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Table 1. 听Recommended Checklist Items to Address in a Clinical Trial Protocol From the SPIRIT 2013 Statement and the SPIRIT-Outcomes 2022 Extensiona
Table 2. 听The 5 Core Elements of a Defined Outcomea
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Special Communication
December 13, 2022

Guidelines for Reporting Outcomes in Trial Protocols: The SPIRIT-Outcomes 2022 Extension

Author Affiliations
  • 1Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
  • 2Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
  • 3Department of Chronic Disease Epidemiology, School of Public Health, Yale University, New Haven, Connecticut
  • 4Department of Medicine, Women鈥檚 College Research Institute, University of Toronto, Toronto, Ontario, Canada
  • 5Centre for Journalology, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • 6School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
  • 7Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill
  • 8Amsterdam University Medical Centers, Vrije Universiteit, Department of Epidemiology and Data Science, Amsterdam, the Netherlands
  • 9Department of Methodology, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands
  • 10public panel member, Toronto, Ontario, Canada
  • 11Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • 12Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  • 13Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada
  • 14Children鈥檚 Hospital Research Institute of Manitoba, Winnipeg, Canada
  • 15Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
  • 16NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia
  • 17patient panel member, Ottawa, Ontario, Canada
  • 18MRC-NIHR Trials Methodology Research Partnership, Department of Health Data Science, University of Liverpool, Liverpool, England
  • 19Cundill Centre for Child and Youth Depression, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
  • 20Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada
  • 21Bruy猫re Research Institute, Ottawa, Ontario, Canada
  • 22Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • 23Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 24Departments of Pediatrics and Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
  • 25Clinical Trials Ontario, Toronto, Canada
  • 26Department of Public Health Sciences, Queen鈥檚 University, Kingston, Ontario, Canada
  • 27Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada
  • 28Division of Neonatology, The Hospital for Sick Children, Toronto, Ontario, Canada
JAMA. 2022;328(23):2345-2356. doi:10.1001/jama.2022.21243
Key Points

QuestionWhat outcome-specific information should be included in a clinical trial protocol?

FindingsUsing an evidence-based and international consensus鈥揵ased 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.

MeaningInclusion of these items in clinical trial protocols may enhance trial utility, replicability, and transparency and may help limit selective nonreporting of trial results.

Abstract

ImportanceComplete 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.

ObjectiveTo 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.

Evidence ReviewUsing 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.

FindingsThe 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 RelevanceThis 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.

Introduction

Trial protocols describe objectives, designs, methods, planned analyses, organization, and amendments of randomized clinical trials. Trial protocols are used by trial investigators, trial staff, funding and regulatory agencies, health technology assessment bodies, ethics review boards, systematic reviewers, academic journals, and more. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 statement1-3 provided a checklist of 33 reporting items to be included in trial protocols. The SPIRIT 2013 statement encompassed trial protocol items recommended by the International Conference on Harmonisation good clinical practice guidance.4 Even though a SPIRIT extension for reporting patient-reported outcomes is available,5 no evidence-based guideline exists for reporting outcome-specific information applicable to all systematically collected outcome types, populations, and trial designs.

Complete reporting of outcome-specific information in trial protocols is important for obtaining ethical and regulatory approvals, and ensuring the trial is conducted in accordance with predetermined aims and methods. Although a clearly described trial protocol promotes the transparency of an individual trial鈥檚 methods and facilitates the reporting and interpretation of the trial results, a recent scoping review6 revealed that recommendations on how to prospectively report the selection, assessment, and analyses of trial outcomes in trial protocols by academic, regulatory, and public sources are diverse, inconsistent, and dispersed across a large number of documents. Even though the SPIRIT 2013 statement1,2 provides general guidance on how to report trial outcomes, well-documented problems in reporting trial outcomes persist.7-11 These reporting problems can affect the conclusions of systematic reviews and meta-analyses, contributing to ongoing research waste.12,13

The aim of the SPIRIT-Outcomes 2022 extension was to develop harmonized, evidence- and consensus-based outcome reporting standards for trial protocols.

