0/6 5 2004-2014 neuropathic pain Oxcarbazepine Placebo 28 Adult patients with 29 Cochrane an ischaemic stroke, 30 Database of haemorrhagic stroke 31 Systematic Medicine, General Not or transient Blood pressure-lowering Zonneveld107 2018 Reviews 6.8 & Internal reported 0/7 11 1970-2017 ischaemic attack drugs (BPLDs) - 5 types Placebo, no treatment 32 General Medicine (n = 33) 33 Direct acting oral 34 Adults with non- anticoagulants - 5 types, 35 Medicine, General Non- valvular atrial vitamin K antagonists, Network Meta- 108 36 López-López 2017 BMJ 23.6 & Internal industry 018 23 1989-2014 fibrillation antiplatelet agents analysis Children and adults No treatment, other 37 Medicine, General Non- with uncomplicated antibiotics - Network 38 Wang109 2018 BMJ Open 2.4 & Internal industry 0/8 14 1977-2017 skin abscesses Antibiotics - 10 types meta-analysis 39 1979- Adults (18 years and Medicine, General Non- Unpublishe over) with major Placebo - Network 40 Cipriani110 2018 Lancet 53.3 & Internal industry 4/18 522 d depressive disorder Antidepressants - 21 types meta-analysis 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Medicine, General Non- 4 Chen111 2018 Medicine 2.0 & Internal industry 0/3 9 2009-2017 Patients with sepsis Statins - 3 types Placebo Patients with 5 hormone receptor- 6 positive or human 7 epidermal growth 8 factor receptor 2 Medicine, General No negative advanced Cyclin-dependent kinases 9 Ding112 2018 Medicine 2.0 & Internal funding 0/6 6 2014-2017 breast cancer 4/6 inhibitors - 3 types Placebo 10 Adults undergoing 11 Medicine, General Non- total knee Guo113 2018 Medicine 2.0 & Internal industry 0/8 5 2004-2017 arthroplasty (TKA) Tranexamic acid (TXA) Placebo, no treatment 12 For peer review onlyPatients with 13 Medicine, General Not myocardial 14 Han114 2018 Medicine 2.0 & Internal reported 0/7 18 2007-2016 infarction Statins - 3 types Placebo Patients with acute 15 coronary syndrome, 16 percutaneous coronary 17 http://bmjopen.bmj.com/ intervention, or 18 coronary stents 19 given combination 20 Medicine, General Not therapy with aspirin 115 21 Hu 2018 Medicine 2.0 & Internal reported 0/5 4 2010-2016 and clopidogrel Proton pump inhibitors Placebo Patients with Antivascular endothelial 22 Medicine, General Not pterygium or growth factor agents - 3 23 Huang116 2018 Medicine 2.0 & Internal reported 0/5 18 2010-2015 glaucoma included Placebo, sham 24 Patients with Medicine, General Non- diabetic peripheral Fasudil + methylcobalamin Methylcobalamin or 25 Jiang117 2018 Medicine 2.0 & Internal industry 0/5 13 2010-2017 neuropathy or lipoic on September 24, 2021 by guest. Protected copyright. acid lipoic acid alone 26 Adult women with Antiangiogenic therapy (7 27 pathologically included) alone or Medicine, General Non- confirmed epithelial combined with Placebo or 28 Jiang118 2018 Medicine 2.0 & Internal industry 0/4 15 2011-2016 ovarian cancer chemotherapy chemotherapy alone 29 Patients with Immune checkpoint 30 Medicine, General Non- advanced non-small inhibitors: anti-PD1/PD-L1 Chemotherapy - 6 119 31 Khan 2018 Medicine 2.0 & Internal industry 0/8 7 2015-2017 cell lung cancer therapies - 3 types regimens Patients undergoing 32 Medicine, General No total knee or hip Normal saline or 33 Liang120 2017 Medicine 2.0 & Internal funding 0/4 3 2016-2017 arthroplasty Acetaminophen placebo 34 Medicine, General No Adults with social Liu121 2018 Medicine 2.0 & Internal funding 0/7 5 1999-2007 anxiety disorder Fluvoxamine Placebo 35 Children and adults 36 requiring Normal saline, K-Y 37 Medicine, General No nasogastric lubricant gel, or no Lor122 2017 Medicine 2.0 & Internal funding 0/8 10 1999-2015 intubation Lidocaine treatment 38 Adults with 39 intertrochanteric 40 Medicine, General No fractures preparing 123 41 Wang 2017 Medicine 2.0 & Internal funding 0/2 4 2015-2017 for internal fixation Tranexamic acid Placebo, no treatment 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 (dynamic hip 4 screws, proximal femoral nail 5 antirotations) 6 Placebo, octreotide, 7 norepinephrine, 8 Patients with dopamine + Medicine, General No hepatorenal furosemide, octreotide 9 Wang124 2018 Medicine 2.0 & Internal funding 0/5 18 2001-2016 syndrome Terlipressin + midodrine 10 Medicine, General Not Patients undergoing 11 Wang125 2018 Medicine 2.0 & Internal reported 0/3 4 1993-2011 bronchoscopy Propofol Midazolam Chemotherapy, 12 Medicine, General Not everolimus, 126 For peer review only 13 Wei 2017 Medicine 2.0 & Internal reported 0/2 14 2015-2017 Cancer patients PD-1 inhibitors - 2 types ipilimumab 14 Women of Non-steroidal anti- reproductive age inflammatory drugs, 15 Medicine, General Non- with primary analgesics, oral 16 Woo127 2018 Medicine 2.0 & Internal industry 0/7 34p 1998-2017 dysmenorrhea contraceptives Acupuncture Patients who were 17 http://bmjopen.bmj.com/ administered xenon 18 Medicine, General Non- versus propofol as a 19 Xia128 2018 Medicine 2.0 & Internal industry 0/6 13 2004-2012 general anesthetic Xenon Propofol 20 Patients prepared for 21 Medicine, General Not primary total hip Yang129 2017 Medicine 2.0 & Internal reported 0/4 7 2008-2016 arthroplasty (THA) Glucocorticoids - 3 types Placebo, no treatment 22 Patients undergoing 23 Medicine, General Not laparoscopic 24 Ye130 2017 Medicine 2.0 & Internal reported 0/3 5 2004-2016 cholecystectomy Ketamine Placebo Medicine, General No Adults with acute 25 Yu131 2018 Medicine 2.0 & Internal funding 0/6 8 2009-2017 heart failure Serelaxin on September 24, 2021 by guest. Protected copyright. Placebo 26 Patients with 27 locoregionally advanced 28 Medicine, General Non- nasopharyngeal Neoadjuvant chemotherapy 29 Yuan132 2018 Medicine 2.0 & Internal industry 0/9 31 1995-2016 carcinoma regimens - 16 included Network meta-analysis 30 Aspirin, aspirin + 31 dipyridamole, aspirin + clopidogrel, aspirin + 32 Medicine, General Not Adults with cerebral warfarin, cilostazol, 33 Zhang133 2018 Medicine 2.0 & Internal reported 0/2 13 2001-2014 infarction warfarin, and ticlopidine Network meta-analysis 34 Healthy volunteers and people with Placebo, other 35 Medicine, General Non- congestive heart Histamine H2 antagonists - conventional therapy 36 Zhang134 2018 Medicine 2.0 & Internal industry 0/8 10 1989-2006 failure 5 types medicines - 3 types 37 Adult patients prepared to undergo 38 Medicine, General Not laparoscopic 39 Zhao135 2018 Medicine 2.0 & Internal reported 0/7 5 2008-2017 cholecystectomy Lidocaine Placebo, saline 40 Medicine, General No Patients with a 136 41 Zhao 2018 Medicine 2.0 & Internal funding 0/3 4 2013-2017 diagnosis of Nefopam Saline or usual care 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 symptomatic 4 cholelithiasis and acute cholecystitis 5 who prepared for 6 laparoscopic 7 cholecystectomy 8 Adults with end- staged knee 9 osteoarthritis 10 Medicine, General No undergoing total 11 Zhou137 2018 Medicine 2.0 & Internal funding 0/4 6 2013-2017 knee arthroplasty Dexamethasone Placebo, no treatment Non-selective non- 12 For peer review only Selective non-steroidal steroidal anti- 13 Patients who anti-inflammatory drugs inflammatory drugs 14 Medicine, General Not underwent total hip (selective COX-2 (non-selective COX-2 Zhu138 2018 Medicine 2.0 & Internal reported 0/3 8 2002-2016 arthroplasty inhibitors) - 4 types inhibitors) - 4 types 15 Postgraduate Medicine, General No Patients with Placebo, placebo + 16 Zhou139 2018 Medicine 2.1 & Internal funding 0/5 10 2007-2017 dyslipidemia Anacetrapib usual care Patients with 17 http://bmjopen.bmj.com/ complicated intra- 18 Revista da abdominal 19 Associação infections and 20 Médica Medicine, General Non- Not complicated urinary Other antibiotics - 3 140 21 Zhang 2018 Brasileira 0.7 & Internal industry reported/6 6 2012-2016 tract infections Ceftazidime-avibactam types, usual care 22 Specialty medicine (n = 100) Prostaglandin analogues, 23 Patients with alpha-2 adrenergic 24 Acta primary open-angle agonists, beta-blockers,

25 Ophthalmologic Non- Not glaucoma or ocular carbonic on September 24, 2021 by guest. Protected copyright. anhydrase Placebo - Network 141 26 Li 2018 a 3.3 Ophthalmology industry reported/3 72 1995-2015 hypertension inhibitors, miotics meta-analysis Cardiac & 27 American Heart Cardiovascular No Patients with acute P2Y12 receptor inhibitors - 28 Tarantini142 2018 Journal 4.2 Systems funding 0/7 5 2007-2016 coronary syndrome 2 types Clopidogrel 29 Cardiac & American Cardiovascular 30 Journal of Systems; Adults aged 18–65 Placebo, other lipid- 31 Cardiovascular Pharmacology & Non- years with lowering agents - 32 Wang143 2018 Drugs 2.7 Pharmacy industry 0/3 5 2014-2017 hyperlipidemia Inclisiran Network meta-analysis Patients undergoing 33 Anesthesiology; caesarean section Opioid analgesics - 3 34 Anaesthesia and Critical Care Non- Not under general types, non-opioid 35 Aman144 2018 Intensive Care 1.7 Medicine industry reported/5 10 1995-2015 anaesthesia analgesics - 5 types Placebo 36 Conventional Autoimmunity Non- Patients with treatment, placebo + 37 Li145 2018 Reviews 8.7 Immunology industry 0/7 15 2004-2017 rheumatoid arthritis Statins - 2 types conventional treatment 38 Biotechnology & Patients with left Placebo, milrinone, 39 Applied ventricular dopamine, intra-aortic Biomed Microbiology; dysfunction balloon pump (IABP), 40 Research Medicine, Research Non- undergoing cardiac and standard inotropic 41 Wang146 2018 International 2.6 & Experimental industry 0/4 15 2006-2017 surgery Levosimendan agents 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Aspirin, non-aspirin 4 Adults with history nonsteroidal anti- No of colorectal cancer inflammatory drugs 5 Veettil147 2017 BMC Cancer 3.3 Oncology funding 0/6 8 2003-2014 or adenoma (NSAIDs) Placebo, no treatment 6 Purine-like xanthine 7 oxidase inhibitors - 2 8 BMC Cardiac & Adults under types, non-purine-like Cardiovascular Cardiovascular No treatment for any xanthine oxidase inhibitors 9 Bredemeier148 2018 Disorders 1.8 Systems funding 0/9 91 1973-2017 clinical condition - 2 types Placebo, no treatment 10 Patients with post- 11 endoscopic retrograde 12 BMC For peer review onlycholangiopancreatog Nonsteroidal anti- 13 Gastroenterolog Gastroenterology & Non- raphy pancreatitis inflammatory drugs 14 Lyu149 2018 y 2.7 Hepatology industry 0/5 22 2003-2017 (PEP) (NSAIDs) - 6 types Placebo Patients with 15 BMC Infectious Non- invasive fungal Other antifungal 16 Xing150 2017 Diseases 2.6 Infectious Diseases industry 0/6 16 2001-2016 infections Voriconazole agents - 7 types Patients undergoing 17 http://bmjopen.bmj.com/ total shoulder 18 BMC arthroplasty or 19 Musculoskeletal Orthopedics; No reverse shoulder 20 Kuo151 2018 Disorders 2.0 Rheumatology funding 0/4 3 2015-2017 arthroplasty Tranexamic acid Placebo 21 Pharmacological agents for traumatic brain injury – 14 22 types, pharmacological 23 agents for stroke – 23 24 types, pharmacological agents for bacterial 25 meningitis on September 24, 2021 by guest. Protected copyright. – 1 type, 26 Patients with pharmacological agents for 27 ischemic or intracerebral haemorrhage hemorrhagic stroke, – 6 types, pharmacological 28 traumatic brain agents for aneurysmal 29 BMC No injury, or bacterial subarachnoid hemorrhage 30 Beez152 2017 Neurology 2.2 Clinical Neurology funding 0/3 110q 1983-2015 meningitis – 19 types Unspecified control 31 Patients with primary or recurrent 32 pterygium Anti-fibrotic and anti- 33 undergoing surgical VEGF (vascular 34 BMC No removal combined endothelial growth factor) Placebo - Network Zeng153 2017 Ophthalmology 1.8 Ophtamology funding 0/7 32 1990-2016 with toxic agents medications - 3 types meta-analysis 35 Patients with acute 36 coronary syndrome 37 and patients who underwent 38 BMC Pharmacology & percutaneous 39 Pharmacology Pharmacy; Non- coronary 40 Bundhun154 2017 & Toxicology 1.9 Toxicology industry 0/3 4 2013-2016 intervention Prasugrel Ticagrelor 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 People with 4 schizophrenia or related disorders that 5 had a duration of 6 BMC No treatment that was Antipsychotic drugs - 12 Placebo - Network 7 Zhang155 2017 Psychiatry 2.4 Psychiatry funding 0/11 47 2003-2015 no more than 1 year types meta-analysis 8 Patients with acute exacerbations of 9 BMC chronic obstructive 10 Pulmonary No pulmonary disease Placebo - Network 11 Zhang156 2017 Medicine 2.7 Respiratory System funding 0/5 19 1996-2016 (COPD) Antibiotics - 17 types meta-analysis BMC 12 Pulmonary Non- 157 For peer review only 13 Zhang 2017b Medicine 2.7 Respiratory System industry 0/4 25 1993-2016 Preterm infants Corticosteroids Placebo 14 Post-menopausal women with 15 metastatic HR- Cyclin-dependent kinase 16 Oncology; positive, HER2- 4/6 inhibitors - 3 types + Ramos-Esquivel Obstetrics & No negative breast aromatase inhibitor - 2 Aromatase inhibitors - 17 http://bmjopen.bmj.com/ 158 2018 Breast Cancer 1.8 Gynecology funding 0/4 3 2016-2017 cancer types 2 types 18 British Journal Patients with Non-steroidal anti- 19 of Sports Non- osteoarthritis in any inflammatory drugs - 9 20 Zeng159 2018 Medicine 7.9 Sport Sciences industry 0/12 36 1979-2016 joint types Network meta-analysis 21 FOLFOX (leucovorin + fluorouracil + 22 oxaliplatin) + 23 bevacizumab, 24 FOLFIRI (leucovorin Cellular Patients with FOLFOXIRI (leucovorin + + fluorouracil + 25 Physiology and Cell Biology; Not metastatic colorectal fluorouracil on September 24, 2021 by guest. Protected copyright. + oxaliplatin + irinotecan) + 26 Shui160 2018 Biochemistry 5.5 Physiology reported 0/6 4 2015-2017 cancer irinotecan) + bevacizumab bevacizumab 27 Miltefosine, paromomycin, 28 Clinical Patients with antimonial compounds 29 Microbiology Infectious Diseases; No visceral - 2 types, pentamidine, 30 Rodrigo161 2018 and Infection 5.4 Microbiology funding 0/4 28 1996-2017 leishmaniasis Amphotericin B sitamaquine 31 Placebo, nonsteroidal Patients with anti-inflammatory 32 ankylosing Tumor necrosis factor drugs (NSAIDs), 33 spondylitis and non- (TNF) inhibitors - 5 types, disease modifying 34 Clinical Non- radiographic axial non-tumor necrosis factor antirheumatic drugs Wang162 2018 Rheumatology 2.1 Rheumatology industry 0/3 25 2002-2014 spondyloarthritis (TNF) inhibitors - 2 types (DMARDs) 35 Low molecular-weight 36 Critical heparin (LMWH) – 5 37 Reviews in Adults with acute types, enoxaparin + Rivaroxaban, Oncology / Oncology; No venous vitamin K antagonists unfractionated heparin 38 Hong163 2018 Hematology 4.5 Hematology funding 1/5 13 1996-2015 thromboembolism (VKA) (UFH) 39 Patients with Proprotein convertase Placebo, placebo + 40 Endocrinology & Not familial or subtilisin/kexin type 9 gene other lipid-lowering 164 r 41 de Carvalho 2018 Diabetes Care 13.4 Metabolism reported 0/3 20 2012-2017 nonfamilial inhibitors (PCSK9i) therapy 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 hypercholesterolemi 4 a Digestive Adults (18 and over) Placebo, standard 5 Diseases and Gastroenterology & Not with organic or treatment, no 6 Jaafar165 2018 Sciences 2.8 Hepatology reported 0/5 17 2000-2016 functional dyspepsia Rebamipide treatment 7 Patients with 8 Pharmacology & Not neurodegenerative Liu166 2018 Drug Delivery 3.1 Pharmacy reported 0/2 9 2002-2015 movement disorders Riluzole Placebo 9 Patients undergoing 10 coronary 11 Chemistry, angiography (CAG) Drug Design, Medicinal; or percutaneous 12 Development Pharmacology & Not coronary 167 For peer review only 13 Liu 2018 and Therapy 2.9 Pharmacy reported 0/5 9 2010-2016 intervention (PCI) Atorvastatin Placebo 14 Chemistry, Drug Design, Medicinal; Adults ( ≥ 18 years) 15 Development Pharmocology & Not undergoing spinal 16 Sun168 2017 and Therapy 2.9 Pharmacy reported 0/5 9 2009-2016 anesthesia Dexmedetomidine Fentanyl Adults with 17 http://bmjopen.bmj.com/ East Asian traumatic brain 18 Archives of Not injuries and 19 Paraschakis169 2017 Psychiatry None Not applicable reported 0/2 4 2005-2010 depressive disorders Antidepressants - 2 types Placebo 20 Emergency 21 Medicine Emergency No Patients taking acute D’Souza170 2018 Journal 2.0 Medicine funding 0/8 4 2001-2016 antiemetic drugs Diphenhydramine Placebo 22 Adult women with 23 epithelial ovarian 24 cancer, fallopian tube cancer, or 25 primary peritoneal on September 24, 2021 by guest. Protected copyright. 26 cancer who have 27 achieved complete European clinical remission 28 Journal of Oncology; after debulking 29 Gynecological Obstetrics & Not Not surgery and first-line CA125-targeted antibody – 30 Mei171 2016 Oncology 0.6 Gynecology reported reported/4 4 2004-2013 chemotherapy 2 types Placebo 31 European Patients with Respiratory Non- chronic 32 Verberkt172 2017 Journal 12.2 Respiratory System industry 3/9s 35 1982-2015 breathlessness Opioids - 8 types Placebo 33 Expert Opinion Critically ill patients Antacids, proton pump 34 on receiving stress inhibitors (PPI), histamine- Pharmacotherap Pharmacology & No ulcer prophylaxis 2 receptor antagonists Placebo - Network 35 Sridharan173 2018 y 3.5 Pharmacy funding 0/3 51 1980-2016 (SUP) (H2RA), and sucralfate meta-analysis 36 Expert Review Patients undergoing 37 of Clinical Pharmacology & No coronary artery Habibi174 2018 Pharmacology 2.8 Pharmacy funding 0/4 5 1999-2012 bypass surgery Lidocaine Placebo 38 Patients with stable 39 Expert Review angina pectoris Placebo (saline, 40 of Clinical Pharmacology & Non- requiring elective isosorbide dinitrate), 175 41 Li 2018 Pharmacology 2.8 Pharmacy industry 0/4 14 2002-2017 percutaneous Nicorandil no treatment 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 coronary 4 intervention (PCI) Expert Review Patients diagnosed Anti-vascular endothelial 5 Sangroongruang of Clinical Pharmacology & Non- with retinal vein growth factor (VEGF) Sham injection - 6 sri176 2018 Pharmacology 2.8 Pharmacy industry 0/5 11 2010-2017 occlusion drugs - 3 types Network meta-analysis 7 Adult patients with 8 foot or ankle trauma treated with below 9 Foot and Ankle Not knee cast or splint Low molecular weight 10 Hickey177 2018 Surgery 1.5 Orthopedics reported 0/7 7 1993-2015 immobilization heparin - 5 types Placebo, no treatment 11 Oncology; Patients with Targeted agents - 11 types, Gastroenterology & Non- advanced gastric targeted agents + Placebo - Network 12 Zhao178 2018 Gastric Cancer 5.0 ForHepatology peerindustry 0/9 review16 2002-2017 onlycancer chemotherapy meta-analysis 13 Orlistat, loracaserin, 14 Obese and naltrexone-bupropion, Gastroenterolog Gastroenterology & No overweight adults phentermine-topiramate, Placebo - Network 15 Khera179 2018 y 20.8 Hepatology funding 0/9 29 1998-2015 (18 years and over) liraglutide meta-analysis 16 Methotrexate (MEX) based Patients with low- chemotherapy regimens, 17 http://bmjopen.bmj.com/ Oncology; risk gestational actinomycin-d (Act-D) 18 Gynecologic Obstetrics & Non- trophoblastic based chemotherapy 19 Li180 2018 Oncology 4.5 Gynecology industry 0/6 7 2005-2016 neoplasia (LRGTN) regimens Network meta-analysis 20 Gastroenterology & Patients with 21 Hepatology; Non- helicobacter pylori Other antibiotics - 7 Zhuge181 2018 Helicobacter 4.1 Microbiology industry 0/6 18 1999-2016 infection Furazolidone types 22 Indian Journal No Adults at risk of 23 Kim182 2017 of Cancer 0.7 Oncology funding 0/4 21 1993-2011 developing cancer Statins - 7 types Placebo 24 Patients undergoing Indian Journal endoscopic 25 of retrograde on September 24, 2021 by guest. Protected copyright. 26 Gastroenterolog Not cholangiopancreatog 27 Garg183 2018 y None Not applicable reported 0/4 6 2007-2016 raphy Indomethacin Placebo Immunosuppressed 28 Infectious Not haematology- Other antifungal 29 Rosanova184 2017 Diseases 1.9 Infectious Diseases reported 0/5 7 2002-2011 oncology patients Voriconazole agents or placebo 30 Adults (17 years and Non-steroidal anti- 31 Inflammopharm Immunology; Non- over) diagnosed infammatory drugs Yu185 2018 acology 3.3 Toxicology industry 0/6 3 2007-2016 with acute gout Prednisolone (NSAIDs) - 2 types 32 Patients with 33 chronic venous 34 International Peripheral Vascular Not disorders (CVD) or Micronized purified Kakkos186 2018 Angiology 1.2 Disease reported 2/2 7 1982-2015 venous edema flavonoid faction (Daflon) Placebo 35 International Immunology; Adults with 36 Immunopharma Pharmacology & No Not moderate-to-severe 37 Ou187 2018 cology 3.1 Pharmacy funding reported/5 8 2014-2017 atopic dermatitis Dupilumab Placebo Children diagnosed 38 International Immunology; with recurrent 39 Immunopharma Pharmacology & No respiratory tract Placebo, routine 40 Yin188 2018 cology 3.1 Pharmacy funding 0/4 53 1984-2017 infections (RRTIs) Broncho-Vaxom therapies 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 International 4 Journal of Clinical Non- Anti-EGFR monoclonal 5 Zhu189 2018 Oncology 2.6 Oncology industry 0/7 35 2005-2016 Cancer patients antibodies (EGFR-MoAbs) Placebo, usual care 6 International 7 Journal of Not Patients with 190 8 Liu 2018 Neuroscience 1.8 Neurosciences reported 0/2 4 2007-2016 seizures Lacosamide Placebo Patients with 9 International advanced gastric and No neoadjuvant 10 Journal of No esophago-gastric Neoadjuvant chemotherapy chemotherapy (only 11 Coccolini191 2018 Surgery 2.7 Surgery funding 0/12 15 1993-2014 cancer (with surgery) surgery) Placebo, no treatment 12 International For peer review onlyPatients with ("nothing controlled 13 Journal of Non- scheduled total knee multimodal analgesia 14 Fan192 2018 Surgery 2.7 Surgery industry 0/8 7 2005-2016 arthroplasty Dexamethasone method") Patients with a 15 diagnosis of 16 symptomatic cholelithiasis and 17 http://bmjopen.bmj.com/ acute cholecystitis 18 International who prepared for 19 Journal of No laparoscopic 20 Li193 2018 Surgery 2.7 Surgery funding 0/5 6 2008-2017 cholecystectomy Lidocaine Placebo, saline 21 Patients undergoing anaesthesia as part 22 of endoscopic 23 International retrograde 24 Journal of No cholangiopancreatog Anaesthetic medications - No drug - Network Li194 2018 Surgery 2.7 Surgery funding 0/4 17 1998-2017 raphy 12 types meta-analysis 25 Patients undergoing on September 24, 2021 by guest. Protected copyright. 26 International total knee 27 Journal of Non- arthroplasty or total Liu195 2018 Surgery 2.7 Surgery industry 0/5 3t 2005-2017 hip arthroplasty Tranexamic acid Aminocaproic acid 28 International Patients with 29 Journal of No symptomatic knee 30 Ran196 2018 Surgery 2.7 Surgery funding 0/5 5 2002-2016 osteoarthritis Hyaluronic acid Methylprednisolone 31 International Patients with Journal of No hepatocellular 32 Zhao197 2018 Surgery 2.7 Surgery funding 0/3 4u 2010-2017 carcinoma Anthracyclines Platinum 33 Adult patients 34 International prepared for Journal of Non- laparoscopic 35 Zhu198 2018 Surgery 2.7 Surgery industry 0/5 6 2004-2017 cholecystectomy Ketamine Saline 36 Journal of 1990- 37 Affective Clinical Neurology; Non- Not Unpublishe Adults with major Second generation Placebo - Network Wagner199 2018 Disorders 3.8 Psychiatry industry reported/6 119 d depressive disorder antidepressants - 16 types meta-analysis 38 Journal of 39 Assisted Genetics & Women with Gonadotropin-releasing 40 Reproduction Heredity; Obstetrics Not lymphoma, ovarian hormone agonists (GnRHa) Standard treatment 200 41 Hickman 2018 and Genetics 2.8 & Gynecology; reported 0/5 10 2007-2016 cancer, or breast - 7 types (chemotherapy only) 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Reproductive cancer undergoing 4 Biology chemotherapy Journal of 5 Cancer Programmed death 1 (PD- 6 Research and Patients with non- 1)/programmed death 7 Clinical Non- small-cell lung ligand 1 (PD-L1) inhibitors Chemotherapy - 2 201 8 Luo 2018 Oncology 3.3 Oncology industry 0/4 8 2015-2017 carcinoma - 3 types types Journal of 9 Cancer Patients with 10 Research and metastatic 11 Clinical Non- castration-resistant Placebo - Network Wang202 2018 Oncology 3.3 Oncology industry 0/5 26 2010-2017 prostate cancer Targeted agents - 16 types meta-analysis 12 Journal of For peer review only 13 Cancer Cancer patients with 14 Research and No moderate to severe Wang203 2018 Therapeutics 0.8 Oncology funding 0/4 35 1997-2011 pain Fentanyl Morphine 15 Adults (18 years and Placebo, 16 Cardiac & over) undergoing discontinuation of Aboul- Journal of Cardiovascular No any type of cardiac aspirin greater than 7 17 http://bmjopen.bmj.com/ Hassan204 2017 Cardiac Surgery 1.2 Systems; Surgery funding 0/8 12 1985-2016 surgery Aspirin days before surgery 18 Cardiac & 19 Cardiovascular Patients undergoing 20 Journal of Systems; Surgery; isolated coronary 21 Cardiovascular Peripheral Vascular Not artery bypass graft Wang205 2018 Surgery 1.2 Disease reported 0/6 5 1999-2010 (CABG) surgery Statins - 3 types No preoperative statin 22 Antiandrogens, insulin 23 sensitizers, estrogen- 24 progestin oral contraceptives pills 25 (OCPs), OCPs on September 24, 2021 by guest. Protected copyright. + 26 Journal of antiandrogen, OCPs + 27 Clinical insulin sensitizer, Endocrinology Endocrinology & Non- Women with antiandrogen + insulin Placebo - Network 28 Barrionuevo206 2018 and Metabolism 5.8 Metabolism industry 0/8 32 1989-2016 hirsutism sensitizer meta-analysis 29 Journal of 30 Clinical 31 Pharmacy and Pharmacology & Not Patients with type 2 Placebo - Network Cui207 2018 Therapeutics 1.7 Pharmacy reported 0/6 23 1993-2014 diabetes Statins - 6 types meta-analysis 32 Adults with 33 Journal of moderate-to-severe 34 Dermatological chronic plaque-type Apremilast, biological Placebo - Network Sawyer208 2018 Treatment 2.1 Dermatology Industry 6/6v 54 2001-2016 psoriasis therapies - 7 types meta-analysis 35 Patients with onset 36 of atrial fibrillation 37 (AF) within 48 h, who were 38 hemodynamically 39 Journal of stable and without Placebo, verapamil, 40 Emergency Emergency Not Not evidence of acute and other active anti- 209 41 Markey 2018 Medicine 1.2 Medicine reported reported/3 11 1989-2004 coronary syndrome, Flecainide dysrhythmics 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 congestive heart 4 failure, or structural heart disease 5 Adult patients (18 6 years and over) 7 Journal of taking low-dose 8 Gastrointestinal aspirin for a Histamine-2 receptor and Liver Gastroenterology & Not minimum of 2 Proton-pump inhibitors antagonists (H2RAs) - 9 Szabó210 2017 Diseases 2.0 Hepatology reported 0/15 10w 2009-2016 weeks (PPIs) - 5 types 2 types 10 Patients with 11 Journal of histologically Immunology Non- confirmed solid Immune checkpoint Placebo or 12 Su211 2018 Research 3.3 ForImmunology peerindustry 0/6 review15 2011-2017 onlycancer inhibitors (ICIs) - 5 types chemotherapy 13 Journal of 14 Interventional Cardiac Cardiac & Patients with 15 Electrophysiolo Cardiovascular Non- persistent atrial 16 Chen212 2018 gy 1.5 Systems industry 0/9 8 2006-2017 fibrillation Antiarrhythmic drugs Catheter ablation Journal of 17 http://bmjopen.bmj.com/ Orthopaedic 18 Surgery and No Patients undergoing 19 Chen213 2017 Research 1.6 Orthopedics funding 0/4 6 2008-2014 knee arthroscopy Midazolam Placebo 20 Journal of 21 Orthopaedic Patients undergoing Surgery and Not a primary total hip Placebo or no 22 Li214 2018 Research 1.6 Orthopedics reported 0/5 3x 2002-2017 or knee arthroplasty Aminocaproic acid treatment 23 Journal of 24 Orthopaedic Surgery and Not Patients treated with 25 Luo215 2018 Research 1.6 Orthopedics reported 0/4 3y 2002-2017 spine surgery Tranexamic on September 24, 2021 by guest. Protected copyright. acid Control (not specified) 26 Journal of 27 Orthopaedic Patients who Surgery and No underwent hip 28 Ma216 2018 Research 1.6 Orthopedics funding 0/4 4 1991-2015 surgery Naproxen Placebo 29 Patients with a 30 Journal of primary diagnosis of Vortioxetine, 31 Psychiatric Non- major depressive levomilnacipran, He217 2018 Research 4.0 Psychiatry industry 0/8 22 2009-2015 disorder (MDD) vilazodone Placebo 32 Journal of 33 Stroke & Neurosciences; Asian patients with Warfarin, direct oral 34 Cerebrovascular Peripheral Vascular Non- non-valvular atrial anticoagulants (DOACs) - Wang218 2018 Diseases 1.6 Disease industry 4/8 6 2003-2013 fibrillation (AF) 5 types Network meta-analysis 35 Journal of the 36 American 37 Academy of No Dhana219 2018 Dermatology 6.9 Dermatology funding 0/6 15 2000-2016 People with scabies Permethrin Ivermectin 38 Proprotein convertase 39 Journal of the Cardiac & Adults with subtilisin/kexin type 9 40 American Heart Cardiovascular Not hypercholesterolemi (PCSK9) inhibitors - 2 Placebo, ezetimibe, 220 z 41 Karatasakis 2017 Association 4.5 Systems reported 3/12 35 2012-2017 a types standard therapy 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Journal of the 4 European Academy of Adult patients (≥ 18) 5 Dermatology with moderate-to- 6 and Non- severe plaque 7 Kuo221 2018 Venereology 4.3 Dermatology industry 2/4 4 2012-2016 psoriasis Tofacitinib Placebo 8 Journal of Traditional Integrative & 9 Chinese Complementary Non- Not Patients with 10 Liu222 2016 Medicine 0.9 Medicine industry reported/6 16 2005-2015 rheumatoid arthritis Methotrexate Sinomenine 11 Biochemistry & Molecular Biology; 12 ForBiotechnology & peer review only 13 Journal of Applied Adult patients 14 Zhejiang Microbiology; undergoing cardiac University- Medicine, Research Not surgery requiring 15 Zheng223 2017 SCIENCE B 1.8 & Experimental reported 0/7 8 1990-2014 aortic cross-clamp Amiodarone, lidocaine Placebo 16 Patients with isoniazid-resistant, Usual care (REZ = 17 http://bmjopen.bmj.com/ Lancet Critical Care rifampicin- rifampicin, 18 Respiratory Medicine; Non- susceptible Fluoroquinolone, ethambutol, 19 Fregonese224 2018 Medicine 21.5 Respiratory System industry 0/57 2 2010-2014 tuberculosis streptomycin pyrazinamide) 20 2010- 21 Neurological Clinical Neurology; Not Not Unpublishe Patients during early Bornstein225 2018 Sciences 2.3 Neurosciences reported reported/10 9 d post-stroke period Cerebrolysin Placebo 22 Patients arranged for Bevacizumab, Placebo, 23 Ophthalmic primary bevacizumab + antimetabolite - 2 24 Chen226 2018 Research 1.8 Ophthalmology 0/4 3 2013-2015 trabeculectomy antimetabolite - 2 types types Anesthesiology; No Patients undergoing 25 Han227 2017 Pain Physician 2.6 Clinical Neurology funding 0/4 10 2004-2016 spinal surgery Gabapentin on September 24, 2021 by guest. Protected copyright. Placebo 26 Adult patients 27 Anesthesiology; No undergoing surgical Dexmedetomidine + Peng228 2017 Pain Physician 2.6 Clinical Neurology funding 0/5 18 2004-2016 procedures opioids Opioids 28 Chemistry, 29 Medicinal; 30 Chemistry, 31 Multidisciplinary; Usual care Pharmacology & Not Patients with (chemotherapy), usual 32 Feng229 2016 Pharmazie 1.0 Pharmacy reported 0/7 2aa 2011-2012 tuberculosis V-5 immunitor care + placebo 33 Chemistry, 34 Medicinal; Chemistry, 35 Multidisciplinary; Patients with non- 36 Pharmacology & Not Not cystic fibrosis Placebo, symptomatic 37 Xu230 2016 Pharmazie 1.0 Pharmacy reported reported/8 12 1999-2014 bronchiectasis Antibiotics - 7 types treatment only PLOS 38 Neglected Patients infected 39 Tropical Parasitology; Non- with soil transmitted Albendazole, 40 Palmeirim231 2018 Diseases 4.4 Tropical Medicine industry 0/9 14bb 1997-2015 helminths Albendazole + ivermectin ivermectin 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Adults with 4 persistent depressive disorder (DSM-5), 5 chronic major 6 depression, recurrent Antidepressants - 6 types, 7 major depression cognitive-behavioral 8 with incomplete analysis system of interepisode psychotherapy, 9 recovery or combination of 10 dysthymia (DSM- antidepressants and 11 Psychotherapy IV), or any cognitive-behavioral and Psychiatry; Non- corresponding analysis system of 12 Furukawa232 2018 Psychosomatics 13.1 ForPsychology peerindustry 2/11 review3 2000-2015 onlyconditions psychotherapy Network meta-analysis 13 Adult patients with 14 Urology & Not chronic kidney Uric acid-lowering therapy Placebo, usual therapy, Liu233 2018 Renal Failure 1.4 Nephrology reported 0/6 12 2006-2015 disease - 2 types no treatment 15 Adults with a Tiotropium or 16 history of chronic olodaterol as obstructive monotherapy, 17 http://bmjopen.bmj.com/ Respiratory pulmonary disease salmeterol + 18 Miravitlles234 2017 Research 3.8 Respiratory System Industry 3/4 10 2014-2016 (COPD) Tiotropium + olodaterol fluticasone 19 Patients with Corticosteroid + fast- 20 Respiratory Non- intermittent or mild Corticosteroids, fast-onset- onset-acting β2- 235 21 Wang 2017 Research 3.8 Respiratory System industry 1/7 6 2006-2016 persistent asthma acting β2-agonists agonist Adults (18 years and 22 over) with moderate Tumor necrosis factor 23 Rheumatology No to severe psoriatic (antiTNF)-α inhibitors - 4 Placebo - Network 24 Kawalec236 2018 International 2.0 Rheumatology funding 0/4 8 2011-2016 arthritis (PsA) types meta-analysis Adult patients (18 25 years and over) on September 24, 2021 by guest. Protected copyright. 26 treated for the 27 secondary prevention of 28 cardiovascular, 29 Clinical Neurology; peripheral vascular, 30 Peripheral Vascular Not and cerebrovascular Proton pump inhibitors Thienopyridines - 2 237 31 Malhotra 2018 Stroke 6.2 Disease reported 0/6 12 2009-2016 disease (PPI) + thienopyridines types Surgical 32 Laparoscopy Adults (18 and over) 33 Endoscopy & undergoing 34 Percutaneous Not gastrointestinal Zhang238 2018 Techniques 1.0 Surgery reported 0/3 5 1995-2018 endoscopy Midazolam Propofol 35 Asian and non- 36 Asian adults (18 37 Hematology; years and older) Thrombosis Peripheral Vascular No with acute venous Direct oral anticoagulants Vitamin K antagonists 38 Yamashita239 2018 Research 2.8 Disease funding 3/7 6 2009-2014 thromboembolism (DOACs) - 4 types (VKAs), heparin 39 Immunology; 40 Medicine, Research No 240 41 Zhang 2018 Vaccine 3.3 & Experimental funding 1/6 13 1999-2014 HIV-positive people Influenza vaccine, Placebo Network meta-analysis 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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17 Multidisciplinary Non- anxiety disorder http://bmjopen.bmj.com/ 18 Li245 2018 PLOS ONE 2.8 Sciences industry 0/7 8 2007-2014 (GAD) Duloxetine Placebo 19 Patients with hypertension and Angiotensin- 20 chronic kidney converting enzyme 21 Multidisciplinary Non- disease stage 3 to 5 inhibitors, angiotensin 22 Lin246 2017 PLOS ONE 2.8 Sciences industry 0/6 21 1992-2012 and dialysis Calcium channel blockers receptor blockers Adults (19 years and 23 Multidisciplinary Non- Not over) undergoing Propofol, morphine, 24 Ling247 2018 PLOS ONE 2.8 Sciences industry reported/6 9 2003-2017 cardiac surgery Dexmedetomidine placebo

