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Cited by 171Meta-analysis and systematic reviewsStatistical Methods in Clinical TrialsClinical practice guidelines implementation

SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials

Open access
Hróbjartsson, Asbjørn, Boutron, Isabelle, Hopewell, Sally, Moher, David, Schulz, Kenneth F, Collins, Gary S, Tunn, Ruth, Aggarwal, Rakesh +31 more·2025·BMJ
DOI 10.1136/bmj-2024-081660PMC PMC12128891
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Abstract

High quality protocols facilitate proper planning, conduct, reporting, and external review of randomised trials, yet their completeness varies and key elements are often not considered. To strengthen good reporting of trial protocols, the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 statement has been updated to incorporate new evidence and emerging perspectives. This SPIRIT 2025 explanation and elaboration document provides users with exemplars of reporting in contemporary trial protocols, contextual elaboration, more detailed guidance on reporting, references to key empirical studies, an expanded checklist, and a link to a website for further information. The document is intended to be used in conjunction with the SPIRIT 2025 statement and serves as a resource for researchers planning a trial and for others interested in trial protocols.

AI snapshot

Written from a shortened version of the paper’s full text (it is longer than we read).

TL;DR

SPIRIT 2025 explanation and elaboration provides updated guidance for reporting protocols of randomised trials, expanding the 34-item SPIRIT 2025 checklist with exemplars, rationale, and references. It is intended to be used with the SPIRIT 2025 statement to improve the completeness and transparency of trial protocols.

Key findings

  • SPIRIT 2025 comprises a 34-item checklist of minimum recommended protocol items, plus a schedule-of-enrolment/interventions/assessments diagram; this E&E explains each item and gives published protocol exemplars.
  • The update was developed using a scoping review, an online Delphi survey with 317 international participants, and a two-day online expert consensus meeting with 30 international experts; SPIRIT 2025 was developed in parallel with CONSORT 2025.
  • The document reports persistent protocol reporting gaps from two 2016 samples of 108 and 292 protocols, including 11% and 17% reporting protocol contributor names, 57% and 78% reporting sponsor name/contact details, and 23% and 32% reporting plans for access to the full dataset.
  • It provides an expanded checklist and a joint SPIRIT-CONSORT website to support implementation.

Methods

  • Guideline development followed EQUATOR Network guidance; briefly, a project database, scoping review of comments, identification of SPIRIT/CONSORT extensions, evidence collection, Delphi survey (317 participants), and a two-day online consensus meeting (30 experts) informed the updated checklists.
  • For this E&E, the authors modelled their approach on the SPIRIT 2013 E&E: each checklist item is presented with at least one exemplar from a protocol, followed by rationale, main issues, and selected references.
  • Exemplars were obtained from public websites, journal publications, and appendices to published trials; references to empirical studies were identified through a continuously updated project database, preferring systematic reviews when available.

Limitations

  • The paper states challenges in balancing brevity and comprehensiveness, generalisability and specificity, and notes that SPIRIT 2025 focuses on the most prevalent design—parallel group randomised trials—although most items apply to other designs.
  • The paper states that some items had little or no identified empirical evidence (e.g., item 1a, Title) and were included based on pragmatic or ethical rationale; it also notes overlap among SPIRIT extensions and the need for better alignment.
  • Evident from the text: this is a guidance/explanation document, not an empirical evaluation of whether SPIRIT 2025 improves protocol quality, and the exemplars are selected examples rather than a systematic sample.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1136/bmj-2024-081660

Cites

474 of 474 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 453 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Concerns about inadequate reporting of key content in trial protocols provided the impetus for the development of the original SPIRIT statement published in 2013.

    “Concerns about inadequate reporting of key content in trial protocols3 4 5 provided the impetus for the development of the original SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement published in 2013.6”
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  • Premisecitation

    Restrictions on publication have been imposed by various groups, including industry sponsors.

    “Restrictions on publication have been imposed by various groups, including industry sponsors.38 49 50”
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  • Premisecitation

    Previous reviews have reported frequent discrepancies in primary outcomes defined in registries compared with those specified in protocols of randomised trials.

    “as previous reviews have reported frequent discrepancies in the primary outcomes defined in registries compared with those specified in protocols of randomised trials.64”
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  • Premisecitation

    These restrictions are sometimes not fully described in the protocol but rather in separate publication agreements.

    “These restrictions are sometimes not fully described in the protocol but rather in separate publication agreements.38 51”
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  • Premisecitation

    Reviews of two samples of 108 and 292 unpublished trial protocols from 2016 found that 11% and 17%, respectively, reported the names of protocol contributors or authors.

    “Reviews of two samples of 108 and 292 unpublished trial protocols from 2016 found that 11% and 17%, respectively, reported the names of protocol contributors or authors.9 10”
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    Findingcitation

    SPIRIT 2025 consists of a 34-item checklist of the minimum recommended protocol items and a diagram illustrating the schedule of enrolment, interventions, and assessments.

    “an international group developed and published the updated SPIRIT 2025 statement13—consisting of a 34 item checklist of the minimum recommended protocol items (table 1); a diagram illustrating the schedule of enrolment, interventions, and assessments (fig 1).”
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    Findingnone given

    The SPIRIT 2025 statement comprises a checklist of 34 essential items for reporting protocols of randomised trials.