Methods

The SPIRIT-Outcomes 2022 extension was developed as part of the Instrument for Reporting Planned Endpoints in Clinical Trials (InsPECT) project14 in accordance with the Enhancing Quality and Transparency of Health Research (EQUATOR) methodological framework for reporting guideline development.15 Ethics approval was not required as determined by the research ethics committee at The Hospital for Sick Children. Specific guidance for the content of statistical analysis plans has been published.16 The development of the SPIRIT-Outcomes 2022 extension occurred in parallel with the Consolidated Standards of Reporting Trials (CONSORT)鈥揙utcomes 2022 extension for clinical trial reports.17

Key Development Phases

First, we created an initial list of recommendations relevant to reporting outcomes for randomized clinical trials that were synthesized from 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 as described.6,18 Second, a 3-round international Delphi voting process took place from November 2018 to February 2019 to identify additional items and assess the importance of each item using a 9-point Likert scale and completed by 124 panelists from 22 countries (eTable 1 in the Supplement). Third, an in-person expert consensus meeting was held (April 9-10, 2019), which was attended by 25 panelists from 4 countries, including a patient partner and a public partner, to identify the set of essential items relevant to reporting outcome-specific information in trial protocols and establish dissemination activities. Selection and wording of the items was finalized at a postconsensus meeting by executive panel members and via email with consensus meeting panelists.

Other Information

The detailed methods describing development of the SPIRIT-Outcomes 2022 extension appear in eAppendix 1 in the Supplement, including the number of items evaluated at each phase and the process toward the final set of included items (eFigure in the Supplement). The scoping review trial protocol and findings have been published6,18 and appear in eAppendix 1 in the Supplement and the search strategy appears in eAppendix 2 in the Supplement. The self-reported characteristics of the Delphi voting panelists and the consensus meeting panelists appear in eTables 1-2 in the Supplement. Details regarding the involvement of the patient partner and public partner appear in eAppendix 1 in the Supplement.

Results

In addition to the inclusion of the SPIRIT 2013 statement checklist items, the SPIRIT-Outcomes 2022 extension recommends that descriptions of a minimum of 9 outcome-specific reporting items should be included prospectively in trial protocols, regardless of trial design or population. 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 not 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 the criteria for further evaluation at the consensus meeting and possible inclusion in the SPIRIT-Outcomes 2022 extension. The SPIRIT 2013 statement checklist items and the 9 outcome-specific reporting items added by the SPIRIT-Outcomes 2022 extension appear in Table 1.19

A fillable version of the checklist appears in eTables 3-4 in the Supplement and on the SPIRIT website.3 When using the updated checklist, users should refer to definitions of key terms in the glossary20-37 (Box) because variations in the terminologies and definitions exist across disciplines and geographic areas. The 5 core elements of a defined outcome (with examples) appear in Table 2.38,39

Box Section Ref ID
Box.

Glossary of Terms Used in the SPIRIT-Outcomes 2022 Extension

  • Composite outcome: A composite outcome consists of 鈮2 component outcomes (eg, proportion of participants who died or experienced a nonfatal stroke). Participants who have experienced any of the events specified by the components are considered to have experienced the composite outcome.20,21

  • CONSORT 2010: Consolidated Standards of Reporting Trials (CONSORT) statement that was published in 2010.22,23

  • CONSORT-Outcomes 2022 extension: Additional essential checklist items describing outcome-related content that are not covered by the CONSORT 2010 statement.

  • Construct validity: The degree to which the scores reported in a trial are consistent with the hypotheses (eg, with regard to internal relationships, the relationships of the scores to other instruments, or relevant between-group differences) based on the assumption that the instrument validly measures the domain to be measured.33

  • Criterion validity: The degree to which the scores of a study instrument are an adequate reflection of a gold standard.33

  • Minimal important change: The smallest within-patient change that is considered important by patients, clinicians, or relevant others.24,25 The change may be in a score or unit of measure (continuous or ordinal measurements) or in frequency (dichotomous outcomes). This term is often used interchangeably in health literature with the term minimal important difference. In the SPIRIT-Outcomes 2022 extension, the minimal important change conceptually refers to important intrapatient change (item 12.2) and the minimum important difference refers to the important between-group difference. Minor variants of the term, such as minimum instead of minimal, or the addition of the adjective clinically or clinical are common (eg, the minimum clinically important change).26

  • Minimal important difference: The smallest between-group difference that is considered important by patients, clinicians, or relevant others.24,27-29 The difference may be in a score or unit of measure (continuous or ordinal measurements) or in frequency (dichotomous outcomes). Minor variants of the term, such as minimum instead of minimal, or the addition of the adjective clinically or clinical are common (eg, the minimum clinically important difference).26

  • Outcome: Refers to what is being assessed to examine the effect of exposure to a health intervention.30 The 5 core elements of a defined outcome appear in Table 2.