25 Multidisciplinary Non- Erythropoiesis-stimulating on September 24, 2021 by guest. Protected copyright. 248 26 Rohner 2017 PLOS ONE 2.8 Sciences industry 2/7 94 1993-2014 Cancer patients agents Usual care Placebo, no 27 intervention, beta 28 Patients with atrial blockers, calcium 29 Multidisciplinary No fibrillation or atrial antagonists, Sethi249 2018 PLOS ONE 2.8 Sciences funding 0/6 28 1986-2017 flutter Digoxin amiodarone 30 Multidisciplinary Post renal transplant 31 Wolf250 2018 PLOS ONE 2.8 Sciences Industry 1/9 13 2002-2016 patients mTOR-inhibitors - 2 types Calcineurin-inhibitors 32 aOnly 3 studies reported that authors were employed by industry and therefore we included them as ties for the purposes of this table; b11/12 included RCTs had a drug arm; c33/38 included RCTs had a drug arm; d4/14 included RCTs had a drug arm; eOne author reported pharmaceutical company employment; f9/11 included RCTs had a drug arm; g71/120 included studies were RCTs; h24/25 included 33 studies were RCTs; iMeta-analysis funding sources reported as 'None, Other" we coded as no study funding; j10/27 included RCTs had a drug arm; kFlow chart indicates that 0 RCTs were included in 34 the quantitative synthesis, but 2 RCTs were quantitatively synthesized and 13 were included; lDeclarations of interest were provided for only 3 out of 5 meta-analysis authors; m24/31 included RCTs had 35 a drug arm; n103/106 included RCTs had a drug arm; o3/5 included RCTs had a drug arm; p34/60 included RCTs had a drug arm; q110/123 included RCTs had an eligible drug arm; rSalary was reported s t u 36 under 'funding' but they did not specify whether there was any funding for the study itself; ICMJE forms only provided for 5/9 authors; 3/4 included studies were RCTs; 4/11 included studies were RCTs; vFour authors reported financial ties with a pharmaceutical company and employment by Symmetron, a company that provides health economic research services to pharmaceutical companies, 37 and two authors reported employment by a pharmaceutical company; w10/12 included studies were RCTs; x3/7 included studies were RCTs; y3/4 included studies were RCTs; z Of the 3 authors that 38 reported financial ties, one also reported industry employment; aa2/4 included studies were RCTs; bb14/30 included studies were RCTs; cc20/30 included studies were RCTs with a drug arm 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 4 eTable2. – Detailed reporting of study funding sources (F), author-industry financial ties (T), and author-industry employment (E) form included RCTs 5 6 Location Reported First Author Year Journal Funding Author- Author- Risk of Risk of Main Text, Other in Main Abstract Lay Online 7 Sources of Industry Industry Bias Text Bias Other than Document summary appendix 8 Included Financial Employment Figure or Risk of (Characteristic 9 Trials Ties of of Included Table Bias s of Included 10 Reported in Included Trials Studies Table, Meta-analysis? Trials Reported in other table, 11 Reported in Meta- footnote) 12 Meta- analysis? For peeranalysis? review only 13 14 Cochrane Reviews (n = 107) 15 Cochrane Database of Abdel-Rahman1 2018 Systematic Reviews Full No No F F F F F 16 Cochrane Database of 2 17 Adams 2018 Systematic Reviews Full No No F F F http://bmjopen.bmj.com/ 18 Cochrane Database of Agabio3 2018 Systematic Reviews Full Partial No F, T F, T F 19 Cochrane Database of 20 Al-Shahi Salman4 2018 Systematic Reviews Partial No No F F 21 Cochrane Database of Alabed5 2018 Systematic Reviews Partial No Partial F, E 22 Cochrane Database of 23 Allegretti6 2017 Systematic Reviews Full No No F F F F 24 Cochrane Database of Arechabala7 2018 Systematic Reviews Full Partial Partial F F, E F, T F, T, E F 25 Cochrane Database of on September 24, 2021 by guest. Protected copyright. 26 Baandrup8 2018 Systematic Reviews Full Full Partial F F F F, T, E F 27 Cochrane Database of 9 28 Bala 2018 Systematic Reviews Full No No F F Cochrane Database of 29 Barbato10 2018 Systematic Reviews No No No 30 Cochrane Database of 31 Bergman11 2018 Systematic Reviews Full Partial No F, T Cochrane Database of 32 Bighelli12 2018 Systematic Reviews Full Full Partial F F, T, E F F, T, E F F 33 Cochrane Database of 34 Birks13 2018 Systematic Reviews Full Partial No F F, T F Cochrane Database of 35 Boyapati14 2018 Systematic Reviews No No No 36 Cochrane Database of 37 Brown15 2018 Systematic Reviews Partial Partial No F F F F, T F F 38 Cochrane Database of Bruins Slot16 2018 Systematic Reviews Full No No F 39 Cochrane Database of 40 Bryan17 2017 Systematic Reviews Partial No No F 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane Database of 4 Bryant-Smith18 2018 Systematic Reviews Full No No F Cochrane Database of 5 Burry19 2018 Systematic Reviews Full No No F F F 6 Cochrane Database of 7 Campschroer20 2018 Systematic Reviews Full Full No F, T 8 Cochrane Database of Candy21 2018 Systematic Reviews Full No No F F 9 Cochrane Database of 10 Chiew22 2018 Systematic Reviews No No No 11 Cochrane Database of Das23 2018 Systematic Reviews Full No No F F F 12 Cochrane Database of 24 Fora peer review only 13 Demicheli 2018 Systematic Reviews Full Partial Partial F, T, E 14 Cochrane Database of Demicheli25 2018 Systematic Reviews No No No 15 Cochrane Database of 16 Di Nisio26 2018 Systematic Reviews Partial Partial No F, T Cochrane Database of 17 http://bmjopen.bmj.com/ El-Sayeh27 2018 Systematic Reviews Full No No F F 18 Cochrane Database of 19 Engelen28 2018 Systematic Reviews No No No 20 Cochrane Database of 29 21 Eshun-Wilson 2018 Systematic Reviews Full Full No F, T Cochrane Database of 22 Essali30 2018 Systematic Reviews Full No No F 23 Cochrane Database of 24 Everitt31 2018 Systematic Reviews Partial Partial No F, T F, T F F, T Cochrane Database of 25 Fanshawe32 2017 Systematic Reviews No No No on September 24, 2021 by guest. Protected copyright. 26 Cochrane Database of 27 Franik33 2018 Systematic Reviews Full Partial No F, T Cochrane Database of 28 González34 2018 Systematic Reviews Full No No F 29 Cochrane Database of 30 Grabosch35 2018 Systematic Reviews No No No 31 Cochrane Database of Graves36 2018 Systematic Reviews Partialb No No F 32 Cochrane Database of 33 Haas37 2018 Systematic Reviews Full Full No F, T F, T 34 Cochrane Database of Hakoum38 2018 Systematic Reviews Full Full No F, T 35 Cochrane Database of 36 Heras-Mosteiro39 2017 Systematic Reviews Partialc Partiald Partial F, T, E 37 Cochrane Database of Janmaat40 2017 Systematic Reviews No No No 38 Cochrane Database of 39 Jefferson41 2018 Systematic Reviews Full No No F 40 Cochrane Database of 42 41 Jung 2017 Systematic Reviews Full Full Partial F, T F, T, E 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane Database of 4 Kaempfen43 2018 Systematic Reviews No No No Cochrane Database of 5 Kahale44 2017 Systematic Reviews Full Full Partiale F, T, E 6 Cochrane Database of 7 Kahale45 2018 Systematic Reviews Full Partial No F, T 8 Cochrane Database of Kahale46 2018 Systematic Reviews Full Partial No F, T 9 Cochrane Database of 10 Kapur47 2018 Systematic Reviews Full No No F 11 Cochrane Database of Kelly48 2018 Systematic Reviews Partialf Partial No F F, T 12 Cochrane Database of 49 For peer review only 13 Knightly 2017 Systematic Reviews Full No No F 14 Cochrane Database of Kopsaftis50 2018 Systematic Reviews No No No 15 Cochrane Database of 16 Lawrie51 2018 Systematic Reviews Full Partial Partial F, T, E Cochrane Database of 17 http://bmjopen.bmj.com/ Leathersich52 2018 Systematic Reviews Full Full No F, T F, T F, T F, T 18 Cochrane Database of 19 Lethaby53 2017 Systematic Reviews Full No No F F F 20 Cochrane Database of 54 21 López-Briz 2018 Systematic Reviews Full No No F Cochrane Database of 22 Marchant55 2018 Systematic Reviews Partial No No F 23 Cochrane Database of 24 Matar56 2018 Systematic Reviews Full No No F Cochrane Database of 25 Matar57 2018 Systematic Reviews Full Full No F, T on September 24, 2021 by guest. Protected copyright. 26 Cochrane Database of 27 McNicol58 2018 Systematic Reviews Full No No F Cochrane Database of 28 McTague59 2018 Systematic Reviews No No No 29 Cochrane Database of 30 Mhaskar60 2017 Systematic Reviews Full Full Partial F, T, E 31 Cochrane Database of Milligan61 2018 Systematic Reviews Partialg No No F F 32 Cochrane Database of 33 Monk62 2017 Systematic Reviews Full Full No F, T F, T 34 Cochrane Database of Montero63 2018 Systematic Reviews Partial No No F 35 Cochrane Database of 36 Mücke64 2018 Systematic Reviews Full Full Partial F, T F, T, E 37 Cochrane Database of Narula65 2018 Systematic Reviews No No No 38 Cochrane Database of 39 Nevitt66 2017 Systematic Reviews Partial No No F F 40 Cochrane Database of 67 41 Nevitt 2018 Systematic Reviews Full No No F 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane Database of 4 Norman68 2018 Systematic Reviews Full No Partial F F, E Cochrane Database of 5 Normansell69 2018 Systematic Reviews Full Noh No F F 6 Cochrane Database of 7 Novoa70 2018 Systematic Reviews Full Partialh No F F F, T F F 8 Cochrane Database of Ohlsson71 2017 Systematic Reviews Partial No No F F 9 Cochrane Database of 10 Ostinelli72 2018 Systematic Reviews Full No No F F 11 Cochrane Database of Ostinelli73 2018 Systematic Reviews Partial Partial No F F, T F 12 Cochrane Database of 74 For peer review only 13 Ostuzzi 2018 Systematic Reviews Full Partial No F F, T F 14 Cochrane Database of Parker75 2018 Systematic Reviews No No No 15 Cochrane Database of 16 Pasquali76 2018 Systematic Reviews Partial Partial No F, T F, T F F F Cochrane Database of 17 http://bmjopen.bmj.com/ Pike77 2018 Systematic Reviews Full No No F F 18 Cochrane Database of 19 Rirash78 2017 Systematic Reviews No No No 20 Cochrane Database of 79 21 Robertson 2017 Systematic Reviews No No No Cochrane Database of 22 Romero80 2017 Systematic Reviews Full No No F F F F F F 23 Cochrane Database of 24 Rosumeck81 2018 Systematic Reviews Full Full No F, T Cochrane Database of 25 Rüschen82 2018 Systematic Reviews Full Full No F, T F, T on September 24, 2021 by guest. Protected copyright. 26 Cochrane Database of 27 Ruthirakuhan83 2018 Systematic Reviews Full No Partial F F, E Cochrane Database of 28 Sankar84 2018 Systematic Reviews No No No 29 Cochrane Database of 30 Schumann85 2018 Systematic Reviews Full Partial Partial F, T F F, T, E F, T F 31 Simancas- Cochrane Database of Racines86 2018 Systematic Reviews Full Full No F F F F, T 32 Cochrane Database of 33 Smith87 2017 Systematic Reviews Full Full Full F, T, E F, T, E 34 Cochrane Database of Smith88 2018 Systematic Reviews Full Full No F, T F, T 35 Cochrane Database of 36 Soares-Weiser89 2018 Systematic Reviews Partial No No F 37 Cochrane Database of Squizzato90 2017 Systematic Reviews Full Partiali No F F, T F F 38 Cochrane Database of 39 St George91 2018 Systematic Reviews Full Partial Partial F, T F, T, E F F, T, E 40 Cochrane Database of 92 41 Stern 2017 Systematic Reviews Full No No F F F 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane Database of 4 Sturman93 2017 Systematic Reviews Full Full No F, T F, T F, T Tammenmaa- Cochrane Database of 5 Aho94 2018 Systematic Reviews Partial No No F 6 Cochrane Database of 7 Temmingh95 2018 Systematic Reviews Full Partial Partial F, T F, T, E F, T, E F, T 8 Cochrane Database of Tenforde96 2018 Systematic Reviews Full Full No F, T F, T F, T 9 Cochrane Database of 10 Toews97 2018 Systematic Reviews Full Full Partial F, E F F, T 11 Cochrane Database of Venekamp98 2018 Systematic Reviews Full Full No F F, T 12 Cochrane Database of 99 For peer review only 13 Vermeij 2018 Systematic Reviews No No No 14 Cochrane Database of Vietto100 2018 Systematic Reviews Full No No F F 15 Cochrane Database of 16 Wall101 2018 Systematic Reviews Full Full No F, T F F F Cochrane Database of 17 http://bmjopen.bmj.com/ Weibel102 2018 Systematic Reviews Full No No F F 18 Cochrane Database of 19 Wright103 2018 Systematic Reviews Partial Partial No F F, T 20 Cochrane Database of 104 21 Xiao 2018 Systematic Reviews Full No No F Cochrane Database of 22 Zhang105 2017 Systematic Reviews Full No No F F F F F 23 Cochrane Database of 24 Zhou106 2017 Systematic Reviews Full Full No F F, T F Cochrane Database of 25 Zonneveld107 2018 Systematic Reviews Partialj No No F on September 24, 2021 by guest. Protected copyright. 26 General Medicine (n = 33) 27 López-López108 2017 BMJ Full No No F F 28 Wang109 2018 BMJ Open No No No 29 Cipriani110 2018 Lancet Fullk No No F F Chen111 2018 Medicine No No No 30 Ding112 2018 Medicine No No No 31 Guo113 2018 Medicine No No No 32 Han114 2018 Medicine No No No Hu115 2018 Medicine No No No 33 Huang116 2018 Medicine Full Partial No F, T 34 Jiang117 2018 Medicine No No No 35 Jiang118 2018 Medicine No No No 119 36 Khan 2018 Medicine No No No Liang120 2017 Medicine No No No 37 Liu121 2018 Medicine Partiall No No F 38 Lor122 2017 Medicine No No No 39 Wang123 2017 Medicine No No No Wang124 2018 Medicine No No No 40 Wang125 2018 Medicine No No No 41 Wei126 2017 Medicine No No No 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Woo127 2018 Medicine No No No 4 Xia128 2018 Medicine No No No Yang129 2017 Medicine No No No 5 Ye130 2017 Medicine No No No 6 Yu131 2018 Medicine No No No 7 Yuan132 2018 Medicine No No No 133 8 Zhang 2018 Medicine No No No Zhang134 2018 Medicine No No No 9 Zhao135 2018 Medicine No No No 10 Zhao136 2018 Medicine No No No 11 Zhou137 2018 Medicine No No No Zhu138 2018 Medicine No No No 12 Zhou139 2018 Postgraduate MedicineForNo peerNo reviewNo only 13 Revista da Associação 14 Zhang140 2018 Médica Brasileira Full Fullm No F, T 15 Specialty medicine (n = 100) 16 Li141 2018 Acta Ophthalmologica Fulln No No F F American Heart

17 Tarantini142 2018 Journal No No No http://bmjopen.bmj.com/ 18 American Journal of 19 Wang143 2018 Cardiovascular Drugs No No No Anaesthesia and 20 Aman144 2018 Intensive Care No No No 21 Autoimmunity 22 Li145 2018 Reviews No No No Biomed Research 23 Wang146 2018 International No No No 24 Veettil147 2017 BMC Cancer No No No

25 BMC Cardiovascular on September 24, 2021 by guest. Protected copyright. 148 26 Bredemeier 2018 Disorders Full No No F BMC 27 Lyu149 2018 Gastroenterology No No No 28 BMC Infectious 29 Xing150 2017 Diseases No No No BMC Musculoskeletal 30 Kuo151 2018 Disorders No No No 31 Beez152 2017 BMC Neurology No No No 32 Zeng153 2017 BMC Ophthalmology No No No BMC Pharmacology & 33 Bundhun154 2017 Toxicology No No No 34 Zhang155 2017 BMC Psychiatry No No No 35 BMC Pulmonary 156 36 Zhang 2017 Medicine No No No BMC Pulmonary 37 Zhang157 2017 Medicine Full No No 38 Ramos-Esquivel15 39 8 2018 Breast Cancer No No No British Journal of 40 Zeng159 2018 Sports Medicine Partialo No No F F 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cellular Physiology 4 Shui160 2018 and Biochemistry No No No Clinical Microbiology 5 Rodrigo161 2018 and Infection Partial No No F 6 Clinical 7 Wang162 2018 Rheumatology No No No 8 Critical Reviews in Oncology / 9 Hong163 2018 Hematology No No No 10 de Carvalho164 2018 Diabetes Care No No No 11 Digestive Diseases and Jaafar165 2018 Sciences No No No 12 Liu166 2018 Drug Delivery ForNo peerNo reviewNo only 13 Drug Design, 14 Development and Liu167 2018 Therapy No No No 15 Drug Design, 16 Development and Sun168 2017 Therapy No No No 17 http://bmjopen.bmj.com/ East Asian Archives of 18 Paraschakis169 2017 Psychiatry No No No 19 Emergency Medicine 20 D’Souza170 2018 Journal No No No 21 European Journal of Gynecological 22 Mei171 2016 Oncology No No No 23 European Respiratory 24 Verberkt172 2017 Journal No No No Expert Opinion on 25 Sridharan173 2018 Pharmacotherapy No No No on September 24, 2021 by guest. Protected copyright. 26 Expert Review of 27 Habibi174 2018 Clinical Pharmacology No No No Expert Review of 28 Li175 2018 Clinical Pharmacology No No No 29 Sangroongruangsr Expert Review of 30 i176 2018 Clinical Pharmacology Full No No F 31 Foot and Ankle Hickey177 2018 Surgery No No No 32 Zhao178 2018 Gastric Cancer Partialp No No F F F 33 Khera179 2018 Gastroenterology No No No 34 Gynecologic Li180 2018 Oncology No No No 35 Zhuge181 2018 Helicobacter No No No 36 Indian Journal of 37 Kim182 2017 Cancer No No No Indian Journal of 38 Garg183 2018 Gastroenterology No No No 39 Rosanova184 2017 Infectious Diseases No No No 40 Inflammopharmacolog 185 41 Yu 2018 y No No No 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 International 4 Kakkos186 2018 Angiology No No No International 5 Ou187 2018 Immunopharmacology Full No No F 6 International 7 Yin188 2018 Immunopharmacology No No No 8 International Journal Zhu189 2018 of Clinical Oncology No No No 9 International Journal 10 Liu190 2018 of Neuroscience No No No 11 International Journal Coccolini191 2018 of Surgery No No No 12 International Journal 192 For peer review only 13 Fan 2018 of Surgery No No No 14 International Journal Li193 2018 of Surgery No No No 15 International Journal 16 Li194 2018 of Surgery No No No International Journal 17 http://bmjopen.bmj.com/ Liu195 2018 of Surgery No No No 18 International Journal 19 Ran196 2018 of Surgery Noq No No 20 International Journal 197 21 Zhao 2018 of Surgery No No No International Journal 22 Zhu198 2018 of Surgery No No No 23 Journal of Affective 24 Wagner199 2018 Disorders Partial No No F Journal of Assisted 25 Reproduction and on September 24, 2021 by guest. Protected copyright. 26 Hickman200 2018 Genetics No No No 27 Journal of Cancer Research and Clinical 28 Luo201 2018 Oncology No No No 29 Journal of Cancer 30 Research and Clinical 202 r 31 Wang 2018 Oncology Partial No No F F Journal of Cancer 32 Research and 33 Wang203 2018 Therapeutics No No No 34 Journal of Cardiac Aboul-Hassan204 2017 Surgery No No No 35 Journal of 36 Cardiovascular 37 Wang205 2018 Surgery No No No Journal of Clinical F 38 Endocrinology and 39 Barrionuevo206 2018 Metabolism Full No No F 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Journal of Clinical 4 Pharmacy and Cui207 2018 Therapeutics Fulls No No F 5 Journal of 6 Dermatological 7 Sawyer208 2018 Treatment No No No 8 Journal of Emergency Markey209 2018 Medicine No No No 9 Journal of 10 Gastrointestinal and 11 Szabó210 2017 Liver Diseases No No No Journal of 12 Su211 2018 Immunology ResearchForNo peerNo reviewNo only 13 Journal of 14 Interventional Cardiac Chen212 2018 Electrophysiology No No No 15 Journal of Orthopaedic 16 Chen213 2017 Surgery and Research No No No Journal of Orthopaedic 17 http://bmjopen.bmj.com/ Li214 2018 Surgery and Research No No No 18 Journal of Orthopaedic 19 Luo215 2018 Surgery and Research No No No 20 Journal of Orthopaedic 216 21 Ma 2018 Surgery and Research No No No Journal of Psychiatric 22 He217 2018 Research Full No No F 23 Journal of Stroke & 24 Cerebrovascular Wang218 2018 Diseases No No No 25 Journal of the on September 24, 2021 by guest. Protected copyright. 26 American Academy of 27 Dhana219 2018 Dermatology No No No Journal of the 28 American Heart 29 Karatasakis220 2017 Association No No No 30 Journal of the 31 European Academy of Dermatology and 32 Kuo221 2018 Venereology Full No No 33 Journal of Traditional 34 Liu222 2016 Chinese Medicine No No No Journal of Zhejiang 35 University-SCIENCE 36 Zheng223 2017 B No No No 37 Lancet Respiratory Fregonese224 2018 Medicine No No No 38 Bornstein225 2018 Neurological Sciences No No No 39 Chen226 2018 Ophthalmic Research No No No 40 Han227 2017 Pain Physician No No No 228 41 Peng 2017 Pain Physician No No No 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Feng229 2016 Pharmazie No No No 4 Xu230 2016 Pharmazie No No No PLOS Neglected 5 Palmeirim231 2018 Tropical Diseases No No No 6 Psychotherapy and 7 Furukawa232 2018 Psychosomatics No No No 233 8 Liu 2018 Renal Failure No No No Miravitlles234 2017 Respiratory Research Full No No F 9 Wang235 2017 Respiratory Research No No No 10 Rheumatology 11 Kawalec236 2018 International No No No Malhotra237 2018 Stroke No No No 12 Surgical LaparoscopyFor peer review only 13 Endoscopy & 14 Percutaneous Zhang238 2018 Techniques No No No 15 Yamashita239 2018 Thrombosis Research No No Partial E 16 Zhang240 2018 Vaccine No No No

17 Other (n = 10) http://bmjopen.bmj.com/ 18 Medical Science 19 Chen241 2018 Monitor No No No Arteagoitia242 2018 PLOS ONE No No No 20 Feng243 2018 PLOS ONE No No No 21 Kawakami244 2018 PLOS ONE No No No 22 Li245 2018 PLOS ONE No No No Lin246 2017 PLOS ONE No No No 23 Ling247 2018 PLOS ONE No No No 24 Rohner248 2017 PLOS ONE No No No 249

25 Sethi 2018 PLOS ONE Partial No No F on September 24, 2021 by guest. Protected copyright. 250 26 Wolf 2018 PLOS ONE No No No aFunding sources categorized as government funded, industry funded, or mixed for most trials. Specific details about funding were reported for 2 trials and details on author ties and employment were 27 reported for a single trial; bAuthors reported extracting funding sources from included RCTs but funding sources are only reported for a single study; cReported funding sources for all included studies 28 except for one; dReported author financial ties for all included studies except for 2; eNon-industry author employment reported for some included RCTs; fFunding sources and author ties reported for all 29 included RCTs except one that was a conference abstract; gFunding sources only reported for a single RCT; hAuthors reported whether or not included RCTs had decaled COI (yes, no) and, if yes, indicated the page of the original study the declaration could be found on. This was coded as partially reporting because the nature of these COI was not reported within the meta-analysis publication 30 itself and it was unclear whether these were financial ties and whether they were with industry; iNon-industry author financial ties reported for some included RCTs; jA single RCT was reported as 31 'industry sponsored' with no specifics about the sponsor; kAuthors coded studies as sponsored by industry or not, and any of author industry affiliation, industry funding, or data obtained from 32 pharmaceutical company qualified an RCT as ‘sponsored'; lAuthors report that ‘some trials had a high risk of reporting bias because they were sponsored by pharmaceutical companies’ but do not specify which or even how many trials; mAuthors reported that all included RCTs had authors with financial ties to industry but provided no further information; nReported whether each included RCT 33 was industry funded (yes or no) but provided no further information; oFor some analyses the authors reported how many included RCTs were non-commercially funded and present results including only 34 non-commercially funded trials, but do not provide further information on which trials were commercially funded; pAuthors state 14 trials were industry-sponsored and reference figure 1 in the 35 supplementary material where 14 studies were marked as high risk for other bias, but it is not explicitly specified what was considered as 'other bias'; qAuthors considered RCT funding sources within r 36 'other bias’. In their risk of bias assessment but did not report any specific information; Authors report that most studies were funded by the pharmaceutical industry and refer readers to figure 2 (risk of bias figure), but the figure does not give any information about which RCTs; sIncluded RCTs were coded as having company funding (Yes/No). 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 82 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 4 5 References for eTable1 and eTable2 6 7 8 1. Abdel-Rahman O, Elsayed Z, Elhalawani H. Gemcitabine-based chemotherapy for 9 advanced biliary tract carcinomas. Cochrane Database of Syst Rev. 2018;4. 10 11 2. Adams SP, Sekhon SS, Tsang M, Wright JM. Fluvastatin for lowering lipids. Cochrane 12 13 Database of Syst Rev. 2018;3. 14 3. Agabio R, Trogu E, Pani PP. Antidepressants for the treatment of people with co- 15 16 occurring depressionFor andpeer alcohol dependence. review Cochrane only Database of Syst Rev. 2018;4. 17 18 4. Al-Shahi Salman, Law ZK, Bath PM, Steiner T, Sprigg N. Haemostatic therapies for 19 20 acute spontaneous intracerebral haemorrhage. Cochrane Database of Syst Rev. 2018;4. 21 5. Alabed S, Latifeh Y, Mohammad HA, Bergman H. Gamma-aminobutyric acid agonists 22 23 for antipsychotic-induced tardive dyskinesia. Cochrane Database of Syst Rev. 2018;4. 24 25 6. Allegretti AS, Israelsen M, Krag A, Jovani M, Goldin AH, Schulman AR, et al. 26 27 Terlipressin versus placebo or no intervention for people with cirrhosis and hepatorenal 28 syndrome. Cochrane Database of Syst Rev. 2017;6. 29 30 7. Arechabala MC, Catoni MI, Claro JC, Rojas NP, Rubio ME, Calvo MA, et al. 31 Antimicrobial lock solutions for preventing catheter-related infections in haemodialysis. 32 http://bmjopen.bmj.com/ 33 Cochrane Database of Syst Rev. 2018;4. 34 35 8. Baandrup L, Ebdrup BH, JØ R, Lindschou J, Gluud C, Glenthøj BY. Pharmacological 36 37 interventions for benzodiazepine discontinuation in chronic benzodiazepine users. 38 39 Cochrane Database of Syst Rev. 2018;3.