    “The SPIRIT 2025 statement comprises a checklist of 34 essential items for reporting protocols of randomised trials”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Members of the core writing group developed a draft for individual items, which was revised iteratively after comments from all authors.

    “Members of the core writing group (IB, A-WC, GSC, SH, AH, DM, KFS, RT) developed a draft for individual items. The draft was revised iteratively after comments from all authors.”
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    Study design and conductcitation

    The approach for developing the SPIRIT 2025 explanation and elaboration document was modelled on the procedures for the SPIRIT 2013 explanation and elaboration document.

    “We modelled our approach for developing the SPIRIT 2025 explanation and elaboration document on the procedures for the SPIRIT 2013 explanation and elaboration document.25”
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  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Premisenone given

    High quality protocols facilitate proper planning, conduct, reporting, and external review of randomised trials.

    “High quality protocols facilitate proper planning, conduct, reporting, and external review of randomised trials”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Some items had little or no identified empirical evidence but their inclusion in the checklist was supported by a strong pragmatic or ethical rationale.

    “Some items had little or no identified empirical evidence (eg, item 1a, Title) but their inclusion in the checklist was supported by a strong pragmatic or ethical rationale.”
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    Study design and conductreasoning

    Examples are quoted verbatim from the trial protocol.

    “Examples are quoted verbatim from the trial protocol.”
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    Premisereasoning

    As the content and context of randomised trials evolve, both SPIRIT and CONSORT statements require periodic updating to reflect new evidence, methodological advances, and feedback from users.

    “Also, as the content and context of randomised trials evolve, both SPIRIT and CONSORT statements require periodic updating to reflect new evidence, methodological advances, and feedback from users.”
    Quote in the paperNot a substantial claim

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    Study design and conductnone given

    To identify examples for each checklist item, protocols were obtained from public websites, journal publications, and appendices to published trials.

    “To identify examples for each checklist item, we obtained protocols from public websites, journal publications, and appendices to published trials.”
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  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Study design and conductnone given

    When citing empirical evidence, the authors aimed to reference a systematic review when available.

    “When citing empirical evidence, we aimed to reference a systematic review when available.”
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    Study design and conductcitation

    For each checklist item, references to core empirical studies supporting its inclusion were provided, identified through a continuously updated project database.

    “For each checklist item, we provided references to core empirical studies supporting its inclusion, which we identified through a continuously updated project database.20”
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    Study design and conductreasoning

    Studies were cited if they provided empirical data to support or challenge a given protocol concept.

    “Studies were cited if they provided empirical data to support or challenge a given protocol concept.”
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    Study design and conductcitation

    The methods used to update the SPIRIT and CONSORT statements followed the EQUATOR Network guidance for developers of health research guidelines.

    “The methods used to update the SPIRIT and CONSORT statements followed the EQUATOR (Enhancing the Quality and Transparency Of Health Research) Network guidance for developers of health research guidelines.16”
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    Premisecitation

    The completeness of trial protocols varies and key elements are often not considered.

    “yet their completeness varies and key elements are often not considered”
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    Study design and conductnone given

    Exemplars were selected to reflect how key elements could be appropriately described in a trial protocol.

    “Exemplars were selected to reflect how key elements could be appropriately described in a trial protocol.”
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    Study design and conductown data

    The SPIRIT 2025 update identified relevant SPIRIT or CONSORT extensions and related guidelines.

    “identified relevant SPIRIT or CONSORT extensions and related guidelines (eg,21 22 23 24)”
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    Study design and conductown data

    The SPIRIT 2025 update generated a list of potential modifications or additions to SPIRIT and CONSORT, which was presented to interested parties in an online Delphi survey involving 317 international participants.

    “We then generated a list of potential modifications or additions to SPIRIT and CONSORT, which we presented to interested parties in an online Delphi survey involving 317 international participants.”
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    Premisecitation

    The title provides an important means of trial identification.

    “The title provides an important means of trial identification.”
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    Study design and conductcitation

    SPIRIT 2025 was developed in parallel with the updated CONSORT 2025 to harmonise recommendations and terminology.

    “SPIRIT 2025 was developed in parallel with the updated CONSORT 2025 to harmonise recommendations and terminology.7 14”
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    Study design and conductcitation

    The SPIRIT 2025 update included a scoping review of published comments suggesting changes to SPIRIT 2013 and CONSORT 2010.

    “conducted a scoping review of published comments suggesting changes to SPIRIT 2013 and CONSORT 2010,18”
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    Premisenone given

    A structured summary provides an accessible overview of the planned trial for users of the protocol.

    “A structured summary provides an accessible overview of the planned trial for users of the protocol.”
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    Study design and conductown data

    The Delphi survey results were discussed at a two day online expert consensus meeting attended by 30 international experts before drafting the updated SPIRIT 2025 and CONSORT 2025 checklists.

    “The Delphi survey results were then discussed at a two day online expert consensus meeting attended by 30 international experts before we drafted the updated SPIRIT 2025 and CONSORT 2025 checklists and finalised them based on further feedback from people who attended the meeting.”
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    Premisecitation

    The WHO Trial Registration Data Set defines the minimum information to be included in a trial registry for a trial to be considered fully registered.

