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Figure.  CONSERVE Implementation Tool
CONSERVE Implementation Tool

The CONSERVE implementation tool is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International license.

Table.  Examples of Trials Undergoing Important Modifications in Extenuating Circumstances
Examples of Trials Undergoing Important Modifications in Extenuating Circumstances
1.
Getz  KA, Zuckerman  R, Cropp  AB,  et al.  Measuring the incidence, causes, and repercussions of protocol amendments.   Ther Innov Regul Sci. 2011;45(3):265-275. doi:10.1177/009286151104500307Google Scholar
2.
Altman  DG.  The scandal of poor medical research.   BMJ. 1994;308(6924):283-284. doi:10.1136/bmj.308.6924.283PubMedGoogle ScholarCrossref
3.
Macleod  MR, Michie  S, Roberts  I,  et al.  Biomedical research: increasing value, reducing waste.   Lancet. 2014;383(9912):101-104. doi:10.1016/S0140-6736(13)62329-6PubMedGoogle ScholarCrossref
4.
Carlisle  BG. Clinical trials stopped by COVID-19. Updated January 29, 2021. Accessed May 31, 2021. https://covid19.bgcarlisle.com/
5.
US Food and Drug Administration. FDA guidance on conduct of clinical trials of medical products during the COVID-19 public health emergency. Published March 2020. Accessed February 5, 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency
6.
South African Health Products Regulatory Authority. SAHPRA policy on conduct of clinical trials of health products during the current COVID-19 pandemic. Published March 25, 2020. Accessed February 5, 2021. http://www.sahpra.org.za/wp-content/uploads/2020/03/SAHPRA-Communication_COVID_19-Final-25032020.pdf
7.
Norwegian Medicines Agency. Management of clinical trials in relation to COVID-19. Updated May 20, 2020. Accessed February 5, 2021. https://legemiddelverket.no/english/clinical-trials/management-of-clinical-trials-in-relation-to-covid-19
8.
European Medicines Agency. Implications of coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials. Published June 29, 2020. Accessed February 5, 2021. https://www.ema.europa.eu/en/implications-coronavirus-disease-covid-19-methodological-aspects-ongoing-clinical-trials
9.
Schulz  KF, Altman  DG, Moher  D; CONSORT Group.  CONSORT 2010 statement.   PLoS Med. 2010;7(3):e1000251. doi:10.1371/journal.pmed.1000251PubMedGoogle Scholar
10.
Chan  A-W, Tetzlaff  JM, Altman  DG,  et al.  SPIRIT 2013 statement.   Ann Intern Med. 2013;158(3):200-207. doi:10.7326/0003-4819-158-3-201302050-00583PubMedGoogle ScholarCrossref
11.
Moher  D, Schulz  KF, Simera  I, Altman  DG.  Guidance for developers of health research reporting guidelines.   PLoS Med. 2010;7(2):e1000217. doi:10.1371/journal.pmed.1000217PubMedGoogle Scholar
12.
Orkin  A, Gill  P, Jüni  P,  et al. Development protocol: CONSORT and SPIRIT extension for RCTs revised in extenuating circumstances. Open Science Framework. Published 2020. Accessed February 7, 2021. https://osf.io/ms8bz
13.
Canadian Institutes of Health Research; Natural Sciences and Engineering Research Council of Canada; Social Sciences and Humanities Research Council. Tri-council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS2). Government of Canada; 2014.
14.
Khangura  S, Konnyu  K, Cushman  R,  et al.  Evidence summaries: the evolution of a rapid review approach.   Syst Rev. 2012;1(1):10. doi:10.1186/2046-4053-1-10PubMedGoogle ScholarCrossref
15.
Ayala  A, Orkin  A, Rombey  T,  et al. Managing and reporting major modifications to trial protocols and trial conduct due to extenuating circumstances: a rapid review protocol. Open Science Framework. Published 2020. Accessed February 7, 2021. https://osf.io/t49ev/
16.
McGowan  J, Sampson  M, Salzwedel  DM,  et al.  PRESS Peer Review of Electronic Search Strategies.   J Clin Epidemiol. 2016;75:40-46. doi:10.1016/j.jclinepi.2016.01.021PubMedGoogle ScholarCrossref
17.
Moher  D, Hopewell  S, Schulz  KF,  et al; CONSORT.  CONSORT 2010 explanation and elaboration.   Int J Surg. 2012;10(1):28-55. doi:10.1016/j.ijsu.2011.10.001PubMedGoogle ScholarCrossref
18.
Chan  A-W, Tetzlaff  JM, Gøtzsche  PC,  et al.  SPIRIT 2013 explanation and elaboration.   BMJ. 2013;346:e7586. doi:10.1136/bmj.e7586PubMedGoogle Scholar
19.
Getz  KA, Stergiopoulos  S, Short  M,  et al.  The impact of protocol amendments on clinical trial performance and cost.   Ther Innov Regul Sci. 2016;50(4):436-441. doi:10.1177/2168479016632271PubMedGoogle ScholarCrossref
20.
Vaillancourt  C, Charette  M, Taljaard  M,  et al.  Pragmatic strategy empowering paramedics to assess low-risk trauma patients with the Canadian C-Spine Rule and selectively transport them without immobilization.   JMIR Res Protoc. 2020;9(6):e16966. doi:10.2196/16966PubMedGoogle Scholar
21.
Siegal  DM, Belley-Cote  E, Arnold  DM,  et al.  Small-Volume Tubes to Reduce Anemia and Transfusion (STRATUS).   Blood. 2019;134(suppl 1):3685. doi:10.1182/blood-2019-130257Google ScholarCrossref
22.
Isanaka  S, Guindo  O, Langendorf  C,  et al.  Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger.   N Engl J Med. 2017;376(12):1121-1130. doi:10.1056/NEJMoa1609462PubMedGoogle ScholarCrossref
23.
James  ND, Sydes  MR, Mason  MD,  et al.  Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer.   Lancet Oncol. 2012;13(5):549-558. doi:10.1016/S1470-2045(12)70088-8PubMedGoogle ScholarCrossref
24.
Morse  SS, Mazet  JA, Woolhouse  M,  et al.  Prediction and prevention of the next pandemic zoonosis.   Lancet. 2012;380(9857):1956-1965. doi:10.1016/S0140-6736(12)61684-5PubMedGoogle ScholarCrossref
25.
Lancaster  GA, Dodd  S, Williamson  PR.  Design and analysis of pilot studies.   J Eval Clin Pract. 2004;10(2):307-312. doi:10.1111/j..2002.384.doc.xPubMedGoogle ScholarCrossref
26.
Martinaud  C, Tiberghien  P, Bégué  S,  et al.  Rational and design of the T-STORHM study.   Transfus Clin Biol. 2019;26(4):198-201. doi:10.1016/j.tracli.2019.09.004PubMedGoogle ScholarCrossref
27.
Schulz  KF, Grimes  DA.  Multiplicity in randomised trials, II.   Lancet. 2005;365(9471):1657-1661. doi:10.1016/S0140-6736(05)66516-6PubMedGoogle ScholarCrossref
28.
Bassler  D, Montori  VM, Briel  M,  et al.  Early stopping of randomized clinical trials for overt efficacy is problematic.   J Clin Epidemiol. 2008;61(3):241-246. doi:10.1016/j.jclinepi.2007.07.016PubMedGoogle ScholarCrossref
