What outcome-specific information should be included in a clinical trial protocol?
Using an evidence-based and international consensus–based approach that applied methods from the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework, 9 outcome-specific reporting items to be addressed in clinical trial protocols were identified.
Inclusion of these items in clinical trial protocols may enhance trial utility, replicability, and transparency and may help limit selective nonreporting of trial results.
Complete information in a trial protocol regarding study outcomes is crucial for obtaining regulatory approvals, ensuring standardized trial conduct, reducing research waste, and providing transparency of methods to facilitate trial replication, critical appraisal, accurate reporting and interpretation of trial results, and knowledge synthesis. However, recommendations on what outcome-specific information should be included are diverse and inconsistent. To improve reporting practices promoting transparent and reproducible outcome selection, assessment, and analysis, a need for specific and harmonized guidance as to what outcome-specific information should be addressed in clinical trial protocols exists.
To develop harmonized, evidence- and consensus-based standards for describing outcomes in clinical trial protocols through integration with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 statement.
Using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework, the SPIRIT-Outcomes 2022 extension of the SPIRIT 2013 statement was developed by (1) generation and evaluation of candidate outcome reporting items via consultation with experts and a scoping review of existing guidance for reporting trial outcomes (published within the 10 years prior to March 19, 2018) identified through expert solicitation, electronic database searches of MEDLINE and the Cochrane Methodology Register, gray literature searches, and reference list searches; (2) a 3-round international Delphi voting process (November 2018-February 2019) completed by 124 panelists from 22 countries to rate and identify additional items; and (3) an in-person consensus meeting (April 9-10, 2019) attended by 25 panelists to identify essential items for outcome-specific reporting to be addressed in clinical trial protocols.
The scoping review and consultation with experts identified 108 recommendations relevant to outcome-specific reporting to be addressed in trial protocols, the majority (72%) of which were not included in the SPIRIT 2013 statement. All recommendations were consolidated into 56 items for Delphi voting; after the Delphi survey process, 19 items met criteria for further evaluation at the consensus meeting and possible inclusion in the SPIRIT-Outcomes 2022 extension. The discussions during and after the consensus meeting yielded 9 items that elaborate on the SPIRIT 2013 statement checklist items and are related to completely defining and justifying the choice of primary, secondary, and other outcomes (SPIRIT 2013 statement checklist item 12) prospectively in the trial protocol, defining and justifying the target difference between treatment groups for the primary outcome used in the sample size calculations (SPIRIT 2013 statement checklist item 14), describing the responsiveness of the study instruments used to assess the outcome and providing details on the outcome assessors (SPIRIT 2013 statement checklist item 18a), and describing any planned methods to account for multiplicity relating to the analyses or interpretation of the results (SPIRIT 2013 statement checklist item 20a).
Conclusions and Relevance
This SPIRIT-Outcomes 2022 extension of the SPIRIT 2013 statement provides 9 outcome-specific items that should be addressed in all trial protocols and may help increase trial utility, replicability, and transparency and may minimize the risk of selective nonreporting of trial results.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Corresponding Author: Nancy J. Butcher, PhD, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St, Toronto, ON M5G 0A4, Canada (firstname.lastname@example.org).
Accepted for Publication: October 28, 2022.
Published Online: December 13, 2022. doi:10.1001/jama.2022.21243
Author Contributions: Dr Butcher had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Butcher.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Monsour.
Obtained funding: Offringa.
Administrative, technical, or material support: Monsour, Mew, Baba.
Supervision: Butcher, Offringa.
Conflict of Interest Disclosures: Dr Butcher reported receiving grant funding from CHILD-BRIGHT and the Cundill Centre for Child and Youth Depression at the Centre for Addiction and Mental Health (CAMH) and receiving personal fees from Nobias Therapeutics. Ms Mew reported receiving salary support through a Canadian Institutes of Health Research doctoral foreign study award. Dr Grimshaw reported holding a Canada research chair in health knowledge transfer and uptake and receiving funding from the Ontario Ministry of Health, the Ottawa Hospital Academic Medical Organization, the National Institute of Health Research, and the National Health and Medical Research Council. Dr Kelly reported receiving funding from the Canadian Cancer Society, Research Manitoba, the Children’s Hospital Research Institute of Manitoba, Mitacs, and the SickKids Foundation. Dr Askie reported being a co-convenor of the Cochrane Prospective Meta-Analysis Methods Group. Dr Farid-Kapadia reported currently being an employee of Hoffmann La-Roche and holding shares in the company. Dr Williamson reported chairing the COMET initiative management group. Dr Szatmari reported receiving funding from the CAMH. Dr Tugwell reported co-chairing the OMERACT executive committee; receiving personal fees from the Reformulary Group, UCB Pharma GmbH, Parexel International, PRA Health Sciences, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Roche, Genzyme, Sanofi, Horizon Therapeutics, Merck, Novartis, Pfizer, PPD Inc, QuintilesIMS (now IQVIA), Regeneron Pharmaceuticals, Savient Pharmaceuticals, Takeda Pharmaceutical Co Ltd, Vertex Pharmaceuticals, Forest Pharmaceuticals, and Bioiberica; serving on data and safety monitoring boards for UCB Pharma GmbH, Parexel International, and PRA Health Sciences; and receiving unrestricted educational grants from the American College of Rheumatology and the European League of Rheumatology. Dr Monga reported receiving funding from the Cundill Centre for Child and Youth Depression at CAMH; receiving royalties from Springer for Assessing and Treating Anxiety Disorders in Young Children; and receiving personal fees from the TD Bank Financial Group for serving as a chair in child and adolescent psychiatry. Dr Ungar reported being supported by the Canada research chair in economic evaluation and technology assessment in child health. No other disclosures were reported.
Funding/Support: This work, project 148953, received financial support from the Canadian Institutes of Health Research.
Role of the Funder/Sponsor: The Canadian Institutes of Health Research 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.
Disclaimers: Dr Golub is Executive Deputy Editor of JAMA, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance. This article reflects the views of the authors, the Delphi panelists, and the consensus meeting panelists and may not represent the views of the broader stakeholder groups, the authors’ institutions, or other affiliations.
Additional Contributions: We gratefully acknowledge the additional contributions made by the project core team, the executive team, the operations team, the Delphi panelists, and the international consensus meeting panelists (eAppendix 3 in the Supplement). We thank Andrea Chiaramida, BA, for administrative project support and Lisa Stallwood, MSc, for administrative manuscript support (both with The Hospital for Sick Children). We thank Petros Pechlivanoglou, PhD, and Robin Hayeems, PhD, for piloting and providing feedback on the format of the Delphi survey (both with The Hospital for Sick Children). None of these individuals received compensation for their role in the study.
Additional Information: The project materials and data are publicly available on the Open Science Framework at https://osf.io/arwy8/.
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