    “This dataset defines the minimum information to be included in a trial registry for a trial to be considered fully registered (item 4).30”
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    • cites [30] World Health Organization. WHO Trial Registration Data Set (Version 1.3.1). https://www.who.int/clinical-trials-registry-platform/network/who-data-set [Accessed 12 Mar 2024].

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    Premisecitation

    A succinct description that conveys the topic and trial design will facilitate retrieval from electronic database or internet searches and rapid judgment of relevance.

    “A succinct description that conveys the topic (study population, intervention, comparator) and trial design (eg, parallel group randomised trial) will facilitate retrieval from electronic database or internet searches and rapid judgment of relevance.28”
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    Study design and conductnone given

    SPIRIT 2025 reflects the collaboration and input of multiple contributors, including trial investigators, healthcare professionals, methodologists, statisticians, patient and public contributors, journal editors, and research funders.

    “SPIRIT 2025 reflects the collaboration and input of multiple contributors, including trial investigators, healthcare professionals, methodologists, statisticians, patient and public contributors, journal editors, and research funders.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    The reporting of protocols for randomised trials has improved somewhat since 2013 but remains far from adequate.

    “Although the reporting of protocols for randomised trials has improved somewhat since 2013 it remains far from adequate.9 10 11 12”
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    Premisecitation

    Naming of authors can help to identify conflicts of interest and reduce ghost and gift authorship.

    “Naming of authors can also help to identify conflicts of interest (item 7b) and reduce ghost and gift authorship.38 39 40 41”
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    Premisecitation

    For some investigator initiated trials, the principal investigator can be considered to be a sponsor-investigator, assuming the roles of both sponsor and investigator.

    “For some investigator initiated trials, the principal investigator can be considered to be a sponsor-investigator, assuming the roles of both sponsor and investigator.46”
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    • cites [46] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Integrated addendum to ICH E6(R1): guideline for good clinical practice E6(R2). Step 4 version dated 9 November 2016. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf.

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    Premisecitation

    Documentation of a trial's existence and prespecified outcomes in a publicly accessible registry helps increase transparency, decrease unnecessary duplication of research effort, facilitate identification of ongoing trials for prospective participants, and identify and deter selective reporting of study results.

    “Documentation of a trial’s existence and prespecified outcomes in a publicly accessible registry helps to increase transparency, decrease unnecessary duplication of research effort, facilitate identification of ongoing trials for prospective participants, and identify and deter selective reporting of study results.63 64”
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    Interpretationreasoning

    Transparent tracking of versions and amendments facilitates trial conduct, review, and oversight.

    “Transparent tracking of versions and amendments facilitates trial conduct, review, and oversight.”
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    Premisecitation

    Typically, the statistical analysis plan is a separate document that should be read in conjunction with the protocol, but for some trials with simple analyses, it can be included as part of the protocol.

    “Typically, the statistical analysis plan is a separate document that should be read in conjunction with the protocol, but for some trials with simple analyses, it can be included as part of the protocol.72”
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    Interpretationreasoning

    Listing the protocol authors, their affiliations, and their role in the protocol development process provides due recognition, accountability, and transparency.

    “Listing the protocol authors, their affiliations, and their role in the protocol development process provides due recognition, accountability, and transparency.”
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    Premisecitation

    Reviews of two samples of 108 and 292 trial protocols from 2016 found that 57% and 78%, respectively, reported the name and contact details of the sponsor.

    “Reviews of two samples of 108 and 292 trial protocols from 2016 found that 57% and 78%, respectively, reported the name and contact details of the sponsor.9 10”
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    Interpretationreasoning

    Reporting of the WHO Trial Registration Data Set in the protocol can facilitate the prospective transfer of accurate information to a trial registry.

    “Reporting of the dataset in the protocol can facilitate the prospective transfer of accurate information to a trial registry (ie, before inclusion of the first trial participant).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In two samples of 108 and 292 trial protocols from 2016, 98% and 92% respectively reported steering committee membership and roles.

    “Reviews of two samples of 108 and 292 trial protocols from 2016 found that 98% and 92%, respectively, reported the steering committee membership and roles.9 10”
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    Premisecitation

    Most industry initiated trials are controlled by the company sponsoring and funding the trial; this authority is often enforced by contractual agreements signed between the company and trial investigators.

    “Most industry initiated trials are controlled by the company sponsoring and funding the trial; this authority is often enforced by contractual agreements signed between the company and trial investigators.38 48”
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    Premisecitation

    Randomised trials often include various committees or groups (e.g., a trial management group for day-to-day conduct and a trial steering committee for executive decisions) to facilitate trial coordination and conduct.

    “A randomised trial will often include various committees or groups to facilitate trial coordination and conduct—for example, a trial management group (day-to-day trial conduct) and a trial steering committee (executive decisions).54 55”
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    Premisecitation

    A trial registration number can serve to link all documents related to a trial, starting with the protocol.

    “A trial registration number can serve to link all of the documents related to a trial, starting with the protocol.65”
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    Interpretationnone given

    Identification of the trial sponsor provides transparency and accountability and can help to identify conflicts of interest.

    “Identification of the trial sponsor provides transparency and accountability and can also help to identify conflicts of interest (item 7b).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In general, the company is the sponsor in industry initiated trials, whereas the institution of the primary investigator is often the sponsor for investigator initiated trials.