29.
Mueller  PS, Montori  VM, Bassler  D,  et al.  Ethical issues in stopping randomized trials early because of apparent benefit.   Ann Intern Med. 2007;146(12):878-881. doi:10.7326/0003-4819-146-12-200706190-00009PubMedGoogle ScholarCrossref
30.
Montori  VM, Devereaux  PJ, Adhikari  NKJ,  et al.  Randomized trials stopped early for benefit.   JAMA. 2005;294(17):2203-2209. doi:10.1001/jama.294.17.2203PubMedGoogle ScholarCrossref
31.
Tharmanathan  P, Calvert  M, Hampton  J, Freemantle  N.  The use of interim data and data monitoring committee recommendations in randomized controlled trial reports.   BMC Med Res Methodol. 2008;8(1):12. doi:10.1186/1471-2288-8-12PubMedGoogle ScholarCrossref
32.
Coskinas  X, Simes  J, Schou  M, Martin  AJ.  Changes to aspects of ongoing randomised controlled trials with fixed designs.   Trials. 2020;21(1):457. doi:10.1186/s13063-020-04374-3PubMedGoogle ScholarCrossref
33.
Alirol  E, Kuesel  AC, Guraiib  MM,  et al.  Ethics review of studies during public health emergencies—the experience of the WHO ethics review committee during the Ebola virus disease epidemic.   BMC Med Ethics. 2017;18(1):43. doi:10.1186/s12910-017-0201-1PubMedGoogle ScholarCrossref
34.
Sweetman  EA, Doig  GS.  Failure to report protocol violations in clinical trials.   Trials. 2011;12:214. doi:10.1186/1745-6215-12-214PubMedGoogle ScholarCrossref
35.
Girardis  M, Busani  S, Damiani  E,  et al.  Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit.   JAMA. 2016;316(15):1583-1589. doi:10.1001/jama.2016.11993PubMedGoogle ScholarCrossref
36.
Eisenberg  MJ, Hébert-Losier  A, Windle  SB,  et al.  Effect of e-cigarettes plus counseling vs counseling alone on smoking cessation.   JAMA. 2020;324(18):1844-1854. doi:10.1001/jama.2020.18889PubMedGoogle ScholarCrossref
37.
Tomazini  BM, Maia  IS, Cavalcanti  AB,  et al.  Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19.   JAMA. 2020;324(13):1307-1316. doi:10.1001/jama.2020.17021PubMedGoogle ScholarCrossref
38.
Laine  C, Goodman  SN, Griswold  ME, Sox  HC.  Reproducible research: moving toward research the public can really trust.   Ann Intern Med. 2007;146(6):450-453. doi:10.7326/0003-4819-146-6-200703200-00154PubMedGoogle ScholarCrossref
39.
Medicines and Healthcare Products Regulatory Agency. Managing clinical trials during coronavirus (COVID-19): how investigators and sponsors should manage clinical trials during COVID-19. Published 2020. Accessed March 2, 2021. https://www.gov.uk/guidance/managing-clinical-trials-during-coronavirus-covid-19
40.
US Food and Drug Administration. Statistical considerations for clinical trials during the COVID-19 public health emergency: guidance for industry. Published June 2020. Accessed May 3, 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/statistical-considerations-clinical-trials-during-covid-19-public-health-emergency-guidance-industry
41.
Cro  S, Morris  TP, Kahan  BC,  et al.  A four-step strategy for handling missing outcome data in randomised trials affected by a pandemic.   BMC Med Res Methodol. 2020;20(1):208. doi:10.1186/s12874-020-01089-6PubMedGoogle ScholarCrossref
42.
Meagher  KM, Cummins  NW, Bharucha  AE,  et al.  COVID-19 ethics and research.   Mayo Clin Proc. 2020;95(6):1119-1123. doi:10.1016/j.mayocp.2020.04.019PubMedGoogle ScholarCrossref
43.
Vissers  MFJM, Cohen  AF, Van Gerven  JMA, Groeneveld  GJ.  The impact of the global COVID-19 pandemic on the conduct of clinical trials.   Br J Clin Pharmacol. 2021;87(3):837-844. doi:10.1111/bcp.14480PubMedGoogle ScholarCrossref
44.
Rusen  ID.  Challenges in tuberculosis clinical trials in the face of the COVID-19 pandemic.   Trop Med Infect Dis. 2020;5(2):E86. doi:10.3390/tropicalmed5020086PubMedGoogle Scholar
45.
Davis  S, Pai  S.  Challenges and opportunities for sponsors in conducting clinical trials during a pandemic.   Perspect Clin Res. 2020;11(3):115-120. doi:10.4103/picr.PICR_177_20PubMedGoogle ScholarCrossref
46.
Anker  SD, Butler  J, Khan  MS,  et al.  Conducting clinical trials in heart failure during (and after) the COVID-19 pandemic.   Eur Heart J. 2020;41(22):2109-2117. doi:10.1093/eurheartj/ehaa461PubMedGoogle ScholarCrossref
47.
de Paula  BHR, Araújo  I, Bandeira  L,  et al.  Recommendations from national regulatory agencies for ongoing cancer trials during the COVID-19 pandemic.   Lancet Oncol. 2020;21(5):624-627. doi:10.1016/S1470-2045(20)30226-6PubMedGoogle ScholarCrossref
48.
Waterhouse  DM, Harvey  RD, Hurley  P,  et al.  Early impact of COVID-19 on the conduct of oncology clinical trials and long-term opportunities for transformation.   JCO Oncol Pract. 2020;16(7):417-421. doi:10.1200/OP.20.00275PubMedGoogle ScholarCrossref
49.
Moskowitz  CS, Panageas  KS.  Implications for design and analyses of oncology clinical trials during the COVID-19 pandemic.   JAMA Oncol. 2020;6(9):1326-1327. doi:10.1001/jamaoncol.2020.2370PubMedGoogle ScholarCrossref
50.
Lau  G, Sharma  M; APASL Covid-19 Task Force.  Clinical practice guidance for hepatology and liver transplant providers during the COVID-19 pandemic.   Hepatol Int. 2020;14(4):415-428. doi:10.1007/s12072-020-10054-wPubMedGoogle ScholarCrossref
51.
Perlis  RH, Haneuse  SJPA, Rubenfeld  GD,  et al.  Reporting clinical studies affected by the COVID-19 pandemic.   JAMA Netw Open. 2021;4(1):e2036155. doi:10.1001/jamanetworkopen.2020.36155PubMedGoogle Scholar
52.
McDermott  MM, Newman  AB.  Preserving clinical trial integrity during the coronavirus pandemic.   JAMA. 2020;323(21):2135-2136. doi:10.1001/jama.2020.4689PubMedGoogle ScholarCrossref
53.
Parikh  PM, Mehta  P, Mvt  KM,  et al.  “Serious adverse events” faced by clinical trials.   Indian J Med Paediatr Oncol. 2020;41(2):127. doi:10.4103/ijmpo.ijmpo_114_20Google Scholar
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    1 Comment for this article
    EXPAND ALL
    Anti-Industry Bias in CONSERVE 2021 Authorship?
    Kenneth Gorelick, MD | Zymo Consulting Group LLC
    Among the author affiliations in this article, well-represented are academic institutions, regulatory bodies, medical journals, and government agencies, all of which are important stakeholders in this conversation. Conspicuously absent however is a single individual identified with the biotechnology, pharmaceutical, or medical device industries.