40 9. Bala MM, Paszek E, Lesniak W, Wloch-Kopec D, Jasinska K, Undas A. Antiplatelet and on September 24, 2021 by guest. Protected copyright. 41 42 anticoagulant agents for primary prevention of thrombosis in individuals with 43 44 antiphospholipid antibodies. Cochrane Database of Syst Rev. 2018;7. 45 46 10. Barbato A, Avanzo BD, Parabiaghi A. Couple therapy for depression. Cochrane 47 Database of Syst Rev. 2018;6. 48 49 11. Bergman H, Bhoopathi PS, Soares-Weiser K. Benzodiazepines for antipsychotic-induced 50 51 tardive dyskinesia. Cochrane Database of Syst Rev. 2018;1. 52 12. Bighelli I, Castellazzi M, Cipriani A, Girlanda F, Guaiana G, Koesters M, et al. 53 54 Antidepressants versus placebo for panic disorder in adults. Cochrane Database of Syst 55 56 Rev. 2018;4. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 83 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 13. Birks JS, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane 4 5 Database of Syst Rev. 2018;6. 6 7 14. Boyapati RK, Torres J, Palmela C, Parker CE, Silverberg OM, Upadhyaya SD, et al. 8 Withdrawal of immunosuppressant or biologic therapy for patients with quiescent 9 10 Crohn's disease. Cochrane Database of Syst Rev. 2018;5. 11 12 15. Brown J, Crawford TJ, Datta S, Prentice A. Oral contraceptives for pain associated with 13 14 endometriosis. Cochrane Database of Syst Rev. 2018;5. 15 16. Bruins Slot KMH, Berge E. Factor Xa inhibitors versus vitamin K antagonists for 16 For peer review only 17 preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane 18 19 Database of Syst Rev. 2018;3. 20 21 17. Bryan EJ, Purcell MA, Kumar A. Zuclopenthixol dihydrochloride for schizophrenia. 22 Cochrane Database of Syst Rev. 2017;11. 23 24 18. Bryant-Smith AC, Lethaby A, Farquhar C, Hickey M. Antifibrinolytics for heavy 25 26 menstrual bleeding. Cochrane Database of Syst Rev. 2018;4. 27 19. Burry L, Mehta S, Perreault MM, Luxenberg JS, Siddiqi N, Hutton B, et al. 28 29 Antipsychotics for treatment of delirium in hospitalised non-ICU patients. Cochrane 30 31 Database of Syst Rev. 2018;6.

40 on September 24, 2021 by guest. Protected copyright. 41 22. Chiew AL, Gluud C, Brok J, Buckley NA. Interventions for paracetamol 42 43 (acetaminophen) overdose. Cochrane Database of Syst Rev. 2018;2. 44 45 23. Das RR, Singh M, Naik SS. Vitamin D as an adjunct to antibiotics for the treatment of 46 acute childhood pneumonia. Cochrane Database of Syst Rev. 2018;7. 47 48 24. Demicheli V, Jefferson T, Ferroni E, Rivetti A, Pietrantonj CD. Vaccines for preventing 49 50 influenza in healthy adults. Cochrane Database of Syst Rev. 2018;2. 51 52 25. Demicheli V, Jefferson T, Pietrantonj CD, Ferroni E, Thorning S, Thomas RE, et al. 53 Vaccines for preventing influenza in the elderly. Cochrane Database of Syst Rev. 2018;2. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 84 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 26. Di Nisio M, Wichers IM, Middeldorp S. Treatment for superficial thrombophlebitis of 4 5 the leg. Cochrane Database of Syst Rev. 2018;2. 6 7 27. El-Sayeh HG, Rathbone J, Soares-Weiser K, Bergman H. Non-antipsychotic 8 catecholaminergic drugs for antipsychotic-induced tardive dyskinesia. Cochrane 9 10 Database of Syst Rev. 2018;1. 11 12 28. Engelen ET, Schutgens RE, Mauser-Bunschoten EP, Es RJv, Galen KPv. Antifibrinolytic 13 14 therapy for preventing oral bleeding in people on anticoagulants undergoing minor oral 15 surgery or dental extractions. Cochrane Database of Syst Rev. 2018;7. 16 For peer review only 17 29. Eshun-Wilson I, Siegfried N, Akena DH, Stein DJ, Obuku EA, Joska JA. Antidepressants 18 19 for depression in adults with HIV infection. Cochrane Database of Syst Rev. 2018;1. 20 21 30. Essali A, Soares-Weiser K, Bergman H, Adams CE. Calcium channel blockers for 22 antipsychotic-induced tardive dyskinesia. Cochrane Database of Syst Rev. 2018;3. 23 24 31. Everitt H, Baldwin DS, Stuart B, Lipinska G, Mayers A, Malizia AL, et al. 25 26 Antidepressants for insomnia in adults. Cochrane Database of Syst Rev. 2018;5. 27 32. Fanshawe TR, Halliwell W, Lindson N, Aveyard P, Livingstone-Banks J, Hartmann- 28 29 Boyce J. Tobacco cessation interventions for young people. Cochrane Database of Syst 30 31 Rev. 2017;11.

40 on September 24, 2021 by guest. Protected copyright. 41 2018;3. 42 43 35. Grabosch SM, Shariff OM, Helm CW. Non-steroidal anti-inflammatory agents to induce 44 45 regression and prevent the progression of cervical intraepithelial neoplasia. Cochrane 46 Database of Syst Rev. 2018;2. 47 48 36. Graves PM, Choi L, Gelband H, Garner P. Primaquine or other 8-aminoquinolines for 49 50 reducing Plasmodium falciparum transmission. Cochrane Database of Syst Rev. 2018;2. 51 52 37. Haas DM, Morgan S, Contreras K, Enders S. Vaginal preparation with antiseptic solution 53 before cesarean section for preventing postoperative infections. Cochrane Database of 54 55 Syst Rev. 2018;7. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 85 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 38. Hakoum MB, Kahale LA, Tsolakian IG, Matar CF, Yosuico VE, Terrenato I, et al. 4 5 Anticoagulation for the initial treatment of venous thromboembolism in people with 6 7 cancer. Cochrane Database of Syst Rev. 2018;1. 8 39. Heras-Mosteiro J, Monge-Maillo B, Pinart M, Pereira PL, Reveiz L, Garcia-Carrasco E, 9 10 et al. Interventions for Old World cutaneous leishmaniasis. Cochrane Database of Syst 11 12 Rev. 2017;12. 13 14 40. Janmaat VT, Steyerberg EW, Gaast Avd, Mathijssen RH, Bruno MJ, Peppelenbosch MP, 15 et al. Palliative chemotherapy and targeted therapies for esophageal and gastroesophageal 16 For peer review only 17 junction cancer. Cochrane Database of Syst Rev. 2017;11. 18 19 41. Jefferson T, Rivetti A, Pietrantonj CD, Demicheli V. Vaccines for preventing influenza in 20 21 healthy children. Cochrane Database of Syst Rev. 2018;2. 22 42. Jung JH, Kim J, MacDonald R, Reddy B, Kim MH, Dahm P. Silodosin for the treatment 23 24 of lower urinary tract symptoms in men with benign prostatic hyperplasia. Cochrane 25 26 Database of Syst Rev. 2017;11. 27 43. Kaempfen S, Neumann RP, Jost K, Schulzke SM. Beta-blockers for prevention and 28 29 treatment of retinopathy of prematurity in preterm infants. Cochrane Database of Syst 30 31 Rev. 2018;3.

40 on September 24, 2021 by guest. Protected copyright. 41 of Syst Rev. 2018;6. 42 43 46. Kahale LA, Hakoum MB, Tsolakian IG, Matar CF, Terrenato I, Sperati F, et al. 44 45 Anticoagulation for the long-term treatment of venous thromboembolism in people with 46 cancer. Cochrane Database of Syst Rev. 2018;6. 47 48 47. Kapur N, Petsky HL, Bell S, Kolbe J, Chang AB. Inhaled corticosteroids for 49 50 bronchiectasis. Cochrane Database of Syst Rev. 2018;5. 51 52 48. Kelly C, Chalmers JD, Crossingham I, Relph N, Felix LM, Evans DJ, et al. Macrolide 53 antibiotics for bronchiectasis. Cochrane Database of Syst Rev. 2018;3. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 86 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 49. Knightly R, Milan SJ, Hughes R, Knopp-Sihota JA, Rowe BH, Normansell R, et al. 4 5 Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database of Syst 6 7 Rev. 2017;11. 8 50. Kopsaftis Z, Wood-Baker R, Poole P. Influenza vaccine for chronic obstructive 9 10 pulmonary disease (COPD). Cochrane Database of Syst Rev. 2018;6. 11 12 51. Lawrie TA, Green JT, Beresford M, Wedlake L, Burden S, Davidson SE, et al. 13 14 Interventions to reduce acute and late adverse gastrointestinal effects of pelvic 15 radiotherapy for primary pelvic cancers. Cochrane Database of Syst Rev. 2018;1. 16 For peer review only 17 52. Leathersich SJ, Vogel JP, Tran TS, Hofmeyr GJ. Acute tocolysis for uterine tachysystole 18 19 or suspected fetal distress. Cochrane Database of Syst Rev. 2018;7. 20 21 53. Lethaby A, Puscasiu L, Vollenhoven B. Preoperative medical therapy before surgery for 22 uterine fibroids. Cochrane Database of Syst Rev. 2017;11. 23 24 54. López-Briz E, Garcia VR, Cabello JB, Bort-Martí S, Sanchis RC, Burls A. Heparin 25 26 versus 0.9% sodium chloride locking for prevention of occlusion in central venous 27 catheters in adults. Cochrane Database of Syst Rev. 2018;7. 28 29 55. Marchant JM, Petsky HL, Morris PS, Chang AB. Antibiotics for prolonged wet cough in 30 31 children. Cochrane Database of Syst Rev. 2018;7.

40 on September 24, 2021 by guest. Protected copyright. 41 58. McNicol ED, Rowe E, Cooper TE. Ketorolac for postoperative pain in children. 42 43 Cochrane Database of Syst Rev. 2018;7. 44 45 59. McTague A, Martland T, Appleton R. Drug management for acute tonic-clonic 46 convulsions including convulsive status epilepticus in children. Cochrane Database of 47 48 Syst Rev. 2018;1. 49 50 60. Mhaskar R, Kumar A, Miladinovic B, Djulbegovic B. Bisphosphonates in multiple 51 52 myeloma: an updated network meta-analysis. Cochrane Database of Syst Rev. 2017;12. 53 61. Milligan R, Paul M, Richardson M, Neuberger A. Vaccines for preventing typhoid fever. 54 55 Cochrane Database of Syst Rev. 2018;5. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 87 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 62. Monk AB, Harrison JE, Worthington HV, Teague A. Pharmacological interventions for 4 5 pain relief during orthodontic treatment. Cochrane Database of Syst Rev. 2017;11. 6 7 63. Montero N, Favà A, Rodriguez E, Barrios C, Cruzado JM, Pascual J, et al. Treatment for 8 hepatitis C virus-associated mixed cryoglobulinaemia. Cochrane Database of Syst Rev. 9 10 2018;5. 11 12 64. Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-based medicines for 13 14 chronic neuropathic pain in adults. Cochrane Database of Syst Rev. 2018;3. 15 65. Narula N, Dhillon A, Zhang D, Sherlock ME, Tondeur M, Zachos M. Enteral nutritional 16 For peer review only 17 therapy for induction of remission in Crohn's disease. Cochrane Database of Syst Rev. 18 19 2018;4. 20 21 66. Nevitt SJ, Sudell M, Weston J, Smith CT, Marson AG. Antiepileptic drug monotherapy 22 for epilepsy: a network meta-analysis of individual participant data. Cochrane Database 23 24 of Syst Rev. 2017;12. 25 26 67. Nevitt SJ, Smith CT, Weston J, Marson AG. Lamotrigine versus carbamazepine 27 monotherapy for epilepsy: an individual participant data review. Cochrane Database of 28 29 Syst Rev. 2018;6. 30 31 68. Norman G, Westby MJ, Rithalia AD, Stubbs N, Soares MO, Dumville JC. Dressings and

40 on September 24, 2021 by guest. Protected copyright. 41 2018;4. 42 43 71. Ohlsson A, Aher SM. Early erythropoiesis-stimulating agents in preterm or low birth 44 45 weight infants. Cochrane Database of Syst Rev. 2017;11. 46 72. Ostinelli EG, Jajawi S, Spyridi S, Sayal K, Jayaram MB. Aripiprazole (intramuscular) for 47 48 psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database of 49 50 Syst Rev. 2018;1. 51 52 73. Ostinelli EG, Hussein M, Ahmed U, Rehman FU, Miramontes K, Adams CE. 53 Risperidone for psychosis-induced aggression or agitation (rapid tranquillisation). 54 55 Cochrane Database of Syst Rev. 2018;4. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 88 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 74. Ostuzzi G, Matcham F, Dauchy S, Barbui C, Hotopf M. Antidepressants for the treatment 4 5 of depression in people with cancer. Cochrane Database of Syst Rev. 2018;4. 6 7 75. Parker CE, Nguyen TM, Segal D, MacDonald JK, Chande N. Low dose naltrexone for 8 induction of remission in Crohn's disease. Cochrane Database of Syst Rev. 2018;4. 9 10 76. Pasquali S, Hadjinicolaou AV, Sileni VC, Rossi CR, Mocellin S. Systemic treatments for 11 12 metastatic cutaneous melanoma. Cochrane Database of Syst Rev. 2018;2. 13 14 77. Pike KC, Akhbari M, Kneale D, Harris KM. Interventions for autumn exacerbations of 15 asthma in children. Cochrane Database of Syst Rev. 2018;3. 16 For peer review only 17 78. Rirash F, Tingey PC, Harding SE, Maxwell LJ, Ghogomu ET, Wells GA, et al. Calcium 18 19 channel blockers for primary and secondary Raynaud's phenomenon. Cochrane Database 20 21 of Syst Rev. 2017;12. 22 79. Robertson L, Yeoh SE, Ramli A. Secondary prevention of recurrent venous 23 24 thromboembolism after initial oral anticoagulation therapy in patients with unprovoked 25 26 venous thromboembolism. Cochrane Database of Syst Rev. 2017;12. 27 80. Romero L, Huerfano C, Grillo-Ardila CF. Macrolides for treatment of Haemophilus 28 29 ducreyi infection in sexually active adults. Cochrane Database of Syst Rev. 2017;12. 30 31 81. Rosumeck S, Nast A, Dressler C. Ivermectin and permethrin for treating scabies.

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40 on September 24, 2021 by guest. Protected copyright. 41 228.Peng K, Zhang J, Meng XW, Liu HY, Ji FH. Optimization of Postoperative Intravenous 42 43 Patient-Controlled Analgesia with Opioid-Dexmedetomidine Combinations: An Updated 44 45 Meta-Analysis with Trial Sequential Analysis of Randomized Controlled Trials. Pain 46 Physician. 2017;20(7):569-96. 47 48 229.Feng M, Ding Q, Zhong C, Li J, Wang Q, Yuan Z, et al. Adjunctive therapy with V-5 49 50 Immunitor (V5) for the treatment of tuberculosis patients: a meta-analysis. Pharmazie. 51 52 2016;71(9):499-503. 53 230.Xu L, Zhang F, Du S, Yu Q, Chen L, Long LH, et al. Inhaled antibiotics in non-cystic 54 55 fibrosis bronchiectasis: A meta-analysis. Pharmazie. 2016;71(9):491-8. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 103 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 231.Palmeirim MS, Hürlimann E, Knopp S, Speich B, Belizario V, Joseph SA, et al. Efficacy 4 5 and safety of co-administered ivermectin plus albendazole for treating soil-transmitted 6 7 helminths: A systematic review, meta-analysis and individual patient data analysis. PLoS 8 Negl Trop Dis. 2018;12(4):e0006458. 9 10 232.Furukawa TA, Efthimiou O, Weitz ES, Cipriani A, Keller MB, Kocsis JH, et al. 11 12 Cognitive-Behavioral Analysis System of Psychotherapy, Drug, or Their Combination for 13 14 Persistent Depressive Disorder: Personalizing the Treatment Choice Using Individual 15 Participant Data Network Metaregression. Psychother Psychosom. 2018;87(3):140-53. 16 For peer review only 17 233.Liu X, Zhai T, Ma R, Luo C, Wang H, Liu L. Effects of uric acid-lowering therapy on the 18 19 progression of chronic kidney disease: a systematic review and meta-analysis. Ren Fail. 20 21 2018;40(1):289-97. 22 234.Miravitlles M, Urrutia G, Mathioudakis AG, Ancochea J. Efficacy and safety of 23 24 tiotropium and olodaterol in COPD: a systematic review and meta-analysis. Respir Res. 25 26 2017;18(1):196. 27 235.Wang G, Zhang X, Zhang HP, Wang L, Kang Y, Barnes PJ, et al. Corticosteroid plus β 2- 28 29 agonist in a single inhaler as reliever therapy in intermittent and mild asthma: a proof-of- 30 31 concept systematic review and meta-analysis. Respir Res. 2017;18(1):203.

40 on September 24, 2021 by guest. Protected copyright. 41 Meta-Analysis. Stroke. 2018;49(2):312-8. 42 43 238.Zhang R, Lu Q, Wu Y. The Comparison of Midazolam and Propofol in Gastrointestinal 44 45 Endoscopy: A Systematic Review and Meta-analysis. Surg Laparosc Endosc Percutan 46 Tech. 2018;28(3):153-8. 47 48 239.Yamashita Y, Morimoto T, Toyota T, Shiomi H, Makiyama T, Ono K, et al. Asian 49 50 patients versus non-Asian patients in the efficacy and safety of direct oral anticoagulants 51 52 relative to vitamin K antagonist for venous thromboembolism: A systemic review and 53 meta-analysis. Thromb Res. 2018;166:37-42. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 104 of 107 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 240.Zhang W, Sun H, Atiquzzaman M, Sou J, Anis AH, Cooper C. Influenza vaccination for 4 5 HIV-positive people: Systematic review and network meta-analysis. Vaccine. 6 7 2018;36(28):4077-86. 8 241.Chen H, Shen FE, Tan XD, Jiang WB, Gu YH. Efficacy and Safety of Acupuncture for 9 10 Essential Hypertension: A Meta-Analysis. Med Sci Monit. 2018;24:2946. 11 12 242.Arteagoitia I, Andrés CR, Ramos E. Does chlorhexidine reduce bacteremia following 13 14 tooth extraction? A systematic review and meta-analysis. PloS one. 15 2018;13(4):e0195592. 16 For peer review only 17 243.Feng X, Tian M, Zhang W, Mei H. Gastrointestinal safety of etoricoxib in osteoarthritis 18 19 and rheumatoid arthritis: A meta-analysis. PloS one. 2018;13(1). 20 21 244.Kawakami H, Mihara T, Nakamura N, Ka K, Goto T. Effect of magnesium added to local 22 anesthetics for caudal anesthesia on postoperative pain in pediatric surgical patients: A 23 24 systematic review and meta-analysis with Trial Sequential Analysis. PloS one. 25 26 2018;13(1):e0190798. 27 245.Li X, Zhu L, Zhou C, Liu J, Du H, Wang C, et al. Efficacy and tolerability of short-term 28 29 duloxetine treatment in adults with generalized anxiety disorder: A meta-analysis. PloS 30 31 one. 2018;13(3):e0194501.

40 on September 24, 2021 by guest. Protected copyright. 41 antiarrhythmic effect on cardiac patients? A meta-analysis of randomized controlled 42 43 trials. PloS one. 2018;13(3):e0193303. 44 45 248.Rohner E, Grabik M, Tonia T, Jüni P, P√©tavy F, Pignatti F, et al. Does access to clinical 46 study reports from the European Medicines Agency reduce reporting biases? A 47 48 systematic review and meta-analysis of randomized controlled trials on the effect of 49 50 erythropoiesis-stimulating agents in cancer patients. PloS one. 2017;12(12):e0189309. 51 52 249.Sethi NJ, Nielsen EE, Safi S, Feinberg J, Gluud C, Jakobsen JC. Digoxin for atrial 53 fibrillation and atrial flutter: A systematic review with meta-analysis and trial sequential 54 55 analysis of randomised clinical trials. PloS one. 2018;13(3):e0193924. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 105 of 107 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 250.Wolf S, Hoffmann VS, Habicht A, Kauke T, Bucher J, Schoenberg M, et al. Effects of 4 5 mTOR-Is on malignancy and survival following renal transplantation: A systematic 6 7 review and meta-analysis of randomized trials with a minimum follow-up of 24 months. 8 PloS one. 2018;13(4):e0194975. 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

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1 PRISMA 2009 Checklist 2 3 4 Reported Section/topic # Checklist item 5 on page # 6 7 TITLE 8 Title 1 Identify the report as a systematic review, meta-analysis, or both. 9 N/A 10 ABSTRACT 11 Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility 12 3,4 criteria, Forparticipants, andpeer interventions; studyreview appraisal and synthesis only methods; results; limitations; conclusions and 13 implications of key findings; systematic review registration number. 14 15 INTRODUCTION 16 Rationale 3 Describe the rationale for the review in the context of what is already known. 5,6 17 http://bmjopen.bmj.com/ 18 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, 6 19 comparisons, outcomes, and study design (PICOS). 20 21 METHODS 22 Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide 6 23 registration information including registration number. 24 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, 6,7 25 on September 24, 2021 by guest. Protected copyright. language, publication status) used as criteria for eligibility, giving rationale. 26 27 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify 7 28 additional studies) in the search and date last searched. 29 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be eMethods1 30 repeated. 31 32 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, 6-8 33 included in the meta-analysis). 34 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes 8-10 35 for obtaining and confirming data from investigators. 36 37 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and 8-12 38 simplifications made. 39 Risk of bias in individual 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was N/A 40 studies done at the study or outcome level), and how this information is to be used in any data synthesis. 41 42 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 3, 10,11 43 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency 10,11 44 (e.g., I2) for each meta-analysis. 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 PRISMA 2009 Checklist 2 3 4 Page 1 of 2 5 Reported Section/topic # Checklist item 6 on page # 7 8 Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective N/A 9 reporting within studies). 10 Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating 11 11 which were pre-specified. 12 For peer review only 13 RESULTS 14 Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at 12, 15 each stage, ideally with a flow diagram. Figure 1 16

17 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS,http://bmjopen.bmj.com/ follow-up period) and 12, 13, 18 provide the citations. 26, 27 19 (Table 1) 20 21 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). N/A 22 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each N/A 23 intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. 24 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 25 on September 24, 2021 by guest. Protected copyright. N/A 26 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). N/A 27 28 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 28 (Table 29 2) 30 31 DISCUSSION 32 Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to 15-17 33 key groups (e.g., healthcare providers, users, and policy makers). 34 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of 35 17 identified research, reporting bias). 36 37 Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 15-17 38 39 FUNDING 40 Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the 19 41 systematic review. 42 43 44 From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 45 For more information, visit: www.prisma-statement.org. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 PRISMA 2009 Checklist 2 3 4 Page 2 of 2 5 6 7 8 9 10 11 12 For peer review only 13 14 15 16

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25 on September 24, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

Article Type: Original research

Date Submitted by the 07-Feb-2020 Author:

Primary Subject Research methods Heading:

Secondary Subject Heading: Epidemiology

Keywords: EPIDEMIOLOGY, STATISTICS & RESEARCH METHODS, MEDICAL ETHICS on September 24, 2021 by guest. Protected copyright.

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36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

44 on September 24, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 1 Reporting of Drug Trial Funding Sources and Author Financial Conflicts of Interest in 4 5 6 2 Cochrane and non-Cochrane Meta-analyses: A Cross-sectional Study 7 8 3 9 10 11 4 Kimberly A Turner, Andrea Carboni-Jiménez, Carla Benea, Katharine Elder, Brooke Levis, 12 13 5 Jill Boruff, Michelle Roseman, Lisa A Bero, Joel Lexchin, Erick H Turner, Andrea Benedetti, 14 15 16 6 Brett D Thombs For peer review only 17 18 19 7 20 21 8 Affiliations: 22 23 9 Lady Davis Institute for Medical Research, Jewish General Hospital and McGill University, 24 25 26 10 Montreal, Quebec, Canada 27 28 11 Kimberly A Turner (masters student) 29 30 12 Andrea Carboni-Jiménez (research assistant) 31

32 http://bmjopen.bmj.com/ 33 13 Carla Benea (undergraduate student) 34 35 14 Katharine Elder (research assistant) 36 37 15 Brooke Levis (doctoral student) 38 39 16 Brett D Thombs (professor) 40 on September 24, 2021 by guest. Protected copyright. 41 42 17 43 44 45 18 Schulich Library of Physical Sciences, Life Sciences, and Engineering, McGill University, 46 47 19 Montreal, Quebec, Canada 48 49 20 Jill Boruff (associate librarian) 50 51 21 52 53 54 22 Kingsway Medical Centre Family Health Organization, Toronto, Ontario, Canada 55 56 57 1 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 23 Michelle Roseman (family physician) 4 5 6 24 7 8 9 25 Charles Perkins Centre, and Faculty of Medicine and Health, and School of Pharmacy, The 10 11 26 University of Sydney, Sydney, Australia 12 13 27 Lisa A Bero (professor) 14 15 28 16 For peer review only 17 18 29 School of Health Policy and Management, Faculty of Health, York University, Toronto, Ontario, 19 20 30 Canada 21 22 31 Joel Lexchin (professor emeritus) 23 24 25 32 26 27 33 Department of Psychiatry and Department of Pharmacology, Oregon Health and Science 28 29 34 University, Portland, Oregon, USA 30 31 35 Erick H Turner (associate professor) 32 http://bmjopen.bmj.com/ 33 34 36 35 36 37 Department of Epidemiology, Biostatistics and Occupational Health, McGill University, 37 38 39 38 Montreal, Quebec, Canada

40 on September 24, 2021 by guest. Protected copyright. 41 39 Andrea Benedetti (associate professor) 42 43 40 44 45 41 Correspondence to: Brett D. Thombs, PhD; Jewish General Hospital; 4333 Cote Ste. Catherine 46 47 48 42 Road; Montreal, Quebec, Canada H3T 1E4; Tel (514) 340-8222 ext. 25112; E-mail: 49 50 43 [email protected]; ORCID: 0000-0002-5644-8432 51 52 53 44 54 55 45 Word count: 4,277 56 57 2 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 46 ABSTRACT 4 5 6 47 Objective: To (1) investigate the extent to which recently published meta-analyses report trial 7 8 48 funding, author-industry financial ties, and author-industry employment from included RCTs, 9 10 49 comparing Cochrane and non-Cochrane meta-analyses; (2) examine characteristics of meta- 11 12 50 analyses independently associated with reporting funding sources of included RCTs; and (3) 13 14 15 51 compare reporting among recently published Cochrane meta-analyses to Cochrane reviews 16 For peer review only 17 52 published in 2010. 18 19 53 Design: Review of consecutive sample of recently published meta-analyses. 20 21 22 54 Data sources: MEDLINE database via PubMed searched on October 19, 2018. 23 24 55 Eligibility criteria for selecting articles: We selected the 250 most recent meta-analyses listed 25 26 56 in PubMed that included a documented search of at least one database, statistically combined 27 28 29 57 results from ≥ 2 RCTs, and evaluated the effects of a drug or class of drugs. 30 31 58 Results: 90 of 107 (84%) Cochrane meta-analyses reported funding sources for some or all

32 http://bmjopen.bmj.com/ 33 59 included trials compared with 21 of 143 (15%) non-Cochrane meta-analyses, a difference of 69% 34 35 60 (95% confidence interval [CI], 59% to 77%). Percent reporting was also higher for Cochrane 36 37 38 61 meta-analyses compared with non-Cochrane meta-analyses for trial author-industry financial ties 39

40 62 (44% versus 1%; 95% CI for difference, 33% to 52%) and employment (17% versus 1%; 95% on September 24, 2021 by guest. Protected copyright. 41 42 63 CI for difference, 9% to 24%). In multivariable analysis, compared with Cochrane meta- 43 44 45 64 analyses, the odds ratio for reporting trial funding was ≤ 0.11 for all other journal category and 46 47 65 impact factor combinations. Compared with Cochrane reviews from 2010, reporting of funding 48 49 66 sources of included RCTs among recently published Cochrane meta-analyses improved by 54% 50 51 52 67 (95% CI, 42% to 63%), and reporting of trial author-industry financial ties and employment 53 54 68 improved by 37% (95% CI, 26% to 47%) and 10% (95% CI, 2% to 19%). 55 56 57 3 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 69 Conclusions: Reporting of trial funding sources, trial author-industry financial ties, and trial 4 5 6 70 author-industry employment in Cochrane meta-analyses has improved since 2010 and is higher 7 8 71 than in non-Cochrane meta-analyses. 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 4 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 72 Strengths and limitations of this study 4 5 6 73  The meta-analyses selected for inclusion in our study was a consecutive sample of 7 8 74 meta-analyses of drug interventions published in 2016-2018. 9 10 75  We compared reporting of funding and financial conflicts of interest among trials 11 12 13 76 included in recent Cochrane and non-Cochrane meta-analyses. 14 15 77  We compared reporting of funding and financial conflicts of interest among trials 16 For peer review only 17 78 included in recent Cochrane meta-analyses with Cochrane systematic reviews 18 19 20 79 from 2010. 21 22 80  We were unable to examine whether meta-analyses published in different types of 23 24 81 journals or journals with different impact factors are more or less likely to report 25 26 27 82 on financial conflicts of interest from included trials because most meta-analyses 28 29 83 of drug trials are published as Cochrane reviews or in relatively low-impact 30 31 84 specialty medicine journals.

32 http://bmjopen.bmj.com/ 33 34 85  Our study examined only disclosed financial conflicts of interest and did not 35 36 86 attempt to identify non-disclosed conflicts. 37 38 39

40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 5 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 87 INTRODUCTION 4 5 6 88 Financial conflicts of interest (FCOIs) can introduce bias in drug trials by influencing 7 8 89 how a trial is designed, inclusion and exclusion criteria, choice of drug dosages and comparators, 9 10 90 selection of trial outcomes, how analyses are conducted, interpretation of findings, which 11 12 91 outcomes are reported, and whether trial results are published.1-10 Drug trials funded by industry 13 14 15 92 are approximately 30% more likely to report favourable efficacy findings than non-industry 16 For peer review only 17 93 trials,8 and drug trials with principal investigators with FCOIs have higher odds of reporting 18 19 94 favourable outcomes than those led by principal investigators without FCOIs, even after 20 21 7 22 95 controlling for trial funding sources. 23 24 96 Previous studies that have examined meta-analyses of drug trials published in high- 25 26 97 impact journals and Cochrane systematic reviews of drug trials have found that funding sources 27 28 11, 12 29 98 and author FCOIs of included randomized controlled trials (RCTs) were rarely reported. A 30 31 99 2011 study found that only 2 of a sample of 29 (7%) meta-analyses on the effects of drug

32 http://bmjopen.bmj.com/ 33 100 interventions published in high-impact journals in 2009 reported the funding sources of included 34 35 101 drug trials and that none reported trial author-industry financial ties or author-industry 36 37 38 102 employment.11 A second study, published in 2012, examined Cochrane systematic reviews of 39

40 103 drug trials and found that only 46 of 151 (30%) eligible reviews published in 2010 reported on September 24, 2021 by guest. Protected copyright. 41 42 104 information on the funding source of some or all included trials, 11 (7%) provided any 43 44 45 105 information on author-industry financial ties, and 10 (7%) provided any information on author- 46 47 106 industry employment from included trials.12 48 49 107 In 2012, the Cochrane Collaboration began to require that Cochrane reviews report trial 50 51 52 108 funding sources and FCOIs of the primary researchers of all included trials in the characteristics 53 54 109 of included studies table (Methodolgical Expectations of Cochrane Intervention Reviews 55 56 57 6 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 110 (MECIR), standards R69 and R70) .13, 14 The Preferred Reporting Items for Systematic Reviews 4 5 6 111 and Meta-analyses (PRISMA) statement, however, has not been updated since its publication in 7 8 112 200915, 16 and does not address the reporting of trial funding or author FCOIs of trials included in 9 10 113 systematic reviews and meta-analyses. 11 12 114 We do not know of any studies that have compared reporting among Cochrane meta- 13 14 15 115 analyses with meta-analyses published in other journals or examined whether reporting in 16 For peer review only 17 116 Cochrane reviews has improved since Cochrane implemented its reporting policy. The objectives 18 19 117 of the present study were to (1) investigate the extent to which Cochrane and non-Cochrane 20 21 22 118 meta-analyses of drug trials report trial funding sources, author-industry financial ties, and 23 24 119 author-industry employment; (2) examine characteristics of meta-analyses that are independently 25 26 120 associated with reporting funding sources of included RCTs; and (3) compare reporting among 27 28 29 121 recently published Cochrane meta-analyses to reporting from Cochrane systematic reviews 30 31 122 published in 2010,11 prior to implementation of Cochrane’s reporting policy.