    “In general, the company is the sponsor in industry initiated trials, whereas the institution of the primary investigator is often the sponsor for investigator initiated trials.”
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    • cites [46] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Integrated addendum to ICH E6(R1): guideline for good clinical practice E6(R2). Step 4 version dated 9 November 2016. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf.

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    Premisecitation

    The naming of authors and a description of their roles are standard for protocols published in journals such as Trials and BMJ Open, but they are less common for unpublished protocols.

    “The naming of authors and a description of their roles are standard for protocols published in journals such as Trials and BMJ Open, but they are less common for unpublished protocols.”
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    Premisecitation

    Registration of clinical trials should occur before recruitment of the first trial participant, as mandated by ICMJE and jurisdictional legislation.

    “As mandated by the ICMJE and jurisdictional legislation,31 32 66 registration of clinical trials should occur before recruitment of the first trial participant.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [31] European Commission. Clinical trials - Regulation EU No 536/2014. 2022. https://health.ec.europa.eu/medicinal-products/clinical-trials/clinical-trials-regulation-eu-no-5362014_en.

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    • cites [32] source

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    • cites [66] United States Congress. Food and Drug Administration Amendments Act of 2007, Title VIII, Section 801. Expanded clinical trial registry data bank. 2007. https://www.govtrack.us/congress/bills/110/hr3580/text.

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Sequentially labelling and dating each protocol version helps to mitigate potential confusion over which document is the most recent.

    “Sequentially labelling and dating each protocol version helps to mitigate potential confusion over which document is the most recent.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Reporting of the WHO Trial Registration Data Set in the protocol can signal the need for updates to the registry record when associated protocol sections are amended, thereby promoting consistency of information between the protocol and registry.

    “This can also signal the need for updates to the registry record when associated protocol sections are amended—thereby promoting consistency of information between the protocol and registry.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Changes to the protocol and statistical analysis plan may happen after the trial begins, often for legitimate reasons-for example, in response to new evidence or unanticipated challenges.

    “Changes to the protocol and statistical analysis plan may happen after the trial begins, often for legitimate reasons—for example, in response to new evidence or unanticipated challenges.73”
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    Premisecitation

    Amendments to the trial protocol are common.

    “Amendments to the trial protocol are common.35 36”
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    Premisecitation

    The WHO Trial Registration Data Set standards are supported by the International Committee of Medical Journal Editors, other journal editors, and legislation in many countries.

    “These standards are supported by the International Committee of Medical Journal Editors (ICMJE), other journal editors, and legislation in many countries.31 32 33”
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    • cites [31] European Commission. Clinical trials - Regulation EU No 536/2014. 2022. https://health.ec.europa.eu/medicinal-products/clinical-trials/clinical-trials-regulation-eu-no-5362014_en.

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    • cites [32] source

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    • cites [33] National Institutes of Health Department of Health and Human Services. Final Rule 81 FR 64982: Clinical Trials Registration and Results Information Submission. https://www.federalregister.gov/documents/2016/09/21/2016-22129/clinical-trials-registration-and-results-information-submission. 2016:64982-5157.

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In two samples of 108 and 292 trial protocols from 2016, 65% and 62% respectively reported declarations of interests.

    “Reviews of two samples of 108 and 292 trial protocols from 2016 found that 65% and 62%, respectively, reported declarations of interests.9 10”
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    • cites [9] source

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    Premisecitation

    Although peer reviewers and journal editors can be biased in favour of positive findings, lack of publication seems primarily due to trial investigators or sponsors failing to submit negative or null results, rather than journals rejecting them.

    “Although peer reviewers and journal editors can be biased in favour of positive findings,119 lack of publication seems to be primarily due to trial investigators or sponsors failing to submit negative or null results, rather than journals rejecting them.114 120”
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    • cites [119] source

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    Premisecitation

    In a growing number of jurisdictions, some funders require a commitment on the part of researchers to share their data; similarly, some journals require data sharing statements as part of the article submission process.

    “In a growing number of jurisdictions (eg, Canada, US, UK), some funders now require a commitment on the part of researchers to share their data (eg, US National Institutes of Health, UK National Institute for Health and Care Research, Gates Foundation). Similarly, some journals require data sharing statements as part of the article submission process (eg, The BMJ, PLOS Medicine).91 92”
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    • cites [91] source

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    • cites [92] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Randomised trials require considerable funding, typically from drug or device companies (industry funded) or from scientific or private foundations, or governmental or non-governmental organisations (non-industry funded).

    “A randomised trial requires considerable funding, typically from drug or device companies (ie, industry funded) or from scientific or private foundations, or governmental or non-governmental organisations (ie, non-industry funded).102”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] source

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  • May combine two claims.

    Premisecitation

    Undue influence on trials from non-industry funders with a strong interest in a specific trial result has been described, although studied less.

    “Undue influence on trials from non-industry funders with a strong interest in a specific trial result has been described,107 although studied less.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] source

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  • May combine two claims.

    Premisecitation

    Meta-research studies found more than a quarter of unpublished trials in various countries had results available in trial registries, and some data (particularly harms) were more completely reported in registries than in journal publications.