  • Primary outcome: The planned outcome that is most directly related to the primary objective of the trial.5 It is typically the outcome used in the sample size calculation for trials with the primary objective of assessing efficacy or effectiveness.31 Many trials have 1 primary outcome, but some have >1. The term primary end point is sometimes used in the medical literature when referring to the primary outcome.6

  • Responsiveness: The ability of a study instrument to accurately detect and measure change in the outcome domain over time.25,32 Distinct from an instrument鈥檚 construct validity and criterion validity, which refer to the validity of a single score, responsiveness refers to the validity of a change score (ie, longitudinal validity).33

  • Secondary outcomes: The outcomes prespecified in the trial protocol to assess any additional effects of the intervention.5

  • Smallest worthwhile effect: The smallest beneficial effect of an intervention that justifies the costs, potential harms, and inconvenience of the interventions as determined by patients.34

  • SPIRIT 2013: Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement that was published in 2013.1,2

  • SPIRIT-Outcomes 2022 extension: Additional essential checklist items describing outcome-related trial protocol content that are not covered by the SPIRIT 2013 statement.

  • Study instrument: The scale or tool used to make an assessment. A study instrument may be a questionnaire, a clinical rating scale, a laboratory test, a score obtained through a physical examination or an observation of an image, or a response to a single question.35

  • Target difference: The value that is used in sample size calculations as the difference sought to be detected on the primary outcome between intervention groups and that should be considered realistic or important (such as the minimal important difference or the smallest worthwhile effect) by 鈮1 key stakeholder groups.36,37

  • Validity: The degree to which a study instrument measures the domain it purports to measure.33

Application of these new checklist items from the SPIRIT-Outcomes 2022 extension, in conjunction with SPIRIT 2013 statement, ensures trial outcomes will be comprehensively defined prospectively in trial protocols and reported in trial reports. The estimated list of key users, their proposed actions, and the consequential potential benefits of implementing the 9 SPIRIT-Outcomes 2022 extension checklist items appears in eTable 5 in the Supplement and was generated from the consensus meeting鈥檚 knowledge translation session. Examination and application of these outcome reporting recommendations may be helpful for trial authors, journal editors, peer reviewers, systematic reviewers, patients, the public, and trial participants (eTable 5 in the Supplement).

This report contains a brief explanation of the 9 checklist items generated from the SPIRIT-Outcomes 2022 extension. Guidance on how to report the existing checklist items can be found in the SPIRIT 2013 statement,1 in Table 1, and in an explanatory guideline report.2 Additional items that may be useful to include in some trial protocols or in associated trial documents (eg, the statistical analysis plan) appear in eTable 6 in the Supplement, but were not considered essential reporting items for all trial protocols.

SPIRIT-Outcomes 2022 Extension Checklist Items for the Descriptions of the Outcomes
Item 12.1. Provide a Rationale for the Selection of the Domain for the Trial鈥檚 Primary Outcome

This item expands on SPIRIT 2013 statement checklist item 12 to prompt authors to report on the rationale underlying the selection of the outcome domain for use as the primary outcome, which includes its clinical relevance. At a broad conceptual level, the outcome鈥檚 domain refers to the name or concept used to describe an outcome (eg, pain).13,38 The word domain can be closely linked to and sometimes used equivalently with the terms construct and attribute in the literature.39 Even though a complete outcome definition is expected to be provided in the trial protocol (as recommended by SPIRIT 2013 statement checklist item 12),2 the rationale for the choice of the outcome domain for the trial鈥檚 primary outcome is also essential to communicate because it underpins the purpose of the proposed trial.

Important aspects for the rationale may include (1) the importance of the outcome domain to individuals involved in the trial (eg, patients, the public, clinicians, policy makers, funders, or health payers), (2) the expected effect of the intervention on the outcome domain, and (3) the ability to assess it accurately, safely, and feasibly during the trial. It also should be reported whether the selected outcome domain originated from a core outcome set (ie, an agreed standardized set of outcomes that should be measured in all trials for a specific clinical area).40-44

Item 12.2. If the Analysis Metric for the Primary Outcome Represents Within-Participant Change, Define and Justify the Minimal Important Change in Individuals

