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Figure.  Flow Diagram of the Guidelines Development Process
Flow Diagram of the Guidelines Development Process

PRO indicates patient-reported outcome.

aSee eTable 1 in the Supplement for details regarding Delphi survey and consensus meeting participant characteristics.

bSix additional stakeholders provided comments prior to or after the meeting.

Table.  Implementation Tool for PRO Researchers and Research Ethics Committeesa
Implementation Tool for PRO Researchers and Research Ethics Committeesa
1.
Calvert  M, Kyte  D, Price  G, Valderas  JM, Hjollund  NH.  Maximising the impact of patient reported outcome assessment for patients and society.   BMJ. 2019;364:k5267. doi:10.1136/bmj.k5267 PubMedGoogle ScholarCrossref
2.
Basch  E, Deal  AM, Dueck  AC,  et al.  Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment.   JAMA. 2017;318(2):197-198. doi:10.1001/jama.2017.7156 PubMedGoogle ScholarCrossref
3.
Cruz Rivera  S, Mercieca-Bebber  R, Aiyegbusi  OL,  et al.  The need for ethical guidance for the use of patient-reported outcomes in research and clinical practice.   Nat Med. 2021;27(4):572-573. doi:10.1038/s41591-021-01275-z PubMedGoogle ScholarCrossref
4.
Kyte  D, Retzer  A, Ahmed  K,  et al.  Systematic evaluation of patient-reported outcome protocol content and reporting in cancer trials.   J Natl Cancer Inst. 2019;111(11):1170-1178. doi:10.1093/jnci/djz038 PubMedGoogle ScholarCrossref
5.
Kyte  D, Ives  J, Draper  H, Calvert  M.  Management of patient-reported outcome (PRO) alerts in clinical trials: a cross sectional survey.   PLoS One. 2016;11(1):e0144658. doi:10.1371/journal.pone.0144658 PubMedGoogle ScholarCrossref
6.
Kyte  D, Draper  H, Calvert  M.  Patient-reported outcome alerts: ethical and logistical considerations in clinical trials.   JAMA. 2013;310(12):1229-1230. doi:10.1001/jama.2013.277222 PubMedGoogle ScholarCrossref
7.
Hagell  P, Reimer  J, Nyberg  P.  Whose quality of life? ethical implications in patient-reported health outcome measurement.   Value Health. 2009;12(4):613-617. doi:10.1111/j.1524-4733.2008.00488.x PubMedGoogle ScholarCrossref
8.
Calvert  M, Kyte  D, Mercieca-Bebber  R,  et al; the SPIRIT-PRO Group.  Guidelines for inclusion of patient-reported outcomes in clinical trial protocols: the SPIRIT-PRO Extension.   JAMA. 2018;319(5):483-494. doi:10.1001/jama.2017.21903 PubMedGoogle ScholarCrossref
9.
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.1000217 PubMedGoogle ScholarCrossref
10.
Cruz Rivera  S, Stephens  R, Mercieca-Bebber  R,  et al.  ‘Give Us The Tools!’: development of knowledge transfer tools to support the involvement of patient partners in the development of clinical trial protocols with patient-reported outcomes (PROs), in accordance with SPIRIT-PRO Extension.   BMJ Open. 2021;11(6):e046450. doi:10.1136/bmjopen-2020-046450 PubMedGoogle ScholarCrossref
11.
COMET Initiative. DelphiManager. Accessed May 5, 2021. https://www.comet-initiative.org/delphimanager/
12.
NHS Health Research Authority. Guidance and policy for REC members: standard operating procedures for research ethics committees (SOPs). Accessed October 21, 2021. https://www.hra.nhs.uk/about-us/committees-and-services/res-and-recs/research-ethics-committee-members-area/guidance-and-policy-for-rec-members/
13.
Williamson  PR, Altman  DG, Bagley  H,  et al.  The COMET handbook: version 1.0.   Trials. 2017;18(3)(suppl 3):280. doi:10.1186/s13063-017-1978-4 PubMedGoogle ScholarCrossref
14.
Kyte  D, Duffy  H, Fletcher  B,  et al.  Systematic evaluation of the patient-reported outcome (PRO) content of clinical trial protocols.   PLoS One. 2014;9(10):e110229. doi:10.1371/journal.pone.0110229 PubMedGoogle ScholarCrossref
15.
Mercieca-Bebber  R, Friedlander  M, Kok  P-S,  et al.  The patient-reported outcome content of international ovarian cancer randomised controlled trial protocols.   Qual Life Res. 2016;25(10):2457-2465. doi:10.1007/s11136-016-1339-x PubMedGoogle ScholarCrossref
16.
Food and Drug Administration. Patient-reported outcome measures: use in medical product development to support labeling claims: guidance for industry. December 2009. Accessed February 2, 2021. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf
17.
Emanuel  EJ, Wendler  D, Grady  C.  What makes clinical research ethical?   JAMA. 2000;283(20):2701-2711. doi:10.1001/jama.283.20.2701 PubMedGoogle ScholarCrossref
18.
Rothrock  NE, Kaiser  KA, Cella  D.  Developing a valid patient-reported outcome measure.   Clin Pharmacol Ther. 2011;90(5):737-742. doi:10.1038/clpt.2011.195 PubMedGoogle ScholarCrossref
19.
Beauchamp  TL, Childress  JF.  Principles of Biomedical Ethics. Oxford University Press; 2001.
20.
Truog  RD, Robinson  W, Randolph  A, Morris  A.  Is informed consent always necessary for randomized, controlled trials?   N Engl J Med. 1999;340(10):804-807. doi:10.1056/NEJM199903113401013 PubMedGoogle ScholarCrossref
21.
Bacchetti  P, Wolf  LE, Segal  MR, McCulloch  CE.  Ethics and sample size.   Am J Epidemiol. 2005;161(2):105-110. doi:10.1093/aje/kwi014 PubMedGoogle ScholarCrossref
22.
Rutherford  C, Costa  D, Mercieca-Bebber  R, Rice  H, Gabb  L, King  M.  Mode of administration does not cause bias in patient-reported outcome results: a meta-analysis.   Qual Life Res. 2016;25(3):559-574. doi:10.1007/s11136-015-1110-8 PubMedGoogle ScholarCrossref
23.
Mercieca-Bebber  R, Palmer  MJ, Brundage  M, Calvert  M, Stockler  MR, King  MT.  Design, implementation and reporting strategies to reduce the instance and impact of missing patient-reported outcome (PRO) data: a systematic review.   BMJ Open. 2016;6(6):e010938. doi:10.1136/bmjopen-2015-010938 PubMedGoogle ScholarCrossref
24.
Mercieca-Bebber  R, Calvert  M, Kyte  D, Stockler  M, King  MT.  The administration of patient-reported outcome questionnaires in cancer trials: interviews with trial coordinators regarding their roles, experiences, challenges and training.   Contemp Clin Trials Commun. 2017;9:23-32. doi:10.1016/j.conctc.2017.11.009 PubMedGoogle ScholarCrossref
25.
Kyte  D, Ives  J, Draper  H, Keeley  T, Calvert  M.  Inconsistencies in quality of life data collection in clinical trials: a potential source of bias? interviews with research nurses and trialists.   PLoS One. 2013;8(10):e76625. doi:10.1371/journal.pone.0076625 PubMedGoogle ScholarCrossref
26.
Ford  JG, Howerton  MW, Lai  GY,  et al.  Barriers to recruiting underrepresented populations to cancer clinical trials: a systematic review.   Cancer. 2008;112(2):228-242. doi:10.1002/cncr.23157 PubMedGoogle ScholarCrossref
27.
Basch  E, Stover  AM, Schrag  D,  et al.  Clinical utility and user perceptions of a digital system for electronic patient-reported symptom monitoring during routine cancer care: findings from the PRO-TECT Trial.   JCO Clin Cancer Inform. 2020;4:947-957. doi:10.1200/CCI.20.00081 PubMedGoogle ScholarCrossref
28.
European Medicines Agency. Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man: the use of patient-reported outcome (PRO) measures in oncology studies. April 1, 2016. Accessed February 2, 2021. https://www.ema.europa.eu/documents/other/appendix-2-guideline-evaluation-anticancer-medicinal-products-man_en.pdf
29.
Basch  E, Abernethy  AP, Mullins  CD,  et al.  Recommendations for incorporating patient-reported outcomes into clinical comparative effectiveness research in adult oncology.   J Clin Oncol. 2012;30(34):4249-4255. doi:10.1200/JCO.2012.42.5967 PubMedGoogle ScholarCrossref
30.
Shepshelovich  D, McDonald  K, Spreafico  A,  et al.  Feasibility assessment of using the complete Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) item library.   Oncologist. 2019;24(4):e146-e148. doi:10.1634/theoncologist.2018-0332 PubMedGoogle ScholarCrossref
31.
Calvert  M, King  M, Mercieca-Bebber  R,  et al.  SPIRIT-PRO Extension explanation and elaboration: guidelines for inclusion of patient-reported outcomes in protocols of clinical trials.   BMJ Open. 2021;11(6):e045105. doi:10.1136/bmjopen-2020-045105 PubMedGoogle ScholarCrossref
32.
Bausewein  C, Daveson  BA, Currow  DC,  et al.  EAPC white paper on outcome measurement in palliative care: improving practice, attaining outcomes and delivering quality services: recommendations from the European Association for Palliative Care (EAPC) Task Force on Outcome Measurement.   Palliat Med. 2016;30(1):6-22. doi:10.1177/0269216315589898 PubMedGoogle ScholarCrossref
33.
Legislation.gov.uk. Mental Capacity Act 2005. Accessed October 21, 2021. https://www.legislation.gov.uk/ukpga/2005/9/contents
34.
Evans  CJ, Benalia  H, Preston  NJ,  et al; MORECare.  The selection and use of outcome measures in palliative and end-of-life care research: the MORECare International Consensus Workshop.   J Pain Symptom Manage. 2013;46(6):925-937. doi:10.1016/j.jpainsymman.2013.01.010 PubMedGoogle ScholarCrossref
35.
Turner  G, Aiyegbusi  OL, Price  G, Skrybant  M, Calvert  M.  Moving beyond project-specific patient and public involvement in research.   J R Soc Med. 2020;113(1):16-23. doi:10.1177/0141076819890551 PubMedGoogle ScholarCrossref
36.
Wilson  P, Mathie  E, Keenan  J,  et al. Health services and delivery research. In:  Research With Patient and Public Involvement: A Realist Evaluation: The RAPPORT Study. NIHR Journals Library; 2015.
37.
Wilson  R.  Patient led PROMs must take centre stage in cancer research.   Res Involv Engagem. 2018;4(7). doi:10.1186/s40900-018-0092-4 Google ScholarCrossref
38.
National Institute for Health and Care Research. Briefing notes for researchers: public involvement in NHS, health and social care research. April 5, 2021. Accessed September 9, 2021. https://www.nihr.ac.uk/documents/briefing-notes-for-researchers-public-involvement-in-nhs-health-and-social-care-research/27371
39.
Ives  J, Damery  S, Redwod  S.  PPI, paradoxes and Plato: who’s sailing the ship?   J Med Ethics. 2013;39(3):181-185. doi:10.1136/medethics-2011-100150 PubMedGoogle Scholar
40.
Hughes  SE, Haroon  S, Subramanian  A,  et al.  Development and validation of the Symptom Burden Questionnaire for Long COVID (SBQ-LC): Rasch analysis.   BMJ. 2022;377:e70230Google Scholar
41.
Bernhard  J, Cella  DF, Coates  AS,  et al.  Missing quality of life data in cancer clinical trials: serious problems and challenges.   Stat Med. 1998;17(5-7):517-532. doi:10.1002/(SICI)1097-0258(19980315/15)17:5/7<517::AID-SIM799>3.0.CO;2-S PubMedGoogle Scholar
42.
Ware  JH, Harrington  D, Hunter  DJ, D’Agostino  RB.  Missing data.   N Engl J Med. 2012;367:1353-1354. doi:10.1056/NEJMsm1210043 Google Scholar
43.
Retzer  A, Calvert  M, Ahmed  K,  et al.  International perspectives on suboptimal patient-reported outcome trial design and reporting in cancer clinical trials: a qualitative study.   Cancer Med. 2021;10(16):5475-5487. doi:10.1002/cam4.4111 PubMedGoogle Scholar
44.
Brundage  M, Leis  A, Bezjak  A,  et al.  Cancer patients’ preferences for communicating clinical trial quality of life information: a qualitative study.   Qual Life Res. 2003;12(4):395-404. doi:10.1023/A:1023404731041 PubMedGoogle Scholar
45.
Bottomley  A, Efficace  F, Thomas  R, Vanvoorden  V, Ahmedzai  SH.  Health-related quality of life in non-small-cell lung cancer: methodologic issues in randomized controlled trials.   J Clin Oncol. 2003;21(15):2982-2992. doi:10.1200/JCO.2003.01.203 PubMedGoogle Scholar
46.
Calvert  M, Blazeby  J, Altman  DG, Revicki  DA, Moher  D, Brundage  MD; CONSORT PRO Group.  Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO Extension.   JAMA. 2013;309(8):814-822. doi:10.1001/jama.2013.879 PubMedGoogle Scholar
47.
National Institutes of Health. Guiding principles for ethical research. Accessed March 23, 2022. https://www.nih.gov/health-information/nih-clinical-research-trials-you/guiding-principles-ethical-research
48.
Canadian Institutes of Health Research; Natural Sciences and Engineering Research Council of Canada; Social Sciences and Humanities Research Council of Canada. Chapter 1: ethical framework. In:  Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. Government of Canada; December 2018.
49.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053 PubMedGoogle Scholar
50.
Department of Health, Education, and Welfare.  The Belmont Report. Department of Health, Education, and Welfare; 1979.
51.
Council for International Organizations of Medical Sciences.  2016 International Ethical Guidelines for Health-Related Research Involving Humans. Council for International Organizations of Medical Sciences; 2016.
Special Communication
May 17, 2022