    “Meta-research studies have found that more than a quarter of unpublished trials in various countries had results available in trial registries, and some data (particularly harms) were more completely reported in registries than in journal publications.113 124 125 126 127”
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    • cites [113] source

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    • cites [124] source

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    • cites [125] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    One study estimated the median cost for each phase 3 industry funded trial to be $21.4m (£16.9m; €20.5m), with substantial variation.

    “One study estimated the median cost for each phase 3 industry funded trial to be $21.4m (£16.9m; €20.5m),103 with substantial variation.”
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    • cites [103] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In two samples of 108 and 292 trial protocols from 2016, 91% and 83% respectively described funding sources.

    “Reviews of two samples of 108 and 292 trial protocols from 2016 found that 91% and 83%, respectively, described funding sources.9 10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] source

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    • cites [10] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Beyond journal publication, trial registries and preprint servers are important venues for dissemination.

    “Beyond journal publication, trial registries and preprint servers are important venues for dissemination.121 122 123”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [121] source

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    • cites [122] source

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    • cites [123] source

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  • May combine two claims.

    Premisecitation

    For some trials, especially those sponsored by industry, access to the final trial dataset is restricted to the sponsor, which can introduce concerns about potential conflicts of interest.

    “For some trials, especially those sponsored by industry, access to the final trial dataset is restricted to the sponsor, which can introduce concerns about potential conflicts of interest (item 3c).99”
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    • cites [99] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Conflicts of interest are most often associated with drug and device industries, but may exist with support from or affiliation with government agencies, charities, and professional and civic organisations, although these associations have been much less investigated.

    “Conflicts of interest are most often associated with drug and device industries, but they may exist with support from or affiliation with government agencies, charities (not-for-profit organisations), and professional and civic organisations,107 although these associations have been much less investigated.”
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    • cites [107] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The World Medical Association supports the principle that trial investigators retain the right to access the data.

    “The World Medical Association supports the principle that trial investigators retain the right to access the data.98”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] World Medical Association. World Medical Association statement on conflicts of interest. Adopted by the 60 WMA General Assembly, New Delhi, India, October 2009 and editorially revised by the 201st WMA Council Session, Moscow, Russia, October 2015. https://www.wma.net/policies-post/wma-statement-on-conflict-of-interest/.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Access to protocols and statistical analysis plans may help with trial appraisal, interpretation, and replication, as well as identification of selective outcome reporting.

    “Having access to these documents may help with trial appraisal, interpretation, and replication, as well as identification of selective outcome reporting.81 82”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] source

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    • cites [82] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Funding of a trial typically involves direct monetary support, but financial support might also be provided indirectly in the form of free trial drugs, equipment, or services such as statistical analysis or use of medical writers.

    “Funding of a trial typically involves direct monetary support, but financial support might also be provided indirectly in the form of free trial drugs, equipment, or services such as statistical analysis or use of medical writers.105”
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    • cites [105] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Consent for data sharing can be obtained from trial participants upon enrolment, whereas approval for data sharing is typically obtained from research ethics committees and data access committees.

    “Consent for data sharing can be obtained from trial participants upon enrolment, whereas approval for data sharing is typically obtained from research ethics committees and data access committees.90”
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    • cites [90] source

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  • May combine two claims.

    Premisecitation

    The medical literature represents a biased subset of existing data, potentially leading to overestimation of benefits, underestimation of harms, and detrimental impact on patient care and research.

    “Overall, the medical literature represents a biased subset of existing data, potentially leading to overestimation of benefits, underestimation of harms, and a detrimental impact on patient care and research.112 117 118”
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    • cites [112] source

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    • cites [117] source

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    • cites [118] source

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  • May combine two claims.

    Premisecitation

    Among 224 randomised trials of interventions for covid-19, 68 (30%) reported in a trial registry the intention to share data, but only 50 (22%) actually shared individual patient data upon request or in a repository.

    “For example, among 224 randomised trials of interventions for covid-19, 68 (30%) reported in a trial registry the intention to share data, but only 50 (22%) actually shared individual patient data upon request or in a repository.96”
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    • cites [96] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The mean cost of clinical trials funded by the UK National Institute for Health and Care Research was about £1.3m, with considerable variation.

    “The mean cost of clinical trials funded by the UK National Institute for Health and Care Research was lower but still sizeable at about £1.3m, and also with considerable variation.104”
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    • cites [104] source

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  • May combine two claims.

    Premisecitation

    One review of eight published meta-epidemiological studies found that on average odds ratios from industry funded trials did not differ significantly from non-industry funded trials; however, in the subset of trials with a high risk of industry funder influence, the difference was 12% (95% CI 3% to 19%).

    “One review of eight published meta-epidemiological studies reported that, on average, odds ratios from industry funded trials did not differ significantly from those of non-industry funded trials. However, in the subset of trials with a high risk of industry funder influence (eg, on trial design, conduct, and analysis), the difference was 12% (95% CI 3% to 19%).52”
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    • cites [52] source

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  • May combine two claims.

    Premisecitation

    Although both industry funded and non-industry funded trials are susceptible to bias, industry funding is associated with conclusions that favour the intervention.

    “Although both industry funded and non-industry funded trials are susceptible to bias, industry funding is associated with conclusions that favour the intervention.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many journals routinely publish a statement about sharing of protocols, statistical codes, and datasets for all their published research articles.