This item expands on SPIRIT 2013 statement checklist item 12. In cases in which the participant-level analysis metric for the primary outcome represents intraindividual change from an earlier value (such as those measured at baseline), a definition and justification of what will be considered the minimal important change (MIC) for the relevant study instrument should be provided. In the SPIRIT-Outcomes 2022 extension, the MIC was defined as the smallest within-patient change that is considered important by patients, clinicians, or relevant others (common alternative terminologies appear in the Box).24,25,27 The MIC is important to report for all trials that use a within-participant change metric, such as those that plan to analyze the proportion of participants showing a change larger than the MIC value in each treatment group (eg, to define the proportion who improved)45 or in n-of-1 designs.46

Trialists and those involved with trials may be interested in the MIC itself as the benchmark or, alternatively, in a value larger than the known MIC. If the MIC is unknown for the study instrument with respect to the planned trial population and setting, this should be reported along with any efforts planned to determine the MIC as part of the trial. Describing the justification for the selected MIC in the trial protocol is important because there can be numerous MICs available for the same study instrument, with varying clinical relevance and methodological quality depending on how and in whom they were determined.47-51

Item 12.3. If the Outcome Data Collected Are Continuous, but Will Be Analyzed as Categorical (Method of Aggregation), Specify the Cutoff Values to Be Used

This item expands on SPIRIT 2013 statement checklist item 12 to prompt authors to prospectively describe the cutoff values to be used and that any outcome data collected on a continuous (or ordinal) scale should be converted into a categorical variable for their analyses.2,13,52 Providing an explanation of the rationale for the choice of the cutoff value is recommended. The cutoff values selected are most useful when they have clear clinical relevance.53 Failure to include cutoff values in the trial protocol (and in the statistical analysis plan)16 facilitates undetectable multiple testing (known as 鈥減-hacking鈥), data cherry-picking, and selective nonreporting of results in the trial report.7,13,54

Item 12.4. If Outcome Assessments Will Be Performed at Several Time Points After Randomization, State the Time Points That Will Be Used for the Analysis

This item expands on SPIRIT 2013 statement checklist item 12 to prompt authors to specify the time point to be used in the main analysis if outcome assessments are planned to be performed at multiple time points after randomization (eg, trial will assess blood pressure daily for 12 weeks after randomization). Specifying the preplanned time points of assessment for the analyses will help limit the possibility of unplanned analyses of multiple time points for assessment and the selective nonreporting of time points that did not yield large or significant results.2,38 Providing a rationale for the choice of time point is encouraged (eg, based on the expected clinical trajectory after the intervention or the duration of treatment needed to achieve a clinically meaningful exposure to treatment). The length of follow-up should be appropriate to the management decision the trial is designed to inform.55

Item 12.5. If a Composite Outcome Is Used, Define All Individual Components of the Composite Outcome

A composite outcome consists of 2 or more component outcomes that may be related. Participants who have experienced any 1 of the defined component outcomes comprising the composite outcome are considered to have experienced the composite outcome.20,21 When used, composite outcomes should be prespecified, justified, and fully defined in the trial protocol,53 which includes a complete definition of each individual component outcome (SPIRIT 2013 statement checklist item 12 and SPIRIT-Outcomes 2022 extension checklist items 12.1-12.4) and a description of how those outcomes will be combined (eg, what analytic steps define the occurrence of the composite outcome). The use and interpretation of composite outcomes are complex, debated in the literature, and are an important trial design consideration.21,56

Item 14.1. Define and Justify the Target Difference Between Treatment Groups (eg, the Minimal Important Difference)

This item expands on SPIRIT 2013 statement checklist item 14 describing sample size calculations to prompt authors to specify an a priori target between-group treatment difference at the specific time point for the analysis. The target difference is the value used in sample size calculations as the difference sought to be detected in the primary outcome between the intervention groups at the specific time point for the analysis that should be considered realistic or important by 1 or more key stakeholder groups.36 The Difference Elicitation in Trials project has published extensive evidence-based guidance on selecting a target difference for a trial, sample size calculation, and reporting.36,37 The target difference may be the minimal important difference (the smallest difference between patients perceived as important by patients, clinicians, or relevant others)24,28,29 or the smallest worthwhile effect (the smallest beneficial effect of an intervention that justifies the costs, harms, and inconvenience of the interventions as determined by patients).34