32 http://bmjopen.bmj.com/ 33 123 METHODS 34 35 124 The methods for the present study were based on our previous study of reporting of 36 37 38 125 funding sources, author-industry financial ties, and author-industry employment from trials 39

40 126 included in Cochrane systematic reviews published in 2010; however in the present study, we on September 24, 2021 by guest. Protected copyright. 41 42 127 included only Cochrane reviews that contained a meta-analysis, whereas in the previous study all 43 44 12 45 128 Cochrane reviews that included results from at least one RCT were eligible. Because of this 46 47 129 difference, in our comparison, in addition to main analyses, we conducted sensitivity analyses 48 49 130 that only included systematic reviews with meta-analyses from the previous study. A study 50 51 52 131 protocol was developed prior to initiating the present study and was posted on the Open Science 53 54 132 Framework (https://osf.io/njk5w/). 55 56 57 7 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 133 Selection of meta-analyses 4 5 6 134 Meta-analyses in any language were eligible if they (1) included a documented search for 7 8 135 eligible RCTs using at least one database, (2) statistically combined results from ≥ 2 RCTs, and 9 10 136 (3) evaluated the efficacy/effectiveness or harm of a drug or class of drugs against an alternative 11 12 137 treatment (e.g., placebo, alternative drug, non-pharmacological treatment) or no treatment. Meta- 13 14 15 138 analyses that only assessed different methods of administration, dosages, or dosage schedules of 16 For peer review only 17 139 the same drug were excluded. Drugs were defined broadly to include biologics and vaccines, but 18 19 140 not nutritional supplements or medical devices without a drug component. Meta-analyses that 20 21 22 141 investigated a combination of pharmacological and non-pharmacological interventions or 23 24 142 interventions which may or may not involve a drug (e.g., amnioinfusion) were included if a study 25 26 143 group was exclusively given a drug intervention or if the meta-analysis assessed the addition of a 27 28 29 144 drug to a treatment received by both intervention and control groups. Interventions were 30 31 145 classified as having a drug component if any form of the active ingredient (e.g., dosage, route,

32 http://bmjopen.bmj.com/ 33 146 strength, compound) was listed as an approved or discontinued brand name, generic drug or 34 35 147 therapeutic biological product by the US Food and Drug Administration (FDA) as listed in the 36 37 38 148 Drugs@FDA database at the time of review.17 If an agent was not listed in the Drugs@FDA 39

40 149 database and was classified by the FDA as a non-drug (e.g., food additive, supplement), then it on September 24, 2021 by guest. Protected copyright. 41 42 150 was not considered a drug. If an agent was not regulated as a drug and was not listed as a non- 43 44 45 151 drug by the FDA, drug status was determined based on consensus among investigators using 46 47 152 publicly available sources that provided information on the agent. 48 49 153 We searched the MEDLINE database via PubMed on October 19, 2018 using a search 50 51 52 154 developed by a medical librarian (see eMethods1 for strategy). Citations were uploaded into the 53 54 155 systematic review software DistillerSR (Evidence Partners, Ottawa, Canada), which was used to 55 56 57 8 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 156 code and track results. Two investigators independently evaluated titles and abstracts for 4 5 6 157 potential eligibility. Full texts of titles and abstracts deemed potentially eligible by either 7 8 158 investigator were then reviewed by two investigators independently. Disagreements at the full- 9 10 159 text level were resolved through consensus with a third investigator consulted as necessary. 11 12 160 Because we sought to include the most recently published meta-analyses that met eligibility 13 14 15 161 criteria, prior to reviewing, citations were organized by PubMed reference identification numbers 16 For peer review only 17 162 with the most recent first. Title and abstract and full-text reviews were conducted sequentially 18 19 163 until we obtained our desired number of included meta-analyses based on our power analysis. 20 21 22 164 Data extraction 23 24 165 For each eligible meta-analysis, one reviewer initially extracted all data into a pre-defined 25 26 166 form in DistillerSR, and a second reviewer validated all extracted data using the DistillerSR 27 28 29 167 Quality Control function. Discrepancies were resolved by consensus and consultation with a 30 31 168 third investigator, if needed. For each included meta-analysis, reviewers extracted first author

32 http://bmjopen.bmj.com/ 33 169 last name; year of publication; journal name; Clarivate Analytics 2017 journal impact factor; 34 35 170 journal speciality area based on Clarivate Analytics classification; whether it was a Cochrane 36 37 38 171 meta-analysis published in the Cochrane Database of Systematic Reviews or elsewhere; funding 39

40 172 source for the meta-analysis and author-industry financial ties and employment; reporting in the on September 24, 2021 by guest. Protected copyright. 41 42 173 meta-analysis of trial funding sources, trial author-industry financial ties, and trial author- 43 44 45 174 industry employment; and whether the meta-analysis referenced a published protocol or 46 47 175 contained a PROSPERO registration number. If a registration number was not provided, we 48 49 176 searched the PROSPERO website (https://www.crd.york.ac.uk/PROSPERO/) using key terms 50 51 52 177 from the published article, then attempted to match the principal investigator, funding source, 53 54 55 56 57 9 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 178 intervention, non-intervention comparator group, and design from the article to registrations 4 5 6 179 obtained in the search. 7 8 180 To extract information on meta-analysis funding source, meta-analysis author-industry 9 10 181 financial ties, and meta-analysis author-industry employment and to determine whether or not 11 12 182 trial funding sources, trial author-industry financial ties, and trial author-industry employment 13 14 15 183 were reported in the meta-analysis, for each included meta-analysis, reviewers examined all text, 16 For peer review only 17 184 tables, figures, appendices, disclosure statements, acknowledgements and any online 18 19 185 supplemental material, published with the manuscript or linked to the manuscript. Funding 20 21 22 186 sources for meta-analyses were classified as (1) non-industry (e.g., public granting agency, 23 24 187 private not-for-profit granting agency), (2) pharmaceutical industry, (3) combined 25 26 188 pharmaceutical industry and non-industry, (4) no funding or (5) not reported. Financial ties of 27 28 29 189 meta-analysis authors to industry were defined per the International Committee of Medical 30 31 190 Journal Editors Uniform Disclosure Form for Potential Conflicts of Interest18 and included

32 http://bmjopen.bmj.com/ 33 191 current or former board membership, current or former consultancy, current or former industry 34 35 192 employment, expert testimony, industry grants (issued or pending), payment for lectures 36 37 38 193 including service on speakers bureaus, payment for manuscript preparation, patents (planned, 39

40 194 pending, or issued), royalties, payment for development of educational presentations, stock or on September 24, 2021 by guest. Protected copyright. 41 42 195 stock options, travel reimbursement, or other relationships with industry, as disclosed in the 43 44 45 196 review. Of these, we specifically coded if industry employees were part of the author group. If a 46 47 197 meta-analysis did not contain a disclosure statement, meta-analysis author-industry financial ties 48 49 198 were coded as not reported. 50 51 52 199 For reporting of (1) trial funding sources, (2) trial author-industry financial ties, and (3) 53 54 200 trial author-industry employment, meta-analyses were coded as (1) reporting for all included 55 56 57 10 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 201 trials; (2) reporting for some, but not all, included trials (partial reporting); or (3) not reporting. 4 5 6 202 Meta-analyses that included data from a pharmaceutical industry database or noted that trial 7 8 203 drugs were supplied by the manufacturers for certain trials, but that did not make any explicit 9 10 204 statement of trial funding sources, were coded as not reporting. For meta-analyses that reported 11 12 205 information on funding sources or author FCOIs from included trials, either fully or partially, we 13 14 15 206 recorded where in the meta-analysis the information was reported. Specifically, we recorded 16 For peer review only 17 207 whether the information was reported in the abstract, lay summary, risk of bias material (text, 18 19 208 figure or table, both), main text other than risk of bias, elsewhere in the main document (e.g., 20 21 22 209 characteristics of included studies table, other table, footnote of a table), or in an online 23 24 210 appendix. See eMethods2. 25 26 211 Power analysis 27 28 29 212 To determine the number of meta-analyses to target, we first calculated the number of 30 31 213 included meta-analyses that would be needed for 80% power to find a statistically significant

32 http://bmjopen.bmj.com/ 33 214 difference if there were a 20% difference in reporting trial funding sources based on meta- 34 35 36 215 analysis characteristics, with  = 0.05. We varied the rates of reporting from 10% versus 30% to 37 38 216 70% versus 90% and considered scenarios where the proportion of reporting meta-analyses with 39

40 217 each characteristic (e.g., high-impact journals versus low-impact journals) was 50% versus 50% on September 24, 2021 by guest. Protected copyright. 41 42 43 218 and 30% versus 70%. For a two-tailed binomial test with  = 0.05, the maximum number of 44 45 219 included meta-analyses needed in any scenario was 239. Because the consequence of 46 47 220 overpowering the study was additional labour and not risk to human participants, we rounded 48 49 50 221 this number up to 250 meta-analyses. See eMethods3. 51 52 222 Statistical analyses 53 54 55 56 57 11 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 223 We presented characteristics of included meta-analyses descriptively, including funding 4 5 6 224 sources and FCOIs. We determined the proportion of meta-analyses that reported trial funding 7 8 225 source, author-industry financial ties, and author-industry employment of included trials for (1) 9 10 226 all included trials, (2) some, but not all, included trials, and (3) no included trials, along with 11 12 227 95% confidence intervals (CIs). We compared the difference between the proportion of recently 13 14 15 228 published Cochrane meta-analyses that reported study funding, author-industry financial ties, and 16 For peer review only 17 229 author-industry employment from included RCTs with recently published non-Cochrane meta- 18 19 230 analyses and with Cochrane systematic reviews published in 2010. Because the present study 20 21 22 231 included meta-analyses only, but the previous study of Cochrane reviews included systematic 23 24 232 reviews with or without meta-analyses,12 we conducted a sensitivity analysis in which we 25 26 233 excluded Cochrane systematic reviews from 2010 that did not include a meta-analysis and would 27 28 29 234 not have been eligible for inclusion in the present study. We calculated 95% CIs for all 30 31 235 differences.19

32 http://bmjopen.bmj.com/ 33 236 To assess the relationship between meta-analysis characteristics and reporting of funding 34 35 237 sources for some or all included trials, versus not reporting, we fit unadjusted (bivariate) and 36 37 38 238 adjusted (multivariate) logistic regression models with all predictors using the glm function in R 39 20, 21 40 239 (R version 3.2.3; RStudio Version 1.0.136). The predictor variables that were considered in on September 24, 2021 by guest. Protected copyright. 41 42 240 bivariate and. adjusted analyses were: (1) combined category (Cochrane, specialty medicine, 43 44 45 241 general medicine, multidisciplinary) and impact factor of the journal in which the meta-analysis 46 47 242 was published; and (2) whether there was industry funding for the meta-analysis or any FCOI 48 49 243 disclosed by meta-analysis authors. We combined journal category and impact factor because of 50 51 52 244 the small number of journals in some categories and the small number of journals with impact 53 54 245 factor greater than that of Cochrane. Thus, meta-analyses were categorized as (1) low-impact ( 55 56 57 12 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 246 3.0) specialty medicine journals, (2) low-impact ( 3.0) general medicine or multidisciplinary 4 5 6 247 journals, (3) medium-impact (3.1 - 6.7) specialty medicine journals, (4) high-impact (> 6.8) 7 8 248 specialty medicine or general medicine journals, and (5) Cochrane meta-analyses (impact factor 9 10 249 = 6.8; reference category). Because 28 of 33 meta-analyses in general medicine journals were 11 12 13 250 from a single journal (Medicine) and not necessarily representative of general medicine as a 14 15 251 category, and because 9 of the 10 meta-analyses published in multidisciplinary science journals 16 For peer review only 17 252 were published in a single journal (PLOS ONE), we combined general medicine and 18 19 20 253 multidisciplinary journals. 21 22 254 Our initial protocol indicated that, if possible, we would include in the logistic regression 23 24 255 model the year of publication of the meta-analysis and whether there was meta-analysis funding 25 26 256 by industry, meta-analysis author-industry financial ties, and meta-analysis author-industry 27 28 29 257 employment, separately. However, 246 of 250 included meta-analyses were published in 2017- 30 31 258 2018, and only 3 meta-analyses had industry funding; thus, we did not include year of

32 http://bmjopen.bmj.com/ 33 259 publication, and we grouped meta-analysis funding source and author FCOIs into a single 34 35 36 260 variable (No FCOIs including funding source versus any FCOI). Additionally, we only 37 38 261 conducted a multivariable analysis for the reporting of funding sources of included RCTs and not 39

40 262 for reporting of author-industry financial ties and author-industry employment, because there on September 24, 2021 by guest. Protected copyright. 41 42 43 263 were not enough examples of meta-analyses that reported author-industry financial ties and 44 45 264 author-industry employment. 46 47 265 Patient and Public Involvement 48 49 50 266 Patients and members of the public were not involved in the design, conduct, 51 52 53 267 reporting, or plan for dissemination of our research. 54 55 268 RESULTS 56 57 13 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 269 Selection of eligible meta-analyses 4 5 6 270 Our initial search of PubMed without date restrictions retrieved 9,725 unique citations. 7 8 271 To select 250 eligible meta-analyses, working backwards from the most recent, a total of 401 9 10 272 citations were screened for eligibility; 64 were excluded at the title and abstract level and 76 at 11 12 273 the full-text level. See Figure1. 13 14 15 274 As shown in Table 1, of the 250 included meta-analyses, 107 (43%) were Cochrane 16 For peer review only 17 275 reviews, all of which were published in the Cochrane Database of Systematic Reviews. Among 18 19 276 the 143 non-Cochrane meta-analyses, 33 (23%) were published in general medicine journals 20 21 22 277 (including 28 in the journal Medicine), 100 (70%) in specialty medicine journals, and 10 (7%) in 23 24 278 multidisciplinary journals (including 9 in PLOS ONE). The mean number of included RCTs for 25 26 279 both Cochrane and non-Cochrane meta-analyses was approximately 20. Among the 143 non- 27 28 29 280 Cochrane meta-analyses, 25 (17%) referenced a published protocol or were registered in 30 31 281 PROSPERO, and 106 (74%) were published in a journal with impact factor ≤ 3.

32 http://bmjopen.bmj.com/ 33 282 Of the 250 meta-analyses, 3 (1%) reported being funded by industry, 148 (59%) reported 34 35 36 283 funding from non-industry sources, 56 (22%) reported no funding, and 43 (17%) did not report 37 38 284 funding source; 3 (1%) had at least 1 author who reported current industry employment, 51 39

40 285 (20%) had at least 1 author that reported other financial ties with industry, 187 (75%) reported on September 24, 2021 by guest. Protected copyright. 41 42 286 that there were no authors with FCOIs, and 12 (5%) did not report any information about author 43 44 45 287 FCOIs. Characteristics of each of the 250 included meta-analyses are shown in eTable1. 46 47 288 Reporting in meta-analyses of funding sources and author FCOIs from included drug trials 48 49 289 As shown in Table 2, 111 of the 250 (44%) included meta-analyses reported the funding 50 51 52 290 sources for some or all included trials, 49 (20%) reported author-industry financial ties for some 53 54 291 or all included trials, and 19 (8%) reported author-industry employment for some or all included 55 56 57 14 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 292 trials. Of the 107 Cochrane meta-analyses, 90 (84%) reported funding sources for some or all 4 5 6 293 included trials compared with 21 of 143 (15%) non-Cochrane meta-analyses, a difference of 69% 7 8 294 (95% CI, 59% to 77%); 47 (44%) Cochrane meta-analyses reported author-industry financial ties 9 10 295 for some or all included trials compared with 2 (1%) non-Cochrane meta-analyses, a difference 11 12 296 of 43% (95% CI, 33% to 52%); 18 (17%) Cochrane meta-analyses reported, fully or partially 13 14 15 297 (for some but not all trials), author-industry employment compared with 1 (1%) non-Cochrane 16 For peer review only 17 298 meta-analysis, a difference of 16% (95% CI, 9% to 24%). 18 19 299 Among the 90 Cochrane meta-analyses that reported funding sources for some or all 20 21 22 300 included trials, 77 (86%) provided this information in the characteristics of included studies 23 24 301 table, including 23 (26%) that also included it in the assessment of risk of bias of included trials; 25 26 302 7 (8%) included it in the risk of bias assessment and at least one other place, but not the 27 28 29 303 characteristics of included studies table, and 6 (7%) reported only as part of the risk of bias 30 31 304 assessment. In total, 36 (40%) reported in the context of the risk of bias assessment. See eTable2

32 http://bmjopen.bmj.com/ 33 305 for reporting for all 250 included meta-analyses. 34 35 306 Factors associated with reporting FCOIs from included trials in multivariable analysis 36 37 38 307 As shown in Table 3, the odds ratio for reporting funding sources for some or all included 39

40 308 RCTs among non-Cochrane meta-analyses was  0.11 compared with Cochrane meta-analyses on September 24, 2021 by guest. Protected copyright. 41 42 43 309 for all journal category and impact factor combinations. Meta-analyses with any declared FCOI 44 45 310 (OR 1.29, 95% CI 0.53 to 3.19) and meta-analyses for which the presence of FCOIs was not 46 47 311 reported (OR 1.18, 95% CI 0.40 to 3.44) did not differ significantly in reporting compared with 48 49 312 those with no declared FCOIs. 50 51 52 313 Comparison of recent Cochrane meta-analyses versus Cochrane reviews published in 2010 53 54 55 56 57 15 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 314 Reporting of funding sources for some or all included trials improved from 30% in 4 5 6 315 Cochrane reviews of drug trials published in 2010 to 84% in recently published Cochrane meta- 7 8 316 analyses, an improvement of 54% (95% CI, 42% to 63%). Reporting of author-industry financial 9 10 317 ties for some or all included trials improved from 7% in 2010 to 44% in recent meta-analyses, a 11 12 318 37% change (95% CI, 26% to 47%). Reporting of author-industry employment for some or all 13 14 15 319 included trials improved from 7% in 2010 to 17% in recent meta-analyses (10%; 95% CI, 2% to 16 For peer review only 17 320 19%). Results did not change when the comparison was restricted to Cochrane reviews published 18 19 321 in 2010 that included a meta-analysis. See Table 2. Figure 2 summarizes reporting among 20 21 22 322 recently published Cochrane and non-Cochrane meta-analyses and Cochrane reviews from 2010. 23 24 323 DISCUSSION 25 26 324 Principal findings 27 28 29 325 We reviewed the 250 most recent meta-analyses of drug treatments listed in PubMed at 30 31 326 the time of our search. Of these, 107 (43%) were Cochrane reviews, 100 (40%) were published

32 http://bmjopen.bmj.com/ 33 327 in specialty medicine journals, and 43 (17%) were published in general medicine or 34 35 328 multidisciplinary journals, including 28 in Medicine and 9 in PLOS ONE. Of the 143 non- 36 37 38 329 Cochrane meta-analyses, 106 (74%) were published in journals with impact factor  3. 39

40 330 Among Cochrane meta-analyses, 84% reported funding sources for some or all included on September 24, 2021 by guest. Protected copyright. 41 42 43 331 RCTs compared with 15% of non-Cochrane meta-analyses. Cochrane meta-analyses were also 44 45 332 more likely than non-Cochrane meta-analyses to report author-industry financial ties (44% 46 47 333 versus 1%) and author-industry employment (17% versus 1%). 48 49 334 In 2010, only 30% of 151 Cochrane systematic reviews of drug treatments reported trial 50 51 12 52 335 funding sources. This improved to 84% among recent Cochrane meta-analyses. Cochrane 53 54 336 reviews also improved reporting of author-industry financial ties and author-industry 55 56 57 16 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 337 employment of included RCTs from 7% to 44% and from 7% to 17%. It is possible that the 4 5 6 338 reason that few meta-analyses reported author-industry employment is because some may have 7 8 339 assumed that author-industry employment would be considered a type of author-industry 9 10 340 financial tie and did not report employment separately, whereas we considered author-industry 11 12 341 financial ties and employment separately. 13 14 15 342 Among the 90 Cochrane meta-analyses that reported funding sources of included trials in 16 For peer review only 17 343 the present study, 86% included the information in the characteristics of included studies table, 18 19 344 as required by Cochrane, and 40% included the information in the risk of bias assessment. 20 21 22 345 Findings in context 23 24 346 In 2012, soon after our previous results showed that few Cochrane systematic reviews of 25 26 347 drug trials reported funding sources and author FCOIs of included trials,12 the Cochrane 27 28 29 348 Collaboration began to require that trial funding sources and FCOIs be reported for every 30 31 349 included RCT in the characteristics of included studies table.13, 14 Reporting of trial funding

32 http://bmjopen.bmj.com/ 33 350 sources among recent Cochrane meta-analyses has not reached 100%, and work is needed to 34 35 351 improve the reporting of other types of author FCOIs, which was under 50% despite being 36 37 38 352 required by Cochrane. Nonetheless, the improvements documented in the present study are 39

40 353 substantial, both compared with previous Cochrane reviews and with contemporary non- on September 24, 2021 by guest. Protected copyright. 41 42 354 Cochrane meta-analyses. Cochrane is a global organization consisting of a large number of 43 44 45 355 different review and methods groups that span numerous fields of health research. This diversity 46 47 356 suggests that changes that have occurred likely resulted from change in the mandatory reporting 48 49 357 requirements for Cochrane reviews and widespread adoption by the organization. We did not 50 51 52 358 examine whether performance differed by review groups or whether updated reviews based on 53 54 359 initial protocols that pre-dated Cochrane’s reporting policy may have been less likely to fully 55 56 57 17 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 360 report. It is possible that reporting in Cochrane reviews could be improved even further by 4 5 6 361 ensuring that all review groups are fully compliant and that even reviews with older initial 7 8 362 protocols report per Cochrane’s current MECIR standards, as required by Cochrane.14 9 10 363 The improved performance in reporting in Cochrane reviews suggests the possibility that 11 12 364 other journals could improve the transparency of reporting of trial funding and trial author FCOI 13 14 15 365 in evidence syntheses by adopting similar reporting requirements. Most journals that specify 16 For peer review only 17 18 366 reporting requirements stipulate that authors follow reporting standards for meta- 19 20 367 analyses articulated in the PRISMA statement. The current version of the PRISMA 21 22 23 368 statement does not address reporting of trial funding sources and FCOIs of trial authors by 24 25 369 investigators who publish systematic reviews and meta-analyses.16, 17 The forthcoming updated 26 27 28 370 PRISMA statement, however, will require that trial funding, although not trial author FCOIs, be 29 30 371 reported (personal communication, David Moher, May 22, 2019). Adoption and enforcement of 31

32 372 the updated PRISMA reporting standards by journals could result in authors being better http://bmjopen.bmj.com/ 33 34 35 373 informed about the need for reporting funding sources and FCOI and in peer reviewers and 36 37 374 journals being more likely to require transparent reporting. 38 39 375 Members of our research team have previously recommended that risk of bias from trial

40 on September 24, 2021 by guest. Protected copyright. 41 42 376 funding and trial author FCOIs be included in the Cochrane Risk of Bias Tool based on evidence 43 44 377 that links trial sponsorship and trial author FCOIs to outcomes.11 This recommendation was 45 46 378 debated at a Cochrane Methods Symposium in 2013, but consensus was not reached for 47 48 13, 22 49 379 inclusion. The present study found that 40% of Cochrane meta-analyses that 50 51 380 reported on FCOIs from included trials included this as part of a risk of bias assessment, 52 53 54 381 even though this has not been recommended by Cochrane. Currently, a new tool, the 55 56 57 18 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 382 Tool for Addressing Conflicts of Interest in Trials (TACIT),23 which specifically addresses risk 4 5 6 383 of bias from industry sponsorship of trials and author-industry financial ties and employment, is 7 8 384 being developed for inclusion in Cochrane reviews. Once the TACIT tool is completed, risk of 9 10 385 bias from trial funding and trial author FCOIs will be explicitly considered in Cochrane reviews 11 12 386 and, potentially, in non-Cochrane reviews, as well. Meanwhile, authors should, at a minimum, 13 14 15 387 describe FCOIs and discuss the degree to which they may influence confidence in findings. 16 For peer review only 17 388 Strengths and limitations 18 19 389 A strength of the present study is that we assessed reporting in a large number of recently 20 21 22 390 published meta-analyses, including 107 Cochrane meta-analyses, which allowed us to compare 23 24 391 reporting practices among Cochrane and non-Cochrane meta-analyses and recent Cochrane 25 26 392 meta-analyses with Cochrane systematic reviews from 2010. However, there are limitations that 27 28 29 393 should be considered. First, we used impact factor as a rough proxy of the quality of the meta- 30 31 394 analyses included, but journal impact factor is very much an imperfect proxy; it does not

32 http://bmjopen.bmj.com/ 33 395 necessarily reflect the quality of the methods of the included meta-analyses. Rating meta- 34 35 396 analysis quality in all included meta-analyses was beyond the scope of our study, given the 36 37 38 397 resources that would have been required. Second, since most meta-analyses of drug trials are 39

40 398 published as Cochrane reviews or in relatively low-impact specialty medicine journals, we were on September 24, 2021 by guest. Protected copyright. 41 42 399 not able to conduct robust assessments of whether meta-analyses published in different types of 43 44 45 400 journals or journals with different impact factors are more or less likely to report on trial funding 46 47 401 and trial author FCOIs for included drug trials. The vast majority of meta-analyses published in 48 49 402 general medicine journals were from a single journal (Medicine), which further limited our 50 51 52 403 ability to examine this factor. However, the meta-analyses included in our study constituted a 53 54 404 consecutive sample of the most recent meta-analyses listed in PubMed and, thus, represented all 55 56 57 19 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 405 meta-analyses of drug interventions listed in PubMed during the study period. Third, our study 4 5 6 406 examined only disclosed FCOIs. A surprising finding was that a higher proportion of Cochrane 7 8 407 meta-analysis authors indicated that they had FCOIs compared with non-Cochrane authors; it is 9 10 408 not known if this reflects greater industry involvement among Cochrane authors or a higher 11 12 409 propensity to report transparently and completely among this group of authors. Fourth, 13 14 15 410 information about FCOIs from included RCTs was not extracted from the RCT publications. 16 For peer review only 17 411 Fifth, our previous study of Cochrane reviews from 2010 included all systematic reviews, 18 19 412 whereas the present study was restricted to reviews with meta-analyses. However, a sensitivity 20 21 22 413 analysis showed that results did not change when we compared recent results to those from 2010 23 24 414 that were restricted to reviews with a meta-analysis. 25 26 415 Conclusions and policy implications 27 28 29 416 In summary, the percentage of recent Cochrane meta-analyses on the effects of 30 31 417 drug interventions that transparently reported funding sources and trial author-industry

32 http://bmjopen.bmj.com/ 33 34 418 financial ties and employment for included trials far exceeds reporting in other journals. 35 36 37 419 It also far exceeds reporting in Cochrane systematic reviews published in 2010, before 38 39 420 the implementation by Cochrane of its policy requiring the reporting of trial funding sources and

40 on September 24, 2021 by guest. Protected copyright. 41 42 421 author-industry FCOIs. These results suggest that it is possible to achieve more transparent 43 44 422 reporting of FCOIs from trials included in meta-analyses. We encourage the uptake and 45 46 423 enforcement of reporting requirements in the forthcoming updated PRISMA statement.24 We 47 48 424 also encourage the adoption of Cochrane’s new TACIT tool23 by journals and authors in order to 49 50 51 425 assess trial funding sources and author FCOIs as risks of bias. Continued non-disclosure of 52 53 426 FCOIs when evidence is synthesized in meta-analyses misleads readers of medical journals into 54 55 56 57 20 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 427 believing that there is not risk of bias from FCOIs to be considered, even though an increasingly 4 5 7, 8 6 428 robust evidence base tells us that this is often not the case. 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 21 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 429 Acknowledgement: The authors thank Drs. Ian Shrier and Jonathan Kimmelman for providing 4 5 6 430 helpful comments on an earlier version of the manuscript. They were not compensated for their 7 8 431 contribution. Ms. Turner was supported by a Fonds de Recherche Québec - Santé (FRQ-S) 9 10 11 432 masters training award, Ms. Levis was supported by a Canadian Institutes of Health Research 12 13 433 doctoral research award, and Drs. Benedetti and Thombs were supported by FRQ-S researcher 14 15 434 awards, all outside of the submitted work. 16 For peer review only 17 435 Contributors: KAT, MR, JB, LAB, JL, EHT, AB, and BDT were responsible for the study 18 19 20 436 conception and design. KAT, ACJ, CB, and KE were responsible for title and abstract and full- 21 22 437 text review. KAT and ACJ were responsible for data extraction and validation. KAT, BL, AB, 23 24 25 438 and BDT analysed and interpreted results. KAT and BDT drafted the manuscript. All 26 27 439 authors provided a critical review and approved the final manuscript. BDT is the 28 29 30 440 guarantor. 31

32 441 http://bmjopen.bmj.com/ 33 Copyright for authors: The Corresponding Author has the right to grant on behalf of 34 35 442 all authors and does grant on behalf of all authors, a worldwide licence 36 37 38 443 (http://www.bmj.com/sites/default/files/BMJ%20Author%20Licence%20March%202013. 39

40 444 doc) to the Publishers and its licensees in perpetuity, in all forms, formats and media on September 24, 2021 by guest. Protected copyright. 41 42 43 445 (whether known now or created in the future), to i) publish, reproduce, distribute, 44 45 46 446 display and store the Contribution, ii) translate the Contribution into other languages, 47 48 447 create adaptations, reprints, include within collections and create summaries, extracts 49 50 51 448 and/or, abstracts of the Contribution and convert or allow conversion into any format 52 53 54 449 including without limitation audio, iii) create any other derivative work(s) based in whole 55 56 57 22 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 450 or part on the on the Contribution, iv) to exploit all subsidiary rights to exploit all 4 5 6 451 subsidiary rights that currently exist or as may exist in the future in the Contribution, v) 7 8 9 452 the inclusion of electronic links from the Contribution to third party material where-ever 10 11 453 it may be located; and, vi) licence any third party to do any or all of the above. All 12 13 14 454 research articles will be made available on an open access basis (with authors being 15 16 For peer review only 17 455 asked to pay an open access fee—seehttp://www.bmj.com/about-bmj/resources- 18 19 456 authors/forms-policies-and-checklists/copyright-open-access-and-permission-reuse). 20 21 22 457 The terms of such open access shall be governed by a Creative Commons licence— 23 24 25 458 details as to which Creative Commons licence will apply to the research article are set 26 27 459 out in our worldwide licence referred to above. 28 29 30 460 Funding: There was no funding for the study. 31

32 http://bmjopen.bmj.com/ 33 461 Declaration of Competing Interests: All authors have completed the ICMJE uniform 34 35 462 disclosure form at www.icmje.org/coi_disclosure.pdf. Dr. Bero disclosed that she is Senior 36 37 38 463 Editor, Cochrane Public Health and Health Systems, for which the University of Sydney 39

40 464 receives remuneration. Dr. Thombs disclosed that he is a content editor with the on September 24, 2021 by guest. Protected copyright. 41 42 43 465 Cochrane Common Mental Disorders review group (no remuneration received). All other 44 45 46 466 authors declared: no support from any organisation for the submitted work; no financial 47 48 467 relationships with any organisations that might have an interest in the submitted work in the 49 50 468 previous three years; no other relationships or activities that could appear to have influenced the 51 52 53 469 submitted work. 54 55 56 57 23 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 470 Ethics Statement: As this study involved only the review of published articles, research ethics 4 5 6 471 approval was not required. 7 8 472 Transparency Declaration: The manuscript’s guarantor affirms that this manuscript is an 9 10 473 honest, accurate, and transparent account of the study being reported; that no important aspects 11 12 474 of the study have been omitted; and that any discrepancies from the study as planned (and, if 13 14 15 475 relevant, registered) have been explained. 16 For peer review only 17 476 Data Sharing: All extracted data are available in the main tables or in online supplementary 18 19 477 material. No additional data were extracted. 20 21 22 23 24 25 26 27 28 29 30 31

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40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 24 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 478 REFERENCES 4 5 6 7 479 1. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and 8 9 480 research outcome and quality: systematic review. BMJ. 2003;326(7400):1167-70. 10 11 481 2. Bero LA, Rennie D. Influences on the quality of published drug studies. Int J Technol Assess 12 13 482 Health Care. 1996;12(2):209-37. 14 15 16 483 3. Melander H, Ahlqvist-RastadFor peer J, Meijer review G, Beermann B. Evidenceonly b (i) ased medicine— 17 18 484 selective reporting from studies sponsored by pharmaceutical industry: review of studies in 19 20 485 new drug applications. BMJ. 2003;326(7400):1171-3. 21 22 23 486 4. Rising K, Bacchetti P, Bero L. Reporting bias in drug trials submitted to the Food and Drug 24 25 487 Administration: review of publication and presentation. PLoS Med. 2008;5(11):e217.4. 26 27 488 5. Sismondo S. How pharmaceutical industry funding affects trial outcomes: causal structures 28 29 30 489 and responses. Soc Sci Med. 2008;66(9):1909-14. 31

32 490 6. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of http://bmjopen.bmj.com/ 33 34 491 antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358(3):252- 35 36 492 60. 37 38 39 493 7. Ahn R, Woodbridge A, Abraham A, Saba S, Korenstein D, Madden E, et al. Financial ties of

40 on September 24, 2021 by guest. Protected copyright. 41 494 principal investigators and randomized controlled trial outcomes: cross sectional study. BMJ 42 43 495 2017;356:i6770. 44 45 46 496 8. Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsorship and research 47 48 497 outcome. Cochrane Database of Syst Rev. 2017;2:MR000033. 49 50 498 9. Lexchin J. Those who have the gold make the evidence: how the pharmaceutical industry 51 52 53 499 biases the outcomes of clinical trials of medications. Sci Eng Ethics. 2012;18(2):247-61. 54 55 56 57 25 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 500 10. Bekelman JE, Li Y, Gross CP. Scope and impact fo financial conflicts of interest in 4 5 6 501 biomedical research: a systematic review. JAMA. 2003;289(4):454-465. 7 8 502 11. Roseman M, Milette K, Bero LA, Coyne JC, Lexchin J, Turner EH, et al. Reporting of 9 10 503 conflicts of interest in meta-analyses of trials of pharmacological treatments. JAMA. 11 12 504 2011;305(10):1008-17. 13 14 15 505 12. Roseman M, Turner EH, Lexchin J, Coyne JC, Bero LA, Thombs BD. Reporting of conflicts 16 For peer review only 17 506 of interest from drug trials in Cochrane reviews: cross sectional study. BMJ. 18 19 507 2012;345:e5155. 20 21 22 508 13. Bero LA. Why the Cochrane risk of bias tool should include funding source as a standard 23 24 509 item. Cochrane Database of Syst Rev. 2013;12:ED000075. 25 26 510 14. Higgins J, Lasserson T, Chandler J, Tovey D, Churchill R. Methodological expectatinos of 27 28 29 511 Cochrane intervention reviews (MECIR). Version July 2019. Available from: 30 31 512 https://community.cochrane.org/mecir-manual. Accessed August 22, 2019.