Ethical Considerations for the Inclusion of Patient-Reported Outcomes in Clinical Research: The PRO Ethics Guidelines

Author Affiliations
  • 1Centre for Patient Reported Outcomes Research, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom
  • 2Birmingham Health Partners Centre for Regulatory Science and Innovation, University of Birmingham, Birmingham, United Kingdom
  • 3DEMAND Hub, University of Birmingham, Birmingham, United Kingdom
  • 4National Institute for Health and Care Research (NIHR) Applied Research Centre West Midlands, Birmingham, United Kingdom
  • 5Centre for Ethics in Medicine, Bristol Medical School, University of Bristol, Bristol, United Kingdom
  • 6Warwick Medical School, University of Warwick, Coventry, United Kingdom
  • 7NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, New South Wales, Australia
  • 8School of Population and Global Health, McGill University, Montreal, Quebec, Canada
  • 9A J Hunn Associates, London, United Kingdom
  • 10PRO Center of Excellence, Global Commercial Strategy Organization, Janssen Global Services, Warrington, United Kingdom
  • 11Division of Pediatric Haematology-Oncology, IWK Health Care Centre, Dalhousie University, Halifax, Nova Scotia, Canada
  • 12Observational and Pragmatic Research Institute, Midview City, Singapore
  • 13US Food and Drug Administration, Silver Spring, Maryland
  • 14European Organization for Research and Treatment of Cancer, Brussels, Belgium
  • 15Medicines and Healthcare Products Regulatory Agency, London, United Kingdom
  • 16Health Research Authority, London, United Kingdom
  • 17Patient partner, University of Birmingham, Birmingham, United Kingdom
  • 18Fast Track Research Ethics Committee, Health Research Authority, London, United Kingdom
  • 19JAMA Network, Chicago, Illinois
  • 20RTI Health Solutions, Research Triangle, North Carolina
  • 21Aparito Limited, Wrexham, Wales, United Kingdom
  • 22MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
  • 23NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, United Kingdom
  • 24NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, United Kingdom
  • 25Aetion, Washington, DC
  • 26Department of Clinical Trial Data Management, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
  • 27Global Patient-Centred Outcomes Research & Policy, UCB, Belgium, Brussels
  • 28Nature Medicine, New York, New York
  • 29Department of Cardiology, Odense University Hospital, Odense, Denmark
  • 30Clinical Institute, University of Southern Denmark, Odense, Denmark
  • 31Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 32Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia
  • 33Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island
  • 34University of North Carolina at Chapel Hill
  • 35Consumer Forum, National Cancer Research Institute, London, United Kingdom
  • 36Patient Involvement Network, Health Research Authority, London, United Kingdom
  • 37Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom
  • 38Health Data Research United Kingdom, London, United Kingdom
  • 39UK SPINE, University of Birmingham, Birmingham, United Kingdom
JAMA. 2022;327(19):1910-1919. doi:10.1001/jama.2022.6421
Key Points

Question  What ethical considerations should be considered by researchers, research ethics committees, and funders when conducting or reviewing patient-reported outcome (PRO) clinical research?

