SPIRIT 2025 statement: updated guideline for protocols of randomized trials

Abstract

The protocol of a randomized trial is the foundation for study planning, conduct, reporting and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. Here, we aimed to systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomized trial. We completed a scoping review and developed a project-specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (Harms, Outcomes, Non-pharmacological Treatment) and other reporting guidelines (TIDieR). The potential modifications were rated in a three-round Delphi survey followed by a consensus meeting. Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of two new protocol items, revision to five items, deletion/merger of five items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct and reporting. The updated SPIRIT 2025 statement consists of an evidence-based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrollment, interventions and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policymakers, regulators and other reviewers.

Main

“Readers should not have to infer what was probably done; they should be told explicitly.” Douglas G. Altman¹

Robustly designed, properly conducted and fully reported randomized trials underpin evidence-based practice and policy. As the most important record of planned methods and conduct, a well-written protocol has a key role in promoting consistent and rigorous execution by the trial team. The protocol also serves as the basis for oversight and review of scientific, ethical, safety and operational issues by funders, regulators, research ethics committees/institutional review boards (REC/IRBs), journal editors, researchers, patients and the public^{2,3,4,5,6,7,8,9}. After trial completion, the protocol is essential for understanding and interpreting the results.

Despite the central role of protocols, there is substantial variation in the completeness of protocol content^10,11. Many trial protocols do not adequately describe important elements, including the primary outcomes, treatment allocation methods, use of blinding, measurement of adverse events, sample size calculations, data analysis methods, dissemination policies, and roles of sponsors and investigators in trial design^10,11,12. Gaps in protocol content can lead to avoidable protocol amendments¹³, inconsistent or poor trial conduct, and lack of transparency in terms of what was planned and implemented.

In response to these protocol deficiencies, the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidance was first published in 2013 (refs. ^14,15). Aligned with the CONSORT (Consolidated Standards of Reporting Trials) guidance for reporting completed trials¹⁶, the international SPIRIT initiative aims to improve the completeness of trial protocols by producing evidence-based recommendations for a minimum set of items to be addressed in protocols. The SPIRIT 2013 guidance has been translated into seven languages and is widely endorsed by national funders, research organizations, over 150 medical journals and the World Association of Medical Editors.

In January 2020, the SPIRIT and CONSORT executive groups held a joint meeting in Oxford, UK, to discuss strategic planning. There was broad recognition of the need to update both checklists to reflect the evolving trials environment and methodological advancements, including the growing international support for improved research transparency, accessibility and reproducibility (collectively referred to as open science)¹⁷, as well as greater patient and public involvement in research.

As the SPIRIT 2013 and CONSORT 2010 statements were conceptually linked with overlapping content and implementation strategies, the two groups decided to merge into the joint SPIRIT–CONSORT executive group and to update both checklists simultaneously. The joint update was an opportunity to further align the checklists and provide consistent guidance in the reporting of trial design, conduct and analysis — from study conception to the publication of results. Harmonizing the reporting recommendations could help improve usability and adherence¹⁸. Here, we introduce the updated SPIRIT 2025 statement; the CONSORT 2025 statement is published separately¹⁶.

Methods

The methods have been detailed elsewhere^19,20. In brief, we followed the EQUATOR Network guidance for developers of health research guidelines²¹. We first conducted a scoping review of the literature from 2013 to 2022 to identify published comments suggesting modifications or reflecting on the strengths and challenges of SPIRIT 2013; these findings have been published separately²². We also conducted a broader search for empirical and theoretical evidence published from 2013 to 2024 that was relevant to SPIRIT and risk of bias in randomized trials, producing the SPIRIT–CONSORT Evidence Bibliographic database²³. The evidence identified in the literature was combined with recommendations provided by the lead authors of key SPIRIT and CONSORT extensions (Harms²⁴, Outcomes²⁵, Non-pharmacological Treatment²⁶), and the Template for Intervention Description and Replication (TIDieR)²⁷, along with user feedback.

Based on the gathered evidence, a preliminary list of five potential additions to the SPIRIT 2013 checklist was created for review in an international, three-round online Delphi survey. A total of 317 participants were recruited through professional research networks, societies and the project website. Participants represented a broad range of roles in clinical trials, including statisticians/methodologists/epidemiologists (n = 198), trial investigators (n = 73), systematic reviewers/guideline developers (n = 73), clinicians (n = 58), journal editors (n = 47), and patients and members of the public (n = 17) (numbers are not mutually exclusive). During each survey round, participants rated the importance of modifications on a five-point Likert scale and provided comments or suggestions for additional items. A high level of agreement was defined by at least 80% of respondents rating the importance of a proposed modification as high (score of 4 or 5) or low (score of 1 or 2).

The Delphi survey results were then discussed at a two-day online consensus meeting in March 2023, attended by 30 invited international experts representing a range of relevant groups. Meeting participants discussed potential new and modified SPIRIT checklist items, with anonymous polling of participants in cases of ongoing disagreement.

The executive group met in person in April 2023 to develop a draft checklist based on the consensus meeting discussion. After a further round of review by consensus meeting participants, the executive group finalized the SPIRIT 2025 statement.