    “Many journals routinely publish a statement about sharing of protocols, statistical codes, and datasets for all their published research articles.83”
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    • cites [83] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some trial groups have worked collaboratively to conduct individual patient data meta-analysis.

    “Some trial groups have worked collaboratively to conduct individual patient data meta-analysis.86”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Concerns about data sharing involve a perceived risk of reidentification of individuals, especially in trials enrolling participants with rare diseases, and inappropriate use of the data by other researchers or groups with a particular agenda can be a barrier to sharing.

    “Concerns about data sharing involve a perceived risk of reidentification of individuals, especially in trials enrolling participants with rare diseases. Also, inappropriate use of the data by other researchers or groups with a particular agenda can be a barrier to sharing.89”
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    • cites [89] source

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  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisecitation

    Understanding the rationale or theory underpinning an intervention helps readers understand which aspects or components are likely essential to its efficacy or harm, and which are likely incidental.

    “Understanding the rationale or theory underpinning an intervention helps readers to understand which aspects or components are likely to be essential to its efficacy or harm, and which are likely to be incidental.24”
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    • cites [24] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Almost all journals are supportive of preprinting trial protocols and completed studies before formal journal submission.

    “Almost all journals are supportive of preprinting trial protocols and completed studies128 before formal journal submission.129 130 131”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [128] Sherpa Romeo. https://www.sherpa.ac.uk/romeo/ [Accessed 8 Nov 2023].

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    • cites [129] ASAPbio. Preprint resource centre. https://asapbio.org/preprint-info [Accessed 8 Nov 2023].

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    • cites [130] source

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  • Classified as probably not a substantial claim.

    Premisecitation

    The choice of comparator has important implications for trial ethics, recruitment, results, and interpretation.

    “The choice of comparator has important implications for trial ethics, recruitment, results, and interpretation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [156] source

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    • cites [157] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Substantive contributions to the design, conduct, interpretation, and reporting of a clinical trial are recognised through the granting of authorship on the final trial report.

    “Substantive contributions to the design, conduct, interpretation, and reporting of a clinical trial are recognised through the granting of authorship on the final trial report.43”
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    • cites [43] International Committee of Medical Journal Editors. Defining the Role of Authors and Contributors. https://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-authors-and-contributors.html.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several funders request background information on the cumulative evidence in grant applications.

    “Several funders request this background information in grant applications.146 147”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [146] Canadian Institutes of Health Research. RCT evaluation criteria and headings. 2024. https://www.cihr.ca/e/39187.html.

      Not checked in the free run.

    • cites [147] British Heart Foundation. Clinical Study Grant full application guidance. https://www.bhf.org.uk/for-professionals/information-for-researchers/what-we-fund/clinical-study/full-clinical-study-grant-application-guidance [Accessed 12 Sep 2023].

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    23 of 147 investigator sponsored trials (16%) reported their results in a trial registry, compared with 150 of 179 industry sponsored trials (84%).

    “Twenty three of 147 investigator sponsored trials (16%) reported their results in a trial registry in contrast with 150 of 179 industry sponsored trials (84%).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Information about background is particularly important to trial participants as it provides motivation for contributing to the trial.

    “This information is particularly important to the trial participants as it provides motivation for contributing to the trial.140”
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    • cites [140] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Initial data suggest a few differences between trial results on preprint servers and those on final publication.

    “Initial data suggest a few differences between trial results on preprint servers and those on final publication.132 133 134”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [132] source

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    • cites [133] source

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    • cites [134] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The appropriateness of using comparator groups only receiving placebo has been the subject of extensive debate.

    “The appropriateness of using comparator groups only receiving placebo has been the subject of extensive debate and merits careful consideration of the existence of other effective treatments, the potential risks to trial participants, and the need for assay sensitivity—that is, the ability to distinguish an effective intervention from less effective or ineffective interventions.160”
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    • cites [160] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A plain language summary of results for the wider public serves to increase public knowledge and inform future patients.

    “A plain language summary of results for the wider public also serves to increase public knowledge and inform future patients.137”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Concerns have been raised that the precise research questions that randomised trials are intended to answer are often unclear.

    “Concerns have been raised that the precise research questions that randomised trials are intended to answer are often unclear.168”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Communication of the trial results directly to the trial participants is widely considered an ethical responsibility supported by both researchers and participants.

    “Communication of the trial results directly to the trial participants is widely considered an ethical responsibility supported by both researchers and participants.136”
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    • cites [136] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Surgical placebo interventions require additional ethical and methodological considerations.

    “Surgical placebo interventions require additional ethical and methodological considerations, as detailed by the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines.162”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The Declaration of Helsinki states that biomedical research involving people should be based on thorough knowledge of scientific literature, as it is unethical to expose humans unnecessarily to risks of research.

    “The World Medical Association’s Declaration of Helsinki states that biomedical research involving people should be based on a thorough knowledge of the scientific literature, as it is unethical to expose humans unnecessarily to the risks of research.2”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In an analysis of Medicare National Claim files of 167 208 patients undergoing coronary stent surgery, patients treated by high volume doctors and at high volume centres experienced better outcomes compared with those treated by low volume doctors at low volume centres.