Findings  An international consensus Delphi process was developed according to the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodology; 14 items addressing ethical considerations were recommended for inclusion in the PRO ethics guidelines.

Meaning  Addressing the items in the PRO ethics guidelines has the potential to improve the quality of PRO in clinical research while promoting and protecting participant autonomy and protecting participant and researcher welfare.

Abstract

Importance  Patient-reported outcomes (PROs) can inform health care decisions, regulatory decisions, and health care policy. They also can be used for audit/benchmarking and monitoring symptoms to provide timely care tailored to individual needs. However, several ethical issues have been raised in relation to PRO use.

Objective  To develop international, consensus-based, PRO-specific ethical guidelines for clinical research.

Evidence Review  The PRO ethics guidelines were developed following the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network’s guideline development framework. This included a systematic review of the ethical implications of PROs in clinical research. The databases MEDLINE (Ovid), Embase, AMED, and CINAHL were searched from inception until March 2020. The keywords patient reported outcome* and ethic* were used to search the databases. Two reviewers independently conducted title and abstract screening before full-text screening to determine eligibility. The review was supplemented by the SPIRIT-PRO Extension recommendations for trial protocol. Subsequently, a 2-round international Delphi process (n = 96 participants; May and August 2021) and a consensus meeting (n = 25 international participants; October 2021) were held. Prior to voting, consensus meeting participants were provided with a summary of the Delphi process results and information on whether the items aligned with existing ethical guidance.

Findings  Twenty-three items were considered in the first round of the Delphi process: 6 relevant candidate items from the systematic review and 17 additional items drawn from the SPIRIT-PRO Extension. Ninety-six international participants voted on the relevant importance of each item for inclusion in ethical guidelines and 12 additional items were recommended for inclusion in round 2 of the Delphi (35 items in total). Fourteen items were recommended for inclusion at the consensus meeting (n = 25 participants). The final wording of the PRO ethical guidelines was agreed on by consensus meeting participants with input from 6 additional individuals. Included items focused on PRO-specific ethical issues relating to research rationale, objectives, eligibility requirements, PRO concepts and domains, PRO assessment schedules, sample size, PRO data monitoring, barriers to PRO completion, participant acceptability and burden, administration of PRO questionnaires for participants who are unable to self-report PRO data, input on PRO strategy by patient partners or members of the public, avoiding missing data, and dissemination plans.

Conclusions and Relevance  The PRO ethics guidelines provide recommendations for ethical issues that should be addressed in PRO clinical research. Addressing ethical issues of PRO clinical research has the potential to ensure high-quality PRO data while minimizing participant risk, burden, and harm and protecting participant and researcher welfare.

Introduction

Patient-reported outcomes (PROs) are used in clinical research and routine care to provide information on the physical, functional, and psychological effects of disease and treatment from the patient perspective.1 PRO data can inform health care decisions, regulatory decisions, health care policy, and cost-effectiveness analyses. PROs can also be used for audit/benchmarking and monitoring of symptoms to provide timely care tailored to individual needs.1,2 Notwithstanding the potential benefits of incorporating PROs in research and routine practice, ethical considerations have been highlighted.3 For example, the PRO content of clinical trial protocols and reporting of PRO results is commonly inadequate. A 2019 evaluation of 160 cancer trials showed nearly 50 000 participants were included in studies that failed to publish their PRO data.4

The increasing use of PROs may lead to uncertainties for patients about why data are being collected and used. There is a lack of guidance on how research personnel should manage situations in which PRO data reveal concerning levels of psychological distress or physical symptoms.5 If concerning data are not managed appropriately, those data could lead to suboptimal participant care or biased trial results.6 In addition, PRO research may not reflect the perspectives of underserved groups such as older individuals, socioeconomically disadvantaged populations, and racial and ethnic minority groups, which could threaten the scientific validity of results.3,7

Ethical issues should be resolved with justifications that use established principles, theories, and values, as well as consider individual and societal welfare.3 In 2018, the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials)-PRO Extension was developed to provide PRO trial protocol guidance.8 These guidelines were not, however, developed specifically for the use of research ethics committees (RECs) and limited attention has been given to the ethical dimensions of PROs in clinical research.7 Thus, there is a need to develop ethical guidelines to address this. The aim of this international effort was to develop consensus-based guidelines for the specific use of PROs in clinical research.

Methods

The PRO ethics guidelines were developed through an international Delphi process following the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network’s framework for guideline development (Figure).9

The PRO Ethics Steering Group, formed by 11 international experts with patient and public involvement (Acknowledgements in the Supplement), was established to oversee the design and conduct of the study.

Ethical Approval

Ethical approval was given by the University of Birmingham Ethical Review Board (ERN_21-0075).

Systematic Review and Generation of Candidate Items

Candidate items were identified by the steering group from the SPIRIT-PRO Extension8 guidelines and Supplement 3 of the accompanying SPIRIT-PRO Extension article.8 Explanation of the candidate items was derived from lay terminology of the SPIRIT-PRO Extension.10 The candidate items were supplemented with items generated from a systematic review of articles describing the ethical implications of PROs in clinical research. The protocol for the systematic review was registered on PROSPERO (registration No. CRD42020176177). The databases MEDLINE (Ovid), EMBASE, Allied and Complementary Medicine Database (AMED), and CINAHL (Cumulative Index to Nursing and Allied Health Literature) Plus were searched from inception until March 2020 with the keywords patient reported outcome* and ethic*.

Publications were deemed eligible if they discussed ethical implications and/or guidance in the context of PRO clinical trials research, routine clinical practice, and broader PRO research. Two reviewers (SCR and OLA) independently conducted title and abstract screening before full-text screening to determine eligibility. Discrepancies were resolved through the involvement of a third reviewer (MJC). Text excerpts on ethical considerations of PRO research from the included studies were independently extracted by the 2 investigators (SCR and OLA) into a qualitative data analysis software package (NVivo 12; QSR International). Both reviewers independently generated categories and themes under the thematic analysis approach. The review identified 14 relevant articles, including qualitative reports, opinion and debate articles, and special communications that discussed the ethical implications of PRO research.

Based on the review, 6 candidate items were identified, and 17 items were drawn from the SPIRIT-PRO Extension guidelines8 and Supplement 3 of that article.

International Delphi Process

In 2021, 201 international multidisciplinary individuals with interest in PRO research were invited to participate in the online Delphi process to vote on the candidate items and propose additional items. These participants comprised individuals responsible for developing PRO research submissions for ethical review, those undertaking ethical review, or using of data arising from PRO research. Potential participants were identified and contacted via the PRO Ethics Operations Group (S.C.R., M.J.C., O.L.A., A.P.D.) and the Health Research Authority (HRA). A snowballing technique and social media (LinkedIn and Twitter) were used to identify further participants. Participant characteristics are described in eTable 1 in the Supplement. DelphiManager software (version 5.0), developed and maintained by the COMET (Core Outcome Measures in Effectiveness Trials) Initiative, was used to undertake the 2 Delphi surveys.11

Participants were provided with written information about the study prior to consenting to participate. Participants voted anonymously on a 9-point scale (1-3: not important; 4-6: important but not critical; and 7-9: important and critical) on the importance of the 23 items presented. Ninety-six responses were received for round 1 of the Delphi and 85 responses (89% of participants from round 1) were received for round 2. Participants were advised if they did not complete round 2, their round 1 responses would be retained. During round 1, participants had the option to suggest additional items. During round 2, 12 additional items were included. Anonymized item-level round 1 scores per participant group were presented to Delphi panelists for their consideration prior to round 2 voting.