Updated SPIRIT 2025 statement

The SPIRIT 2025 statement comprises a checklist of 34 minimum protocol items (Table 1) and a diagram illustrating the schedule of enrollment, interventions and assessments (Table 2). An accompanying SPIRIT 2025 explanation and elaboration document provides background and context for each checklist item, along with examples of good reporting²⁸. We strongly recommend that the SPIRIT 2025 explanation and elaboration document be used routinely alongside the SPIRIT 2025 statement to facilitate better understanding of and adherence to the checklist items.

Table 1 SPIRIT 2025 checklist of items to address in a randomized trial protocol

Table 2 SPIRIT 2025 diagram of the schedule of enrollment, interventions and assessments

To present the recommendations in diverse formats, we also developed an expanded version of the SPIRIT 2025 checklist with bullet points of key issues to consider for each item (Supplementary Table 1), as done with other initiatives^29,30,31. The expanded checklist comprises an abridged version of elements presented in the SPIRIT 2025 explanation and elaboration document²⁸, with examples and references removed.

Main changes

Substantive changes made in this update are detailed in Box 1. We added two new checklist items, revised the content of five items, deleted three items, merged two items and integrated key items from CONSORT Harms 2022 (ref. ²⁴), SPIRIT-Outcomes 2022 (ref. ²⁵) and TIDieR²⁷ into the main checklist and explanatory document. We also restructured the SPIRIT checklist and created a new open science section consolidating items critical to promoting access to information about trial methods and results, including trial registration; sharing of the full protocol, statistical analysis plan and de-identified participant level data; and disclosure of funding sources and conflicts of interest. We have also harmonized the wording between SPIRIT and CONSORT checklist items and clarified the wording of some items. A comparison of the SPIRIT 2025 and 2013 checklists is available in Supplementary Table 2.

Box 1 Summary of main changes in SPIRIT 2025

Addition of new checklist items:

• Item 11: added item on how patients and the public are involved in the design, conduct, and reporting of the trial

• Item 29: added item on trial monitoring (replaces prior item on auditing)

Revised content of checklist items

• Item 4: revised item to include date of trial registration

• Item 5: revised item to include where the statistical analysis plan can be accessed in addition to the trial protocol (previously covered under item on statistical methods)

• Item 7b: revised item to include financial and other conflicts of interest of steering committee members

• Item 24a/24b: split item into separate sub-items covering (a) who will be blinded and (b) how, and revised to include description of the similarity of interventions

• Item 27d: revised to refer to sensitivity analyses

Deletion/merger of checklist items

• Deleted item on auditing (replaced with trial monitoring)

• Deleted appendix items:

  • Informed consent materials

  • Biological specimens

• Merged item on access to data for trial investigators with item on data management (item 26)

• Merged item on authorship eligibility guidelines and use of professional writers with item on dissemination policy (item 8)

Integration of checklist items from CONSORT Harms 2022 and TIDieR

• Revised items to emphasize reporting of harms (items 10, 17, 27a)²⁴ and to call for additional details relating to interventions and comparators (item 15a)²⁷

Structure and organization of checklist items

• Created a new section on open science that includes trial registration (item 4), access to the trial protocol and statistical analysis plan (item 5), plans for sharing de-identified participant level data (item 6), funding and conflicts of interest (item 7), and plans for dissemination of trial results (item 8)

• Item 14a/b: split item into separate sub-items covering eligibility criteria for (a) participants and (b) sites and personnel

• Item 27b/27c: split item into separate sub-items covering the analysis population and methods for handling missing data

• Aligned wording of SPIRIT checklist items with that of CONSORT checklist items, and vice versa

• Clarified and simplified wording of some items

Definition of a randomized trial protocol

The protocol is a central document that provides sufficient detail to enable (1) understanding of the rationale, objectives, population, interventions, methods, statistical analyses, ethical considerations, dissemination plans and administration of the trial; (2) replication of trial methods and conduct; and (3) appraisal of trial validity, feasibility and ethical rigor¹⁴.

The full protocol must be submitted for approval by an REC/IRB before enrolling participants³². As a living document that is often formally amended during the trial^13,33, every protocol version should contain a transparent audit trail documenting the dates and descriptions of changes. Important protocol amendments should be reported to REC/IRBs and trial registries as they occur, and subsequently described in reports of completed trials³⁴.

Scope of SPIRIT 2025

SPIRIT 2025 addresses the minimum content of a protocol, focusing on the most common type of randomized trial — the two-group parallel design. However, most of the SPIRIT items are relevant to any type of trial. SPIRIT 2025 has been designed to complement and enhance the expanding trial registration requirements mandated by legislation, journals and funding policies³⁵. SPIRIT 2025 encompasses and builds upon recommendations from the International Council for Harmonization Good Clinical Practice E6(R3) guidance³⁶ and 2024 Declaration of Helsinki³², including the Declaration of Helsinki’s requirement that the protocol address potential conflicts of interest and provision of post-trial care.