Reporting the target difference is essential at the trial protocol stage for (1) grant peer reviewers to determine whether a trial will have sufficient plausibility and clinical effect to warrant allocation of funding, and (2) ethics boards, regulators, and other reviewers evaluating whether there is an adequate benefit to harm ratio to approve the trial, and whether the trial will be adequately powered to detect a clinically important difference. Because there can be different pragmatic or clinical factors informing the selected target difference (eg, the availability of a credible minimal important difference for the study instrument used to assess the primary outcome),47 and numerous different options available (eg, 1 of several minimal important differences or values based on pilot studies),47 it is important to explain why the chosen target difference was selected.26,48,49

SPIRIT-Outcomes 2022 Extension Checklist Items for the Descriptions of the Data Collection, Management, and Analysis
Item 18a.1. Describe What Is Known About the Responsiveness of the Study Instruments in a Population Similar to the Study Sample

This item expands on SPIRIT 2013 statement checklist item 18, which asks for a description of the reliability and validity of the study instruments (eg, questionnaires, laboratory tests), to also report on the responsiveness of the study instruments. Responsiveness refers to the ability of evaluative instruments (ie, those that measure longitudinal change and typically the effects of treatment)57 to accurately detect and measure change over time in the health outcome being assessed.25,32,33 Responsiveness is less relevant to discriminative instruments (eg, diagnostic tests), for which diagnostic accuracy is important. Describing whether measurement properties (such as responsiveness) have been evaluated in a population similar to the study sample (or at least not substantively different from the study sample) is helpful because measurement properties of study instruments are context specific and cannot be assumed to be generalizable between different populations (eg, with different health problems or with different age groups) in the absence of evidence.58 If measurement properties are unknown for the study population (eg, use of a scale developed for adults in a trial studying adolescents), this should be stated with a rationale as to why it is expected that this instrument is still useful and preferable to other available options and whether there are any other instruments that could be used.

Item 18a.2. Describe Who Will Assess the Primary Outcome (eg, Nurse, Parent)

This item expands on SPIRIT 2013 statement checklist item 18 to describe who will assess the primary outcome as part of the description of plans for the assessment and collection of outcome data. Blinding of the outcome assessor to the patient鈥檚 treatment assignment and to the emerging trial results is covered under SPIRIT 2013 statement checklist item 17a. Substantially different responses, and therefore different trial results, can be obtained for many types of outcomes (eg, behavioral, psychological outcomes), depending on who is assessing the outcome of interest. This variability may result from differences in assessors鈥 training or experience, different perspectives, or patient recall.59-61 Assessments of a clinical outcome reported by a clinician, a patient, or a nonclinician observer or through a performance-based assessment are correspondingly classified by the US Food and Drug Administration as clinician-reported, patient-reported, observer-reported, and performance outcomes.62 For outcomes that could be assessed by various people, an explanation for the choice of outcome assessor made in the context of the trial should be provided. For outcomes (eg, plasma cholesterol levels) that are not influenced by the assessor, this information is less relevant.

Item 20a.1. Describe Any Planned Methods to Account for Multiplicity in the Analysis or Interpretation of the Primary and Secondary Outcomes (eg, Coprimary Outcomes, Same Outcome Assessed at Multiple Time Points, or Subgroup Analyses of an Outcome)

This item expands on the SPIRIT 2013 statement checklist item 20a to prompt authors to describe any planned methods to account for multiplicity relating to the analysis or interpretation of the outcomes. Outcome multiplicity issues are common in trials and deserve particular attention when there are coprimary outcomes, multiple possible time points resulting from the repeated assessment of a single outcome, multiple planned analyses of a single outcome (eg, interim or subgroup analysis, multigroup trials), or numerous secondary outcomes for analysis.63 The planned methods used to account for such forms of multiplicity include statistical methods (eg, family-wise error rate approaches) or descriptive approaches (eg, noting that the analyses are exploratory, placing the results in the context of the expected number of false-positive outcomes).63,64 Decisions around whether and how to account for multiplicity may be informed by the outcome type (ie, primary vs secondary), the design of the trial (ie, exploratory vs confirmatory), and local or national regulatory requirements.53,64 Such information may be briefly described in the trial protocol or described in more detail in the statistical analysis plan.16

Discussion

The SPIRIT-Outcomes 2022 extension provides evidence- and consensus-based guidance for reporting outcome-specific information in trial protocols, extending the SPIRIT 2013 statement checklist with 9 additional reporting items and harmonizing reporting recommendations with guidance from the CONSORT-Outcomes 2022 extension.17 Alignment across these 2 extension guidelines creates a cohesive continuum of reporting from the trial protocol to the completed trial report that will facilitate both the researchers鈥 production of the trial protocol and trial report and, importantly, enable assessment of researchers鈥 adherence to the trial protocol.