    A look at clinicaltrials.gov (1) shows that in a total database of 384,288 trials, 120,896 (31%) were funded by industry, 34137 (9%) were funded by NIH, and 7,379 (2%) were funded by other US federal agencies. This becomes even more striking when examining currently recruiting Phase 3 interventional trials (n=4323) for which 1874 (43%) were
    funded by industry, 277 (6%) by NIH, and 48 (1%) by other US federal agencies.

    As the single largest stakeholder in the medical publication universe, I am dismayed to see the exclusion of the medical industry from the development of these important guidelines.

    While I am certain to hear protests about "industry bias", it is in fact rare to see retractions of industry-sponsored research because the vetting process for industry studies, in anticipation of regulatory submissions, is in fact far more rigorous than academic peer review. Thousands of physicians with impeccable integrity work in the biotech, pharma, and medical device industries. It is time for them to be recognized and incorporated into the process of clinical research guideline development.

    Reference

    1. https://clinicaltrials.gov/ct2/results?Search=Apply&recrs=a&age_v=&gndr=&type=&rslt= accessed 23 July 2021

    CONFLICT OF INTEREST: I consult for the pharmaceutical industry. Clients have included Wyeth, Pfizer, Shire Takeda, GSK, Infinity, and others
    READ MORE
    Special Communication
    June 21, 2021

    Guidelines for Reporting Trial Protocols and Completed Trials Modified Due to the COVID-19 Pandemic and Other Extenuating Circumstances: The CONSERVE 2021 Statement

    Author Affiliations
    • 1Division of Emergency Medicine, Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
    • 2Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
    • 3Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
    • 4National Health and Medical Research Council, Canberra, Australia
    • 5Clinical Trials Unit, Medicines and Healthcare Products Regulatory Agency, London, England
    • 6Berman Institute of Bioethics, Johns Hopkins University, Baltimore, Maryland
    • 7Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, England
    • 8Université de Paris, AP-HP, Paris, France
    • 9Departments of Medicine, Epidemiology and Biostatistics, and Philosophy, Western University, London, Ontario, Canada
    • 10National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia
    • 11Department of Health Care Management, Technische Universität Berlin, Berlin, Germany
    • 12University of Nottingham, Nottingham, England
    • 13National Institute for Health Research, Nottingham, England
    • 14WCG Statistics Collaborative, Washington, DC
    • 15Centre for Journalology, Clinical Epidemiology Program, Ottawa Hospital Research Institute, School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
    • 16Clinical Trials Ontario, Toronto, Ontario, Canada
    • 17Office of Oncologic Diseases, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
    • 18Tufts Center for the Study of Drug Development, Boston, Massachusetts
    • 19Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, University of Oxford, Oxford, England
    • 20Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
    • 21Chinese Clinical Trial Registry, Sichuan University, Chengdu, China
    • 22Gerstein Science Information Centre, University of Toronto, Toronto, Ontario, Canada
    • 23FHI 360, Durham, North Carolina
    • 24School of Medicine, University of North Carolina at Chapel Hill
    • 25Gerstein Science Information Centre, University of Toronto, Toronto, Ontario, Canada
    • 26Centre of Research in Epidemiology and Statistics, Université de Paris, Inserm, Paris, France
    • 27Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
    • 28The BMJ, London, England
    • 29Deputy Editor, JAMA
    • 30Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
    • 31Canadian Institutes of Health Research Institute of Musculoskeletal Health and Arthritis, Ottawa, Ontario, Canada
    • 32University of Texas Health Science Center, San Antonio
    • 33Alcohol, Tobacco, and Other Drugs Research Unit, South African Medical Research Council, Cape Town, South Africa
    • 34Lawrence Berkeley National Laboratory, Berkeley, California
    • 35The Lancet, London, England
    • 36Office of Extramural Research, Division of Human Subjects Research, National Institutes of Health, Bethesda, Maryland
    • 37Department of Disease Control and Environmental Health, School of Public Health, Makerere University, Kampala, Uganda
    • 38Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark, University of Southern Denmark, Odense, Denmark
    • 39ClinicalTrials.gov, National Library of Medicine, National Institutes of Health, Bethesda, Maryland
    • 40Centre for Health Research and Development, Society for Applied Studies, New Delhi, India
    • 41Applied Health Research Centre, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
    • 42Women’s College Research Institute, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
    JAMA. 2021;326(3):257-265. doi:10.1001/jama.2021.9941
    Key Points

    Question  What information should be included in a trial protocol or completed trial article when the study had to undergo important modifications in response to extenuating circumstances such as COVID-19?