International Consensus Meeting

The operations group mapped the 35 candidate PRO ethics items to existing HRA guidance from the UK, as an initial indicator of what may already be covered in existing ethics guidance,12 removing duplicates and revising wording to aid clarification. The operations group presented the consensus delegates with recommendations for the inclusion or exclusion of items based on the decision tree (eFigure in the Supplement). The COMET Initiative guidance informed the inclusion criteria (eMethods in the Supplement).13

An online consensus meeting took place in October 2021 hosted by the University of Birmingham, UK. Twenty-five international participants purposively selected from the Delphi survey attended the consensus meeting, comprising 7 clinical trialists/health academic researchers, 4 ethicists/members of an ethical review panel, 2 health care professionals, 3 PRO researchers from industry, 2 journal editors, 4 patients and members of the public, 1 policy maker, 1 regulator, and 1 bioethicist (eTable 1 in the Supplement). Delegates were presented with candidate items and anonymously voted using the Zoom poll tool. Participants had the following voting options: include, exclude, or further discussion required (see the Participation in the Voting Process section, eMethods in the Supplement, for further details).

The aim of the meeting was to seek consensus on the content of the PRO ethics guidelines. Consensus panelists considered the focus of the guidelines and agreed that the guidelines covered ethical considerations when undertaking PRO clinical research. In addition, participants discussed the wording and explanatory text of each item. A threshold of 70% or more was prespecified to demonstrate consensus when voting on the items (see the Consensus Meeting section, eMethods in the Supplement, for further details). The items were presented alongside the overall Delphi score and the number of participant groups whereby 70% or more of respondents scored an item as important and critical.

Final Consultation

Following the consensus meeting, attendees commented on the wording and agreed on the final version of the PRO ethics guidelines. Final edits were made to improve clarity and were approved by the steering group and patient partners. The eMethods section in the Supplement provides further information on methods.

Results
The PRO Ethics Guidelines

The final PRO ethics guidelines identified 14 key questions that capture core ethical issues (Table). The items incorporated content from 14 of the 35 original candidate items, comprising 6 items that were merged during the consensus meeting and 8 items that were not modified (see eTables 2 and 3a and 3b in the Supplement). Further details about the 21 excluded items are presented in eTables 4a and 4b in the Supplement. An explanation describing each item with supporting evidence is presented below. The items are presented in accordance with SPIRIT-PRO Extension subheadings and findings from the systematic review.

Introduction: Background and Rationale
Item 1: How Clear Is the PRO-Specific Research Question? What Is the Justification and Rationale for PRO Assessment?

Explanation: Evidence suggests that many trials include PROs without specifying the PRO-specific research question and without a rationale or reference to PROs in related studies.4,14,15 Researchers should carefully consider the PRO-specific research question to inform the selection of measures and methodological approach to help ensure results are meaningful.8 In addition, patients and research personnel should understand why PRO data are being collected and how their data will be used, and this should be communicated effectively.4,14,15 This can help build trust, particularly when participants may share potentially sensitive information. Why data are being collected and how these data will be used should be clearly explained in the information sheet, by research personnel, or both during the consent process.

Item 2: How Clearly Are the PRO Objectives or Hypotheses Defined?

Explanation: Clearly defined PRO objectives and hypotheses inform study design, including the selection of key PRO concepts and measures, time points for assessment, and analyses.16 Poorly defined PRO objectives or hypotheses may affect the quality of research design and reporting. Poor science undermines participant consent (failing to respect autonomy) and exposes participants to unnecessary risk or burden because the results are ultimately not usable or not generalizable.

Methods: Participants, Interventions, and Outcomes
Item 3: Are Any PRO-Specific Eligibility Requirements Identified (eg, Language, Literacy Requirements) and How Clearly Have These Been Justified?

Explanation: Researchers should consider PRO-specific eligibility requirements at the design stage of the study and robustly justify excluding a subpopulation. It would undermine the principle of justice to exclude eligible people either directly or indirectly (eg, as a result of a failure to consider PRO accessibility or other equity, diversity, and inclusion issues).17

Item 4: Which PRO Concepts/Domains (eg, Overall Health-Related Quality of Life, Specific Domain, Specific Symptom) and Instruments Have Been Specified? How Has the PRO Analysis Metric (eg, Change From Baseline, Final Value, Time to Event) and the Principal Time Point, or Period of Interest, Been Specified and Justified?

Explanation: The PRO concept and analysis metric should be clearly outlined and aligned with the PRO objectives and hypothesis to ensure that they capture outcomes that matter to patients and other key interested groups, such as clinicians, regulators, and policy makers. Defining and justifying the selection of PRO instrument(s) are important aspects of ethical research. If possible, the PRO measure should be validated in the target population. The number of questionnaires used, acceptability of the questions, and participant burden should be considered carefully. PRO measures ideally should be used in accordance with existing user manuals to promote data quality and ensure standardized scoring.8 When a PRO is being considered for a new population, representative patient input should be obtained about the suitability and appropriateness of the questions to determine whether the questions are relevant to the target population.18

Item 5: What Is the Schedule of PRO Assessments? How Well Does the Participant Information Sheet Provide Information on the Number and Frequency of PRO Assessments?

Explanation: Providing the schedule of PRO assessments in the study protocol and participant information sheet is the first step to ensuring potential participants understand the commitment and effort involved in taking part in the PRO study. A robust consent process includes information provision and checks on understanding. A poor process compromises respect for participant autonomy.19,20

Item 6: When the PRO Is a Primary End Point, What Justification Is Provided for the Sample Size?

Explanation: Exposing participants to the risks and burdens of PRO research is only justifiable if these are outweighed by the potential value of the PRO data. A sample size that is too small may produce inconclusive and, therefore, not valuable results. A sample size that is too large will expose more participants than necessary to risks and burdens and incur unnecessary costs.21 Item 14 of the SPIRIT-PRO Extension indicates that if PROs are the primary outcome of a study, a priori sample size calculation should be provided for that specific end point. If PROs are a secondary outcome, the sample size should provide enough power to test the principal PRO hypothesis.8 This would not be required for exploratory PRO end points.

Methods: Data Collection, Management, and Analysis
Item 7: What Details About the Data Collection Plan Have Been Provided, Including the Permitted Mode(s) of PRO Administration (eg, Paper, Telephone, Electronic, Other) and Setting (eg, Clinic, Home, Other)?

Explanation: Research personnel should understand how and where PRO data will be collected, and clear communication of this to potential participants is an essential component of a robust informed consent process. The mode(s) of administration should be influenced by the setting in which PRO data will be collected (eg, telephone or electronic completion may be more feasible from home) and the needs of the target population.22 Ideally, participants from the target population would provide input on modes. Offering alternative modes of completion may help improve response rates and promote inclusivity and equity—all of which improve the quality of the results.23 Item 18a(ii) of the SPIRIT-PRO Extension provides further information regarding the modes of PRO administration and setting for PRO randomized clinical trials.8

Item 8: What, If Any, PRO Data Monitoring for Concerning Responses Will Occur During the Study and How Will This Inform the Clinical Care of Individual Study Participants?

Explanation: Responding to PRO alerts (concerning levels of psychological distress or physical symptoms that require timely response)6 may protect the safety and welfare of participants,17 which is an important ethical consideration. The research protocol should state whether, why, and by whom PRO data will be monitored during the study and this information should be shared with participants.5,6 In low-risk studies in which alerts for concerning symptoms are not anticipated, PRO monitoring may not be necessary. Similarly, protocols should state whether research data will be shared with the patient’s care team or entered in the electronic medical record. Alternative support mechanisms (eg, 24-hour helpline) for participants should be outlined. All research personnel involved in the management of PRO alerts should receive appropriate training and have clear pathways for support.24,25 Evidence suggests research personnel handle such data inconsistently, which may lead to inequitable patient care, cointervention bias, and confusion.6 In addition, personnel in charge of collecting PRO data may feel emotional and/or ethical burden while dealing with concerning PRO data (eg, reports from trial participants of low self-esteem, depression, or risk of self-harm or suicide).25

Item 9: How Have Barriers to PRO Completion (eg, Mode of Administration, Language, Cultural Needs, Accessibility) Been Minimized and Addressed to Promote Participant Inclusivity?