    “For example, in an analysis of Medicare National Claim files of 167 208 patients undergoing coronary stent surgery, patients treated by high volume doctors and at high volume centres experienced better outcomes compared with those treated by low volume doctors at low volume centres.225”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [225] source

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  • May combine two claims.

    Premisecitation

    Input from patient and public contributors and partners can help researchers to identify and prioritise research topics and questions, identify relevant outcome measures, boost recruitment and retention, improve trial design and tools, and improve the ethical acceptability of trial protocols to potential participants.

    “Input from the patient and public contributors and partners186 can help researchers to identify and prioritise research topics and questions, identify relevant outcome measures, boost recruitment and retention, improve trial design and tools, and improve the ethical acceptability of trial protocols to potential participants.186 187 188”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [186] Staley K. Exploring Impact: Public involvement in NHS, public health and social care research. 2009. https://wellcomecollection.org/works/wtbmggvr.

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    • cites [187] source

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    • cites [188] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reviews of two samples of 108 and 292 trial protocols from 2016 found that strategies to improve adherence were addressed in 86% to 90%, respectively.

    “Reviews of two samples of 108 and 292 trial protocols from 2016 found that strategies to improve adherence were addressed in 86% to 90%, respectively.9 10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] source

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    • cites [10] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Of the 1000 trials, 88% had two groups, 8% had three groups, and 4% had four or more groups.

    “Of the 1000 trials, 88% had two groups, 8% had three groups, and 4% had four or more groups.191”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [191] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Funding bodies are increasingly encouraging or requiring researchers to include patient and public contributors in grant applications.

    “Funding bodies are increasingly encouraging or requiring researchers to include patient and public contributors in grant applications.179 183 184”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [179] NIHR. Briefing notes for researchers - public involvement in NHS, health and social care research. Version 1.0 - April 2021. https://www.nihr.ac.uk/documents/briefing-notes-for-researchers-public-involvement-in-nhs-health-and-social-care-research/27371.

      Not checked in the free run.

    • cites [183] Consumers Health Forum of Australia. Statement on Consumer and Community involvement in Health and Medical Research. 2016. https://www.nhmrc.gov.au/sites/default/files/documents/reports/consumer-community-involvement.pdf.

      Not checked in the free run.

    • cites [184] Canadian Institutes of Health Research. Strategy for Patient-Oriented Research: Patient Engagement Framework. https://cihr-irsc.gc.ca/e/documents/spor_framework-en.pdf [Accessed 9 Sep 2023].

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reviews of two samples of 108 and 292 trial protocols from 2016 found that patient eligibility criteria were reported in 100% of protocols.

    “Reviews of two samples of 108 and 292 trial protocols from 2016 found that patient eligibility criteria were reported in 100% of protocols.9 10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] source

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    • cites [10] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In articles published in The BMJ family journals, which require a patient and public involvement section, about 40% of these statements reported that such activities were conducted.

    “In articles published in The BMJ family journals, which require a patient and public involvement section, about 40% of these statements reported that such activities were conducted.185”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [185] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Most trials are designed to identify the superiority of an intervention, whereas others are designed to assess non-inferiority or equivalence.

    “Most trials are designed to identify the superiority of an intervention, whereas others are designed to assess non-inferiority or equivalence.196”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [196] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The estimands framework provides a structured description of the treatment effect in an attempt to bring clarity to specifying the research question.

    “The estimands framework provides a structured description of the treatment effect in an attempt to bring clarity to specifying the research question, which can be used to guide the study design, data collection, and statistical analysis methods.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reviews of two samples of 108 and 292 trial protocols from 2016 found that 91% and 94%, respectively, described the specific objectives of the trial.

    “Reviews of two samples of 108 and 292 trial protocols from 2016 found that 91% and 94%, respectively, described the specific objectives of the trial.9 10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] source

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    • cites [10] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Most of these trials included patient and public contributors at the trial design stage.

    “Most of these trials included patient and public contributors at the trial design stage.185”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [185] source

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  • May combine two claims.

    Premisecitation

    A systematic review of 135 trials found that 71% observed a positive association between hospital volume and outcomes and 70% observed an association between care provider volume and outcomes.

    “A systematic review of 135 trials found that 71% observed a positive association between hospital volume and outcomes and 70% observed an association between care provider volume and outcomes.223”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [223] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A review of 1000 randomised trials indexed in PubMed in 2016 showed that 85% had a parallel group design, whereas the other main designs were crossover (7%) and cluster (5%).

    “A review of 1000 randomised trials indexed in PubMed in 2016 showed that 85% had a parallel group design, whereas the other main designs were crossover (7%) and cluster (5%).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [191] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recently, some trials are being designed using the estimands framework to define the research question and trial objectives.

    “Recently, some trials are being designed using the estimands framework to define the research question and trial objectives.177”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [177] source

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  • May combine two claims.

    Premisecitation

    Reviews of two samples of 108 and 292 trial protocols from 2016 found that the specific measurement variable was reported in 89% to 97%, respectively, whereas fewer specified the analysis metric (83% to 90%) and time point of main interest (82% to 94%).

    “Reviews of two samples of 108 and 292 trial protocols from 2016 found that the specific measurement variable was reported in 89% to 97%, respectively, whereas fewer specified the analysis metric (83% to 90%) and time point of main interest (82% to 94%).9 10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] source

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    • cites [10] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Similar findings were observed for a sample of protocols of published oncology trials.