    Findings  Developed using a consensus process, a rapid review, and a survey of the international trials community, CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstances) offers guidance for reporting trials and trial protocols that undergo important modifications in response to extenuating circumstances such as the COVID-19 pandemic.

    Meaning  CONSERVE offers guidance that could help improve the transparency, quality, and completeness of reporting important modifications to trials in extenuating circumstances.

    Abstract

    Importance  Extenuating circumstances can trigger unplanned changes to randomized trials and introduce methodological, ethical, feasibility, and analytical challenges that can potentially compromise the validity of findings. Numerous randomized trials have required changes in response to the COVID-19 pandemic, but guidance for reporting such modifications is incomplete.

    Objective  As a joint extension for the CONSORT and SPIRIT reporting guidelines, CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstances) aims to improve reporting of trial protocols and completed trials that undergo important modifications in response to extenuating circumstances.

    Evidence  A panel of 37 international trial investigators, patient representatives, methodologists and statisticians, ethicists, funders, regulators, and journal editors convened to develop the guideline. The panel developed CONSERVE following an accelerated, iterative process between June 2020 and February 2021 involving (1) a rapid literature review of multiple databases (OVID Medline, OVID EMBASE, and EBSCO CINAHL) and gray literature sources from 2003 to March 2021; (2) consensus-based panelist meetings using a modified Delphi process and surveys; and (3) a global survey of trial stakeholders.

    Findings  The rapid review yielded 41 673 citations, of which 38 titles were relevant, including emerging guidance from regulatory and funding agencies for managing the effects of the COVID-19 pandemic on trials. However, no generalizable guidance for all circumstances in which trials and trial protocols might face unanticipated modifications were identified. The CONSERVE panel used these findings to develop a consensus reporting guidelines following 4 rounds of meetings and surveys. Responses were received from 198 professionals from 34 countries, of whom 90% (n = 178) indicated that they understood the concept definitions and 85.4% (n = 169) indicated that they understood and could use the implementation tool. Feedback from survey respondents was used to finalize the guideline and confirm that the guideline’s core concepts were applicable and had utility for the trial community. CONSERVE incorporates an implementation tool and checklists tailored to trial reports and trial protocols for which extenuating circumstances have resulted in important modifications to the intended study procedures. The checklists include 4 sections capturing extenuating circumstances, important modifications, responsible parties, and interim data analyses.

    Conclusions and Relevance  CONSERVE offers an extension to CONSORT and SPIRIT that could improve the transparency, quality, and completeness of reporting important modifications to trials in extenuating circumstances such as COVID-19.

    Introduction

    Randomized trials are an essential tool to inform health care, policy, and regulatory decisions concerning the effects of medical interventions. Forethought and diligence in trial design, statistical approaches, implementation, and analysis are necessary to minimize trial modifications after participant enrollment, which can introduce methodological, ethical, feasibility, and analytical challenges. Amendments to trial procedures are common, and circumstances such as new safety or efficacy information, regulatory requirements, or changes in the standard of care can make those changes unavoidable.1 Modifications can also introduce biases, raising doubts about the validity of the conclusion of a clinical trial.2,3

    COVID-19 has fundamentally changed everyday life, patient care, and health research. Numerous trials that were underway prior to the COVID-19 pandemic faced unavoidable modifications in response to the pandemic, such as changes to methods of recruitment, intervention delivery, outcome assessment (eg, substituting virtual visits for in-person ones), statistical analysis, and sometimes study design. As of January 29, 2021, 2043 trials registered with ClinicalTrials.gov had been terminated, withdrawn, or suspended because of COVID-19, affecting more than 129 000 participants and interrupting plans to recruit more than 4 million future participants.4 Although some health regulatory agencies released guidance on trial modifications due to the COVID-19 pandemic, no consensus exists on how such changes and their implications should be reported.5-8

    Reporting guidelines can improve the completeness and transparency of research reports by defining a minimum set of items to address. While CONSORT (Consolidated Standards of Reporting Trials) 2010 and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 guide reporting for completed trials and trial protocols, respectively, there is limited guidance for reporting trial modifications.9,10 Thorough and consistent reporting of trials that undergo modifications could enhance trial interpretation and transparency, reduce research waste, and facilitate understanding of how trialists respond and adjust to unforeseen circumstances related to major disruptions, such as the COVID-19 pandemic. As a joint extension for CONSORT and SPIRIT, CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstances) aims to provide guidance to improve the reporting of trials and trial protocols that undergo important modifications in response to extenuating circumstances.

    Methods
    CONSERVE Guideline Development Procedure and Panel

    The CONSERVE Panel that convened to develop the guideline was composed of 37 trial investigators, trial methodologists, patient representatives, ethicists, funders, regulators, and journal editors, including CONSORT and SPIRIT executive committee members. Panelists were recruited through professional networks to ensure global and interprofessional representation. CONSERVE was developed between June 2020 and February 2021 following a process adapted from the reporting guideline development procedure of Moher et al,11 modified to replace face-to-face meetings with virtual meetings and emphasizing rapid completion given the unprecedented disruption of trials in the context of the COVID-19 pandemic. The panel wrote and registered a protocol (available through the Open Science Framework at https://osf.io/ms8bz)12 for the guideline development process involving 3 main elements: (1) rapid review, (2) consensus-based meetings and surveys, and (3) a global survey of the trials community. Although the guideline development timeline was extended, the guideline development process proceeded per protocol. The guideline development process did not involve human subjects research as defined by the Tri-Council Policy Statement (Canada) and therefore was outside the scope of research ethics committee review.13

    Rapid Review

    Panelists conducted a rapid review of guidance on modifications to trials.14 A review protocol and search strategy was registered through the Open Science Framework.15