Explanation: PRO protocols should promote participant inclusivity while recruiting a diverse population that is representative of patients with the condition of interest. Barriers to participation, such as access to technology in rural areas, areas of socioeconomic disadvantage, or both, as well as disability, language, and cultural requirements, should be addressed to promote fairness and ensure results are as accurate and generalizable as possible.26 For example, a clinical trial of adults receiving chemotherapy at 50 community cancer centers promoted inclusivity by offering internet and no-internet (automated telephone call) options to complete PROs remotely. Thirty-five percent of the participants chose the automated call (no-internet) option vs 65% who chose internet-based completion.27 Without an alternative PRO mode, more than one-third of the vulnerable population may have been excluded.

Researchers may consider different modes of completion (item 7) to promote inclusivity and should be explicit about how the PRO strategy promotes or hinders the goal of recruiting a diverse sample representative of the target population. For instance, trials involving participants with different languages require the availability of validated language and culturally adapted PRO questionnaires, while some participants may need physical help or other types of assistance in responding (eg, turning pages, holding a pen, assistance with a telephone or computer keyboard).8,16,24

Item 10: How Has Participant Acceptability and Burden Been Described and Addressed?

Explanation: PROs should be acceptable to the population in which they will be administered, both in terms of the questions they ask and the overall burden to the patient (eg, is the completion time for the PRO measure acceptable).28 The degree of participant burden depends on the frequency and timing of PRO assessments and on issues such as participant cognition, illness severity, treatment toxicity, and literacy.16 Researchers should consider issues such as whether the questionnaire(s) capture important and relevant concepts to interested groups (such as overall health-related quality of life, specific domain or symptoms as described in item 4) and whether PROs include overlapping content and/or particularly sensitive questions. It is also important to consider the length, number of questionnaires, and end points, with respect to burden for subgroups of participants and if the mode of delivery (item 7) and schedule of assessments (item 5) are appropriate. If researchers demonstrate acceptable participant burden via robust involvement from representatives of the target patient population in the PRO selection process, RECs should not override the PRO strategy without strong ethical justification (eg, RECs should avoid automatically rejecting a proposal with a large number of PROs if justification is provided).

Short questionnaires minimize participant burden and assure greater completeness of PRO data while minimizing missing data.29 However, patient input during the selection of PRO measures is key because participants may be willing to complete lengthy questionnaires if they understand the value of data collection and how the data will be used.30 Thus, the views of the affected population are authoritative in this regard. Failure to seek participant input to core design issues, such as concepts to measure that matter most to patients, selection of questionnaires, time points, and mode of assessment, may lead to poor concordance, and therefore flawed results that cannot inform clinical practice. Poorly designed studies mislead participants who participate to help others and misuse research resources.

Item 11: In Contexts Where Participants Are Not Able to Report for Themselves or May Become Unable to Self-report PRO Data, How Will PRO Questionnaire(s) Be Completed or Managed (eg, Proxy Reporting)?

Explanation: It is well recognized in research governance that participants who lack capacity (eg, young children and adults who are cognitively impaired) are potentially vulnerable, and their interests in the context of research need to be protected. However, it is also important that such people are not unjustifiably excluded from relevant research. PRO research needs to meet the same well-defined standards.

These individuals may require a proxy: someone else to report the participant’s outcomes on their behalf.8 This is different to assisting a participant to document their own answers (see item 9).31,32 The correct administration of PRO tools when proxies need to be used contributes to the collection of robust and reliable data. The justification for including vulnerable participants in research is that it will either benefit them directly or it will benefit the population to which they belong.33

In many research contexts, it is reasonable to anticipate the need for proxy response throughout all or some of the research (although the possibility can never be excluded) and this should be clearly documented in the research protocol. Researchers should be aware that proxy reporting is acceptable in some contexts and not in others. For example, the European Medicines Agency discourages proxy reporting because their data are often subject to biases and should only be used if it is the only effective means of obtaining vital information that might otherwise be lost.28 The US Food and Drug Administration also discourages the use of proxy-reported outcomes to inform labeling claims, recommending observer reports for observable phenomenon only (eg, vomiting, but not nausea) instead.16 However, in palliative care, collecting both proxy and observer measures is acceptable.34

It is important to recognize that lack or loss of capacity to consent to research participation will not always be accompanied by an inability to self-complete PROs (with or without assistance), and appropriate support for such participants should be specified.

Item 12: How Has Input From Patient Partners and/or Members of the Public Been Incorporated in the PRO Study Design? If Input Has Not Been Sought or Incorporated, How Has This Been Justified?

Explanation: Patient and public involvement refers to the partnership between patients, members of the public, and researchers in the codevelopment of research.35 Patients and members of the public have unique insight derived from their lived experiences making research more relevant and enhancing the design, conduct, and quality of the research.36-38 Incorporating these insights into research can make it prima facie more ethical in 2 ways: by democratizing the research agenda and/or helping to improve participant-facing documents and processes.39

The inclusion of patient and/or public involvement should be considered best practice during the study design stage. Involvement of individuals with the disease can provide valuable insights into their lived experience and help ensure the research is relevant to their needs and acceptable, while public involvement may generate broader insights from a societal perspective. In addition, their inclusion should be integral to all the stages of research. The inclusion of patient involvement, public involvement, or both in the development of the PRO strategy may help to ensure that research measures what matters to patients, thereby maximizing its beneficial effect. It is also the best means of ensuring that PRO tools, and how they are administered, are acceptable (see item 10), and thereby may be influential in maximizing the response rate (see item 13). For example, recent patient involvement in the Therapies for Long COVID Study has led to the development of a new Symptom Burden Questionnaire because existing measures were felt to omit key symptoms experienced by those with the condition.40

Item 13: What Mechanisms Have Been Introduced to Minimize Missing PRO Data? How Have These Been Explained to Participants (eg, Reminders/Notifications in an App or Follow-up Calls)?

Explanation: Missing PRO data are a major problem in clinical research.23,41 Missing data are normally caused by a combination of factors relating to methodology, logistic, administrative, and patient-related issues.41 Protocols should describe how missing data will be minimized. Missing PRO data can complicate interpretation, lead to invalid conclusions, or may mean that the PRO data are not published.4,42,43 When this occurs, it undermines the consent of participants who took part in the study and wastes research resources.

Although not all missing PRO data can be avoided, different strategies exist to mitigate this problem.23 Specific recommendations related to data collection and management include using the minimum number of questionnaires appropriate to address the PRO research question, establishing standardized and documented PRO administration procedures, engaging and educating participants in the study by providing updates or incentives, using active quality assurance measures (such as monitoring of completion rates, reminders for upcoming or missed assessments), appointing a dedicated staff member responsible for PRO assessment at each center, training staff, and offering alternative modes of administration.23,31 Reminders, notifications, or follow-up calls may be used to minimize missing data. Although different strategies exist to minimize avoidable PRO missing data, participants should be notified and provide consent, prior to accepting being part of the study, about the mechanisms the study will follow.

Dissemination
Item 14: What Dissemination Plans (eg, Publications and Plain-Language Summaries for the Research Participants and the Public) Are Proposed for Sharing the PRO Findings?

Explanation: The dissemination of PRO findings is essential to achieve beneficial outcomes. PRO data are, however, commonly omitted from primary and secondary publications.4 Failing to report PRO data could limit the interpretation of the results and may hinder the translation of PRO findings into clinical practice, resulting in lost opportunities to benefit patients and the perpetuation of harmful practices. Failure to disseminate PRO findings is disrespectful of participants’ time, effort, and contribution to research. It may also undermine participants’ consent if they were misinformed about dissemination plans.43 Sharing a summary of the PRO research results in accessible plain language for use by patients, participants, and members of the public promotes autonomy by empowering patients in shared decision-making around their care.44

It is recommended that PRO findings should be incorporated into the main research publication or reported in a secondary publication providing a detailed explanation of the PRO data.45 The CONSORT-PRO Extension guideline was developed to address the reporting of PRO trial data. The CONSORT-PRO provides evidence-based recommendations to improve completeness of reporting randomized clinical trials with either a primary or secondary PRO end point.46

The Table shows an implementation tool for PRO researchers and RECs to be completed by research teams preparing PRO research or by reviewers.