It is feasible to address all SPIRIT 2025 checklist items in a single protocol document, as illustrated by the examples we identified from existing protocols for every item²⁸. There are often related documents (for example, full statistical analysis plan³⁷, data management plan) that provide further details on specific items. Any such documents should be referenced in the protocol and made available for review.

The main purpose of SPIRIT 2025 is to promote transparency and an adequate description of what is planned — not to prescribe how a trial should be designed or conducted. The checklist also does not focus on the protocol format, which is often subject to local regulations or practice. The checklist should not be used to appraise the quality of trial design or conduct, as it is possible for the protocol of a poorly designed trial to address all checklist items by fully describing its inadequate design and conduct features. Recent guidance from the World Health Organization (WHO) outlines best practices for designing and conducting trials³⁸.

Implementation

The SPIRIT 2025 statement supersedes the SPIRIT 2013 statement, which should no longer be used or cited. We encourage research organizations, sponsors, funders, REC/IRBs, journal editors and publishers to endorse SPIRIT 2025 and request that they update their resources and instructions to research teams and reviewers with reference to the updated guidance.

When protocols are submitted for review or publication, we recommend the submission of a completed SPIRIT 2025 checklist that indicates where (for example, page number) checklist items are reported in the protocol. Trial investigators and sponsors should address all SPIRIT 2025 checklist items in the protocol before REC/IRB submission. If an item is not relevant for a particular trial (for example, no interim analysis planned), then this should be explicitly stated, along with an explanation. We encourage investigators to ensure consistency of information in the protocol, related documents (for example, full statistical analysis plan)³⁷ and trial registry record³⁹.

To facilitate implementation, a new SPIRIT–CONSORT website (https://consort-spirit.org) provides resources based on the SPIRIT and CONSORT 2025 statements, including a fillable checklist, protocol-writing tools, and training materials for researchers, trainees, journal editors, peer reviewers, patients and the public.

Limitations

As a minimum standard focused on parallel group randomized trials, SPIRIT 2025 may not encompass every protocol item relevant for a particular trial. For example, a factorial trial design has additional analytical considerations related to potential statistical interactions⁴⁰, and trials evaluating patient-reported outcomes have specific considerations regarding data-collection methods⁴¹. Extensions to SPIRIT 2013 were developed to provide additional guidance on reporting different types of trial designs, data and interventions^{25,34,40,41,42,43,44,45,46,47}. We will engage with the leaders of these extensions to implement a process for aligning them with the updated SPIRIT 2025 statement. In the meantime, we recommend that the existing version of the relevant SPIRIT extensions be used.

Potential impact

The updated SPIRIT 2025 statement and its accompanying explanation and elaboration document can be helpful in several ways. SPIRIT 2025 will continue to serve as an educational resource for new investigators, trainees, peer reviewers and REC/IRB members. The explicit incorporation of an open science section in the SPIRIT checklist will support the growing global push for greater transparency and sharing of trial materials and outputs to facilitate evidence synthesis and reproducibility of research.

Trial investigators can consult the guidance when drafting their protocols to ensure that all elements are addressed. Meta-research reviews of protocols have found improved completeness of protocol content after SPIRIT 2013 was introduced^10,11,48,49. In addition to improved reporting, adherence to SPIRIT 2025 may promote high-quality trial design and implementation because SPIRIT is used during the planning stage of a trial. This provides an opportunity to improve the validity and successful completion of trials by reminding investigators about important issues to consider before the study begins. Better protocols can also help study personnel to implement the trial consistently across sites.

Another potential benefit of SPIRIT 2025 is its impact on administrative burden. Improved completeness of protocols may improve the efficiency of external review by reducing avoidable queries to investigators about incomplete or unclear protocol-related information^50,51. High-quality protocols addressing all SPIRIT items may also help to reduce the number and burden of protocol amendments during the trial — many of which can be avoided with careful consideration of key issues when developing the protocol^13,33. Widespread adoption of SPIRIT 2025 as a common standard across REC/IRBs, funding agencies, regulatory agencies and journals could simplify the work of trial investigators and sponsors because a SPIRIT-based protocol would then fulfil the harmonized application requirements of multiple groups.

Further, adherence to SPIRIT 2025 may help ensure that protocols contain the requisite information for critical appraisal and trial interpretation by peer reviewers, funders, REC/IRBs and journals⁷. High-quality protocols provide important information about trial methods and conduct that is usually not available in trial registries or publications reporting completed trials. As a transparent record of the investigators’ original intent, comparison of protocols with reports of completed trials helps to identify selective reporting of results and undisclosed amendments, such as changes to primary outcomes or analyses^52,53. These benefits of SPIRIT based protocols can only be fully realized when trial protocols are routinely made publicly available through trial registries (for example, PDF upload), journals and online repositories^7,54,55.

The SPIRIT 2025 statement incorporates new evidence and emerging perspectives to ensure that the guidance remains relevant to users. Widespread endorsement and adoption of the updated recommendations have the potential to improve protocol content and implementation; facilitate registration, oversight and appraisal of trials; and ultimately enhance transparency and translation to better healthcare.