    In brief, a search was conducted for guidance and processes for reporting on modifications to trials and trial protocols, including any type of document from 2003 through August 2020 indexed in the OVID Medline, OVID EMBASE, or EBSCO CINAHL databases and gray literature sources including the US Food and Drug Administration (FDA), the UK National Health Service’s Health Research Authority, the US National Institutes of Health, and the UK National Institute for Health Research in any language. Reference lists of included articles were manually screened to identify additional documents. Searches were conducted by a health research librarian and peer reviewed using the Peer Review of Electronic Search Strategies (PRESS) guideline.16

    Reports on circumstances in which modifications had been prespecified in the protocol, such as adaptive trial designs, were excluded. Reports that involved analysis techniques for missing data were also excluded. Database searches were updated on February 26, 2021; gray literature searches were updated to March 10, 2021 (Supplement 1). The search yielded 41 673 citations, of which 3735 were duplicates, and panelists conducted independent and duplicate screening of titles and abstracts using Covidence software, yielding 38 relevant titles (Supplement 1). The rapid review identified no comprehensive guidance overlapping with the purpose and intent of CONSERVE. All searches are available in Supplement 1.

    Consensus-Based Meetings and Surveys

    Since CONSERVE was envisioned as a joint extension of the CONSORT 2010 and SPIRIT 2013, the first meeting was a virtual gathering of panelists drawn from the SPIRIT-CONSORT executive committee to develop a prototype for CONSERVE. This prototype offered definitions of key concepts, items from the CONSORT and SPIRIT checklists that would require refinement when trials undergo important modifications, and an implementation tool to be used to report on these modifications.

    The entire CONSERVE panel convened through a series of 4 virtual meetings to revise this prototype and build consensus. These meetings were intended to integrate and accelerate the Delphi processes and replace in-person meetings conventionally used to develop reporting guidelines.11 Consensus was defined as being achieved when no panelist called for further revisions.

    Online surveys conducted using Google Forms presented the evolving CONSERVE prototypes in between meetings and sought dissenting views, gaps, and revisions. Survey results structured discussions at the subsequent virtual meetings, where panelists proposed and discussed solutions to problems prior to developing a new prototype. The panel achieved consensus following 3 meetings. Through a fourth, final meeting, the panel refined the resulting guideline and checklists by incorporating the results of the rapid literature review and survey of the global trials community.

    Global Survey of Trials Community

    The panel developed an online survey targeting an international group of trial stakeholders including trial investigators, trial methodologists, trial staff, funders, regulators, ethicists, patient and patient organization representatives, journal publishers, and editors. The survey was conducted to gather feedback to refine the emerging draft guideline; to determine whether it was appropriate and operable for people who are engaged with trials and trial reporting, including public-facing patient representatives; and to identify case studies. The survey was sent by email to a sample of 113 investigators listed as primary contacts for trials registered as ongoing in April 2020, as identified from the search portal of the World Health Organization’s International Clinical Trials Registry Platform. CONSERVE panelists also distributed the survey widely by email within their professional networks. The panel planned to continue distributing the survey until responses were received from all geographic regions and all target stakeholder groups, including investigators, methodologists and statisticians, trial staff, ethicists, editors and publishers, sponsors, regulators, and funders.

    Responses were received from 198 professionals from 34 countries, including 61 respondents from low- and middle-income countries. The top 5 represented countries were the United Kingdom (n = 59), Canada (n = 24), India (n = 15), United States (n = 11), and Australia (n = 9). Briefly, 90% (178/198) of respondents indicated that they understood the CONSERVE concept definitions and 85.4% (169/198) indicated that they understood and could use the CONSERVE implementation tool. Survey questions and response summaries are included in Supplement 1. Feedback from survey respondents was used to finalize the guideline and confirm that the core concepts were suited for widespread implementation.

    Results
    Scope of CONSERVE

    CONSERVE is an extension to the core CONSORT 2010 and SPIRIT 2013 statements and should be used in conjunction with these statements and their explanatory materials.9,10,17,18 CONSERVE is designed to guide reporting for trials that have undergone important modifications in extenuating circumstances (Figure). The concept of extenuating circumstances is intended to limit the scope of CONSERVE to circumstances in which changes to a trial were prompted by unavoidable situations beyond the control of study investigators, sponsors, or funders. The concept of important modifications is intended to limit the scope of CONSERVE to cases for which those modifications have substantive implications for the study at a scientific, ethical, feasibility, inferential, or analytical level. Although the COVID-19 pandemic is the exemplar that prompted the development of CONSERVE, the approach is applicable to other extenuating circumstances that result in important modifications to a trial, such as natural disaster, strikes and other personnel disruptions, regulatory changes, or changes to the clinical standard of care.

    CONSERVE is not a mechanism to redress poor trial design, and it does not encourage unwarranted trial modifications, especially post hoc changes to favor positive results based on accumulating trial data. CONSERVE is based on the observations that protocol amendments are common and that in some circumstances important modifications can be necessary, unavoidable, or beneficial.1 Rather than abandoning trial data and the investments that contributed to data collection, it is better to report the unanticipated circumstances and trial modifications rigorously and transparently.19 CONSERVE provides guidance to support that rigor and transparency.

    The CONSERVE implementation tool (Figure) provides a pathway to determine when CONSERVE should be used to report on trials and trial protocols and provides guidance for its application.

    CONSERVE Checklists

    The CONSERVE checklists are summarized in the implementation tool and provided in Supplement 2. The CONSERVE checklists consist of 4 sections: (1) extenuating circumstances, (2) important modifications including impacts and mitigating strategies, (3) responsible parties, and (4) interim data. The Table provides narrative case studies of trials20-23 that included important modifications in extenuating circumstances and samples of CONSERVE checklist items that might be addressed in a trial report concerning these types of studies.