32 http://bmjopen.bmj.com/ 33 513 15. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic 34 35 514 reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. 36 37 38 515 16. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The 39

40 516 PRISMA statement for reporting systematic reviews and meta-analyses of studies that on September 24, 2021 by guest. Protected copyright. 41 42 517 evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. 43 44 45 518 17. Administration USFaD. Drugs@FDA: FDA Approved Drug Products Database. Available 46 47 519 from: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed August 22, 2019. 48 49 520 18. Drazen JM, Van Der Weyden MB, Sahni P, Rosenberg J, Marusic A, Laine C, et al. 50 51 52 521 Uniform format for disclosure of competing interests in ICMJE journals. JAMA. 53 54 522 2010;303(1):75-6. 55 56 57 26 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 523 19. Newcombe RG. Interval estimation for the difference between independent proportions: 4 5 6 524 comparison of eleven methods. Stat Med. 1998;17(8):873-90. 7 8 525 20. R Core Team. R: A language and environment for statistical computing. R Foundation for 9 10 526 Statistical Computing; 2018. 11 12 527 21. RStudio Team. RStudio: Integrated development for R. Boston, MA: RStudio, Inc.; 2015. 13 14 15 528 22. Sterne JA. Why the Cochrane risk of bias tool should not include funding source as a 16 For peer review only 17 529 standard item. Cochrane Database Syst Rev. 2013(12). 18 19 530 23. Lundh A. Tool for Addressing Conflicts of Interest in Trials (TACIT) in Cochrane Reviews 20 21 22 531 [PowerPoint slides]. 2018. 23 24 25 532 24. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann T, Mulrow CD, Shamseer L, 26 27 533 Moher, D. Updating the PRISMA reporting guideline for systematic reviews and meta - 28 29 30 534 analyses: study protocol. 2018. Available from: https://osf.io/xwcv5/. Accessed August 22, 31

32 535 2019. http://bmjopen.bmj.com/ 33 34 35 536 36 37 38 39

40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 27 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 537 FIGURES 4 5 6 7 538 Figure 1. Flow diagram of selection of eligible meta-analyses. 8 9 10 539 Figure 2. Percentage of recently published Cochrane and non-Cochrane meta-analyses and 2010 11 12 540 Cochrane systematic reviews that reported included trial funding source, author-industry 13 14 541 financial ties, and author-industry employment for some or all included trials. 15 16 For peer review only 17 18 542 19 20 21 22 23 24 25 26 27 28 29 30 31

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40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 28 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 Table 1. Characteristics of included meta-analyses 4 5 6 Cochrane Non-Cochrane 7 8 Meta-Analyses Meta-Analyses 9 10 (N = 107) (N = 143) 11 12 Year of publication 13 14 2016, N (%) 0 4 (3%) 15 16 For peer review only 17 2017, N (%) 22 (21%) 31 (22%) 18 19 2018, N (%) 85 (79%) 108 (76%) 20 21 Number of Included RCTs, mean ± SD 21.4 ± 24.4 19.6 ± 46.4 22 23 Registered in PROSPERO or Published Protocol, N 107 (100%) 25 (17%)a 24 25 (%) 26 27 Impact Factor, mean ± SD 6.8 ± 0 3.6 ± 5.4 28 29 ≤ 3 0 106 (74%) 30 31 3.1-6.7 0 27 (19%)

32 http://bmjopen.bmj.com/ 33 6.8 107 (100%) 0 34 35 36 > 6.8 0 10 (7.0%) 37 38 Meta-Analysis Funding Sources 39 b

40 Not reported 4 (4%) 39 (27%) on September 24, 2021 by guest. Protected copyright. 41 42 Industry 0 3 (2%) 43 44 Non-Industry 93 (87%) 55 (38%) 45 46 No funding 10 (9%) 46 (32%) 47 48 Meta-Analysis Author Financial Ties to Industry 49 50 (Including Employment)c 51 52 Not reported, N (%) 1 (1%) 11 (8%) 53 54 55 No authors with reported financial ties, N (%) 70 (65%) 117 (81%) 56 57 29 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3  1 author with reported financial ties, N (%) 36 (34%) 15 (10%) 4 5 Proportion of authors with financial ties, 11% ± 17% 4% ± 15% 6

7 d 8 mean ± SD 9 10 Journal Category 11 12 Cochrane review, N (%) 107 (100%) 0 13 14 Specialty medicine N (%) 0 100 (70%) 15 16 General medicineFor (non-Cochrane), peer freview N (%) only0 33 (23%) 17 18 Multidisciplinary,g N (%) 0 10 (7%) 19 20 543 aOne meta-analysis reported that they registered in PROSPERO but did not provide a registration number and one 21 544 could not be found. We contacted the authors and they did not provide us with further information; thus this was 22 545 coded as not registered. bOnly 3 included meta-analyses reported author-industry employment and these were 23 546 grouped with author-industry financial ties for this table cCochrane reviews typically have a “Sources of Support” 24 547 section with funding information. These reviews did not include that section. dProportion of authors with financial 25 548 ties or employment of those that reported. eClassifications for specialty medicine journals (note that some journals 26 549 had more than one classification): Anesthesiology, N = 3; Biochemistry & Molecular Biology, N =1; Biotechnology 27 550 & Applied Microbiology, N =2; Cardiac & Cardiovascular Systems, N = 7; Cell Biology, N = 1; Chemistry, 28 551 Medicinal, N = 4; Chemistry, Multidisciplinary, N =2; Clinical Neurology, N = 6; Critical Care Medicine, N =2; 29 552 Dermatology, N = 3; Emergency Medicine, N = 2; Endocrinology & Metabolism, N = 2; Gastroenterology & 30 553 Hepatology, N = 6; Genetics & Heredity, N = 1; Hematology, N = 2; Immunology, N = 6; Infectious Diseases, N 31 554 =3; Integrative & Complementary Medicine, N =1; Medicine, Research & Experimental, N = 3; Microbiology, N =

32 555 2; Neurosciences, N =3; No classification, N = 2; Obstetrics & Gynecology, N = 4; Oncology, N = 11; http://bmjopen.bmj.com/ 33 556 Ophthalmology, N = 3; Orthopedics, N = 6; Parasitology, N = 1; Peripheral Vascular Disease, N =5; Pharmacology 34 557 & Pharmacy, N = 13; Physiology, N =1; Psychiatry, N = 4; Psychology, N = 1; Reproductive Biology, N = 1; 35 558 Respiratory System, N = 6; Rheumatology, N = 3; Sport Sciences, N = 1; Surgery, N =11; Toxicology, N = 2; f 36 559 Tropical Medicine, N = 1; Urology & Nephrology, N =1. Of the 33 included general medicine journals, 28 were g 37 560 published in the journal “Medicine”. Of the 10 journals classified as multidisciplinary, 9 were published in the 38 561 journal “PLOS ONE”. 39

40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 30 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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17 Non-Cochrane (N = 143), N (%) 14 (10%) 7 (5%) 21 (15%) 1 (1%) 1 (1%) 2 (1%) 0 http://bmjopen.bmj.com/ 1 (1%) 1 (1%) 18 19 20 Difference in Reporting Between 56% 14% 69% 22% 21% 43% 1% 15% 16% 21 22 Cochrane and Non-Cochrane Meta- (44% to 65%) (6% to 23%) (59% to 77%) (14% to 31%) (13% to 30%) (33% to 52 %) (-2% to 5%) (9% to 23%) (9% to 24%) 23 analyses, % (95% CI) 24 2010: 25 on September 24, 2021 by guest. Protected copyright. 26 All Cochrane Systematic Reviews 30 (20%) 16 (11%) 46 (30%) 2 (1%) 9 (6%) 11 (7%) 0 10 (7%) 10 (7%) 27 28 (N = 151), N (%)a 29 30 Difference in Reporting Between 46% 8% 54% 21% 16% 37% 1% 9% 10% 31 Recently Published Cochrane Meta- (34% to 56%) (-1% to 18%) (42% to 63%) (13% to 30%) (7% to 25%) (26% to 47%) (-2% to 5%) (2% to 18%) (2% to 19%) 32 33 analyses versus Cochrane 34 Systematic Reviews Published in 35 36 2010, % (95% CI) 37 2010: 38 39 Cochrane Meta-analyses (N =119), 21 (19%) 15 (13%) 36 (30%) 0 (0%) 7 (6%) 7 (6%) 0 (0%) 7 (6%) 7 (6%) 40 41 42 31 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 N (%) 4 5 Difference in Reporting Between 48% 6% 54% 22% 16% 38% 1% 10% 11% 6 Recently Published Cochrane Meta- (36% to 58%) (-3% to 16%) (42% to 63%) (15% to 31%) (7% to 25%) (27% to 48%) (-2% to 5%0 (2% to 19%) (3% to 20%) 7 8 analyses versus Cochrane Meta- 9 analyses Published in 2010, % (95% 10 11 CI) 12 562 a Results from Roseman et al., 2012. For peer review only 13 14 15 16

17 http://bmjopen.bmj.com/ 18 19 20 21 22 23 24

25 on September 24, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 32 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 34 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 Table 3. Factors associated with reporting funding sources of included RCTs 4 5 6 Proportion that Unadjusted odds Adjusted odds ratio 7 8 reported some or ratio (95% CI) (95% CI) 9 10 all declared 11 12 funding sources 13 14 from included 15 16 For peer RCTsreview only 17 18 19 FCOI of meta-analysis 20 21 (including meta-analysis 22 23 funding) 24 25 reference = no FCOI 67/151 (44%) 26 27 Any disclosed FCOI 35/51 (69%) 2.74 (1.42 to 5.49) 1.29 (0.53 to 3.19) 28 29 Not reported 9/48 (19%) 0.29 (0.12 to 0.62) 1.18 (0.40 to 3.44) 30 31

32 http://bmjopen.bmj.com/ 33 Impact Factor and Journal 34 35 Type 36 37 reference = Cochrane 90/107 (84%) 38 39 Specialty impact factor ≤ 3b 4/65 (6%) 0.01 (< 0.01 to 0.03) 0.01 (< 0.01 to 0.04) 40 on September 24, 2021 by guest. Protected copyright. 41 42 General (N=31) or 4/41 (10%) 0.02 (< 0.01 to 0.06) 0.02 (< 0.01to 0.06) 43 44 Multidisciplinary (N=10) 45 46 impact factor ≤ 3 47 48 Specialty impact factor 3.1 - 10/27 (37%) 0.11 (0.04 to 0.28) 0.11 (0.04 to 0.28) 49 50 6.7c 51 52 Specialty (N=8) or General 3/10 (30%) 0.08 (0.02 to 0.32) 0.08 (0.02 to 0.32) 53 54 (N=2) impact factor > 6.8 55 56 57 33 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 563 aNot reported included meta-analyses for which the presence of FCOI could not be determined 4 564 because either meta-anlaysis funding, meta-analysis author FCOI, or both were not reported. 565 b Two meta-analyses were from journals that did not have an impact factor, and these were coded as having an impact factor of 0.5 for our 5 566 analyses. 6 567 c There were no multidisciplinary or general medicine journals with an impact factor of 3.1-6.7. 7 568 FCOI = financial conflicts of interest 8 9 569 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

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40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 34 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 Records screened, beginning with most 3 recently published 4 5 N = 401 6 7 Records excluded 8 For peer review Nonly = 64 9 •Not a systematic review and 10 11 meta-analysis (N = 35)

12 •Not a drug treatment (N = 29) http://bmjopen.bmj.com/ 13 14 15 Full-text records assessed 16 for eligibility 17 18 N = 327 19

20 Records excluded on September 24, 2021 by guest. Protected copyright. 21 N = 76 22 •Not a systematic review and 23 24 meta-analysis (N = 31) 25 •Not a drug treatment (N = 45) 26 27 28 29 30 Meta-analyses included in 31 study 32 N = 250 33 34 35 36 37 38 39 40 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from BMJ Open http://bmjopen.bmj.com/ on September 24, 2021 by guest. Protected copyright.

For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 108 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 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 BMJ Open Page 38 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 Supplementary Material 4 5 6 7 8 eMethods1. Search strategy 9 10 eMethods2. Data extraction form 11 12 13 eMethods3. Power analysis 14 15 eTable1. Detailed characteristics of included meta-analyses 16 For peer review only 17 eTable2. Detailed reporting of study funding source, author-industry financial ties, and author- 18 19 industry employment from included RCTs 20 21 22 23 24 25 26 27 28 29 30 31

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40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 eMethods1. Search strategy 4 5 6 To obtain our sample, we searched the MEDLINE database via PubMed on October 19, 7 2018 using the following search strategy: 8 9 10 11 (((("Randomized Controlled Trials as Topic"[Mesh] or randomized control trial 12 13 [tiab] or randomized controled trial [tiab] OR randomized controlled trial [tiab] or 14 randomized control trials [tiab] OR randomized controled trials [tiab] OR 15 16 Randomized controlledFor peertrials [tiab] orreview randomised control only trial [tiab] or randomised 17 18 controled trial [tiab] OR randomised controlled trial [tiab] or randomised control 19 trials [tiab] OR randomised controled trials [tiab] OR Randomised controlled trials 20 21 [tiab]) AND ("Therapeutic Uses"[Mesh] OR "Vaccines"[Mesh]) AND ("Meta- 22 23 Analysis" [Publication Type] or meta analysis [tiab]) AND (systematic review 24 25 [tiab] OR search [tiab] or searched [tiab] or MEDLINE [tiab] OR PubMed [tiab])))) 26 27 28 29 30 31

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40 on September 24, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 eMethods 2. Data extraction form 4 5 6 7 8 First Author, last name: Last name of first author of meta-analysis 9 10 11 Year of publication (or in press): Year of publication of meta-analysis 12 13 14 15 Journal: Name of journal in which meta-analysis was published 16 For peer review only 17 18 Journal Impact factor: Where meta-analysis published (low-high split or continuous based on 19 20 data distribution) 21 22 23 Specialty area of Journal: Where meta-analysis published (per Thomson Reuters Journal 24 25 Science Citation Index - Expanded categories) 26 27 28 29 Cochrane Review (Y/N): Is the meta-analysis a Cochrane Review? Select "Yes" even if the 30 Cochrane Review is being published in another journal 31

32 Response from radio options: http://bmjopen.bmj.com/ 33 34 - Y (Yes) 35 36 - N (No) 37 38 39 Journal policies for reporting COI of Included Trials: Presence or absence of instructions for

40 on September 24, 2021 by guest. Protected copyright. 41 reporting in the author instructions 42 - Y (Yes) 43 44 - N (No) 45 46 47 48 # of RCTs synthesized in Meta-Analysis (total RCTs in included meta-analysis related to 49 drugs) 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 Date Range of Included Trials: Date range in years of publication of studies (RCTs) included 4 5 related to drugs in the meta-analysis (XXXX - XXXX). Use "In press" for end date if there are in 6 7 press trials. Use “Unpublished” if a trial is in progress or has never been published. 8 9 10 Study population: Characteristics of study population of included trials (e.g. condition/disorder, 11 12 adult/child) 13 14 15 Pharmacological agent: Pharmacologic treatment evaluated in the meta-analysis 16 For peer review only 17 - Name(s) of treatment if specific drug(s) investigated 18 19 - Class of treatment if broader category of drugs investigated, and number of drugs 20 21 evaluated (e.g. SSRIs – 5 included) 22 23 24 Control/comparison arms: Other treatment arms (control/comparison) included in the meta- 25 26 analysis (e.g. placebo, name of comparison pharmacologic treatment, name of behavioral 27 intervention) 28 29 30 31 Meta-Analysis Author Financial Ties / Funding Sources Reported: Does the meta-analysis

32 http://bmjopen.bmj.com/ 33 report meta-analysis author financial ties (including former and current industry employment) 34 and/or the funding source? Note that reporting “no funding” is different from not reporting. 35 36 Response from radio options: 37 38 - Meta-analysis author financial ties 39 - Meta-analysis funding sources 40 on September 24, 2021 by guest. Protected copyright. 41 - Both financial ties and funding sources 42 43 - Neither reported 44 45 46 Funding Source of Meta-Analysis (if applicable – only shown if above item indicates meta- 47 48 analysis funding sources reported or both financial ties and meta-analysis funding sources 49 50 reported) Source of financial support for the meta-analysis: 51 52 Response from radio options: 53 - Industry 54 55 - Combined industry and non-industry 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 - Non-industry (e.g. public granting agency, private not-for-profit granting agency) 4 5 - No study funding 6 7 8 9 Type of Industry Funding (if applicable – only shown if above item indicates industry 10 funding or combined industry and non-industry present): If the meta-analysis is industry 11 12 funded, what is the type of support provided by industry? Response from radio options: 13 14 - Financial support 15 - Resources (e.g. statistical analyses) 16 For peer review only 17 - Both financial support and resources 18 19 20 21 # of Meta-Analysis Authors: Number of authors of the meta-analysis (count authors named in 22 byline or in an author group) 23 24 25 26 # of Meta-Analysis Authors with Financial Ties to Industry (if applicable – only shown if 27 meta-analysis author financial ties or both financial ties and meta-analysis funding sources 28 29 are reported): Number of authors of the meta-analysis who have financial ties such as industry 30 31 board member, consultant, investments, patents, research funding, royalties (including former,

32 http://bmjopen.bmj.com/ 33 and excluding current industry employment): 34 - Numbers 0 - ≥10 35 36 37 38 # Meta-Analysis Authors with Current Industry Employment (if applicable – only shown if 39 meta-analysis author financial ties or both financial ties and meta-analysis funding sources 40 on September 24, 2021 by guest. Protected copyright. 41 are reported): Number of authors of the meta-analysis who are current industry employees. 42 43 Response from radio options: 44 45 Numbers 0 - ≥10 46 47 48 Quality or Risk Assessment of Included RCTs (Y/N): Was quality or risk assessment of 49 50 included RCTs, by methods from Cochrane, Jadad, etc., reported in the meta-analysis. 51 52 Response from radio options: 53 - Y (Yes) 54 55 - N (No) 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 4 5 Quality or Risk Assessment Method of Included RCTs (if applicable – only shown if 6 7 answer to previous item is yes- quality or risk assessment of included RCTs is reported): If 8 9 the meta-analysis authors report a quality or risk assessment method of included RCTs, what is 10 the reported method of quality assessment? 11 12 13 14 Meta-analysis Authors Report Funding Sources of Included Studies: Response from radio 15 options: 16 For peer review only 17 - Reported for each included study 18 19 - Reported in summary statement or for some, but not all, trials 20 21 - Included study funding sources not reported 22 23 24 Placement in publication of Included RCTs’ Funding Source (if applicable – only shown if 25 26 the response to Meta-analysis Authors Report Funding Sources of Included Studies is (1) 27 Reported for Each included Study or (2) Reported in summary statement or for some, but not all, 28 29 trials): 30 31 - Abstract

32 http://bmjopen.bmj.com/ 33 - Main text, other than risk of bias or quality section 34 - In risk of bias or quality assessment 35 36 - Other in main document (e.g., a characteristics of studies table, other table, in a 37 38 footnote of a table 39 - Online appendix 40 on September 24, 2021 by guest. Protected copyright. 41 - Lay Summary 42 43 44 45 Placement in risk of bias or quality assessment of Included RCTs’ Funding Source (if 46 applicable – only shown if placement in publication of included RCT’s Funding Source is risk of 47 48 bias or quality assessment): 49 50 - Text 51 52 - Figure/table 53 - Both text and figure/table 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 44 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 Meta-analysis Authors Report Author Financial Ties of Included Studies: Response from 4 5 radio options: 6 7 - Reported for each included study 8 9 - Reported in summary statement or for some, but not all, trials 10 - Included study author financial ties not reported 11 12 13 14 Placement in publication of Included RCTs’ Author Financial Ties (if applicable – only 15 shown if the response Meta-analysis Authors Report Author Financial Ties of Included Studies is 16 For peer review only 17 (1) Reported for Each included Study or (2) Reported in summary statement or for some, but not 18 19 all, trials): 20 21 - Abstract 22 - Main text, other than risk of bias or quality section 23 24 - In risk of bias or quality assessment 25 26 - Other in main document (e.g., a characteristics of studies table, other table, in a 27 footnote of a table 28 29 - Online appendix 30 31 - Lay Summary

32 http://bmjopen.bmj.com/ 33 34 Placement in risk of bias or quality assessment of Included RCTs’ Author Financial Ties (if 35 36 applicable – only shown if placement in publication of included RCT’s Author Financial ties is 37 38 risk of bias or quality assessment): 39 - Text 40 on September 24, 2021 by guest. Protected copyright. 41 - Figure/table 42 43 - Both text and figure/table 44 45 46 Meta-analysis Authors Report Author Industry Employment of Included Studies: Do the 47 48 authors of the meta-analysis report current author industry affiliation (employment) for the 49 50 included studies? Response from radio options: 51 52 - Reported for each included study 53 - Reported in summary statement or for some, but not all, trials 54 55 - Included study author industry employment not reported 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 45 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 4 5 Placement in publication of Included RCTs’ Author Industry Employment (if applicable – 6 7 only shown if the response to Meta-analysis Authors Report Author Industry Affiliation 8 9 (Employment) of Included Studies is (1) Reported for Each included Study or (2) Reported in 10 summary statement or for some, but not all, trials): 11 12 - Abstract 13 14 - Main text, other than risk of bias or quality section 15 - In risk of bias or quality assessment 16 For peer review only 17 - Other in main document (e.g., a characteristics of studies table, other table, in a 18 19 footnote of a table) 20 21 - Online appendix 22 - Lay Summary 23 24 25 26 Placement in risk of bias or quality assessment of Included RCTs’ Author Industry 27 Employment (only shown if placement in publication of included RCT’s Author Industry 28 29 Affiliation is risk of bias or quality assessment): 30 31 - Text

32 http://bmjopen.bmj.com/ 33 - Figure/table 34 - Both text and figure/table 35 36 37 38 Do the authors report a PROSPERO registration number in the text? 39 - Yes 40 on September 24, 2021 by guest. Protected copyright. 41 - No 42 43 What is the registration number (e.g., CRD42017062454)? (if applicable – only shown if the 44 45 response to Do the authors report a PROSPERO registration number in the text? Is yes) 46 47 48 What stages were completed (ignore started) at the time of registration. Make sure to select 49 50 the earliest registration version at the bottom of the page. Please check all stages that were 51 52 completed. (if applicable – only shown if the response to Do the authors report a PROSPERO 53 registration number in the text? Is yes) 54 55 - Preliminary searches 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 46 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 - Piloting of the study selection process 4 5 - Formal screening of search results against eligibility criteria 6 7 - Data extraction 8 9 - Risk of bias (quality) assessment 10 - Data analysis 11 12 - None completed 13 14 15 Was a registration found in PROSPERO? (if applicable – only shown if the response to Do 16 For peer review only 17 the authors report a PROSPERO registration number in the text? Is no) 18 19 20 21 What is the registration number (e.g., CRD42017062454)? (if applicable – only shown if the 22 response to Was a registration found in PROSPERO? Is yes) 23 24 25 26 What stages were completed (ignore started) at the time of registration. Make sure to select 27 the earliest registration version at the bottom of the page. Please check all stages that were 28 29 completed. (if applicable – only shown if the response to Was a registration found in 30 31 PROSPERO? Is yes)

32 http://bmjopen.bmj.com/ 33 - Preliminary searches 34 - Piloting of the study selection process 35 36 - Formal screening of search results against eligibility criteria 37 38 - Data extraction 39 - Risk of bias (quality) assessment 40 on September 24, 2021 by guest. Protected copyright. 41 - Data analysis 42 43 - None completed 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 47 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 eMethods3. Power analysis 4 5 6 7 Allocation ratio: 50% and 50% (1:1) 8 20% difference 9 Proportion reporting Sample size Sample size Sample size Actual power Actual alpha 10 COI group 1 group 2 total 11 Low impact High 12 impact 13 10% 30% 69 69 138 .807 .033 14 20% 40% 90 90 180 .802 .037 15 30% 50% 102 102 204 .806 .042 16 40% For60% peer102 review102 only204 .801 .038 17 50% 70% 102 102 204 .806 .036 18 60% 80% 90 90 180 .802 .032 19 70% 90% 69 69 138 .807 .025 20 21 22 23 24 Allocation ratio: 30% and 70% (3:7) 25 20% difference 26 Proportion reporting Sample size Sample size Sample size Actual power Actual alpha 27 COI group 1 group 2 total 28 Low impact High 29 impact 30 10% 30% 105 44 149 .815 .038 31 20% 40% 141 59 200 .807 .040

32 30% 50% 165 69 234 .801 .045 http://bmjopen.bmj.com/ 33 40% 60% 168 71 239 .805 .043 34 50% 70% 166 70 236 .864 .042 35 60% 80% 148 62 210 .802 .040 36 70% 90% 133 47 160 .802 .035 37 38 39

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17 http://bmjopen.bmj.com/ 18 Cochrane Reviews (n = 107) Gemcitabine, vandetanib, 19 Cochrane Adults (19 years and S-1 (tegafur + gimeracil + Best supportive care, 20 Database of over) with advanced oteracil), gemcitabine + 5-fluorouracil + 21 Systematic Medicine, General Non- biliary tract oxaliplatin, 5-fluorouracil cisplatin + 1 22 Abdel-Rahman 2018 Reviews 6.8 & Internal industry 0/3 7 2004-2016 carcinomas + folinic acid, capecitabine radiotherapy Cochrane Participants with or 23 Database of without evidence of 24 Systematic Medicine, General Non- cardiovascular Adams2 2018 Reviews 6.8 & Internal industry 0/4 36 1994-2012 disease Fluvastatin Placebo 25 on September 24, 2021 by guest. Protected copyright. Cochrane People with co- 26 Database of occurring depression 27 Systematic Medicine, General Non- and alcohol Antidepressants - 16 types, Placebo, 28 Agabio3 2018 Reviews 6.8 & Internal industry 0/3 27 1969-2015 dependence diazepam, memantine psychotherapy Adults (16 years and 29 Cochrane over) with acute 30 Database of spontaneous 31 Al-Shahi Systematic Medicine, General Not intracerebral Blood clotting factors, Placebo, open control, 4 b 32 Salman 2018 Reviews 6.8 & Internal reported 0/5 11 1999-2015 haemorrhage antifibrinolytic drugs fresh frozen plasma Cochrane Patients with 33 Database of antipsychotic- 34 Systematic Medicine, General Non- induced tardive Gamma-aminobutyric acid 5 35 Alabed 2018 Reviews 6.8 & Internal industry 0/4 11 1976-2008 dyskinesia (TD) agonists - 6 types Placebo Cochrane 36 Database of Patients with 37 Systematic Medicine, General No hepatorenal Terlipressin, terlipressin + Placebo, no 38 Allegretti6 2017 Reviews 6.8 & Internal funding 3/8 8 1998-2016 syndrome albumin intervention, albumin Cochrane Patients undergoing Antibiotic antimicrobial 39 Database of haemodialysis using lock solutions - 11 types, 40 Systematic Medicine, General Non- a central venous non-antibiotic 41 Arechabala7 2018 Reviews 6.8 & Internal industry 0/7 37 1998-2017 catheter antimicrobial lock Heparin, saline 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 solutions - 10 types, 4 antibiotic + non-antibiotic 5 antimicrobial lock solutions - 3 types 6 Valproate, carbamazepine, 7 lithium, pregabalin, 8 captodiame, paroxetine, tricyclic antidepressants - 4 9 types, alpidem, buspirone, 10 flumazenil, propranolol, 11 Cochrane Adult (18 years and progesterone, magnesium Database of over) chronic aspartate, bromazepam, 12 Systematic Medicine, General No benzodiazepine cyamemazine, zopiclone, Placebo, no 8 For peer reviewc only 13 Baandrup 2018 Reviews 6.8 & Internal funding 1/6 33 1981-2016 users flunitrazepam intervention 14 Individuals with Cochrane antiphospholipid 15 Database of antibodies and no Aspirin + anticoagulants, Placebo, 16 Systematic Medicine, General Non- history of aspirin, aspirin + low immunoglobulin, 9

17 Bala 2018 Reviews 6.8 & Internal industry 3/6 9 1997-2016 thrombosis molecularhttp://bmjopen.bmj.com/ weight heparin unfractionated heparin 18 Heterosexual adult couples (18 years or 19 Cochrane more) with a partner 20 Database of having a clinical 21 Systematic Medicine, General Non- diagnosis of Barbato10 2018 Reviews 6.8 & Internal industry 0/3 4d 2000-2012 depressive disorder Antidepressants - 9 types Couples therapy 22 Cochrane Psychiatric patients 23 Database of with antipsychotic- 24 Systematic Medicine, General Non- induced tardive Bergman11 2018 Reviews 6.8 & Internal industry 0/3 4 1981-1997 dyskinesia Benzodiazepines - 3 types Placebo, usual care 25 Tricyclic on September 24, 2021 by guest. Protected copyright. antidepressants 26 (TCAs), selective serotonin 27 reuptake inhibitors 28 (SSRIs), monoamine oxidase inhibitors 29 (MAOIs), serotonin– 30 norepinephrine reuptake 31 Cochrane inhibitors (SNRIs), Database of Adults (18 years and norepinephrine reuptake 32 Systematic Medicine, General Non- over) with panic inhibitors (NRIs), 33 Bighelli12 2018 Reviews 6.8 & Internal industry 2/9 41 1989-2011 disorder nefazodone, ritanserin Placebo 34 Cochrane Database of 35 Systematic Medicine, General Non- People with 36 Birks13 2018 Reviews 6.8 & Internal industry 0/2 30 1996-2017 Alzheimer’s disease Donepezil Placebo 37 Cochrane Database of Adults (18 years and No treatment, usual 38 Systematic Medicine, General Non- over) with quiescent care (azathioprine + 39 Boyapati14 2018 Reviews 6.8 & Internal industry 3/8 6 1978-2017 Crohn’s disease Azathioprine, infliximab infliximab) 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane 4 Database of Women of 5 Systematic Medicine, General Non- reproductive age Combined oral contractive Placebo, leuprolide, Brown15 2018 Reviews 6.8 & Internal industry 0/4 5 1993-2017 with endometriosis pill - 3 types goserelin 6 Cochrane 7 Database of 8 Systematic Medicine, General Non- Adults with atrial Factor Xa inhibitors - 7 Bruins Slot16 2018 Reviews 6.8 & Internal industry 1/2e 13 2008-2014 fibrillation types Warfarin 9 People with 10 schizophrenia and 11 schizophrenia-like disorders such as 12 For peer review onlyschizophreniform 13 Cochrane disorder, delusional 14 Database of disorder, or Systematic Medicine, General No schizoaffective Zuclopenthixol Placebo, other drugs - 15 Bryan17 2017 Reviews 6.8 & Internal funding 0/3 20 1968-2007 disorder dihydrochloride 11 types 16 Antifibrinolytic agents - 2

17 Cochrane Women of types, nonhttp://bmjopen.bmj.com/ -steroidal anti- Placebo, herbal 18 Database of reproductive age inflammatory drugs medicines, Systematic Medicine, General No with heavy (NSAIDs), progestogens, levonorgestrel 19 Bryant-Smith18 2018 Reviews 6.8 & Internal funding 1/4 13 1970-2016 menstrual bleeding ethamsylate intrauterine system 20 Adults (17 years and 21 Cochrane over) in non-ICU Database of acute care settings 22 Systematic Medicine, General Non- diagnosed with Nonantipsychotics, 23 Burry19 2018 Reviews 6.8 & Internal industry 0/9 9 1996-2016 delirium Antipsychotics - 5 types placebo 24 Cochrane Adult patients (18 Database of years and older) 25 Systematic Medicine, General Non- with ureteral stone on September 24, 2021 by guest. Protected copyright. 26 Campschroer20 2018 Reviews 6.8 & Internal industry 0/4 67 2002-2017 disease Alpha-blockers - 6 types Placebo, usual care 27 Adults with cancer 28 Cochrane and adults receiving Database of palliative care with 29 Systematic Medicine, General Non- opioid-induced Mu-opioid antagonists - 3 30 Candy21 2018 Reviews 6.8 & Internal industry 0/5 8 1996-2017 bowel dysfunction types Placebo 31 Cochrane Patients with Database of paracetamol 32 Systematic Medicine, General Non- (acetaminophen) Methionine, cysteamine, 33 Chiew22 2018 Reviews 6.8 & Internal industry 0/4 9f 1976-2014 overdose dimercaprol, acetylcysteine Placebo, no treatment 34 Children aged up to Cochrane five years with a 35 Database of clinical diagnosis of 36 Systematic Medicine, General Not community-acquired Placebo, antibiotics 37 Das23 2018 Reviews 6.8 & Internal reported 0/3 7 2010-2017 pneumonia (CAP) Vitamin D alone Cochrane Healthy individuals 38 Database of (16 to 65 years) and 39 Systematic Medicine, General Non- pregnant women and Inactivated parenteral 40 Demicheli24 2018 Reviews 6.8 & Internal industry 1/5 71g 1969-2014 their newborns influenza vaccine Placebo, no treatment 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane 4 Database of 5 Systematic Medicine, General Non- Elderly participants Demicheli25 2018 Reviews 6.8 & Internal industry 1/7 8 1969-2004 (65 years and over) Influenza vaccines Placebo 6 Fondaparinux, 7 rivaroxaban, low molecular 8 weight heparin, nonsteroidal anti-inflammatory 9 drugs, vasotonin, 10 Patients with sulodexide, 11 superficial heparansulphate, vitamin K Cochrane thrombophlebitis of antagonists, enzyme 12 Database of For peer review onlythe leg or diagnosis therapy, unfractionated 13 Systematic Medicine, General Non- of a thrombus in a heparin, heparin calcium, Placebo, elastic 14 Di Nisio26 2018 Reviews 6.8 & Internal industry 2/3 32 1970-2017 superficial vein defibrotide stockings Cochrane Patients with 15 Database of antipsychotic- Noradrenergic drugs - 2 16 Systematic Medicine, General Non- induced tardive types, dopaminergic drugs 27