Discussion

The PRO ethics guidelines provide international consensus-based recommendations on questions that should be asked of a study’s design to facilitate the evaluation of its ethical acceptability. The guidelines highlight the ethical imperative to conduct robust science and the ethical issues to consider in the design and review of PRO clinical research. While a number of ethical issues identified are not unique to PROs and apply to research more widely, they raise particular challenges in the context of PROs, which is the focus of the work developed. The PRO ethics guidelines comprise 14 items to consider for use alongside the existing SPIRIT-PRO and CONSORT-PRO Extension guidelines8,46 and other ethical recommendations relevant to the jurisdiction of interest.12,47,48

The guidelines do not aim to mandate how ethical research should look, nor to mandate the correct response to the questions it asks. Instead, the guidelines aim to highlight issues that should be considered by research groups and ethics committees, including patients, research participants, and the public.

The recommendations within the PRO ethics guidelines reflect widely accepted ethical norms encapsulated in instruments such as the Declaration of Helsinki,49 the Belmont Report,50 and the Council for International Organizations of Medical Sciences guidelines.51 The recommendations are in line with the 3 principles of respect of persons, concern for welfare, and justice outlined in the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans48 and the widely used 4 principles of biomedical ethics: autonomy, justice, beneficence, and nonmaleficence.19 As such, the guiding ethical questions presented here do not set out any new ethical ideas, but rather specify widely accepted norms in the context of PROs and frame them in a way that is accessible to PRO researchers and useful for reviewers of PRO research.

The use of the PRO ethics guidelines has the potential to reduce participant risk and burden. In addition, addressing the items of the PRO ethics guidelines may help promote and protect participant autonomy and the welfare of participants and researchers. Furthermore, it may promote inclusive, equitable PRO research; the sharing of PRO research findings with participants and patients; and minimization of research waste (Box).

Box Section Ref ID
Box.

Aims of the PRO Ethics Guidelines

  • Maximize beneficial effect from research resources

  • Promote and protect participant autonomy

  • Protect participant research welfare

  • Promote accessible research

  • Minimize participant burden and harm

  • Minimize participant risk

  • Promote high-quality research

  • Disseminate PRO research

PRO indicates patient-reported outcome.

The Table provides an implementation tool for PRO researchers to reflect how each item has been addressed prior to ethical submission and for RECs to make notes on the research submitted and discuss in detail any relevant points at the ethics meeting. This tool is a starting point and can be tailored according to the users’ needs. Collaborations with national and international networks are being planned to promote the implementation of the PRO ethics guidelines.

Limitations

This study has several limitations. First, the review identified only limited literature on which to base items for inclusion in the Delphi. Therefore, some relevant candidate items may not have been included; however, additional items were proposed by the steering group, and further items were informed by the SPIRIT-PRO Extension work, based on an extensive review of PRO protocol guidance. Furthermore, participants had the opportunity to propose additional items during round 1 of the Delphi process. Second, only literature available until March 2020 was considered in development of the guidelines. However, an updated search was performed on March 23, 2022; an additional 569 articles were screened and no further relevant literature was identified. Third, because participants ranked items according to their general importance, it is possible that some items might be less relevant for certain types of trials.

Conclusions

The PRO ethics guidelines provide recommendations for ethical issues that should be addressed in PRO clinical research. Addressing ethical issues of PRO clinical research has the potential to ensure high-quality PRO data while minimizing participant risk, burden, and harm and protecting participant and researcher welfare.

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Article Information

Corresponding Author: Melanie J. Calvert, PhD, Centre for Patient Reported Outcome Research, Institute of Applied Health Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, England (m.calvert@bham.ac.uk).

Accepted for Publication: April 5, 2022.

Author Contributions: Drs Cruz Rivera and Calvert 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.

Concept and design: Cruz Rivera, Aiyegbusi, Ives, Mercieca-Bebber, Hunn, Bhatnagar, Bottomley, Campbell, Collis, Golub, von Hildebrand, Mahendraratnam, Wilson, Stover, Calvert.

Acquisition, analysis, or interpretation of data: Cruz Rivera, Aiyegbusi, Ives, Draper, Mercieca-Bebber, Ells, Hunn, Scott, Fernandez, Dickens, Anderson, Bottomley, Campbell, Collett, Craig, Davies, Gosden, Gnanasakthy, Haf Davies, Lord, Miyaji, Monteiro, Morel, Zwisler, Peipert, Roydhouse, Wilson, Yap, Calvert.

Drafting of the manuscript: Cruz Rivera, Draper, Hunn, Dickens, Anderson, Campbell, Collett, Collis, Davies, Gosden, Gnanasakthy, Haf Davies, Monteiro, Stover, Calvert.

Critical revision of the manuscript for important intellectual content: Aiyegbusi, Ives, Draper, Mercieca-Bebber, Ells, Hunn, Scott, Fernandez, Dickens, Anderson, Bhatnagar, Bottomley, Campbell, Craig, Golub, von Hildebrand, Lord, Mahendraratnam, Miyaji, Monteiro, Morel, Zwisler, Peipert, Roydhouse, Wilson, Stover, Yap, Calvert.

Statistical analysis: Bottomley, Haf Davies, Calvert.

Obtained funding: Mercieca-Bebber, Calvert.

Administrative, technical, or material support: Aiyegbusi, Dickens, Gosden, Haf Davies, von Hildebrand, Mahendraratnam.

Supervision: Calvert.

Other - patient partner: Collis.

Other - patient viewpoint and contributor: Wilson.

Other - statistical advice: Yap.

Other - consensus meeting participation: Roydhouse.

Other - Providing options and opinions: Haf Davies.

Other - helped with formulation of interpretation and analysis regarding ethical values/principles: Draper.

Other - Delphi panel member, reviewed and commented on the study documents and publications: Scott.

Conflict of Interest Disclosures: Dr Cruz Rivera reported receiving funding from UK SPINE and European Regional Development Fund–Demand Hub and personal fees from Merck. Dr Aiyegbusi reported receiving grants from the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, NIHR Applied Research Collaboration West Midlands, UK Research and Innovation (UKRI), Health Foundation, Janssen, Gilead, and GlaxoSmithKline and personal fees from Gilead Sciences Ltd, Merck, and GlaxoSmithKline outside the submitted work. Dr Draper reported receiving unrelated research funding from UK SPINE (UKRI), AHRC, and the University of Warwick and being a member of the Defence Medical Services ethics committee, Birmingham Women’s and Children’s NHS Foundation Trust clinical ethics committee, and NHS Blood and Transplant Deceased Donor Family Tissue Advisory Group. Dr Scott reported receiving a pension from Janssen and holding stock in Johnson & Johnson. Drs Ells and Fernandez are members of the Canadian Interagency Panel on Research Ethics, which is responsible for the interpretation and evolution of the Canadian Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. Ms Anderson reported receiving funding from the Health Education England/NIHR Integrated Clinical Academic Program Clinical Doctoral Research Fellowship. Dr Haf Davies reported owning an ePRO software platform called Atom5 through Aparito. Dr Lord reported being a member of the Nuffield Bioethics Working Group on the Future of Ageing. Dr Mahendraratnam reported owning stock options at Aetion Inc. Mr Miyaji reported grants (paid to the Department of Clinical Trial Data Management, Graduate School of Medicine, The University of Tokyo) from AC Medical, A2 Healthcare, New Age Trading, Japan Tobacco Inc, Japan Media Corp, Medidata Solutions, Ono Pharmaceutical, FMD K&L Japan, 3H Medi Solution, NOBORI, Medrio Inc, Welby Inc, Nipro Corp, and Intellim and personal fees from Pfizer Japan Inc, Takeda Pharmaceutical Co, Merck, Ayumi Pharmaceutical, and Welby Inc. Dr Morel reported owning shares of UCB Pharma. Dr Zwisler reported being chair of the national clinical coordinating group on PRO in cardiac diseases. Dr Peipert reported receiving unrelated research funding from the National Cancer Institute, the National Institutes of Health, the Food and Drug Administration, the ECOG-ACRIN Medical Research Foundation, the Peter G. Peterson Foundation, Veloxis Pharmaceuticals, Pfizer, and the Northwestern University George M. O’Brien Kidney Core Center. He has received unrelated personal fees from AstraZeneca, IMPAQ International, and FACIT.org; in addition, he is the International Society for Quality of Life Research’s psychometric special interest group chair. Through his institution, he is supported by unrelated grants and contracts from Bristol Myers Squibb, Clovis Oncology, Pfizer, and Veloxis Pharmaceuticals. Dr Roydhouse reported receiving unrelated personal fees in the last 24 months from Amgen. Through her institution, she is supported by an unrelated Select Foundation Fellowship and has received unrelated research funding from the Royal Hobart Hospital and the Food and Drug Administration. Dr Stover reported receiving unrelated consulting fees or speaking honoraria in the last 24 months from Navigating Cancer, Association of Community Cancer Centers, Genentech, Purchaser Business Group on Health, and Henry Ford Cancer Center and unrelated research funding from Sivan Innovation and UroGen Pharma Ltd. Dr Yap reported receiving unrelated consulting fees and speaking honoraria from Faron Pharmaceuticals and Celgene, respectively, and being an expert advisor for the Medicines and Healthcare products Regulatory Agency’s Clinical Trials, Biologicals and Vaccines Expert Advisory Group and a funding panel member for the Medical Research Council Experimental Medicine and Cancer Research UK Clinical Research Committee. Dr Calvert reported serving as director of the Birmingham Health Partners Centre for Regulatory Science and Innovation, director of the Centre for Patient Reported Outcome Research, and an NIHR senior investigator and receiving funding from the NIHR, UK Research and Innovation (UKRI), NIHR Birmingham Biomedical Research Centre, the NIHR Surgical Reconstruction and Microbiology Research Centre, NIHR ARC West Midlands, UK SPINE, European Regional Development Fund–Demand Hub and Health Data Research UK at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Innovate UK (part of UKRI), Macmillan Cancer Support, UCB Pharma, Janssen, GlaxoSmithKline, and Gilead. Dr Calvert has received personal fees from Astellas, Aparito Ltd, CIS Oncology, Takeda, Merck, Daiichi Sankyo, Glaukos, GlaxoSmithKline, and the Patient-Centered Outcomes Research Institute outside the submitted work. In addition, a family member owns shares in GlaxoSmithKline. No other disclosures were reported.