    CONSERVE provides 2 checklists to support authors in reporting how their trial addressed important modifications in extenuating circumstances. CONSERVE-CONSORT is designed for reporting completed trial results, while CONSERVE-SPIRIT is for reporting trial protocols. Both checklists (Supplement 2) share a common format. The first section of each checklist refers to the extenuating circumstances, responsible parties, interim data, and important modifications. The second section provides an itemized list with rows for each item from the core CONSORT or SPIRIT checklists. The columns offer checkboxes to indicate if that item was unaffected, was directly affected by the extenuating circumstances, or was modified by the study team as a mitigating strategy in response to the extenuating circumstances. A completed checklist should be made available whenever CONSERVE is used for reporting a trial or trial protocol. Because extenuating circumstances can potentially lead to modifications in any aspect of a trial, the CONSERVE checklists incorporate a list of all items from the SPIRIT and CONSORT statements.9,10

    CONSERVE-CONSORT or CONSERVE-SPIRIT should be used instead of CONSORT or SPIRIT when reporting on trials or trial protocols that have undergone important modifications. Authors may add items from other SPIRIT or CONSORT extensions as applicable. Investigators should ensure that the trial registry record is updated to reflect any changes to registered information. Authors should report the items listed in the CONSERVE checklists as applicable throughout the completed trial or protocol. In some circumstances, more limited modifications may be reported with a concise statement or paragraph in the study article’s methods section, whereas in more complex cases modifications may appear throughout the various sections of the article. In cases in which reporting the requisite details requires more space than journal word counts allow, a supplement can be provided to outline the effects of the extenuating circumstances on the trial.

    Extenuating Circumstances

    Authors should describe the circumstances that led to the trial modifications, including how the circumstances are extenuating. Extenuating circumstances refer to unavoidable situations that prompt modifications to a trial and that are not usually under the control of study investigators, sponsors, or funders (Figure). Extenuating circumstances share elements with the contract law concept of force majeure, referring to external events such as wars, strikes, riots, or epidemics that prevent parties from fulfilling their contractual obligations.8 Similarly, extenuating circumstances are unavoidable external events that would prevent trial investigators or participants from adhering to a trial protocol or would necessitate protocol modifications. This is not to suggest that extenuating circumstances must be universally external, unpredictable, and unavoidable but rather that the circumstances would not have been reasonably foreseen or incorporated as part of the study protocol.24 Generally, extenuating circumstances would not include resources shortages, insufficient enrollment to complete the trial as planned, or other factors that might be addressed in a pilot or feasibility study.25

    Circumstances that are extenuating for one trial may not be extenuating for another. For example, while many trials would approach war or an act of terrorism as an extenuating circumstance, trials concerning combat injuries would likely not.26 Therefore, it is important that authors consider and explain how modifications to the study were prompted by unavoidable situations beyond the control of investigators, sponsors, or funders and why those modifications were important from a scientific, ethical, pragmatic, or analytical perspective.

    Important Modifications

    Important modifications incorporate 2 concepts. First, modification refers to any change to a trial. The term modification is used rather than amendment because a modification can be any kind of revision to the anticipated or ongoing trial, regardless of whether it triggers a formal protocol amendment and regardless of whether it represents a change to the trial itself or the context in which the trial occurs. For example, the study by Siegal et al21 conducted in critical care units encountered changes in the populations and underlying conditions of patients admitted to these settings due to the COVID-19 pandemic. The investigators modified their analysis plan to mitigate the effect of these changes (Table). This could represent an important modification to trials conducted in critical care settings regardless of whether such a change triggered an amendment to the study protocol. Second, “important” refers to the subset of modifications that could have a potentially meaningful effect on the study objectives or research question, ethical acceptability (including benefits and harms to participants), internal validity, generalizability, feasibility, or analytical methods and statistical power. Many trials undergo amendments for a range of pragmatic and administrative reasons that do not necessarily constitute important modifications, for example, adding a recruitment site to an existing multicenter trial without modifying the study in any other way. Authors should report the rationale for important modifications and the associated implications for the trial.

    Important modifications can manifest as impacts on the trial or as mitigating strategies. Impacts refer to aspects of the trial that are directly affected or changed by the extenuating circumstance and that are not under the control of investigators, sponsors, or funders. For example, a rotavirus vaccine trial conducted in Niger by Isanaka et al22 was affected by extenuating circumstances when the threat of local terrorism prevented participants from being transported to regional health centers for outcome assessments, precluding some follow-up visits from occurring per protocol (Table). In this case, the extenuating circumstance was terrorism, which affected the outcomes, data collection methods, and participant flow (SPIRIT items 12 and 18; CONSORT items 13 and 17). The trial by Vaillancourt et al20 on out-of-hospital cervical spine immobilization was stopped early when regional authorities enacted a new policy mandating a modified immobilization rule and adopting many aspects of the trial’s experimental intervention as standard of care (Table). In this example, the extenuating circumstance was regional policy change, and the impacts affected both the interventions (SPIRIT item 11; CONSORT item 5) and the numbers analyzed (SPIRIT item 20; CONSORT item 16).

    Mitigating strategies refer to the aspects of the trial that are modified by the study investigators, sponsor, or funder in response to the extenuating circumstances or to manage the impacts on the trial. For example, in the rotavirus vaccine trial,22 investigators were unable to implement mitigating strategies that would enable data collection and therefore reported the cases in which participants could not access outcome assessments or laboratories as protocol deviations (Table). Had security concerns worsened, alternative mitigating strategies might have included revised sample size calculations (SPIRIT item 14; CONSORT item 7), revised outcome assessment procedures for participants facing security concerns (SPIRIT item 18A; CONSORT item 6), or changes to the analysis plan including new ancillary analyses (SPIRIT item 20; CONSORT items 16 and 18). In a trial by James et al23 involving celecoxib for hormone-sensitive prostate cancer, investigators were unable to implement the intended intervention because of unanticipated regulatory changes concerning the use of celecoxib in trials (Table). The investigators’ mitigating strategies included new exclusion criteria for patients with contraindications to celecoxib use (SPIRIT item 10; CONSORT item 4), changes in the intervention duration (SPIRIT item 11; CONSORT item 5), and revisions to the consent materials (SPIRIT item 26).

    Authors should provide a modification timeline, including the dates when extenuating circumstances were identified, the dates when those circumstances took effect on the trial, and the numbers of participants or clusters who had enrolled and completed the trial before and after extenuating circumstances prompted modifications to the trial.8

    Responsible Parties

    Authors should report the parties responsible for planning, reviewing, and approving modifications as well as the responsibilities of each of these parties. Depending on the specifics of the trial, investigators, study staff, participants, regulators, research ethics committees, data monitoring committees, sponsors, and funders may all be involved in planning, reviewing, and approving trial modifications.