Similar to the SPIRIT 2013 statement,1,2 the SPIRIT-Outcomes 2022 extension applies to the content of the trial protocol, regardless of trial design or population. The current recommendations are similarly not prescriptive regarding how information should be included, which varies depending on local requirements, the purpose and audience for which a trial protocol is intended (eg, submission to a regulatory agency vs an academic journal for publication), and the public availability of related trial documents (eg, the statistical analysis plan16).

When other documents are available, the trial protocol should briefly describe or outline the checklist item components and refer to the separate documents such as the statistical analysis plan so that their existence, location, and accessibility are known. To maximize the usefulness and effect of the SPIRIT-Outcomes 2022 extension, it can be used in conjunction with the CONSORT-Outcomes 2022 extension.17 In addition, inclusion of SPIRIT-Outcomes 2022 extension checklist items in trial registry entries (eg, ClinicalTrials.gov) may increase implementation. Endorsement and implementation of the SPIRIT-Outcomes 2022 extension by publishers and editors for their authors could also increase uptake. The information described in the trial protocol should be consistent with the information reported in trial registrations and statistical analysis plans. Trial protocols should be freely and prospectively accessible (eg, via publication or a permanent online repository).

Users of the SPIRIT-Outcomes 2022 extension should note that these additional checklist items represent the minimum essential outcome-specific reporting items and are being added to the SPIRIT 2013 statement guidelines to promote trial transparency, replication, and critical appraisal, and to limit selective nonreporting of results (eTable 5 in the Supplement). In some cases, it may be important to report additional outcome-specific information in the trial protocol such as those in eTable 6 in the Supplement or refer to the SPIRIT-PRO extension5 for guidance in describing patient-reported outcomes in trial protocols. Some of the SPIRIT-Outcomes 2022 extension checklist items that achieved consensus as essential reporting items only for the primary outcome may nevertheless be important to report for other trial outcomes. Authors adhering to the SPIRIT-Outcomes 2022 extension should specify why any items are not relevant to their trial when completing the checklist. For example, this extension checklist, which is for reporting systematically assessed outcomes, might not be applicable to outcomes that are not systematically collected or prespecified such as spontaneously reported adverse events.

We anticipate that the key users of the SPIRIT-Outcomes 2022 extension will be trial protocol authors, ethics review boards, and journal editors. Use of this SPIRIT-Outcomes 2022 extension by these groups may help improve trial utility and transparency and may help reduce the risk of selective nonreporting of results in trial reports when used in conjunction with the CONSORT-Outcomes 2022 extension.17 Patient and public engagement was successfully embedded into a consensus meeting for a methodologically complex topic, a rarity in reporting guideline development to date. Future reporting guideline development should engage patients and members of the public throughout the process. The SPIRIT-Outcomes 2022 extension will be disseminated as outlined previously,14 including through the EQUATOR Network and the SPIRIT website. End users can provide their input on the content, clarity, and usability online,65 which will inform any future updates.

Limitations

This study has several limitations. First, the included checklist items are appropriate for systematically collected outcomes, including most potential benefits and some harms; however, other items might be applicable for reporting harms not systematically assessed.66

Second, because these checklist items are not yet integrated in the main SPIRIT checklist, finding and using multiple checklists may be considered burdensome by some authors and editors, and implementation might be affected because of these obstacles.67 Future efforts to integrate these additional items in the main SPIRIT checklist might promote implementation in practice.

Third, although a large, diverse, international group of experts and end users was involved in the development of these recommendations with the aim of increasing usability among the broader research community, the Delphi voting results could have been affected by a nonresponse bias because panelists were self-selecting (ie, interested individuals signed up to take part in the Delphi process).

Fourth, the consensus meeting panelists were purposively sampled based on their expertise and roles relevant to randomized clinical trial conduct, oversight, reporting, and use of trial results. The views of individuals not well represented by the consensus meeting panelists (eg, trialists outside North America and Europe) might differ. The systematic and evidence-based approach14,15 used to develop this guideline, including a rigorous scoping review of outcome reporting guidance,6,18 may help mitigate the potential effect of these limitations.

Conclusions

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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Article Information

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 (nancy.butcher@sickkids.ca).

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鈥檚 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鈥 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 .

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