Funding/Support: This work was sponsored by the University of Birmingham, the NIHR Birmingham Biomedical Research Centre, UK Research and Innovation, UK SPINE, and the European Regional Development Fund.

Role of the Funder/Sponsor: The funders 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; and decision to submit the manuscript for publication. Several authors are employees of the University of Birmingham; however, beyond the declared author contributions, the sponsor had no additional role.

Disclaimer: The views expressed in this article are those of the author(s) and not necessarily those of national agencies (eg, the NIHR, Food and Drug Administration, Medicines and Healthcare products Regulatory Agency, Health Research Authority, Canadian Institutes of Healthcare Research, the Department of Health and Social Care, Canadian Interagency Panel on Research Ethics, or the Canadian Tri-Council Policy Statement 2. Dr Golub is Executive Deputy Editor of JAMA but was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Additional Information: Dr Scott retired from Janssen Global Services in March 2021; however, she was still involved in the development of the guideline until its final stage. Coauthor Amanda Hunn, MA, died February 8, 2022.

References
1.
Calvert  M, Kyte  D, Price  G, Valderas  JM, Hjollund  NH.  Maximising the impact of patient reported outcome assessment for patients and society.   BMJ. 2019;364:k5267. doi:10.1136/bmj.k5267 PubMedGoogle ScholarCrossref
2.
Basch  E, Deal  AM, Dueck  AC,  et al.  Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment.   JAMA. 2017;318(2):197-198. doi:10.1001/jama.2017.7156 PubMedGoogle ScholarCrossref
3.
Cruz Rivera  S, Mercieca-Bebber  R, Aiyegbusi  OL,  et al.  The need for ethical guidance for the use of patient-reported outcomes in research and clinical practice.   Nat Med. 2021;27(4):572-573. doi:10.1038/s41591-021-01275-z PubMedGoogle ScholarCrossref
4.
Kyte  D, Retzer  A, Ahmed  K,  et al.  Systematic evaluation of patient-reported outcome protocol content and reporting in cancer trials.   J Natl Cancer Inst. 2019;111(11):1170-1178. doi:10.1093/jnci/djz038 PubMedGoogle ScholarCrossref
5.
Kyte  D, Ives  J, Draper  H, Calvert  M.  Management of patient-reported outcome (PRO) alerts in clinical trials: a cross sectional survey.   PLoS One. 2016;11(1):e0144658. doi:10.1371/journal.pone.0144658 PubMedGoogle ScholarCrossref
6.
Kyte  D, Draper  H, Calvert  M.  Patient-reported outcome alerts: ethical and logistical considerations in clinical trials.   JAMA. 2013;310(12):1229-1230. doi:10.1001/jama.2013.277222 PubMedGoogle ScholarCrossref
7.
Hagell  P, Reimer  J, Nyberg  P.  Whose quality of life? ethical implications in patient-reported health outcome measurement.   Value Health. 2009;12(4):613-617. doi:10.1111/j.1524-4733.2008.00488.x PubMedGoogle ScholarCrossref
8.
Calvert  M, Kyte  D, Mercieca-Bebber  R,  et al; the SPIRIT-PRO Group.  Guidelines for inclusion of patient-reported outcomes in clinical trial protocols: the SPIRIT-PRO Extension.   JAMA. 2018;319(5):483-494. doi:10.1001/jama.2017.21903 PubMedGoogle ScholarCrossref
9.
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.1000217 PubMedGoogle ScholarCrossref
10.
Cruz Rivera  S, Stephens  R, Mercieca-Bebber  R,  et al.  ‘Give Us The Tools!’: development of knowledge transfer tools to support the involvement of patient partners in the development of clinical trial protocols with patient-reported outcomes (PROs), in accordance with SPIRIT-PRO Extension.   BMJ Open. 2021;11(6):e046450. doi:10.1136/bmjopen-2020-046450 PubMedGoogle ScholarCrossref
11.
COMET Initiative. DelphiManager. Accessed May 5, 2021. https://www.comet-initiative.org/delphimanager/
12.
NHS Health Research Authority. Guidance and policy for REC members: standard operating procedures for research ethics committees (SOPs). Accessed October 21, 2021. https://www.hra.nhs.uk/about-us/committees-and-services/res-and-recs/research-ethics-committee-members-area/guidance-and-policy-for-rec-members/
13.
Williamson  PR, Altman  DG, Bagley  H,  et al.  The COMET handbook: version 1.0.   Trials. 2017;18(3)(suppl 3):280. doi:10.1186/s13063-017-1978-4 PubMedGoogle ScholarCrossref
14.
Kyte  D, Duffy  H, Fletcher  B,  et al.  Systematic evaluation of the patient-reported outcome (PRO) content of clinical trial protocols.   PLoS One. 2014;9(10):e110229. doi:10.1371/journal.pone.0110229 PubMedGoogle ScholarCrossref
15.
Mercieca-Bebber  R, Friedlander  M, Kok  P-S,  et al.  The patient-reported outcome content of international ovarian cancer randomised controlled trial protocols.   Qual Life Res. 2016;25(10):2457-2465. doi:10.1007/s11136-016-1339-x PubMedGoogle ScholarCrossref
16.
Food and Drug Administration. Patient-reported outcome measures: use in medical product development to support labeling claims: guidance for industry. December 2009. Accessed February 2, 2021. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf
17.
Emanuel  EJ, Wendler  D, Grady  C.  What makes clinical research ethical?   JAMA. 2000;283(20):2701-2711. doi:10.1001/jama.283.20.2701 PubMedGoogle ScholarCrossref
18.
Rothrock  NE, Kaiser  KA, Cella  D.  Developing a valid patient-reported outcome measure.   Clin Pharmacol Ther. 2011;90(5):737-742. doi:10.1038/clpt.2011.195 PubMedGoogle ScholarCrossref
19.
Beauchamp  TL, Childress  JF.  Principles of Biomedical Ethics. Oxford University Press; 2001.
20.
Truog  RD, Robinson  W, Randolph  A, Morris  A.  Is informed consent always necessary for randomized, controlled trials?   N Engl J Med. 1999;340(10):804-807. doi:10.1056/NEJM199903113401013 PubMedGoogle ScholarCrossref
21.
Bacchetti  P, Wolf  LE, Segal  MR, McCulloch  CE.  Ethics and sample size.   Am J Epidemiol. 2005;161(2):105-110. doi:10.1093/aje/kwi014 PubMedGoogle ScholarCrossref
22.
Rutherford  C, Costa  D, Mercieca-Bebber  R, Rice  H, Gabb  L, King  M.  Mode of administration does not cause bias in patient-reported outcome results: a meta-analysis.   Qual Life Res. 2016;25(3):559-574. doi:10.1007/s11136-015-1110-8 PubMedGoogle ScholarCrossref
23.
Mercieca-Bebber  R, Palmer  MJ, Brundage  M, Calvert  M, Stockler  MR, King  MT.  Design, implementation and reporting strategies to reduce the instance and impact of missing patient-reported outcome (PRO) data: a systematic review.   BMJ Open. 2016;6(6):e010938. doi:10.1136/bmjopen-2015-010938 PubMedGoogle ScholarCrossref
24.
Mercieca-Bebber  R, Calvert  M, Kyte  D, Stockler  M, King  MT.  The administration of patient-reported outcome questionnaires in cancer trials: interviews with trial coordinators regarding their roles, experiences, challenges and training.   Contemp Clin Trials Commun. 2017;9:23-32. doi:10.1016/j.conctc.2017.11.009 PubMedGoogle ScholarCrossref