    Interim Data

    Authors should report whether accumulating trial data were used to inform modifications, especially if interim examination of those data had the potential to introduce bias. For example, using data concerning recruitment rate or adherence would not generally introduce bias, whereas using outcome data by study group would have a greater potential to bias the choice of mitigating strategies used to respond to extenuating circumstances. Authors should report who accessed and reviewed the data and should describe how the study data were used. It is also important to report whether data were examined by study group and whether decision-makers were blinded to the intervention allocation. In addition, authors should report whether accumulating data were used in an ad hoc manner or according to an analysis plan.

    Examining interim outcome data can bias trial results and interpretation and introduce analytical and ethical challenges when interim analyses are not prespecified or lead to early study termination.27-32 Similar concerns arise if interim data are used to inform unplanned revisions to study procedures. When trials are affected by extenuating circumstances, however, it may be reasonable in some instances to use outcome data to plan and implement mitigating strategies.

    Rather than conducting ad hoc interim analyses in a fully ad hoc manner, trialists can reduce the chance of introducing bias by creating a plan for these interim analyses a priori and detailing how the findings will inform further decisions. These previously unanticipated analyses can be conducted in a planned manner by documenting the intended analysis in the protocol and determining how those analyses will inform modifications a priori.

    Discussion

    CONSERVE aims to provide guidance to help improve the quality, completeness, and transparency of reporting of important modifications due to extenuating circumstances for completed trials and trial protocols. The guidance is designed to be a practical resource for investigators and methodologists, ethicists, editors and publishers, sponsors, regulators and funders, study participants, and the public as they navigate trial reporting in extenuating circumstances, such as the COVID-19 pandemic. The evolving pandemic with its varied global disease burden and government responses has continued to affect clinical trials in diverse ways. CONSERVE discourages unnecessary modifications to trials but acknowledges that managing unanticipated events is an inherent part of the scientific enterprise.

    Although CONSERVE was developed in the context of the COVID-19 pandemic, it applies to reporting on other important modifications to trials. This could help address a gap in existing trial reporting guidance that predates the COVID-19 pandemic and will persist beyond the pandemic. For example, CONSERVE might have enhanced reporting on trials modified by public health emergencies such as the 2014-2016 Ebola virus epidemic, natural disasters, or other unavoidable logistical and ethical concerns.33-37 By promoting complete and transparent reporting of trial modifications, CONSERVE also allows the research community to learn from how extenuating circumstances have been managed, examine the overall impact of those circumstances, and take modifications into account when interpreting trial results. While the COVID-19 pandemic continues to cause disruption to trials worldwide, it provides an opportunity to assess the manner in which important clinical trial modifications are made in response to a variety of extenuating circumstances. The international survey yielded examples of trials that encountered extenuating circumstances including regulatory changes, new standards of care, and security threats (Table).20-23

    CONSERVE may help to reduce the publication biases and wasted research investments that can occur when trials deviate from their protocols.3 By supporting transparency, CONSERVE may also promote public trust in science when studies encounter unanticipated circumstances.38 Consistent reporting of trials that encounter extenuating circumstances could also prompt trialists to develop plans for a wider range of potential disruptions in trial protocols.

    CONSERVE complements regulatory guidance on modifying trials in the context of the COVID-19 pandemic. For example, the UK Medicines and Healthcare Products Regulatory Agency set guidance for trial investigators to assess the risks and benefits of ongoing trials during COVID-19 and to consider options including halting recruitment, adapting delivery processes, stopping or suspending the trial, or mitigating risks as the trial proceeds.39 Guidance from the FDA on trials during the COVID-19 pandemic recommended that trialists describe the contingency measures implemented, list how and which participants were affected including how participation was altered, and provide analyses and discussions that address the effect on safety and efficacy.5 Similar recommendations were made by the Norwegian Medicines Agency and the South African Health Products Regulatory Authority, while the European Medicines Agency (EMA) provided guidance on the methodological aspects of ongoing clinical trials.6-8 The EMA guidance outlined the importance of describing specific dates and durations of issues external to the trial (eg, lockdowns and travel restrictions) and discussed when data review may be warranted to inform study decisions. Guidance from the FDA also addressed statistical methodology as it relates to meeting trial objectives during the pandemic.40 However, existing guidelines did not describe the connections among modifications to the conduct of trials, statistical analysis, and reporting. Other reports have provided analyses on the management of missing data in trials due to COVID-19,41 ethical dimensions of conducting trials during public health emergencies,33,42,43 and the challenges of trial sponsorship during a pandemic.44-46

    Clinical and research specialty societies have also provided guidance on conducting trials during the pandemic, including in oncology, cardiovascular disease and heart failure, and hepatology.46-50 These resources provide methodological guidance, while CONSERVE delivers a framework for reporting what decisions were made, why they were made, and the corresponding impact. Some journals have provided reporting recommendations to authors regarding trials directly affected by the COVID-19 pandemic. Editorials have called on trial authors to describe pandemic-related issues in the methods sections of articles, including changes in study protocol, trial delays or interruptions, issues with missing data, and effects on statistical power.51-53

    The CONSERVE statement has limitations. First, CONSERVE was developed rapidly using a modified process to engage rapidly with a global community of trial investigators, methodologists, ethicists, funders, regulators, journal editors, and patient representatives. Unlike prior reporting guidelines, this process adapted the conventional Delphi process and incorporated several steps to solicit detailed feedback and achieve consensus with a large group of trial professionals and public representatives who refined the process, but substituted in-person discussions with virtual meetings to ensure that dissenting views could be addressed. Second, given that many ongoing trials affected by the pandemic have not yet been published, only a few reports have described how investigators have responded to the extenuating circumstances, limiting the examples available about COVID-19. Third, the global survey sought to capture a large, international body of interdisciplinary persons working on and with trials, and those respondents provided examples and feedback about how CONSERVE could be used. Despite its international representation, including respondents from low- and middle-income countries, CONSERVE may not have captured all relevant perspectives.

    Implementation will be supported by making CONSERVE widely available, including through the SPIRIT and CONSORT websites and other reporting guideline resources such as the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network (https://www.equator-network.org/). The CONSERVE panel will also work with all trial stakeholders including investigators, journals, regulators, and funders to disseminate and endorse the statement. To reach a larger audience, the panel also encourages translation of the CONSERVE checklists to other languages.

    Conclusions

    CONSERVE offers an extension to CONSORT and SPIRIT that could improve the transparency, quality, and completeness of reporting important modifications to trials in extenuating circumstances such as COVID-19.