17 El-Sayeh 2018 Reviews 6.8 & Internal industry 0/4 10 1973-2010 dyskinesia - 7 types http://bmjopen.bmj.com/ Placebo 18 People of all ages on continuous vitamin 19 K antagonist (VKA) 20 or direct oral 21 Cochrane anticoagulant Usual care (surgical Database of (DOAC) treatment treatment), usual care 22 Systematic Medicine, General Non- undergoing an oral Antifibrinolytic agents - 2 (surgical treatment) + 23 Engelen28 2018 Reviews 6.8 & Internal industry 0/5 3 1989-2015 or dental procedure types placebo 24 Selective serotonin Cochrane reuptake inhibitors (SSRIs) 25 Database of Adults (18 years and - 4 types, on September 24, 2021 by guest. Protected copyright. tricyclic 26 Systematic Medicine, General Non- over) living with antidepressants (TCAs) - 2 27 Eshun-Wilson29 2018 Reviews 6.8 & Internal industry 1/6 10 1994-2014 HIV and depression types Placebo, mirtazapine 28 Cochrane People with Database of antipsychotic- 29 Systematic Medicine, General Non- induced tardive Calcium channel blockers - 30 Essali30 2018 Reviews 6.8 & Internal industry 0/4 3 1992-1997 dyskinesia 3 types Placebo 31 Selective serotonin reuptake inhibitors - 4 32 Cochrane types; tricyclic 33 Database of antidepressants - 3 types; 34 Systematic Medicine, General Non- Adults (18 years and other antidepressants - 6 Placebo, insomnia Everitt31 2018 Reviews 6.8 & Internal industry 3/8 23 1978-2013 over) with insomnia types medication - 2 types 35 Cochrane 36 Database of Regular tobacco 37 Systematic Medicine, General Non- smokers (20 years Nicotine replacement Fanshawe32 2017 Reviews 6.8 & Internal industry 0/6 4 2004-2014 and under) therapy, bupropion Placebo 38 Cochrane Subfertile women of Placebo, selective 39 Database of reproductive age estrogen receptor 40 Systematic Medicine, General Non- with polycystic modulators, 33 41 Franik 2018 Reviews 6.8 & Internal industry 0/5 42 2004-2017 ovary syndrome Letrozole clomiphene citrate 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 followed by 4 intrauterine 5 insemination, laparoscopic ovarian 6 drilling, follicle- 7 stimulating hormone, 8 anastrozole Cochrane Sulfadoxine- 9 Database of Pregnant women pyrimethamine, 10 Systematic Medicine, General Non- living in malaria- cotrimoxazole, 11 González34 2018 Reviews 6.8 & Internal industry 0/6 6 1994-2014 endemic areas Mefloquine placebo Adult women with 12 Cochrane For peer review onlymoderate or severe 13 Database of cervical Non-steroidal anti- 14 Systematic Medicine, General Non- intraepithelial inflammatory agents Grabosch35 2018 Reviews 6.8 & Internal industry 0/3 3 2006-2017 neoplasia (CIN) (NSAIDs) - 2 types Placebo 15 Cochrane 16 Database of Adults and children

17 Systematic Medicine, General Non- being treated for http://bmjopen.bmj.com/ Usual treatment, 36 h 18 Graves 2018 Reviews 6.8 & Internal industry 0/4 24 1981-2017 falciparum malaria Primaquine bulaquine Cochrane Pregnant women 19 Database of who were about to 20 Systematic Medicine, General Non- receive a cesarean Antiseptic solutions - 3 37 21 Haas 2018 Reviews 6.8 & Internal industry 0/4 11 1997-2017 delivery types Placebo, no treatment Cochrane 22 Database of People with cancer Low molecular weight 23 Systematic Medicine, General Non- and venous heparin, unfractioned 24 Hakoum38 2018 Reviews 6.8 & Internal industry 0/10 15 1991-2009 thromboembolism heparin Fondaparinux Placebo, no treatment, 25 Immunocompetent on September 24, 2021 by guest. Protected copyright. alternative therapies - 26 Cochrane patients with 7 types, other drug 27 Database of localised Old World comparators - 6 types, 28 Heras- Systematic Medicine, General Non- cutaneous Antimonials – 2 types, other non-drug Mosteiro39 2017 Reviews 6.8 & Internal industry 0/10 89 1990-2015 leishmaniasis non-antimonials – 22 types comparators - 4 types 29 Cochrane People with Chemotherapy, targeted 30 Database of esophageal or therapy, EGFR-targeting 31 Systematic Medicine, General Non- gastroesophageal agents, cetuximab, Best supportive care, Janmaat40 2017 Reviews 6.8 & Internal industry 0/8 41 1980-2015 junction cancer ramucirumab unspecified control 32 Cochrane 33 Database of 34 Systematic Medicine, General Non- Healthy children (15 Placebo, no Jefferson41 2018 Reviews 6.8 & Internal industry 1/4 41 1971-2016 years and under) Influenza vaccine - 2 types intervention 35 Middle-aged and 36 older men (40 or 37 over) with lower Cochrane urinary tract 38 Database of 2006- symptoms as a result 39 Systematic Medicine, General Non- Unpublishe of benign prostatic Silodosin, tamsulosin, 40 Jung42 2017 Reviews 6.8 & Internal industry 0/6 19 d hyperplasia naftopidil, and alfuzosin Placebo 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane 4 Database of 5 Systematic Medicine, General Non- Kaempfen43 2018 Reviews 6.8 & Internal industry 0/4 3 2013-2017 Preterm infants Propranolol Placebo, no treatment 6 Cochrane 7 Database of 8 Systematic Medicine, General Non- Ambulatory people Kahale44 2017 Reviews 6.8 & Internal industry 0/10 7 1979-2012 with cancer Warfarin, apixaban Placebo, no treatment 9 Cochrane 10 Database of People with cancer 11 Systematic Medicine, General Non- and central venous Kahale45 2018 Reviews 6.8 & Internal industry 0/10 13 1990-2013 catheters Anticoagulant - 6 types Placebo, no treatment 12 For peer review only Vitamin K antagonist - 2 13 Cochrane types, direct oral 14 Database of People with cancer anticoagulant - 4 types; Systematic Medicine, General Non- and venous low molecular weight 15 Kahale46 2018 Reviews 6.8 & Internal industry 0/11 16 2001-2018 thromboembolism heparin - 4 types Anticoagulants 16 Cochrane

17 Database of http://bmjopen.bmj.com/ 18 Systematic Medicine, General Non- Children and adults Kapur47 2018 Reviews 6.8 & Internal industry 3/5 7 1992-2012 with bronchiectasis Corticosteroids - 3 types Placebo, no treatment 19 Cochrane 20 Database of 21 Systematic Medicine, General Non- Adults and children Macrolide antibiotics - 4 Placebo, no Kelly48 2018 Reviews 6.8 & Internal industry 2/8 15 1997-2014 with bronchiectasis types intervention 22 Cochrane Adults and children 23 Database of with acute β2 -agonist, β2 - 24 Systematic Medicine, General Non- exacerbation of agonist + ipratropium, Knightly49 2017 Reviews 6.8 & Internal industry 0/7 25 1996-2017 asthma Magnesium sulfate placebo 25 Cochrane on September 24, 2021 by guest. Protected copyright. 26 Database of People with chronic 27 Systematic Medicine, General Non- obstructive Inactivated influenza 50 28 Kopsaftis 2018 Reviews 6.8 & Internal industry 0/3 11 1961-2004 pulmonary disease vaccine Placebo Aminosalicylates - 4 types, 29 corticosteroids, superoxide 30 dismutase, amifostine, bile 31 acid sequestrants, magnesium oxide, 32 misoprostol, octreotide, 33 Cochrane Adults (18 years and selenium, sodium butyrate, 34 Database of over) undergoing sucralfate, ibuprofen, Systematic Medicine, General Non- radiotherapy for famotidine, smectite, 35 Lawrie51 2018 Reviews 6.8 & Internal industry 0/9 38 1978-2016 pelvic cancers simethicone, tropisetron Placebo, no treatment 36 Cochrane 37 Database of Usual care, emergency Systematic Medicine, General Non- Women with signs delivery, cessation of 38 Leathersich52 2018 Reviews 6.8 & Internal industry 0/4 8 1987-2007 of fetal distress Tocolytic agents – 7 types oxytocic infusion 39 Cochrane Medicine, General Non- Women with uterine Gonadotropin-hormone 40 Lethaby53 2017 Database of 6.8 & Internal industry 1/3 38 1989-2012 fibroids releasing analogue, Placebo, no treatment 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Systematic selective progesterone- 4 Reviews receptor modulators 5 Cochrane Database of 0.9% sodium chloride 6 Systematic Medicine, General Non- Adults with central (normal saline 7 López-Briz54 2018 Reviews 6.8 & Internal industry 0/6 11 2002-2015 venous catheters Heparin solution) 8 Children (18 years Cochrane and under) with 9 Database of prolonged wet 10 Systematic Medicine, General Non- cough (longer than 11 Marchant55 2018 Reviews 6.8 & Internal industry 2/4 3 1993-2012 10 days) Antibiotics - 2 types Placebo, no treatment Cochrane 12 Database of For peer review only 13 Systematic Medicine, General Non- Patients with 14 Matar56 2018 Reviews 6.8 & Internal industry 0/3 7 1963-1999 schizophrenia Fluphenazine Placebo Cochrane 15 Database of People with solid or Low-molecular weight 16 Systematic Medicine, General Non- hematologic cancer heparin (LMWH) - 10 Unfractionated heparin 57

17 Matar 2018 Reviews 6.8 & Internal industry 0/11 20 1986-2018 undergoing surgery types http://bmjopen.bmj.com/ (UFH), fondaparinux 18 Cochrane Database of Postoperative 19 Systematic Medicine, General Non- paediatric patients 20 McNicol58 2018 Reviews 6.8 & Internal industry 1/3 13 1992-2016 (17 years and under) Ketorolac Placebo, opioid 21 Children (16 years and under) 22 presenting to a 23 hospital or 24 Cochrane emergency Diazepam + Database of department in an phenytoin, diazepam, 25 Systematic Medicine, General Non- acute tonic-clonic on September 24, 2021 by guest. Protected copyright. paraldehyde, 26 McTague59 2018 Reviews 6.8 & Internal industry 0/3 18 1995-2014 convulsion Lorazepam midazolam 27 Cochrane 28 Database of Patients with Systematic Medicine, General Non- multiple myeloma Placebo, no treatment - 29 Mhaskar60 2017 Reviews 6.8 & Internal industry 0/4 24 1982-2015 (MM) Bisphosphonates - 5 types Network meta-analysis 30 Cochrane 31 Database of No treatment, placebo, Systematic Medicine, General Non- Typhoid fever vaccines - 4 typhoid-inactive 32 Milligan61 2018 Reviews 6.8 & Internal industry 0/4 18 1980-2016 Adults and children types agents 33 Cochrane Tramadol, non-steroidal 34 Database of People undergoing anti-inflammatory drugs, Systematic Medicine, General Non- orthodontic paracetamol, local 35 Monk62 2017 Reviews 6.8 & Internal industry 0/4 32 1993-2016 treatment anaesthetic Placebo, no treatment 36 Cochrane Patients with 37 Database of hepatitis C virus- Rituximab, interferon, Usual care, Systematic Medicine, General No associated mixed immunosuppressive drug immunoadsorption 38 Montero63 2018 Reviews 6.8 & Internal fundingi 1/7 10 1991-2012 cryoglobulinaemia therapy apheresis 39 Adults (18 years and 40 Cochrane Medicine, General Non- over) with chronic Cannabis-based medicines Placebo, 64 41 Mücke 2018 Database of 6.8 & Internal industry 2/5 16 2004-2017 neuropathic pain - 5 types dihydrocodeine 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Systematic 4 Reviews 5 Cochrane Database of 6 Systematic Medicine, General Non- Adults and children 7 Narula65 2018 Reviews 6.8 & Internal industry 3/7 10j 1990-2014 with Crohn's disease Corticosteroids - 5 types Enteral nutrition 8 Adults or children Cochrane with partial onset 9 Database of seizures or 10 Systematic Medicine, General Non- generalised onset Antiepileptic drugs - 10 11 Nevitt66 2017 Reviews 6.8 & Internal industry 1/5 76 1981-2015 tonic-clonic seizures types Network meta-analysis Cochrane Adults and children 12 Database of For peer review onlywith focal onset or 13 Systematic Medicine, General Non- generalised onset 14 Nevitt67 2018 Reviews 6.8 & Internal industry 1/4 14 1995-2015 seizures Lamotrigine Carbamazepine Cochrane 15 Database of Adults (18 years and 16 Systematic Medicine, General Non- over) with venous Dressings - 12 types; 68

17 Norman 2018 Reviews 6.8 & Internal industry 1/6 78 1985-2016 leg ulcers Topical agentshttp://bmjopen.bmj.com/ - 10 types Network meta-analysis 18 Cochrane Database of Children and adults 19 Systematic Medicine, General Non- with acute asthma 20 Normansell69 2018 Reviews 6.8 & Internal industry 0/6 6 1974-2016 exacerbation Antibiotics - 4 types Placebo 21 Propranolol, timolol maleate, bleomycin, 22 Children (17 years atenolol, prednisolone, 23 Cochrane and under) with captopril, ibuprofen + 24 Database of single or multiple paracetamol, methylene Systematic Medicine, General Non- haemangiomas blue, triamcinolone, Placebo, radiation, 25 Novoa70 2018 Reviews 6.8 & Internal industry 1/7 24 1977-2016 located on the skin methylprednisolone on September 24, 2021 by guest. Protected copyright. lasers 26 Preterm (< 37 27 weeks’ gestation) 28 Cochrane and low birth weight Database of (< 2500 grams) 29 Systematic Medicine, General No infants less than Erythropoiesis-stimulating 30 Ohlsson71 2017 Reviews 6.8 & Internal funding 0/2 34 1991-2017 eight days of age agents (ESAs) - 2 types Placebo, no treatment 31 Cochrane Adults exhibiting Database of aggression or Placebo, other anti- 32 Systematic Medicine, General No agitation (or both) psychotic medications 33 Ostinelli72 2018 Reviews 6.8 & Internal funding 1/5 3 2005-2016 due to psychosis Aripiprazole - 2 types 34 Cochrane Patients with Haloperidol, Database of psychosis-induced olanzapine, quetiapine, 35 Systematic Medicine, General Non- aggression or oxcarbazepine, 36 Ostinelli73 2018 Reviews 6.8 & Internal industry 0/6 9 2010-2014 agitation Risperidone valproic acid 37 Cochrane Database of 1985- Adults (18 years and 38 Systematic Medicine, General Non- Unpublishe over) with cancer 39 Ostuzzi74 2018 Reviews 6.8 & Internal industry 1/5 7 d and depression Antidepressants - 6 types Placebo 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane 4 Database of Children and adults 5 Systematic Medicine, General Non- with active Crohn’s Parker75 2018 Reviews 6.8 & Internal industry 2/5 2 2011-2013 disease Naltrexone Placebo 6 Tamoxifen, interferon- 7 alpha, interleukin-2, 8 interferon-alpha + interleukin-2, Bacille 9 Single agent Calmette-Guérin 10 chemotherapy, (BCG), 11 Patients with polychemotherapy, corynebacterium unresectable lymph temozolomide, parvum, anti-PD1 12 Cochrane For peer review onlynode metastasis and dacarbazine, anti-CTLA4 monoclonal 13 Database of distant metastatic monoclonal antibodies, antibodies, sorafenib, 14 Systematic Medicine, General Non- cutaneous other immunostimulating elesclomo, anti- Pasquali76 2018 Reviews 6.8 & Internal industry 0/5 122 1972-2015 melanoma agents, MEK inhibitors angiogenic drugs 15 Cochrane 16 Database of Children (18 years Omalizumab, leukotriene

17 Systematic Medicine, General Non- and under) with receptor http://bmjopen.bmj.com/ antagonists - 2 77 18 Pike 2018 Reviews 6.8 & Internal industry 0/4 4 2007-2017 asthma types, corticosteroids Placebo Cochrane 19 Database of Patients with 20 Systematic Medicine, General Not Not Raynaud’s 78 21 Rirash 2017 Reviews 6.8 & Internal reported reported/8 38 1982-2000 phenomenon Calcium channel blockers Placebo Cochrane Adults (18 years and 22 Database of over) with 23 Systematic Medicine, General Non- unprovoked venous Warfarin, aspirin, 24 Robertson79 2017 Reviews 6.8 & Internal industry 0/3 6 1995-2016 thromboembolism rivaroxaban Placebo Sexually active 25 Cochrane adults (16 years and on September 24, 2021 by guest. Protected copyright. 26 Database of over) with genital 27 Systematic Medicine, General Non- ulcers compatible Macrolide antibiotics - 3 Other antibiotics - 4 80 28 Romero 2017 Reviews 6.8 & Internal industry 0/3 7 1983-1999 with chancroid types types Cochrane 29 Database of People with scabies 30 Systematic Medicine, General Non- of all ages and either 81 31 Rosumeck 2018 Reviews 6.8 & Internal industry 0/3 15 1996-2016 sex Ivermectin Permethrin Cochrane 32 Database of Adults (18 years and Local anaesthetic 33 Systematic Medicine, General Non- over) undergoing mixture (standard 34 Rüschen82 2018 Reviews 6.8 & Internal industry 0/4 7 1995-2012 intraocular surgery Hyaluronidase treatment) Methylphenidate, 35 modafinil, cholinesterase 36 inhibitors (ChEIs), atypical 37 Cochrane antipsychotics, Database of antidepressants, 38 Systematic Medicine, General Non- People with mibampator, valproate, 39 Ruthirakuhan83 2018 Reviews 6.8 & Internal industry 2/5 21 1998-2017 Alzheimer's Disease semagacestat Placebo 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane 4 Database of Anti-vascular endothelial 5 Systematic Medicine, General No Preterm infants with growth factor agents - 2 Sankar84 2018 Reviews 6.8 & Internal funding 0/3 6 2011-2016 retinopathy types Cryo/laser therapy 6 Levosimendan, 7 dobutamine, enoximone, 8 Adults (18 years and epinephrine, Cochrane over) with norepinephrine- 9 Database of cardiogenic shock or dobutamine, amrinone, 10 Systematic Medicine, General Non- acute low cardiac dopexamine, dopamine, 11 Schumann85 2018 Reviews 6.8 & Internal industry 3/9 13 1990-2013 output syndrome nitric oxid Placebo, no treatment Acetazolamide, ibuprofen, 12 Cochrane For peer review only dexamethasone, oxygen, 13 Database of People suffering nitric oxide, gabapentin, Placebo, normal air, 14 Simancas- Systematic Medicine, General Non- from high altitude magnesium sulphate, unspecified control, Racines86 2018 Reviews 6.8 & Internal industry 0/6 13k 1992-1994 illness sumatriptan paracetamol 15 Cochrane 16 Database of

17 Systematic Medicine, General Non- Adults and children http://bmjopen.bmj.com/ 87 18 Smith 2017 Reviews 6.8 & Internal industry 0/2 4 1998-2015 with cystic fibrosis Salmeterol, tiotropium No treatment, placebo Cochrane Placebo, no treatment, 19 Database of Intramuscular or intramuscular or 20 Systematic Medicine, General Non- intravenous opioids - 16 intravenous opioids - 88 21 Smith 2018 Reviews 6.8 & Internal industry 0/3 70 1958-2017 Women in labour types 16 types Alkaloids - 3 types, 22 antidepressants - 3 types, 23 levetiracetam, 24 cyproheptadin, promethazine, buspiron, 25 cognitive on September 24, 2021 by guest. Protected copyright. enhancers - 2 26 Cochrane types, VMAT2 inhibitors, 27 Database of ethyleicosapentaenoic acid 28 Systematic Medicine, General Non- Adults with chronic (ethyl-EPA), hormones - 3 Soares-Weiser89 2018 Reviews 6.8 & Internal industry 0/5l 24m 1971-2014 psychiatric disorders types, lithium, ceruletide Placebo 29 People with 30 coronary disease, 31 ischaemic cerebrovascular 32 disease, peripheral 33 Cochrane arterial disease, or at 34 Database of high risk of Systematic Medicine, General Non- atherothrombotic Placebo, usual care 35 Squizzato90 2017 Reviews 6.8 & Internal industry 2/5 15 2001-2017 disease Clopidrogel (aspirin) 36 Articaine, articaine + 37 Individuals epinephrine, lidocaine + undergoing dental epinephrine, bupivacaine + 38 Cochrane procedures and epinephrine, mepivacaine 39 Database of volunteers who took + epinephrine, 40 Systematic Medicine, General Non- part in simulated mepivacaine + 91 41 St George 2018 Reviews 6.8 & Internal industry 1/7 123 1954-2017 scenario studies levonordefrin, Local anaesthetics 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 mepivacaine, prilocaine, 4 prilocaine + felypressin, 5 prilocaine + epinephrine Cochrane 6 Database of 7 Systematic Medicine, General Non- Adults and children 92 8 Stern 2017 Reviews 6.8 & Internal industry 0/6 17 1972-2015 with pneumonia Corticosteroids - 7 types Placebo, usual care Children and 9 adolescents (18 10 years or under) with 11 autism spectrum Cochrane disorder (ASD) or 12 Database of For peer review onlypervasive 13 Systematic Medicine, General No developmental 14 Sturman93 2017 Reviews 6.8 & Internal funding 0/3 4 1995-2013 disorder (PDD) Methylphenidate Placebo Cochrane Psychiatric patients 15 Database of with antipsychotic- 16 Tammenmaa- Systematic Medicine, General Non- induced tardive 94

17 Aho 2018 Reviews 6.8 & Internal industry 0/4 14 1976-2014 dyskinesia Cholinergichttp://bmjopen.bmj.com/ drugs - 6 types Placebo 18 Adults (17 years and over) with severe 19 Cochrane mental illness and 20 Database of co-occurring 21 Systematic Medicine, General Non- substance use Other antipsychotics - Temmingh95 2018 Reviews 6.8 & Internal industry 2/4 8 2006-2014 disorder Risperidone 5 types 22 Cochrane Adults with HIV- 23 Database of associated 24 Systematic Medicine, General Non- cryptococcal Antifungal induction Tenforde96 2018 Reviews 6.8 & Internal industry 1/7 13 1997-2018 meningitis therapies - 6 types Network meta-analysis 25 on September 24, 2021 by guest. Protected copyright. H2 receptor 26 antagonists, proton 27 pump inhibitors, 28 prostaglandin analogues, 29 anticholinergics, 30 H2 receptor antagonists, antacids, sucralfate, 31 proton pump inhibitors, teprenone, naloxone, Cochrane prostaglandin analogues, bioflavonoids, 32 Database of anticholinergics, antacids, placebo, no treatment, 33 Systematic Medicine, General Non- People admitted to sucralfate, teprenone, other medication (not 34 Toews97 2018 Reviews 6.8 & Internal industry 0/7 103n 1977-2016 intensive care units naloxone, bioflavonoids defined) Cochrane Children (16 years 35 Database of and under) with 36 Systematic Medicine, General Non- recurrent acute otitis 37 Venekamp98 2018 Reviews 6.8 & Internal industry 1/4 3o 1992-1996 media Antibiotics - 3 types Grommets Cochrane 38 Database of Individuals who had 39 Systematic Medicine, General Non- an ischemic or 40 Vermeij99 2018 Reviews 6.8 & Internal industry 0/6 8 1998-2016 hemorrhagic stroke Preventive antibiotics Placebo, standard care 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Patients with critical 4 Cochrane limb ischaemia 5 Database of 1983- unsuitable for rescue Systematic Medicine, General Non- Unpublishe or reconstructive Placebo, other active 6 Vietto100 2018 Reviews 6.8 & Internal industry 0/6 33 d intervention Prostanoids - 7 types drugs - 4 types 7 Cochrane 8 Database of Systematic Medicine, General Non- Patients with acute 9 Wall101 2018 Reviews 6.8 & Internal industry 0/5 5 1995-2014 bacterial meningitis Glycerol Treatment as usual 10 Adult patients (over 11 18 years) undergoing any 12 Cochrane For peer review onlyelective or urgent 13 Database of surgical procedure Placebo, no treatment, 14 Systematic Medicine, General Non- under general thoracic epidural Weibel102 2018 Reviews 6.8 & Internal industry 3/10 68 1985-2017 anaesthesia Lidocaine analgesia - 3 types 15 Cochrane Thiazides, beta-blockers, 16 Database of Adult patients with angiotensin-converting-

17 Systematic Medicine, General Non- primary enzyme inhibitors,http://bmjopen.bmj.com/ calcium 103 18 Wright 2018 Reviews 6.8 & Internal industry 0/3 24 1966-2008 hypertension channel blockers Placebo Patients with focal 19 Cochrane epilepsy that failed 20 Database of to respond to one or 21 Systematic Medicine, General Non- more antiepileptic Xiao104 2018 Reviews 6.8 & Internal industry 0/4 2 2001-2003 drugs Losigamone Placebo 22 Cochrane 23 Database of Adult and elder 24 Systematic Medicine, General No patients with solid Thrombopoietin receptor Zhang105 2017 Reviews 6.8 & Internal funding 0/5 3 2009-2015 tumours agonists (TPO-RAs) Placebo 25 Cochrane on September 24, 2021 by guest. Protected copyright. 26 Database of Adults (18 years and 27 Systematic Medicine, General Non- over) with 106 28 Zhou 2017 Reviews 6.8 & Internal industry 0/6 5 2004-2014 neuropathic pain Oxcarbazepine Placebo Adult patients with 29 Cochrane an ischaemic stroke, 30 Database of haemorrhagic stroke 31 Systematic Medicine, General Not or transient Blood pressure-lowering Zonneveld107 2018 Reviews 6.8 & Internal reported 0/7 11 1970-2017 ischaemic attack drugs (BPLDs) - 5 types Placebo, no treatment 32 General Medicine (n = 33) 33 Direct acting oral 34 Adults with non- anticoagulants - 5 types, 35 Medicine, General Non- valvular atrial vitamin K antagonists, Network Meta- 108 36 López-López 2017 BMJ 23.6 & Internal industry 018 23 1989-2014 fibrillation antiplatelet agents analysis Children and adults No treatment, other 37 Medicine, General Non- with uncomplicated antibiotics - Network 38 Wang109 2018 BMJ Open 2.4 & Internal industry 0/8 14 1977-2017 skin abscesses Antibiotics - 10 types meta-analysis 39 1979- Adults (18 years and Medicine, General Non- Unpublishe over) with major Placebo - Network 40 Cipriani110 2018 Lancet 53.3 & Internal industry 4/18 522 d depressive disorder Antidepressants - 21 types meta-analysis 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Medicine, General Non- 4 Chen111 2018 Medicine 2.0 & Internal industry 0/3 9 2009-2017 Patients with sepsis Statins - 3 types Placebo 5 Patients with hormone receptor- 6 positive or human 7 epidermal growth 8 factor receptor 2 Medicine, General No negative advanced Cyclin-dependent kinases 9 Ding112 2018 Medicine 2.0 & Internal funding 0/6 6 2014-2017 breast cancer 4/6 inhibitors - 3 types Placebo 10 Adults undergoing 11 Medicine, General Non- total knee Guo113 2018 Medicine 2.0 & Internal industry 0/8 5 2004-2017 arthroplasty (TKA) Tranexamic acid (TXA) Placebo, no treatment 12 For peer review onlyPatients with 13 Medicine, General Not myocardial 14 Han114 2018 Medicine 2.0 & Internal reported 0/7 18 2007-2016 infarction Statins - 3 types Placebo Patients with acute 15 coronary syndrome, 16 percutaneous

17 coronary http://bmjopen.bmj.com/ 18 intervention, or coronary stents 19 given combination 20 Medicine, General Not therapy with aspirin 115 21 Hu 2018 Medicine 2.0 & Internal reported 0/5 4 2010-2016 and clopidogrel Proton pump inhibitors Placebo Patients with Antivascular endothelial 22 Medicine, General Not pterygium or growth factor agents - 3 23 Huang116 2018 Medicine 2.0 & Internal reported 0/5 18 2010-2015 glaucoma included Placebo, sham 24 Patients with Medicine, General Non- diabetic peripheral Fasudil + methylcobalamin Methylcobalamin or 25 Jiang117 2018 Medicine 2.0 & Internal industry 0/5 13 2010-2017 neuropathy or lipoic on September 24, 2021 by guest. Protected copyright. acid lipoic acid alone 26 Adult women with Antiangiogenic therapy (7 27 pathologically included) alone or 28 Medicine, General Non- confirmed epithelial combined with Placebo or Jiang118 2018 Medicine 2.0 & Internal industry 0/4 15 2011-2016 ovarian cancer chemotherapy chemotherapy alone 29 Patients with Immune checkpoint 30 Medicine, General Non- advanced non-small inhibitors: anti-PD1/PD-L1 Chemotherapy - 6 119 31 Khan 2018 Medicine 2.0 & Internal industry 0/8 7 2015-2017 cell lung cancer therapies - 3 types regimens Patients undergoing 32 Medicine, General No total knee or hip Normal saline or 33 Liang120 2017 Medicine 2.0 & Internal funding 0/4 3 2016-2017 arthroplasty Acetaminophen placebo 34 Medicine, General No Adults with social Liu121 2018 Medicine 2.0 & Internal funding 0/7 5 1999-2007 anxiety disorder Fluvoxamine Placebo 35 Children and adults 36 requiring Normal saline, K-Y 37 Medicine, General No nasogastric lubricant gel, or no Lor122 2017 Medicine 2.0 & Internal funding 0/8 10 1999-2015 intubation Lidocaine treatment 38 Adults with 39 intertrochanteric 40 Medicine, General No fractures preparing 123 41 Wang 2017 Medicine 2.0 & Internal funding 0/2 4 2015-2017 for internal fixation Tranexamic acid Placebo, no treatment 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 (dynamic hip 4 screws, proximal 5 femoral nail antirotations) 6 Placebo, octreotide, 7 norepinephrine, 8 Patients with dopamine + Medicine, General No hepatorenal furosemide, octreotide 9 Wang124 2018 Medicine 2.0 & Internal funding 0/5 18 2001-2016 syndrome Terlipressin + midodrine 10 Medicine, General Not Patients undergoing 11 Wang125 2018 Medicine 2.0 & Internal reported 0/3 4 1993-2011 bronchoscopy Propofol Midazolam Chemotherapy, 12 Medicine, General Not everolimus, 126 For peer review only 13 Wei 2017 Medicine 2.0 & Internal reported 0/2 14 2015-2017 Cancer patients PD-1 inhibitors - 2 types ipilimumab 14 Women of Non-steroidal anti- reproductive age inflammatory drugs, 15 Medicine, General Non- with primary analgesics, oral 16 Woo127 2018 Medicine 2.0 & Internal industry 0/7 34p 1998-2017 dysmenorrhea contraceptives Acupuncture

17 Patients who were http://bmjopen.bmj.com/ 18 administered xenon Medicine, General Non- versus propofol as a 19 Xia128 2018 Medicine 2.0 & Internal industry 0/6 13 2004-2012 general anesthetic Xenon Propofol 20 Patients prepared for 21 Medicine, General Not primary total hip Yang129 2017 Medicine 2.0 & Internal reported 0/4 7 2008-2016 arthroplasty (THA) Glucocorticoids - 3 types Placebo, no treatment 22 Patients undergoing 23 Medicine, General Not laparoscopic 24 Ye130 2017 Medicine 2.0 & Internal reported 0/3 5 2004-2016 cholecystectomy Ketamine Placebo Medicine, General No Adults with acute 25 Yu131 2018 Medicine 2.0 & Internal funding 0/6 8 2009-2017 heart failure Serelaxin on September 24, 2021 by guest. Protected copyright. Placebo 26 Patients with 27 locoregionally 28 advanced Medicine, General Non- nasopharyngeal Neoadjuvant chemotherapy 29 Yuan132 2018 Medicine 2.0 & Internal industry 0/9 31 1995-2016 carcinoma regimens - 16 included Network meta-analysis 30 Aspirin, aspirin + 31 dipyridamole, aspirin + clopidogrel, aspirin + 32 Medicine, General Not Adults with cerebral warfarin, cilostazol, 33 Zhang133 2018 Medicine 2.0 & Internal reported 0/2 13 2001-2014 infarction warfarin, and ticlopidine Network meta-analysis 34 Healthy volunteers and people with Placebo, other 35 Medicine, General Non- congestive heart Histamine H2 antagonists - conventional therapy 36 Zhang134 2018 Medicine 2.0 & Internal industry 0/8 10 1989-2006 failure 5 types medicines - 3 types 37 Adult patients prepared to undergo 38 Medicine, General Not laparoscopic 39 Zhao135 2018 Medicine 2.0 & Internal reported 0/7 5 2008-2017 cholecystectomy Lidocaine Placebo, saline 40 Medicine, General No Patients with a 136 41 Zhao 2018 Medicine 2.0 & Internal funding 0/3 4 2013-2017 diagnosis of Nefopam Saline or usual care 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 symptomatic 4 cholelithiasis and 5 acute cholecystitis who prepared for 6 laparoscopic 7 cholecystectomy 8 Adults with end- staged knee 9 osteoarthritis 10 Medicine, General No undergoing total 11 Zhou137 2018 Medicine 2.0 & Internal funding 0/4 6 2013-2017 knee arthroplasty Dexamethasone Placebo, no treatment Non-selective non- 12 For peer review only Selective non-steroidal steroidal anti- 13 Patients who anti-inflammatory drugs inflammatory drugs 14 Medicine, General Not underwent total hip (selective COX-2 (non-selective COX-2 Zhu138 2018 Medicine 2.0 & Internal reported 0/3 8 2002-2016 arthroplasty inhibitors) - 4 types inhibitors) - 4 types 15 Postgraduate Medicine, General No Patients with Placebo, placebo + 16 Zhou139 2018 Medicine 2.1 & Internal funding 0/5 10 2007-2017 dyslipidemia Anacetrapib usual care

17 Patients with http://bmjopen.bmj.com/ 18 complicated intra- Revista da abdominal 19 Associação infections and 20 Médica Medicine, General Non- Not complicated urinary Other antibiotics - 3 140 21 Zhang 2018 Brasileira 0.7 & Internal industry reported/6 6 2012-2016 tract infections Ceftazidime-avibactam types, usual care 22 Specialty medicine (n = 100) 23 Prostaglandin analogues, Patients with alpha-2 adrenergic 24 Acta primary open-angle agonists, beta-blockers,