25.
Kyte  D, Ives  J, Draper  H, Keeley  T, Calvert  M.  Inconsistencies in quality of life data collection in clinical trials: a potential source of bias? interviews with research nurses and trialists.   PLoS One. 2013;8(10):e76625. doi:10.1371/journal.pone.0076625 PubMedGoogle ScholarCrossref
26.
Ford  JG, Howerton  MW, Lai  GY,  et al.  Barriers to recruiting underrepresented populations to cancer clinical trials: a systematic review.   Cancer. 2008;112(2):228-242. doi:10.1002/cncr.23157 PubMedGoogle ScholarCrossref
27.
Basch  E, Stover  AM, Schrag  D,  et al.  Clinical utility and user perceptions of a digital system for electronic patient-reported symptom monitoring during routine cancer care: findings from the PRO-TECT Trial.   JCO Clin Cancer Inform. 2020;4:947-957. doi:10.1200/CCI.20.00081 PubMedGoogle ScholarCrossref
28.
European Medicines Agency. Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man: the use of patient-reported outcome (PRO) measures in oncology studies. April 1, 2016. Accessed February 2, 2021. https://www.ema.europa.eu/documents/other/appendix-2-guideline-evaluation-anticancer-medicinal-products-man_en.pdf
29.
Basch  E, Abernethy  AP, Mullins  CD,  et al.  Recommendations for incorporating patient-reported outcomes into clinical comparative effectiveness research in adult oncology.   J Clin Oncol. 2012;30(34):4249-4255. doi:10.1200/JCO.2012.42.5967 PubMedGoogle ScholarCrossref
30.
Shepshelovich  D, McDonald  K, Spreafico  A,  et al.  Feasibility assessment of using the complete Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) item library.   Oncologist. 2019;24(4):e146-e148. doi:10.1634/theoncologist.2018-0332 PubMedGoogle ScholarCrossref
31.
Calvert  M, King  M, Mercieca-Bebber  R,  et al.  SPIRIT-PRO Extension explanation and elaboration: guidelines for inclusion of patient-reported outcomes in protocols of clinical trials.   BMJ Open. 2021;11(6):e045105. doi:10.1136/bmjopen-2020-045105 PubMedGoogle ScholarCrossref
32.
Bausewein  C, Daveson  BA, Currow  DC,  et al.  EAPC white paper on outcome measurement in palliative care: improving practice, attaining outcomes and delivering quality services: recommendations from the European Association for Palliative Care (EAPC) Task Force on Outcome Measurement.   Palliat Med. 2016;30(1):6-22. doi:10.1177/0269216315589898 PubMedGoogle ScholarCrossref
33.
Legislation.gov.uk. Mental Capacity Act 2005. Accessed October 21, 2021. https://www.legislation.gov.uk/ukpga/2005/9/contents
34.
Evans  CJ, Benalia  H, Preston  NJ,  et al; MORECare.  The selection and use of outcome measures in palliative and end-of-life care research: the MORECare International Consensus Workshop.   J Pain Symptom Manage. 2013;46(6):925-937. doi:10.1016/j.jpainsymman.2013.01.010 PubMedGoogle ScholarCrossref
35.
Turner  G, Aiyegbusi  OL, Price  G, Skrybant  M, Calvert  M.  Moving beyond project-specific patient and public involvement in research.   J R Soc Med. 2020;113(1):16-23. doi:10.1177/0141076819890551 PubMedGoogle ScholarCrossref
36.
Wilson  P, Mathie  E, Keenan  J,  et al. Health services and delivery research. In:  Research With Patient and Public Involvement: A Realist Evaluation: The RAPPORT Study. NIHR Journals Library; 2015.
37.
Wilson  R.  Patient led PROMs must take centre stage in cancer research.   Res Involv Engagem. 2018;4(7). doi:10.1186/s40900-018-0092-4 Google ScholarCrossref
38.
National Institute for Health and Care Research. Briefing notes for researchers: public involvement in NHS, health and social care research. April 5, 2021. Accessed September 9, 2021. https://www.nihr.ac.uk/documents/briefing-notes-for-researchers-public-involvement-in-nhs-health-and-social-care-research/27371
39.
Ives  J, Damery  S, Redwod  S.  PPI, paradoxes and Plato: who’s sailing the ship?   J Med Ethics. 2013;39(3):181-185. doi:10.1136/medethics-2011-100150 PubMedGoogle Scholar
40.
Hughes  SE, Haroon  S, Subramanian  A,  et al.  Development and validation of the Symptom Burden Questionnaire for Long COVID (SBQ-LC): Rasch analysis.   BMJ. 2022;377:e70230Google Scholar
41.
Bernhard  J, Cella  DF, Coates  AS,  et al.  Missing quality of life data in cancer clinical trials: serious problems and challenges.   Stat Med. 1998;17(5-7):517-532. doi:10.1002/(SICI)1097-0258(19980315/15)17:5/7<517::AID-SIM799>3.0.CO;2-S PubMedGoogle Scholar
42.
Ware  JH, Harrington  D, Hunter  DJ, D’Agostino  RB.  Missing data.   N Engl J Med. 2012;367:1353-1354. doi:10.1056/NEJMsm1210043 Google Scholar
43.
Retzer  A, Calvert  M, Ahmed  K,  et al.  International perspectives on suboptimal patient-reported outcome trial design and reporting in cancer clinical trials: a qualitative study.   Cancer Med. 2021;10(16):5475-5487. doi:10.1002/cam4.4111 PubMedGoogle Scholar
44.
Brundage  M, Leis  A, Bezjak  A,  et al.  Cancer patients’ preferences for communicating clinical trial quality of life information: a qualitative study.   Qual Life Res. 2003;12(4):395-404. doi:10.1023/A:1023404731041 PubMedGoogle Scholar
45.
Bottomley  A, Efficace  F, Thomas  R, Vanvoorden  V, Ahmedzai  SH.  Health-related quality of life in non-small-cell lung cancer: methodologic issues in randomized controlled trials.   J Clin Oncol. 2003;21(15):2982-2992. doi:10.1200/JCO.2003.01.203 PubMedGoogle Scholar
46.
Calvert  M, Blazeby  J, Altman  DG, Revicki  DA, Moher  D, Brundage  MD; CONSORT PRO Group.  Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO Extension.   JAMA. 2013;309(8):814-822. doi:10.1001/jama.2013.879 PubMedGoogle Scholar
47.
National Institutes of Health. Guiding principles for ethical research. Accessed March 23, 2022. https://www.nih.gov/health-information/nih-clinical-research-trials-you/guiding-principles-ethical-research
48.
Canadian Institutes of Health Research; Natural Sciences and Engineering Research Council of Canada; Social Sciences and Humanities Research Council of Canada. Chapter 1: ethical framework. In:  Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. Government of Canada; December 2018.
49.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053 PubMedGoogle Scholar
50.
Department of Health, Education, and Welfare.  The Belmont Report. Department of Health, Education, and Welfare; 1979.
51.
Council for International Organizations of Medical Sciences.  2016 International Ethical Guidelines for Health-Related Research Involving Humans. Council for International Organizations of Medical Sciences; 2016.
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