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    Article Information

    Corresponding Author: Aaron M. Orkin, MD, MSc, MPH, Division of Emergency Medicine, Department of Family and Community Medicine, University of Toronto, 500 University Ave, Toronto, ON M5G 1V7, Canada (aaron.orkin@utoronto.ca).

    Accepted for Publication: June 1, 2021.

    Published Online: June 21, 2021. doi:10.1001/jama.2021.9941

    Author Contributions: Drs Orkin and Gill had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed to developing the guideline protocol and participated in the guideline development process as members of the CONSERVE Working Group. Drs Orkin, Gill, Ghersi, Jüni, and Chan conceived of the project and coordinated its implementation. All other authors appear in random order generated by www.random.org. Drs Orkin, Gill, Ghersi, and Chan prepared the original draft of the manuscript and all authors revised and approved the final draft for submission.

    Concept and design: Orkin, Gill, Ghersi, Campbell, Sugarman, Steg, Simes, H. C. Williams, Wittes, Moher, Getz, Hopewell, Schulz, Boutron, Ross, Golub, Khan, Mulrow, Heber, Lee, Hróbjartsson, Jüni, Chan.

    Acquisition, analysis, or interpretation of data: Orkin, Gill, Ghersi, Emsley, Steg, Weijer, Simes, Rombey, H. C. Williams, Moher, Richards, Kasamon, Dickersin, Wu, Ayala, Calleja, Golub, Khan, Siegfried, Kearney, Wanyenze, Hróbjartsson, R. Williams, Bhandari, Jüni, Chan.

    Drafting of the manuscript: Orkin, Gill, Ghersi, Emsley, Moher, Kasamon, Hopewell, Khan, Heber, Kearney, Jüni.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Orkin, Gill, Jüni.

    Administrative, technical, or material support: Orkin, Gill, Moher, Getz, Schulz, Khan, Siegfried, Lee, Wanyenze, Chan.

    Supervision: Orkin, Gill, Chan.

    Conflict of Interest Disclosures: Dr Gill reported grants from the Physicians’ Services Incorporated Foundation, the Canadian Institutes of Health Research (CIHR), and the Hospital for Sick Children and expenses to attend conferences and meetings reimbursed by the EBMLive Steering Committee and the CIHR Institute of Human Development, Child and Youth Health Institute Advisory Board. Dr Sugarman reported receipt of personal fees from Merck, IQVIA, Aspen Neurosciences, Biogen, and Portola Pharmaceuticals; in addition, he receives stock options not yet exercised from Aspen Neurosciences and nonfinancial support from Merck KGaA and IQVIA. Dr Steg reported receipt of grants and personal fees from Amarin, Bayer, Servier and Sanofi/Regeneron; personal fees from Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Idorsia, Novartis, Novo Nordisk, Pfizer, Sanofi/Lexicon, and Myokardia; and personal fees and nonfinancial support from AstraZeneca. In addition, Dr Steg has a patent issued to Sanofi. Dr Weijer reported receipt of consulting income from Cardialen, Eli Lilly & Co, and RTI International. Dr Simes reported receipt of grants from the National Health and Medical Research Council of Australia, the Cancer Institute of New South Wales, Australia, Cancer Australia, Bayer, Roche, Pfizer, AstraZeneca, and Bristol Myers Squibb. Dr Wittes reported involvement in many studies that have been affected by COVID-19; the company for which she works, WCG Statistics Collaborative, has received consulting fees for those consultations. Dr Richards reported receipt of personal fees from Merck, Eli Lilly & Co, Novo Nordisk, and Innomar; consulting fees from Janssen and the CIHR Institute of Musculoskeletal Health and Arthritis; and being volunteer vice president of the Canadian Arthritis Patient Alliance, for which her efforts are supported via independent grants by pharmaceutical firms. Dr Ross reported receipt of grants from Johnson & Johnson, the FDA, the Agency for Healthcare Research and Quality, the Laura and John Arnold Foundation, the National Institutes of Health/National Heart, Lung, and Blood Institute, and the Medical Devices Innovation Consortium and being a current US research and outreach editor at The BMJ. Dr Khan reported being scientific director of the CIHR Institute of Musculoskeletal Health and Arthritis. Dr Jüni reported serving as unpaid member of the steering group of trials funded by Appili Therapeutics, Astra Zeneca, Biotronik, Biosensors, St Jude Medical, and The Medicines Company; receiving research grants to his institution from AstraZeneca, Biotronik, Biosensors International, Eli Lilly & Co, and The Medicines Company; and receiving honoraria to his institution for participation in advisory boards and/or consulting from Amgen, Ava, and Fresenius; he has not received personal payments from any pharmaceutical company or device manufacturer. No other disclosures were reported.

    Funding/Support: Dr Orkin receives salary support from the University of Toronto Department of Family and Community Medicine and the CIHR Postdoctoral Fellowship Program. Dr Emsley is supported by grant NIHR300051 from the National Institute of Health Research. Dr R. Williams’ work was supported by the Intramural Research Program of the National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health.

    Role of the Funder/Sponsor: The supporting organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

    Disclaimer: The views expressed in this article do not necessarily reflect the views or policies of the National Institutes of Health. This article represents the views and findings of the authors and not necessarily of the institutions with which they are affiliated. Dr Golub is Deputy Editor of JAMA but was not involved in any of the decisions regarding review of the manuscript or its acceptance.

    Group Information: The CONSERVE Group members appear in Supplement 3.

    Additional Contributions: We thank all of the respondents to the CONSERVE survey and acknowledge in particular Christian Vaillancourt, MD, MSc (University of Ottawa), Monica Taljaard, PhD (University of Ottawa), Jennifer Brunet, MA, PhD (University of Ottawa), Rebecca Grais, PhD (Médecins Sans Frontières), and Matthew Sydes, MSc, CStat (University College London), for contributing case studies to the project. We thank Joanne Roberti (Unity Health Toronto) and Arani Muthuraja (Women’s College Hospital, Toronto) for administrative support. Dr Orkin acknowledges Ross Upshur, MA, MD, MSc (University of Toronto), for enabling him to pursue this initiative and the SOONER Project Investigators for prompting this work. None of these individuals received compensation for their contributions to this work.

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