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1 2 3 Aspirin, non-aspirin 4 Adults with history nonsteroidal anti- 5 No of colorectal cancer inflammatory drugs Veettil147 2017 BMC Cancer 3.3 Oncology funding 0/6 8 2003-2014 or adenoma (NSAIDs) Placebo, no treatment 6 Purine-like xanthine 7 oxidase inhibitors - 2 8 BMC Cardiac & Adults under types, non-purine-like Cardiovascular Cardiovascular No treatment for any xanthine oxidase inhibitors 9 Bredemeier148 2018 Disorders 1.8 Systems funding 0/9 91 1973-2017 clinical condition - 2 types Placebo, no treatment 10 Patients with post- 11 endoscopic retrograde 12 BMC For peer review onlycholangiopancreatog Nonsteroidal anti- 13 Gastroenterolog Gastroenterology & Non- raphy pancreatitis inflammatory drugs 14 Lyu149 2018 y 2.7 Hepatology industry 0/5 22 2003-2017 (PEP) (NSAIDs) - 6 types Placebo Patients with 15 BMC Infectious Non- invasive fungal Other antifungal 16 Xing150 2017 Diseases 2.6 Infectious Diseases industry 0/6 16 2001-2016 infections Voriconazole agents - 7 types

17 Patients undergoing http://bmjopen.bmj.com/ 18 total shoulder BMC arthroplasty or 19 Musculoskeletal Orthopedics; No reverse shoulder 20 Kuo151 2018 Disorders 2.0 Rheumatology funding 0/4 3 2015-2017 arthroplasty Tranexamic acid Placebo 21 Pharmacological agents for traumatic brain injury – 14 22 types, pharmacological 23 agents for stroke – 23 24 types, pharmacological agents for bacterial 25 meningitis on September 24, 2021 by guest. Protected copyright. – 1 type, 26 Patients with pharmacological agents for 27 ischemic or intracerebral haemorrhage 28 hemorrhagic stroke, – 6 types, pharmacological traumatic brain agents for aneurysmal 29 BMC No injury, or bacterial subarachnoid hemorrhage 30 Beez152 2017 Neurology 2.2 Clinical Neurology funding 0/3 110q 1983-2015 meningitis – 19 types Unspecified control 31 Patients with primary or recurrent 32 pterygium Anti-fibrotic and anti- 33 undergoing surgical VEGF (vascular 34 BMC No removal combined endothelial growth factor) Placebo - Network Zeng153 2017 Ophthalmology 1.8 Ophtamology funding 0/7 32 1990-2016 with toxic agents medications - 3 types meta-analysis 35 Patients with acute 36 coronary syndrome 37 and patients who underwent 38 BMC Pharmacology & percutaneous 39 Pharmacology Pharmacy; Non- coronary 40 Bundhun154 2017 & Toxicology 1.9 Toxicology industry 0/3 4 2013-2016 intervention Prasugrel Ticagrelor 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 People with 4 schizophrenia or 5 related disorders that had a duration of 6 BMC No treatment that was Antipsychotic drugs - 12 Placebo - Network 7 Zhang155 2017 Psychiatry 2.4 Psychiatry funding 0/11 47 2003-2015 no more than 1 year types meta-analysis 8 Patients with acute exacerbations of 9 BMC chronic obstructive 10 Pulmonary No pulmonary disease Placebo - Network 11 Zhang156 2017 Medicine 2.7 Respiratory System funding 0/5 19 1996-2016 (COPD) Antibiotics - 17 types meta-analysis BMC 12 Pulmonary Non- 157 For peer review only 13 Zhang 2017b Medicine 2.7 Respiratory System industry 0/4 25 1993-2016 Preterm infants Corticosteroids Placebo 14 Post-menopausal women with 15 metastatic HR- Cyclin-dependent kinase 16 Oncology; positive, HER2- 4/6 inhibitors - 3 types +

17 Ramos-Esquivel Obstetrics & No negative breast aromatasehttp://bmjopen.bmj.com/ inhibitor - 2 Aromatase inhibitors - 158 18 2018 Breast Cancer 1.8 Gynecology funding 0/4 3 2016-2017 cancer types 2 types British Journal Patients with Non-steroidal anti- 19 of Sports Non- osteoarthritis in any inflammatory drugs - 9 20 Zeng159 2018 Medicine 7.9 Sport Sciences industry 0/12 36 1979-2016 joint types Network meta-analysis 21 FOLFOX (leucovorin + fluorouracil + 22 oxaliplatin) + 23 bevacizumab, 24 FOLFIRI (leucovorin Cellular Patients with FOLFOXIRI (leucovorin + + fluorouracil + 25 Physiology and Cell Biology; Not metastatic colorectal fluorouracil on September 24, 2021 by guest. Protected copyright. + oxaliplatin + irinotecan) + 26 Shui160 2018 Biochemistry 5.5 Physiology reported 0/6 4 2015-2017 cancer irinotecan) + bevacizumab bevacizumab 27 Miltefosine, 28 paromomycin, Clinical Patients with antimonial compounds 29 Microbiology Infectious Diseases; No visceral - 2 types, pentamidine, 30 Rodrigo161 2018 and Infection 5.4 Microbiology funding 0/4 28 1996-2017 leishmaniasis Amphotericin B sitamaquine 31 Placebo, nonsteroidal Patients with anti-inflammatory 32 ankylosing Tumor necrosis factor drugs (NSAIDs), 33 spondylitis and non- (TNF) inhibitors - 5 types, disease modifying 34 Clinical Non- radiographic axial non-tumor necrosis factor antirheumatic drugs Wang162 2018 Rheumatology 2.1 Rheumatology industry 0/3 25 2002-2014 spondyloarthritis (TNF) inhibitors - 2 types (DMARDs) 35 Low molecular-weight 36 Critical heparin (LMWH) – 5 37 Reviews in Adults with acute types, enoxaparin + Rivaroxaban, Oncology / Oncology; No venous vitamin K antagonists unfractionated heparin 38 Hong163 2018 Hematology 4.5 Hematology funding 1/5 13 1996-2015 thromboembolism (VKA) (UFH) 39 Patients with Proprotein convertase Placebo, placebo + 40 Endocrinology & Not familial or subtilisin/kexin type 9 gene other lipid-lowering 164 r 41 de Carvalho 2018 Diabetes Care 13.4 Metabolism reported 0/3 20 2012-2017 nonfamilial inhibitors (PCSK9i) therapy 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 hypercholesterolemi 4 a 5 Digestive Adults (18 and over) Placebo, standard Diseases and Gastroenterology & Not with organic or treatment, no 6 Jaafar165 2018 Sciences 2.8 Hepatology reported 0/5 17 2000-2016 functional dyspepsia Rebamipide treatment 7 Patients with 8 Pharmacology & Not neurodegenerative Liu166 2018 Drug Delivery 3.1 Pharmacy reported 0/2 9 2002-2015 movement disorders Riluzole Placebo 9 Patients undergoing 10 coronary 11 Chemistry, angiography (CAG) Drug Design, Medicinal; or percutaneous 12 Development Pharmacology & Not coronary 167 For peer review only 13 Liu 2018 and Therapy 2.9 Pharmacy reported 0/5 9 2010-2016 intervention (PCI) Atorvastatin Placebo 14 Chemistry, Drug Design, Medicinal; Adults ( ≥ 18 years) 15 Development Pharmocology & Not undergoing spinal 16 Sun168 2017 and Therapy 2.9 Pharmacy reported 0/5 9 2009-2016 anesthesia Dexmedetomidine Fentanyl

17 Adults with http://bmjopen.bmj.com/ 18 East Asian traumatic brain Archives of Not injuries and 19 Paraschakis169 2017 Psychiatry None Not applicable reported 0/2 4 2005-2010 depressive disorders Antidepressants - 2 types Placebo 20 Emergency 21 Medicine Emergency No Patients taking acute D’Souza170 2018 Journal 2.0 Medicine funding 0/8 4 2001-2016 antiemetic drugs Diphenhydramine Placebo 22 Adult women with 23 epithelial ovarian 24 cancer, fallopian tube cancer, or 25 primary peritoneal on September 24, 2021 by guest. Protected copyright. 26 cancer who have 27 achieved complete 28 European clinical remission Journal of Oncology; after debulking 29 Gynecological Obstetrics & Not Not surgery and first-line CA125-targeted antibody – 30 Mei171 2016 Oncology 0.6 Gynecology reported reported/4 4 2004-2013 chemotherapy 2 types Placebo 31 European Patients with Respiratory Non- chronic 32 Verberkt172 2017 Journal 12.2 Respiratory System industry 3/9s 35 1982-2015 breathlessness Opioids - 8 types Placebo 33 Expert Opinion Critically ill patients Antacids, proton pump 34 on receiving stress inhibitors (PPI), histamine- Pharmacotherap Pharmacology & No ulcer prophylaxis 2 receptor antagonists Placebo - Network 35 Sridharan173 2018 y 3.5 Pharmacy funding 0/3 51 1980-2016 (SUP) (H2RA), and sucralfate meta-analysis 36 Expert Review Patients undergoing 37 of Clinical Pharmacology & No coronary artery Habibi174 2018 Pharmacology 2.8 Pharmacy funding 0/4 5 1999-2012 bypass surgery Lidocaine Placebo 38 Patients with stable 39 Expert Review angina pectoris Placebo (saline, 40 of Clinical Pharmacology & Non- requiring elective isosorbide dinitrate), 175 41 Li 2018 Pharmacology 2.8 Pharmacy industry 0/4 14 2002-2017 percutaneous Nicorandil no treatment 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 coronary 4 intervention (PCI) 5 Expert Review Patients diagnosed Anti-vascular endothelial Sangroongruang of Clinical Pharmacology & Non- with retinal vein growth factor (VEGF) Sham injection - 6 sri176 2018 Pharmacology 2.8 Pharmacy industry 0/5 11 2010-2017 occlusion drugs - 3 types Network meta-analysis 7 Adult patients with 8 foot or ankle trauma treated with below 9 Foot and Ankle Not knee cast or splint Low molecular weight 10 Hickey177 2018 Surgery 1.5 Orthopedics reported 0/7 7 1993-2015 immobilization heparin - 5 types Placebo, no treatment 11 Oncology; Patients with Targeted agents - 11 types, Gastroenterology & Non- advanced gastric targeted agents + Placebo - Network 12 Zhao178 2018 Gastric Cancer 5.0 ForHepatology peerindustry 0/9 review16 2002-2017 onlycancer chemotherapy meta-analysis 13 Orlistat, loracaserin, 14 Obese and naltrexone-bupropion, Gastroenterolog Gastroenterology & No overweight adults phentermine-topiramate, Placebo - Network 15 Khera179 2018 y 20.8 Hepatology funding 0/9 29 1998-2015 (18 years and over) liraglutide meta-analysis 16 Methotrexate (MEX) based

17 Patients with low- chemotherapyhttp://bmjopen.bmj.com/ regimens, 18 Oncology; risk gestational actinomycin-d (Act-D) Gynecologic Obstetrics & Non- trophoblastic based chemotherapy 19 Li180 2018 Oncology 4.5 Gynecology industry 0/6 7 2005-2016 neoplasia (LRGTN) regimens Network meta-analysis 20 Gastroenterology & Patients with 21 Hepatology; Non- helicobacter pylori Other antibiotics - 7 Zhuge181 2018 Helicobacter 4.1 Microbiology industry 0/6 18 1999-2016 infection Furazolidone types 22 Indian Journal No Adults at risk of 23 Kim182 2017 of Cancer 0.7 Oncology funding 0/4 21 1993-2011 developing cancer Statins - 7 types Placebo 24 Patients undergoing Indian Journal endoscopic 25 of retrograde on September 24, 2021 by guest. Protected copyright. 26 Gastroenterolog Not cholangiopancreatog 27 Garg183 2018 y None Not applicable reported 0/4 6 2007-2016 raphy Indomethacin Placebo 28 Immunosuppressed Infectious Not haematology- Other antifungal 29 Rosanova184 2017 Diseases 1.9 Infectious Diseases reported 0/5 7 2002-2011 oncology patients Voriconazole agents or placebo 30 Adults (17 years and Non-steroidal anti- 31 Inflammopharm Immunology; Non- over) diagnosed infammatory drugs Yu185 2018 acology 3.3 Toxicology industry 0/6 3 2007-2016 with acute gout Prednisolone (NSAIDs) - 2 types 32 Patients with 33 chronic venous 34 International Peripheral Vascular Not disorders (CVD) or Micronized purified Kakkos186 2018 Angiology 1.2 Disease reported 2/2 7 1982-2015 venous edema flavonoid faction (Daflon) Placebo 35 International Immunology; Adults with 36 Immunopharma Pharmacology & No Not moderate-to-severe 37 Ou187 2018 cology 3.1 Pharmacy funding reported/5 8 2014-2017 atopic dermatitis Dupilumab Placebo Children diagnosed 38 International Immunology; with recurrent 39 Immunopharma Pharmacology & No respiratory tract Placebo, routine 40 Yin188 2018 cology 3.1 Pharmacy funding 0/4 53 1984-2017 infections (RRTIs) Broncho-Vaxom therapies 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 International 4 Journal of 5 Clinical Non- Anti-EGFR monoclonal Zhu189 2018 Oncology 2.6 Oncology industry 0/7 35 2005-2016 Cancer patients antibodies (EGFR-MoAbs) Placebo, usual care 6 International 7 Journal of Not Patients with 190 8 Liu 2018 Neuroscience 1.8 Neurosciences reported 0/2 4 2007-2016 seizures Lacosamide Placebo Patients with 9 International advanced gastric and No neoadjuvant 10 Journal of No esophago-gastric Neoadjuvant chemotherapy chemotherapy (only 11 Coccolini191 2018 Surgery 2.7 Surgery funding 0/12 15 1993-2014 cancer (with surgery) surgery) Placebo, no treatment 12 International For peer review onlyPatients with ("nothing controlled 13 Journal of Non- scheduled total knee multimodal analgesia 14 Fan192 2018 Surgery 2.7 Surgery industry 0/8 7 2005-2016 arthroplasty Dexamethasone method") Patients with a 15 diagnosis of 16 symptomatic

17 cholelithiasis and http://bmjopen.bmj.com/ 18 acute cholecystitis International who prepared for 19 Journal of No laparoscopic 20 Li193 2018 Surgery 2.7 Surgery funding 0/5 6 2008-2017 cholecystectomy Lidocaine Placebo, saline 21 Patients undergoing anaesthesia as part 22 of endoscopic 23 International retrograde 24 Journal of No cholangiopancreatog Anaesthetic medications - No drug - Network Li194 2018 Surgery 2.7 Surgery funding 0/4 17 1998-2017 raphy 12 types meta-analysis 25 Patients undergoing on September 24, 2021 by guest. Protected copyright. 26 International total knee 27 Journal of Non- arthroplasty or total 195 t 28 Liu 2018 Surgery 2.7 Surgery industry 0/5 3 2005-2017 hip arthroplasty Tranexamic acid Aminocaproic acid International Patients with 29 Journal of No symptomatic knee 30 Ran196 2018 Surgery 2.7 Surgery funding 0/5 5 2002-2016 osteoarthritis Hyaluronic acid Methylprednisolone 31 International Patients with Journal of No hepatocellular 32 Zhao197 2018 Surgery 2.7 Surgery funding 0/3 4u 2010-2017 carcinoma Anthracyclines Platinum 33 Adult patients 34 International prepared for Journal of Non- laparoscopic 35 Zhu198 2018 Surgery 2.7 Surgery industry 0/5 6 2004-2017 cholecystectomy Ketamine Saline 36 Journal of 1990- 37 Affective Clinical Neurology; Non- Not Unpublishe Adults with major Second generation Placebo - Network Wagner199 2018 Disorders 3.8 Psychiatry industry reported/6 119 d depressive disorder antidepressants - 16 types meta-analysis 38 Journal of 39 Assisted Genetics & Women with Gonadotropin-releasing 40 Reproduction Heredity; Obstetrics Not lymphoma, ovarian hormone agonists (GnRHa) Standard treatment 200 41 Hickman 2018 and Genetics 2.8 & Gynecology; reported 0/5 10 2007-2016 cancer, or breast - 7 types (chemotherapy only) 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Reproductive cancer undergoing 4 Biology chemotherapy 5 Journal of Cancer Programmed death 1 (PD- 6 Research and Patients with non- 1)/programmed death 7 Clinical Non- small-cell lung ligand 1 (PD-L1) inhibitors Chemotherapy - 2 201 8 Luo 2018 Oncology 3.3 Oncology industry 0/4 8 2015-2017 carcinoma - 3 types types Journal of 9 Cancer Patients with 10 Research and metastatic 11 Clinical Non- castration-resistant Placebo - Network Wang202 2018 Oncology 3.3 Oncology industry 0/5 26 2010-2017 prostate cancer Targeted agents - 16 types meta-analysis 12 Journal of For peer review only 13 Cancer Cancer patients with 14 Research and No moderate to severe Wang203 2018 Therapeutics 0.8 Oncology funding 0/4 35 1997-2011 pain Fentanyl Morphine 15 Adults (18 years and Placebo, 16 Cardiac & over) undergoing discontinuation of

17 Aboul- Journal of Cardiovascular No any type of cardiac http://bmjopen.bmj.com/ aspirin greater than 7 204 18 Hassan 2017 Cardiac Surgery 1.2 Systems; Surgery funding 0/8 12 1985-2016 surgery Aspirin days before surgery Cardiac & 19 Cardiovascular Patients undergoing 20 Journal of Systems; Surgery; isolated coronary 21 Cardiovascular Peripheral Vascular Not artery bypass graft Wang205 2018 Surgery 1.2 Disease reported 0/6 5 1999-2010 (CABG) surgery Statins - 3 types No preoperative statin 22 Antiandrogens, insulin 23 sensitizers, estrogen- 24 progestin oral contraceptives pills 25 (OCPs), OCPs on September 24, 2021 by guest. Protected copyright. + 26 Journal of antiandrogen, OCPs + 27 Clinical insulin sensitizer, 28 Endocrinology Endocrinology & Non- Women with antiandrogen + insulin Placebo - Network Barrionuevo206 2018 and Metabolism 5.8 Metabolism industry 0/8 32 1989-2016 hirsutism sensitizer meta-analysis 29 Journal of 30 Clinical 31 Pharmacy and Pharmacology & Not Patients with type 2 Placebo - Network Cui207 2018 Therapeutics 1.7 Pharmacy reported 0/6 23 1993-2014 diabetes Statins - 6 types meta-analysis 32 Adults with 33 Journal of moderate-to-severe 34 Dermatological chronic plaque-type Apremilast, biological Placebo - Network Sawyer208 2018 Treatment 2.1 Dermatology Industry 6/6v 54 2001-2016 psoriasis therapies - 7 types meta-analysis 35 Patients with onset 36 of atrial fibrillation 37 (AF) within 48 h, who were 38 hemodynamically 39 Journal of stable and without Placebo, verapamil, 40 Emergency Emergency Not Not evidence of acute and other active anti- 209 41 Markey 2018 Medicine 1.2 Medicine reported reported/3 11 1989-2004 coronary syndrome, Flecainide dysrhythmics 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 congestive heart 4 failure, or structural 5 heart disease Adult patients (18 6 years and over) 7 Journal of taking low-dose 8 Gastrointestinal aspirin for a Histamine-2 receptor and Liver Gastroenterology & Not minimum of 2 Proton-pump inhibitors antagonists (H2RAs) - 9 Szabó210 2017 Diseases 2.0 Hepatology reported 0/15 10w 2009-2016 weeks (PPIs) - 5 types 2 types 10 Patients with 11 Journal of histologically Immunology Non- confirmed solid Immune checkpoint Placebo or 12 Su211 2018 Research 3.3 ForImmunology peerindustry 0/6 review15 2011-2017 onlycancer inhibitors (ICIs) - 5 types chemotherapy 13 Journal of 14 Interventional Cardiac Cardiac & Patients with 15 Electrophysiolo Cardiovascular Non- persistent atrial 16 Chen212 2018 gy 1.5 Systems industry 0/9 8 2006-2017 fibrillation Antiarrhythmic drugs Catheter ablation

17 Journal of http://bmjopen.bmj.com/ 18 Orthopaedic Surgery and No Patients undergoing 19 Chen213 2017 Research 1.6 Orthopedics funding 0/4 6 2008-2014 knee arthroscopy Midazolam Placebo 20 Journal of 21 Orthopaedic Patients undergoing Surgery and Not a primary total hip Placebo or no 22 Li214 2018 Research 1.6 Orthopedics reported 0/5 3x 2002-2017 or knee arthroplasty Aminocaproic acid treatment 23 Journal of 24 Orthopaedic Surgery and Not Patients treated with 25 Luo215 2018 Research 1.6 Orthopedics reported 0/4 3y 2002-2017 spine surgery Tranexamic on September 24, 2021 by guest. Protected copyright. acid Control (not specified) 26 Journal of 27 Orthopaedic Patients who 28 Surgery and No underwent hip Ma216 2018 Research 1.6 Orthopedics funding 0/4 4 1991-2015 surgery Naproxen Placebo 29 Patients with a 30 Journal of primary diagnosis of Vortioxetine, 31 Psychiatric Non- major depressive levomilnacipran, He217 2018 Research 4.0 Psychiatry industry 0/8 22 2009-2015 disorder (MDD) vilazodone Placebo 32 Journal of 33 Stroke & Neurosciences; Asian patients with Warfarin, direct oral 34 Cerebrovascular Peripheral Vascular Non- non-valvular atrial anticoagulants (DOACs) - Wang218 2018 Diseases 1.6 Disease industry 4/8 6 2003-2013 fibrillation (AF) 5 types Network meta-analysis 35 Journal of the 36 American 37 Academy of No Dhana219 2018 Dermatology 6.9 Dermatology funding 0/6 15 2000-2016 People with scabies Permethrin Ivermectin 38 Proprotein convertase 39 Journal of the Cardiac & Adults with subtilisin/kexin type 9 40 American Heart Cardiovascular Not hypercholesterolemi (PCSK9) inhibitors - 2 Placebo, ezetimibe, 220 z 41 Karatasakis 2017 Association 4.5 Systems reported 3/12 35 2012-2017 a types standard therapy 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Journal of the 4 European 5 Academy of Adult patients (≥ 18) Dermatology with moderate-to- 6 and Non- severe plaque 7 Kuo221 2018 Venereology 4.3 Dermatology industry 2/4 4 2012-2016 psoriasis Tofacitinib Placebo 8 Journal of Traditional Integrative & 9 Chinese Complementary Non- Not Patients with 10 Liu222 2016 Medicine 0.9 Medicine industry reported/6 16 2005-2015 rheumatoid arthritis Methotrexate Sinomenine 11 Biochemistry & Molecular Biology; 12 ForBiotechnology & peer review only 13 Journal of Applied Adult patients 14 Zhejiang Microbiology; undergoing cardiac University- Medicine, Research Not surgery requiring 15 Zheng223 2017 SCIENCE B 1.8 & Experimental reported 0/7 8 1990-2014 aortic cross-clamp Amiodarone, lidocaine Placebo 16 Patients with

17 isoniazid-resistant, http://bmjopen.bmj.com/ Usual care (REZ = 18 Lancet Critical Care rifampicin- rifampicin, Respiratory Medicine; Non- susceptible Fluoroquinolone, ethambutol, 19 Fregonese224 2018 Medicine 21.5 Respiratory System industry 0/57 2 2010-2014 tuberculosis streptomycin pyrazinamide) 20 2010- 21 Neurological Clinical Neurology; Not Not Unpublishe Patients during early Bornstein225 2018 Sciences 2.3 Neurosciences reported reported/10 9 d post-stroke period Cerebrolysin Placebo 22 Patients arranged for Bevacizumab, Placebo, 23 Ophthalmic primary bevacizumab + antimetabolite - 2 24 Chen226 2018 Research 1.8 Ophthalmology 0/4 3 2013-2015 trabeculectomy antimetabolite - 2 types types Anesthesiology; No Patients undergoing 25 Han227 2017 Pain Physician 2.6 Clinical Neurology funding 0/4 10 2004-2016 spinal surgery Gabapentin on September 24, 2021 by guest. Protected copyright. Placebo 26 Adult patients 27 Anesthesiology; No undergoing surgical Dexmedetomidine + 228 28 Peng 2017 Pain Physician 2.6 Clinical Neurology funding 0/5 18 2004-2016 procedures opioids Opioids Chemistry, 29 Medicinal; 30 Chemistry, 31 Multidisciplinary; Usual care Pharmacology & Not Patients with (chemotherapy), usual 32 Feng229 2016 Pharmazie 1.0 Pharmacy reported 0/7 2aa 2011-2012 tuberculosis V-5 immunitor care + placebo 33 Chemistry, 34 Medicinal; Chemistry, 35 Multidisciplinary; Patients with non- 36 Pharmacology & Not Not cystic fibrosis Placebo, symptomatic 37 Xu230 2016 Pharmazie 1.0 Pharmacy reported reported/8 12 1999-2014 bronchiectasis Antibiotics - 7 types treatment only PLOS 38 Neglected Patients infected 39 Tropical Parasitology; Non- with soil transmitted Albendazole, 40 Palmeirim231 2018 Diseases 4.4 Tropical Medicine industry 0/9 14bb 1997-2015 helminths Albendazole + ivermectin ivermectin 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Adults with 4 persistent depressive 5 disorder (DSM-5), chronic major 6 depression, recurrent Antidepressants - 6 types, 7 major depression cognitive-behavioral 8 with incomplete analysis system of interepisode psychotherapy, 9 recovery or combination of 10 dysthymia (DSM- antidepressants and 11 Psychotherapy IV), or any cognitive-behavioral and Psychiatry; Non- corresponding analysis system of 12 Furukawa232 2018 Psychosomatics 13.1 ForPsychology peerindustry 2/11 review3 2000-2015 onlyconditions psychotherapy Network meta-analysis 13 Adult patients with 14 Urology & Not chronic kidney Uric acid-lowering therapy Placebo, usual therapy, Liu233 2018 Renal Failure 1.4 Nephrology reported 0/6 12 2006-2015 disease - 2 types no treatment 15 Adults with a Tiotropium or 16 history of chronic olodaterol as

17 obstructive http://bmjopen.bmj.com/ monotherapy, 18 Respiratory pulmonary disease salmeterol + Miravitlles234 2017 Research 3.8 Respiratory System Industry 3/4 10 2014-2016 (COPD) Tiotropium + olodaterol fluticasone 19 Patients with Corticosteroid + fast- 20 Respiratory Non- intermittent or mild Corticosteroids, fast-onset- onset-acting β2- 235 21 Wang 2017 Research 3.8 Respiratory System industry 1/7 6 2006-2016 persistent asthma acting β2-agonists agonist Adults (18 years and 22 over) with moderate Tumor necrosis factor 23 Rheumatology No to severe psoriatic (antiTNF)-α inhibitors - 4 Placebo - Network 24 Kawalec236 2018 International 2.0 Rheumatology funding 0/4 8 2011-2016 arthritis (PsA) types meta-analysis Adult patients (18 25 years and over) on September 24, 2021 by guest. Protected copyright. 26 treated for the 27 secondary 28 prevention of cardiovascular, 29 Clinical Neurology; peripheral vascular, 30 Peripheral Vascular Not and cerebrovascular Proton pump inhibitors Thienopyridines - 2 237 31 Malhotra 2018 Stroke 6.2 Disease reported 0/6 12 2009-2016 disease (PPI) + thienopyridines types Surgical 32 Laparoscopy Adults (18 and over) 33 Endoscopy & undergoing 34 Percutaneous Not gastrointestinal Zhang238 2018 Techniques 1.0 Surgery reported 0/3 5 1995-2018 endoscopy Midazolam Propofol 35 Asian and non- 36 Asian adults (18 37 Hematology; years and older) Thrombosis Peripheral Vascular No with acute venous Direct oral anticoagulants Vitamin K antagonists 38 Yamashita239 2018 Research 2.8 Disease funding 3/7 6 2009-2014 thromboembolism (DOACs) - 4 types (VKAs), heparin 39 Immunology; 40 Medicine, Research No 240 41 Zhang 2018 Vaccine 3.3 & Experimental funding 1/6 13 1999-2014 HIV-positive people Influenza vaccine, Placebo Network meta-analysis 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Multidisciplinary sciences (n = 10) 4 Medical Patients with 5 Science Medicine, Research Non- essential Anti-hypertensive drugs - 8 6 Chen241 2018 Monitor 1.9 & Experimental industry 0/5 20cc 2000-2016 hypertension types Acupuncture Adult patients (over 7 18 years old) that 8 underwent the 9 Multidisciplinary No extraction of any Placebo, standard Arteagoitia242 2018 PLOS ONE 2.8 Sciences funding 0/3 8 1989-2015 tooth Chlorhexidine treatment 10 Adults with Placebo, other non- 11 osteoarthritis or steroidal anti- 12 Multidisciplinary No rheumatoid arthritis inflammatory drugs Feng243 2018 PLOS ONE 2.8 ForSciences peerfunding 0/4 review9 2002-2009 onlyof the knee or hip Etoricoxib (NSAIDs) - 2 included 13 Multidisciplinary Non- Pediatric surgical 14 Kawakami244 2018 PLOS ONE 2.8 Sciences industry 0/5 6 2007-2017 patients Magnesium Placebo, no treatment 15 Adults (18 years and 16 over) diagnosed with generalized 17 Multidisciplinary Non- anxiety disorder http://bmjopen.bmj.com/ 18 Li245 2018 PLOS ONE 2.8 Sciences industry 0/7 8 2007-2014 (GAD) Duloxetine Placebo 19 Patients with hypertension and Angiotensin- 20 chronic kidney converting enzyme 21 Multidisciplinary Non- disease stage 3 to 5 inhibitors, angiotensin 22 Lin246 2017 PLOS ONE 2.8 Sciences industry 0/6 21 1992-2012 and dialysis Calcium channel blockers receptor blockers 23 Adults (19 years and Multidisciplinary Non- Not over) undergoing Propofol, morphine, 24 Ling247 2018 PLOS ONE 2.8 Sciences industry reported/6 9 2003-2017 cardiac surgery Dexmedetomidine placebo

25 Multidisciplinary Non- Erythropoiesis on September 24, 2021 by guest. Protected copyright. -stimulating 248 26 Rohner 2017 PLOS ONE 2.8 Sciences industry 2/7 94 1993-2014 Cancer patients agents Usual care Placebo, no 27 intervention, beta 28 Patients with atrial blockers, calcium 29 Multidisciplinary No fibrillation or atrial antagonists, Sethi249 2018 PLOS ONE 2.8 Sciences funding 0/6 28 1986-2017 flutter Digoxin amiodarone 30 Multidisciplinary Post renal transplant 31 Wolf250 2018 PLOS ONE 2.8 Sciences Industry 1/9 13 2002-2016 patients mTOR-inhibitors - 2 types Calcineurin-inhibitors 32 aOnly 3 studies reported that authors were employed by industry and therefore we included them as ties for the purposes of this table; b11/12 included RCTs had a drug arm; c33/38 included RCTs had a drug arm; d4/14 included RCTs had a drug arm; eOne author reported pharmaceutical company employment; f9/11 included RCTs had a drug arm; g71/120 included studies were RCTs; h24/25 included 33 studies were RCTs; iMeta-analysis funding sources reported as 'None, Other" we coded as no study funding; j10/27 included RCTs had a drug arm; kFlow chart indicates that 0 RCTs were included in 34 the quantitative synthesis, but 2 RCTs were quantitatively synthesized and 13 were included; lDeclarations of interest were provided for only 3 out of 5 meta-analysis authors; m24/31 included RCTs had 35 a drug arm; n103/106 included RCTs had a drug arm; o3/5 included RCTs had a drug arm; p34/60 included RCTs had a drug arm; q110/123 included RCTs had an eligible drug arm; rSalary was reported s t u 36 under 'funding' but they did not specify whether there was any funding for the study itself; ICMJE forms only provided for 5/9 authors; 3/4 included studies were RCTs; 4/11 included studies were RCTs; vFour authors reported financial ties with a pharmaceutical company and employment by Symmetron, a company that provides health economic research services to pharmaceutical companies, 37 and two authors reported employment by a pharmaceutical company; w10/12 included studies were RCTs; x3/7 included studies were RCTs; y3/4 included studies were RCTs; z Of the 3 authors that 38 reported financial ties, one also reported industry employment; aa2/4 included studies were RCTs; bb14/30 included studies were RCTs; cc20/30 included studies were RCTs with a drug arm 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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17 Adams 2018 Systematic Reviews Full No No F F F http://bmjopen.bmj.com/ 18 Cochrane Database of Agabio3 2018 Systematic Reviews Full Partial No F, T F, T F 19 Cochrane Database of 20 Al-Shahi Salman4 2018 Systematic Reviews Partial No No F F 21 Cochrane Database of Alabed5 2018 Systematic Reviews Partial No Partial F, E 22 Cochrane Database of 23 Allegretti6 2017 Systematic Reviews Full No No F F F F 24 Cochrane Database of Arechabala7 2018 Systematic Reviews Full Partial Partial F F, E F, T F, T, E F

25 on September 24, 2021 by guest. Protected copyright. Cochrane Database of 26 Baandrup8 2018 Systematic Reviews Full Full Partial F F F F, T, E F 27 Cochrane Database of 9 28 Bala 2018 Systematic Reviews Full No No F F Cochrane Database of 29 Barbato10 2018 Systematic Reviews No No No 30 Cochrane Database of 31 Bergman11 2018 Systematic Reviews Full Partial No F, T Cochrane Database of 32 Bighelli12 2018 Systematic Reviews Full Full Partial F F, T, E F F, T, E F F 33 Cochrane Database of 34 Birks13 2018 Systematic Reviews Full Partial No F F, T F Cochrane Database of 35 Boyapati14 2018 Systematic Reviews No No No 36 Cochrane Database of 37 Brown15 2018 Systematic Reviews Partial Partial No F F F F, T F F 38 Cochrane Database of Bruins Slot16 2018 Systematic Reviews Full No No F 39 Cochrane Database of 40 Bryan17 2017 Systematic Reviews Partial No No F 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane Database of 4 Bryant-Smith18 2018 Systematic Reviews Full No No F 5 Cochrane Database of Burry19 2018 Systematic Reviews Full No No F F F 6 Cochrane Database of 7 Campschroer20 2018 Systematic Reviews Full Full No F, T 8 Cochrane Database of Candy21 2018 Systematic Reviews Full No No F F 9 Cochrane Database of 10 Chiew22 2018 Systematic Reviews No No No 11 Cochrane Database of Das23 2018 Systematic Reviews Full No No F F F 12 Cochrane Database of 24 Fora peer review only 13 Demicheli 2018 Systematic Reviews Full Partial Partial F, T, E 14 Cochrane Database of Demicheli25 2018 Systematic Reviews No No No 15 Cochrane Database of 16 Di Nisio26 2018 Systematic Reviews Partial Partial No F, T

17 Cochrane Database of http://bmjopen.bmj.com/ 27 18 El-Sayeh 2018 Systematic Reviews Full No No F F Cochrane Database of 19 Engelen28 2018 Systematic Reviews No No No 20 Cochrane Database of 29 21 Eshun-Wilson 2018 Systematic Reviews Full Full No F, T Cochrane Database of 22 Essali30 2018 Systematic Reviews Full No No F 23 Cochrane Database of 24 Everitt31 2018 Systematic Reviews Partial Partial No F, T F, T F F, T Cochrane Database of 25 Fanshawe32 2017 Systematic Reviews No No No on September 24, 2021 by guest. Protected copyright. 26 Cochrane Database of 27 Franik33 2018 Systematic Reviews Full Partial No F, T 28 Cochrane Database of González34 2018 Systematic Reviews Full No No F 29 Cochrane Database of 30 Grabosch35 2018 Systematic Reviews No No No 31 Cochrane Database of Graves36 2018 Systematic Reviews Partialb No No F 32 Cochrane Database of 33 Haas37 2018 Systematic Reviews Full Full No F, T F, T 34 Cochrane Database of Hakoum38 2018 Systematic Reviews Full Full No F, T 35 Cochrane Database of 36 Heras-Mosteiro39 2017 Systematic Reviews Partialc Partiald Partial F, T, E 37 Cochrane Database of Janmaat40 2017 Systematic Reviews No No No 38 Cochrane Database of 39 Jefferson41 2018 Systematic Reviews Full No No F 40 Cochrane Database of 42 41 Jung 2017 Systematic Reviews Full Full Partial F, T F, T, E 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane Database of 4 Kaempfen43 2018 Systematic Reviews No No No 5 Cochrane Database of Kahale44 2017 Systematic Reviews Full Full Partiale F, T, E 6 Cochrane Database of 7 Kahale45 2018 Systematic Reviews Full Partial No F, T 8 Cochrane Database of Kahale46 2018 Systematic Reviews Full Partial No F, T 9 Cochrane Database of 10 Kapur47 2018 Systematic Reviews Full No No F 11 Cochrane Database of Kelly48 2018 Systematic Reviews Partialf Partial No F F, T 12 Cochrane Database of 49 For peer review only 13 Knightly 2017 Systematic Reviews Full No No F 14 Cochrane Database of Kopsaftis50 2018 Systematic Reviews No No No 15 Cochrane Database of 16 Lawrie51 2018 Systematic Reviews Full Partial Partial F, T, E

17 Cochrane Database of http://bmjopen.bmj.com/ 52 18 Leathersich 2018 Systematic Reviews Full Full No F, T F, T F, T F, T Cochrane Database of 19 Lethaby53 2017 Systematic Reviews Full No No F F F 20 Cochrane Database of 54 21 López-Briz 2018 Systematic Reviews Full No No F Cochrane Database of 22 Marchant55 2018 Systematic Reviews Partial No No F 23 Cochrane Database of 24 Matar56 2018 Systematic Reviews Full No No F Cochrane Database of 25 Matar57 2018 Systematic Reviews Full Full No F, T on September 24, 2021 by guest. Protected copyright. 26 Cochrane Database of 27 McNicol58 2018 Systematic Reviews Full No No F 28 Cochrane Database of McTague59 2018 Systematic Reviews No No No 29 Cochrane Database of 30 Mhaskar60 2017 Systematic Reviews Full Full Partial F, T, E 31 Cochrane Database of Milligan61 2018 Systematic Reviews Partialg No No F F 32 Cochrane Database of 33 Monk62 2017 Systematic Reviews Full Full No F, T F, T 34 Cochrane Database of Montero63 2018 Systematic Reviews Partial No No F 35 Cochrane Database of 36 Mücke64 2018 Systematic Reviews Full Full Partial F, T F, T, E 37 Cochrane Database of Narula65 2018 Systematic Reviews No No No 38 Cochrane Database of 39 Nevitt66 2017 Systematic Reviews Partial No No F F 40 Cochrane Database of 67 41 Nevitt 2018 Systematic Reviews Full No No F 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane Database of 4 Norman68 2018 Systematic Reviews Full No Partial F F, E 5 Cochrane Database of Normansell69 2018 Systematic Reviews Full Noh No F F 6 Cochrane Database of 7 Novoa70 2018 Systematic Reviews Full Partialh No F F F, T F F 8 Cochrane Database of Ohlsson71 2017 Systematic Reviews Partial No No F F 9 Cochrane Database of 10 Ostinelli72 2018 Systematic Reviews Full No No F F 11 Cochrane Database of Ostinelli73 2018 Systematic Reviews Partial Partial No F F, T F 12 Cochrane Database of 74 For peer review only 13 Ostuzzi 2018 Systematic Reviews Full Partial No F F, T F 14 Cochrane Database of Parker75 2018 Systematic Reviews No No No 15 Cochrane Database of 16 Pasquali76 2018 Systematic Reviews Partial Partial No F, T F, T F F F

17 Cochrane Database of http://bmjopen.bmj.com/ 77 18 Pike 2018 Systematic Reviews Full No No F F Cochrane Database of 19 Rirash78 2017 Systematic Reviews No No No 20 Cochrane Database of 79 21 Robertson 2017 Systematic Reviews No No No Cochrane Database of 22 Romero80 2017 Systematic Reviews Full No No F F F F F F 23 Cochrane Database of 24 Rosumeck81 2018 Systematic Reviews Full Full No F, T Cochrane Database of 25 Rüschen82 2018 Systematic Reviews Full Full No F, T F, T on September 24, 2021 by guest. Protected copyright. 26 Cochrane Database of 27 Ruthirakuhan83 2018 Systematic Reviews Full No Partial F F, E 28 Cochrane Database of Sankar84 2018 Systematic Reviews No No No 29 Cochrane Database of 30 Schumann85 2018 Systematic Reviews Full Partial Partial F, T F F, T, E F, T F 31 Simancas- Cochrane Database of Racines86 2018 Systematic Reviews Full Full No F F F F, T 32 Cochrane Database of 33 Smith87 2017 Systematic Reviews Full Full Full F, T, E F, T, E 34 Cochrane Database of Smith88 2018 Systematic Reviews Full Full No F, T F, T 35 Cochrane Database of 36 Soares-Weiser89 2018 Systematic Reviews Partial No No F 37 Cochrane Database of Squizzato90 2017 Systematic Reviews Full Partiali No F F, T F F 38 Cochrane Database of 39 St George91 2018 Systematic Reviews Full Partial Partial F, T F, T, E F F, T, E 40 Cochrane Database of 92 41 Stern 2017 Systematic Reviews Full No No F F F 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cochrane Database of 4 Sturman93 2017 Systematic Reviews Full Full No F, T F, T F, T 5 Tammenmaa- Cochrane Database of Aho94 2018 Systematic Reviews Partial No No F 6 Cochrane Database of 7 Temmingh95 2018 Systematic Reviews Full Partial Partial F, T F, T, E F, T, E F, T 8 Cochrane Database of Tenforde96 2018 Systematic Reviews Full Full No F, T F, T F, T 9 Cochrane Database of 10 Toews97 2018 Systematic Reviews Full Full Partial F, E F F, T 11 Cochrane Database of Venekamp98 2018 Systematic Reviews Full Full No F F, T 12 Cochrane Database of 99 For peer review only 13 Vermeij 2018 Systematic Reviews No No No 14 Cochrane Database of Vietto100 2018 Systematic Reviews Full No No F F 15 Cochrane Database of 16 Wall101 2018 Systematic Reviews Full Full No F, T F F F

17 Cochrane Database of http://bmjopen.bmj.com/ 102 18 Weibel 2018 Systematic Reviews Full No No F F Cochrane Database of 19 Wright103 2018 Systematic Reviews Partial Partial No F F, T 20 Cochrane Database of 104 21 Xiao 2018 Systematic Reviews Full No No F Cochrane Database of 22 Zhang105 2017 Systematic Reviews Full No No F F F F F 23 Cochrane Database of 24 Zhou106 2017 Systematic Reviews Full Full No F F, T F Cochrane Database of 25 Zonneveld107 2018 Systematic Reviews Partialj No No F on September 24, 2021 by guest. Protected copyright. 26 General Medicine (n = 33) 27 López-López108 2017 BMJ Full No No F F 28 Wang109 2018 BMJ Open No No No 29 Cipriani110 2018 Lancet Fullk No No F F Chen111 2018 Medicine No No No 30 Ding112 2018 Medicine No No No 31 Guo113 2018 Medicine No No No 32 Han114 2018 Medicine No No No Hu115 2018 Medicine No No No 33 Huang116 2018 Medicine Full Partial No F, T 34 Jiang117 2018 Medicine No No No 35 Jiang118 2018 Medicine No No No 119 36 Khan 2018 Medicine No No No Liang120 2017 Medicine No No No 37 Liu121 2018 Medicine Partiall No No F 38 Lor122 2017 Medicine No No No 123 39 Wang 2017 Medicine No No No Wang124 2018 Medicine No No No 40 Wang125 2018 Medicine No No No 41 Wei126 2017 Medicine No No No 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Woo127 2018 Medicine No No No 4 Xia128 2018 Medicine No No No 129 5 Yang 2017 Medicine No No No Ye130 2017 Medicine No No No 6 Yu131 2018 Medicine No No No 7 Yuan132 2018 Medicine No No No 133 8 Zhang 2018 Medicine No No No Zhang134 2018 Medicine No No No 9 Zhao135 2018 Medicine No No No 10 Zhao136 2018 Medicine No No No 11 Zhou137 2018 Medicine No No No Zhu138 2018 Medicine No No No 12 Zhou139 2018 Postgraduate MedicineFor No peerNo reviewNo only 13 Revista da Associação 14 Zhang140 2018 Médica Brasileira Full Fullm No F, T 15 Specialty medicine (n = 100) 141 n 16 Li 2018 Acta Ophthalmologica Full No No F F American Heart 17 Tarantini142 2018 Journal No No No http://bmjopen.bmj.com/ 18 American Journal of 19 Wang143 2018 Cardiovascular Drugs No No No Anaesthesia and 20 Aman144 2018 Intensive Care No No No 21 Autoimmunity 22 Li145 2018 Reviews No No No 23 Biomed Research Wang146 2018 International No No No 24 Veettil147 2017 BMC Cancer No No No

25 BMC Cardiovascular on September 24, 2021 by guest. Protected copyright. 148 26 Bredemeier 2018 Disorders Full No No F BMC 27 Lyu149 2018 Gastroenterology No No No 28 BMC Infectious 29 Xing150 2017 Diseases No No No BMC Musculoskeletal 30 Kuo151 2018 Disorders No No No 31 Beez152 2017 BMC Neurology No No No 32 Zeng153 2017 BMC Ophthalmology No No No BMC Pharmacology & 33 Bundhun154 2017 Toxicology No No No 34 Zhang155 2017 BMC Psychiatry No No No 35 BMC Pulmonary 156 36 Zhang 2017 Medicine No No No BMC Pulmonary 37 Zhang157 2017 Medicine Full No No 38 Ramos-Esquivel15 8 39 2018 Breast Cancer No No No British Journal of 40 Zeng159 2018 Sports Medicine Partialo No No F F 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Cellular Physiology 4 Shui160 2018 and Biochemistry No No No 5 Clinical Microbiology Rodrigo161 2018 and Infection Partial No No F 6 Clinical 7 Wang162 2018 Rheumatology No No No 8 Critical Reviews in Oncology / 9 Hong163 2018 Hematology No No No 10 de Carvalho164 2018 Diabetes Care No No No 11 Digestive Diseases and Jaafar165 2018 Sciences No No No 12 Liu166 2018 Drug Delivery ForNo peerNo reviewNo only 13 Drug Design, 14 Development and Liu167 2018 Therapy No No No 15 Drug Design, 16 Development and 168

17 Sun 2017 Therapy No No No http://bmjopen.bmj.com/ 18 East Asian Archives of Paraschakis169 2017 Psychiatry No No No 19 Emergency Medicine 20 D’Souza170 2018 Journal No No No 21 European Journal of Gynecological 22 Mei171 2016 Oncology No No No 23 European Respiratory 24 Verberkt172 2017 Journal No No No Expert Opinion on 25 Sridharan173 2018 Pharmacotherapy No No No on September 24, 2021 by guest. Protected copyright. 26 Expert Review of 27 Habibi174 2018 Clinical Pharmacology No No No 28 Expert Review of Li175 2018 Clinical Pharmacology No No No 29 Sangroongruangsr Expert Review of 30 i176 2018 Clinical Pharmacology Full No No F 31 Foot and Ankle Hickey177 2018 Surgery No No No 32 Zhao178 2018 Gastric Cancer Partialp No No F F F 33 Khera179 2018 Gastroenterology No No No 34 Gynecologic Li180 2018 Oncology No No No 35 Zhuge181 2018 Helicobacter No No No 36 Indian Journal of 37 Kim182 2017 Cancer No No No Indian Journal of 38 Garg183 2018 Gastroenterology No No No 39 Rosanova184 2017 Infectious Diseases No No No 40 Inflammopharmacolog 185 41 Yu 2018 y No No No 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 International 4 Kakkos186 2018 Angiology No No No 5 International Ou187 2018 Immunopharmacology Full No No F 6 International 7 Yin188 2018 Immunopharmacology No No No 8 International Journal Zhu189 2018 of Clinical Oncology No No No 9 International Journal 10 Liu190 2018 of Neuroscience No No No 11 International Journal Coccolini191 2018 of Surgery No No No 12 International Journal 192 For peer review only 13 Fan 2018 of Surgery No No No 14 International Journal Li193 2018 of Surgery No No No 15 International Journal 16 Li194 2018 of Surgery No No No

17 International Journal http://bmjopen.bmj.com/ 195 18 Liu 2018 of Surgery No No No International Journal 19 Ran196 2018 of Surgery Noq No No 20 International Journal 197 21 Zhao 2018 of Surgery No No No International Journal 22 Zhu198 2018 of Surgery No No No 23 Journal of Affective 24 Wagner199 2018 Disorders Partial No No F Journal of Assisted 25 Reproduction and on September 24, 2021 by guest. Protected copyright. 26 Hickman200 2018 Genetics No No No 27 Journal of Cancer 28 Research and Clinical Luo201 2018 Oncology No No No 29 Journal of Cancer 30 Research and Clinical 202 r 31 Wang 2018 Oncology Partial No No F F Journal of Cancer 32 Research and 33 Wang203 2018 Therapeutics No No No 34 Journal of Cardiac Aboul-Hassan204 2017 Surgery No No No 35 Journal of 36 Cardiovascular 37 Wang205 2018 Surgery No No No Journal of Clinical F 38 Endocrinology and 39 Barrionuevo206 2018 Metabolism Full No No F 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Journal of Clinical 4 Pharmacy and 207 s 5 Cui 2018 Therapeutics Full No No F Journal of 6 Dermatological 7 Sawyer208 2018 Treatment No No No 8 Journal of Emergency Markey209 2018 Medicine No No No 9 Journal of 10 Gastrointestinal and 11 Szabó210 2017 Liver Diseases No No No Journal of 12 Su211 2018 Immunology ResearchFor No peerNo reviewNo only 13 Journal of 14 Interventional Cardiac Chen212 2018 Electrophysiology No No No 15 Journal of Orthopaedic 16 Chen213 2017 Surgery and Research No No No

17 Journal of Orthopaedic http://bmjopen.bmj.com/ 214 18 Li 2018 Surgery and Research No No No Journal of Orthopaedic 19 Luo215 2018 Surgery and Research No No No 20 Journal of Orthopaedic 216 21 Ma 2018 Surgery and Research No No No Journal of Psychiatric 22 He217 2018 Research Full No No F 23 Journal of Stroke & 24 Cerebrovascular Wang218 2018 Diseases No No No 25 Journal of the on September 24, 2021 by guest. Protected copyright. 26 American Academy of 27 Dhana219 2018 Dermatology No No No 28 Journal of the American Heart 29 Karatasakis220 2017 Association No No No 30 Journal of the 31 European Academy of Dermatology and 32 Kuo221 2018 Venereology Full No No 33 Journal of Traditional 34 Liu222 2016 Chinese Medicine No No No Journal of Zhejiang 35 University-SCIENCE 36 Zheng223 2017 B No No No 37 Lancet Respiratory Fregonese224 2018 Medicine No No No 38 Bornstein225 2018 Neurological Sciences No No No 39 Chen226 2018 Ophthalmic Research No No No 40 Han227 2017 Pain Physician No No No 228 41 Peng 2017 Pain Physician No No No 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from

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1 2 3 Feng229 2016 Pharmazie No No No 4 Xu230 2016 Pharmazie No No No 5 PLOS Neglected Palmeirim231 2018 Tropical Diseases No No No 6 Psychotherapy and 7 Furukawa232 2018 Psychosomatics No No No 233 8 Liu 2018 Renal Failure No No No Miravitlles234 2017 Respiratory Research Full No No F 9 Wang235 2017 Respiratory Research No No No 10 Rheumatology 11 Kawalec236 2018 International No No No Malhotra237 2018 Stroke No No No 12 Surgical LaparoscopyFor peer review only 13 Endoscopy & 14 Percutaneous Zhang238 2018 Techniques No No No 15 Yamashita239 2018 Thrombosis Research No No Partial E 16 Zhang240 2018 Vaccine No No No

17 Other (n = 10) http://bmjopen.bmj.com/ 18 Medical Science 19 Chen241 2018 Monitor No No No Arteagoitia242 2018 PLOS ONE No No No 20 Feng243 2018 PLOS ONE No No No 21 Kawakami244 2018 PLOS ONE No No No 22 Li245 2018 PLOS ONE No No No 246 23 Lin 2017 PLOS ONE No No No Ling247 2018 PLOS ONE No No No 24 Rohner248 2017 PLOS ONE No No No 249

25 Sethi 2018 PLOS ONE Partial No No F on September 24, 2021 by guest. Protected copyright. 250 26 Wolf 2018 PLOS ONE No No No aFunding sources categorized as government funded, industry funded, or mixed for most trials. Specific details about funding were reported for 2 trials and details on author ties and employment were 27 reported for a single trial; bAuthors reported extracting funding sources from included RCTs but funding sources are only reported for a single study; cReported funding sources for all included studies 28 except for one; dReported author financial ties for all included studies except for 2; eNon-industry author employment reported for some included RCTs; fFunding sources and author ties reported for all 29 included RCTs except one that was a conference abstract; gFunding sources only reported for a single RCT; hAuthors reported whether or not included RCTs had decaled COI (yes, no) and, if yes, indicated the page of the original study the declaration could be found on. This was coded as partially reporting because the nature of these COI was not reported within the meta-analysis publication 30 itself and it was unclear whether these were financial ties and whether they were with industry; iNon-industry author financial ties reported for some included RCTs; jA single RCT was reported as 31 'industry sponsored' with no specifics about the sponsor; kAuthors coded studies as sponsored by industry or not, and any of author industry affiliation, industry funding, or data obtained from 32 pharmaceutical company qualified an RCT as ‘sponsored'; lAuthors report that ‘some trials had a high risk of reporting bias because they were sponsored by pharmaceutical companies’ but do not specify which or even how many trials; mAuthors reported that all included RCTs had authors with financial ties to industry but provided no further information; nReported whether each included RCT 33 was industry funded (yes or no) but provided no further information; oFor some analyses the authors reported how many included RCTs were non-commercially funded and present results including only 34 non-commercially funded trials, but do not provide further information on which trials were commercially funded; pAuthors state 14 trials were industry-sponsored and reference figure 1 in the 35 supplementary material where 14 studies were marked as high risk for other bias, but it is not explicitly specified what was considered as 'other bias'; qAuthors considered RCT funding sources within r 36 'other bias’. In their risk of bias assessment but did not report any specific information; Authors report that most studies were funded by the pharmaceutical industry and refer readers to figure 2 (risk of bias figure), but the figure does not give any information about which RCTs; sIncluded RCTs were coded as having company funding (Yes/No). 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 83 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 4 5 References for eTable1 and eTable2 6 7 8 1. Abdel-Rahman O, Elsayed Z, Elhalawani H. Gemcitabine-based chemotherapy for 9 advanced biliary tract carcinomas. Cochrane Database of Syst Rev. 2018;4. 10 11 2. Adams SP, Sekhon SS, Tsang M, Wright JM. Fluvastatin for lowering lipids. Cochrane 12 13 Database of Syst Rev. 2018;3. 14 15 3. Agabio R, Trogu E, Pani PP. Antidepressants for the treatment of people with co- 16 occurring depressionFor andpeer alcohol dependence.review Cochrane only Database of Syst Rev. 2018;4. 17 18 4. Al-Shahi Salman, Law ZK, Bath PM, Steiner T, Sprigg N. Haemostatic therapies for 19 20 acute spontaneous intracerebral haemorrhage. Cochrane Database of Syst Rev. 2018;4. 21 5. Alabed S, Latifeh Y, Mohammad HA, Bergman H. Gamma-aminobutyric acid agonists 22 23 for antipsychotic-induced tardive dyskinesia. Cochrane Database of Syst Rev. 2018;4. 24 25 6. Allegretti AS, Israelsen M, Krag A, Jovani M, Goldin AH, Schulman AR, et al. 26 27 Terlipressin versus placebo or no intervention for people with cirrhosis and hepatorenal 28 syndrome. Cochrane Database of Syst Rev. 2017;6. 29 30 7. Arechabala MC, Catoni MI, Claro JC, Rojas NP, Rubio ME, Calvo MA, et al. 31

32 Antimicrobial lock solutions for preventing catheter-related infections in haemodialysis. http://bmjopen.bmj.com/ 33 34 Cochrane Database of Syst Rev. 2018;4. 35 8. Baandrup L, Ebdrup BH, JØ R, Lindschou J, Gluud C, Glenthøj BY. Pharmacological 36 37 interventions for benzodiazepine discontinuation in chronic benzodiazepine users. 38 39 Cochrane Database of Syst Rev. 2018;3.

40 9. Bala MM, Paszek E, Lesniak W, Wloch-Kopec D, Jasinska K, Undas A. Antiplatelet and on September 24, 2021 by guest. Protected copyright. 41 42 anticoagulant agents for primary prevention of thrombosis in individuals with 43 44 antiphospholipid antibodies. Cochrane Database of Syst Rev. 2018;7. 45 46 10. Barbato A, Avanzo BD, Parabiaghi A. Couple therapy for depression. Cochrane 47 Database of Syst Rev. 2018;6. 48 49 11. Bergman H, Bhoopathi PS, Soares-Weiser K. Benzodiazepines for antipsychotic-induced 50 51 tardive dyskinesia. Cochrane Database of Syst Rev. 2018;1. 52 12. Bighelli I, Castellazzi M, Cipriani A, Girlanda F, Guaiana G, Koesters M, et al. 53 54 Antidepressants versus placebo for panic disorder in adults. Cochrane Database of Syst 55 56 Rev. 2018;4. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 84 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 13. Birks JS, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane 4 5 Database of Syst Rev. 2018;6. 6 7 14. Boyapati RK, Torres J, Palmela C, Parker CE, Silverberg OM, Upadhyaya SD, et al. 8 9 Withdrawal of immunosuppressant or biologic therapy for patients with quiescent 10 Crohn's disease. Cochrane Database of Syst Rev. 2018;5. 11 12 15. Brown J, Crawford TJ, Datta S, Prentice A. Oral contraceptives for pain associated with 13 14 endometriosis. Cochrane Database of Syst Rev. 2018;5. 15 16. Bruins Slot KMH, Berge E. Factor Xa inhibitors versus vitamin K antagonists for 16 For peer review only 17 preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane 18 19 Database of Syst Rev. 2018;3. 20 21 17. Bryan EJ, Purcell MA, Kumar A. Zuclopenthixol dihydrochloride for schizophrenia. 22 Cochrane Database of Syst Rev. 2017;11. 23 24 18. Bryant-Smith AC, Lethaby A, Farquhar C, Hickey M. Antifibrinolytics for heavy 25 26 menstrual bleeding. Cochrane Database of Syst Rev. 2018;4. 27 19. Burry L, Mehta S, Perreault MM, Luxenberg JS, Siddiqi N, Hutton B, et al. 28 29 Antipsychotics for treatment of delirium in hospitalised non-ICU patients. Cochrane 30 31 Database of Syst Rev. 2018;6.

32 http://bmjopen.bmj.com/ 33 20. Campschroer T, Zhu X, Vernooij RW, Lock MT. Alpha-blockers as medical expulsive 34 therapy for ureteral stones. Cochrane Database of Syst Rev. 2018;4. 35 36 21. Candy B, Jones L, Vickerstaff V, Larkin PJ, Stone P. Mu-opioid antagonists for opioid- 37 38 induced bowel dysfunction in people with cancer and people receiving palliative care. 39 Cochrane Database of Syst Rev. 2018;6. 40 on September 24, 2021 by guest. Protected copyright. 41 22. Chiew AL, Gluud C, Brok J, Buckley NA. Interventions for paracetamol 42 43 (acetaminophen) overdose. Cochrane Database of Syst Rev. 2018;2. 44 45 23. Das RR, Singh M, Naik SS. Vitamin D as an adjunct to antibiotics for the treatment of 46 acute childhood pneumonia. Cochrane Database of Syst Rev. 2018;7. 47 48 24. Demicheli V, Jefferson T, Ferroni E, Rivetti A, Pietrantonj CD. Vaccines for preventing 49 50 influenza in healthy adults. Cochrane Database of Syst Rev. 2018;2. 51 52 25. Demicheli V, Jefferson T, Pietrantonj CD, Ferroni E, Thorning S, Thomas RE, et al. 53 Vaccines for preventing influenza in the elderly. Cochrane Database of Syst Rev. 2018;2. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 85 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 26. Di Nisio M, Wichers IM, Middeldorp S. Treatment for superficial thrombophlebitis of 4 5 the leg. Cochrane Database of Syst Rev. 2018;2. 6 7 27. El-Sayeh HG, Rathbone J, Soares-Weiser K, Bergman H. Non-antipsychotic 8 9 catecholaminergic drugs for antipsychotic-induced tardive dyskinesia. Cochrane 10 Database of Syst Rev. 2018;1. 11 12 28. Engelen ET, Schutgens RE, Mauser-Bunschoten EP, Es RJv, Galen KPv. Antifibrinolytic 13 14 therapy for preventing oral bleeding in people on anticoagulants undergoing minor oral 15 surgery or dental extractions. Cochrane Database of Syst Rev. 2018;7. 16 For peer review only 17 29. Eshun-Wilson I, Siegfried N, Akena DH, Stein DJ, Obuku EA, Joska JA. Antidepressants 18 19 for depression in adults with HIV infection. Cochrane Database of Syst Rev. 2018;1. 20 21 30. Essali A, Soares-Weiser K, Bergman H, Adams CE. Calcium channel blockers for 22 antipsychotic-induced tardive dyskinesia. Cochrane Database of Syst Rev. 2018;3. 23 24 31. Everitt H, Baldwin DS, Stuart B, Lipinska G, Mayers A, Malizia AL, et al. 25 26 Antidepressants for insomnia in adults. Cochrane Database of Syst Rev. 2018;5. 27 32. Fanshawe TR, Halliwell W, Lindson N, Aveyard P, Livingstone-Banks J, Hartmann- 28 29 Boyce J. Tobacco cessation interventions for young people. Cochrane Database of Syst 30 31 Rev. 2017;11.

32 http://bmjopen.bmj.com/ 33 33. Franik S, Eltrop SM, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors (letrozole) 34 for subfertile women with polycystic ovary syndrome. Cochrane Database of Syst Rev. 35 36 2018;5. 37 38 34. González R, Pons-Duran C, Piqueras M, Aponte JJ, Kuile FOT, Menéndez C. 39 Mefloquine for preventing malaria in pregnant women. Cochrane Database of Syst Rev. 40 on September 24, 2021 by guest. Protected copyright. 41 2018;3. 42 43 35. Grabosch SM, Shariff OM, Helm CW. Non-steroidal anti-inflammatory agents to induce 44 45 regression and prevent the progression of cervical intraepithelial neoplasia. Cochrane 46 Database of Syst Rev. 2018;2. 47 48 36. Graves PM, Choi L, Gelband H, Garner P. Primaquine or other 8-aminoquinolines for 49 50 reducing Plasmodium falciparum transmission. Cochrane Database of Syst Rev. 2018;2. 51 52 37. Haas DM, Morgan S, Contreras K, Enders S. Vaginal preparation with antiseptic solution 53 before cesarean section for preventing postoperative infections. Cochrane Database of 54 55 Syst Rev. 2018;7. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 86 of 108 BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 38. Hakoum MB, Kahale LA, Tsolakian IG, Matar CF, Yosuico VE, Terrenato I, et al. 4 5 Anticoagulation for the initial treatment of venous thromboembolism in people with 6 7 cancer. Cochrane Database of Syst Rev. 2018;1. 8 9 39. Heras-Mosteiro J, Monge-Maillo B, Pinart M, Pereira PL, Reveiz L, Garcia-Carrasco E, 10 et al. Interventions for Old World cutaneous leishmaniasis. Cochrane Database of Syst 11 12 Rev. 2017;12. 13 14 40. Janmaat VT, Steyerberg EW, Gaast Avd, Mathijssen RH, Bruno MJ, Peppelenbosch MP, 15 et al. Palliative chemotherapy and targeted therapies for esophageal and gastroesophageal 16 For peer review only 17 junction cancer. Cochrane Database of Syst Rev. 2017;11. 18 19 41. Jefferson T, Rivetti A, Pietrantonj CD, Demicheli V. Vaccines for preventing influenza in 20 21 healthy children. Cochrane Database of Syst Rev. 2018;2. 22 42. Jung JH, Kim J, MacDonald R, Reddy B, Kim MH, Dahm P. Silodosin for the treatment 23 24 of lower urinary tract symptoms in men with benign prostatic hyperplasia. Cochrane 25 26 Database of Syst Rev. 2017;11. 27 43. Kaempfen S, Neumann RP, Jost K, Schulzke SM. Beta-blockers for prevention and 28 29 treatment of retinopathy of prematurity in preterm infants. Cochrane Database of Syst 30 31 Rev. 2018;3.

32 http://bmjopen.bmj.com/ 33 44. Kahale LA, Hakoum MB, Tsolakian IG, Matar CF, Barba M, Yosuico VED, et al. Oral 34 anticoagulation in people with cancer who have no therapeutic or prophylactic indication 35 36 for anticoagulation. Cochrane Database of Syst Rev. 2017;12. 37 38 45. Kahale LA, Tsolakian IG, Hakoum MB, Matar CF, Barba M, Yosuico VE, et al. 39 Anticoagulation for people with cancer and central venous catheters. Cochrane Database 40 on September 24, 2021 by guest. Protected copyright. 41 of Syst Rev. 2018;6. 42 43 46. Kahale LA, Hakoum MB, Tsolakian IG, Matar CF, Terrenato I, Sperati F, et al. 44 45 Anticoagulation for the long-term treatment of venous thromboembolism in people with 46 cancer. Cochrane Database of Syst Rev. 2018;6. 47 48 47. Kapur N, Petsky HL, Bell S, Kolbe J, Chang AB. Inhaled corticosteroids for 49 50 bronchiectasis. Cochrane Database of Syst Rev. 2018;5. 51 52 48. Kelly C, Chalmers JD, Crossingham I, Relph N, Felix LM, Evans DJ, et al. Macrolide 53 antibiotics for bronchiectasis. Cochrane Database of Syst Rev. 2018;3. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 87 of 108 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2019-035633 on 11 May 2020. Downloaded from 1 2 3 49. Knightly R, Milan SJ, Hughes R, Knopp-Sihota JA, Rowe BH, Normansell R, et al. 4 5 Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database of Syst 6 7 Rev. 2017;11. 8 9 50. Kopsaftis Z, Wood-Baker R, Poole P. Influenza vaccine for chronic obstructive 10 pulmonary disease (COPD). Cochrane Database of Syst Rev. 2018;6. 11 12 51. Lawrie TA, Green JT, Beresford M, Wedlake L, Burden S, Davidson SE, et al. 13 14 Interventions to reduce acute and late adverse gastrointestinal effects of pelvic 15 radiotherapy for primary pelvic cancers. Cochrane Database of Syst Rev. 2018;1. 16 For peer review only 17 52. Leathersich SJ, Vogel JP, Tran TS, Hofmeyr GJ. Acute tocolysis for uterine tachysystole 18 19 or suspected fetal distress. Cochrane Database of Syst Rev. 2018;7. 20 21 53. Lethaby A, Puscasiu L, Vollenhoven B. Preoperative medical therapy before surgery for 22 uterine fibroids. Cochrane Database of Syst Rev. 2017;11. 23 24 54. López-Briz E, Garcia VR, Cabello JB, Bort-Martí S, Sanchis RC, Burls A. Heparin 25 26 versus 0.9% sodium chloride locking for prevention of occlusion in central venous 27 catheters in adults. Cochrane Database of Syst Rev. 2018;7. 28 29 55. Marchant JM, Petsky HL, Morris PS, Chang AB. Antibiotics for prolonged wet cough in 30 31 children. Cochrane Database of Syst Rev. 2018;7.

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