    “Similar findings were observed for a sample of protocols of published oncology trials.266”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [266] source

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  • May combine two claims.

    Interpretationcitation

    Such bias can only be identified and deterred if trial outcomes are clearly defined a priori in the protocol, and if protocol information is made public.

    “Such bias can only be identified and deterred if trial outcomes are clearly defined a priori in the protocol, and if protocol information is made public.78 260 261 262”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [78] source

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    • cites [260] source

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    • cites [261] source

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  • May combine two claims.

    Premisecitation

    18% and 25% of randomised trial protocols that received ethics approval in Switzerland and Denmark, respectively, did not designate any primary outcome.

    “and in 18% and 25% of randomised trial protocols that received ethics approval in Switzerland and Denmark, respectively.249 255”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [249] source

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    • cites [255] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Factors such as participant burden and feasibility can affect the decision of potential investigators and participants to join the trial.

    “These factors can also affect the decision of potential investigators and participants to join the trial (item 20).286”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [286] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A trial might knowingly be undertaken despite being underpowered, when the intent is for the trial to be incorporated into a prospectively planned meta-analysis.

    “A trial might knowingly be undertaken despite being underpowered, when the intent is for the trial to be incorporated into a prospectively planned meta-analysis.292”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [292] Cochrane Prospective Meta-Analysis (PMA) Methods Group . https://methods.cochrane.org/pma/ 2024.

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  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationcitation

    This information could be particularly important to evaluate the risk of bias owing to deviations from the intended intervention or comparator.

    “This information could be particularly important to evaluate the risk of bias owing to deviations from the intended intervention or comparator234; an important domain of the risk of bias tool developed by the Cochrane Collaboration.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [234] source

      Not checked in the free run.

    • Rests on an assumption: Assessing the risk of bias domain for deviations from the intended intervention requires a clear understanding of deviations that occur as planned in the protocol and deviations that arise owing to the experimental context.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Harms outcomes are often grouped by seriousness, severity, body system, discontinuation of interventions owing to harms, and attribution of causality.

    “Harms outcomes are often grouped by seriousness, severity, body system, discontinuation of interventions owing to harms, and attribution of causality.276”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [276] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    These events can be caused by a variety of factors, including harms, improved health status, lack of efficacy, and withdrawal of participant consent.

    “During a clinical trial, situations can emerge that necessitate changes in, or the discontinuation of, the allocated intervention or comparator for a participant. These events can be caused by a variety of factors, including harms, improved health status, lack of efficacy, and withdrawal of participant consent.233”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] US Food and Drug Administration. CFR - Code of Federal Regulations Title 21, Chapter I, Subchapter D, Part 312: Investigational new drug application. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312&showFR=1&subpartNode=21:5.0.1.1.3.4 [Accessed 12 Sep 2023].

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A process of reporting important adverse events to relevant groups is defined by local regulation.

    “a process that is defined by local regulation.284”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [284] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The association between sample size and detectable difference is not linear: for small differences, enormous sample sizes are required for a trial to be sufficiently powered to detect them.

    “The association between sample size and detectable difference is not linear: for small differences, enormous sample sizes are required for a trial to be sufficiently powered to detect them.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The COMET initiative aims to facilitate the development and application of standardised sets of core outcomes for clinical trials of specific conditions.

    “The COMET (Core Outcome Measures in Effectiveness Trials) initiative aims to facilitate the development and application of such standardised sets of core outcomes for clinical trials of specific conditions.265”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [265] The COMET Initiative. https://www.comet-initiative.org/ [Accessed 19 Jun 2024].

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although the many types of monitoring methods have limitations, they can inform the interpretation of the trial result.

    “Although the many types of monitoring methods have limitations,243 they can inform the interpretation of the trial result.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [243] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisenone given

    Sample size calculations need to balance ethical, logistical, clinical, and statistical considerations to ensure the scientific question can be reliably and precisely answered without unnecessarily exposing individuals to ineffective or harmful interventions.

    “Sample size calculations need to balance ethical, logistical, clinical, and statistical considerations to ensure the scientific question can be reliably and precisely answered without unnecessarily exposing individuals to ineffective or harmful interventions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the context of clinical trials, it can be difficult to accurately ascribe causation for an adverse event experienced by an individual participant.

    “In the context of clinical trials, it can be difficult to accurately ascribe causation for an adverse event experienced by an individual participant.275”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [275] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    A concise timeline of planned study visits, enrolment, interventions, and assessments can help guide the conduct of a trial and enable external review of participant burden and feasibility.

    “A concise timeline of the planned study visits, enrolment process, interventions, and assessments performed on participants can help to guide the conduct of a trial and enable external review of participant burden and feasibility.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    A complete description of the sample size calculation in the protocol enables an assessment of whether the trial will be adequately powered to detect a minimal clinically important difference.

    “A complete description of the sample size calculation in the protocol enables an assessment of whether the trial will be adequately powered to detect a minimal clinically important difference.293”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [293] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The sample size calculation is a key component in the design of a randomised trial.

    “The sample size calculation is a key component in the design of a randomised trial.290 291”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [290] source

      Not checked in the free run.

    • cites [291] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    For trials with more than one primary outcome, a separate calculation can be performed for each, and the largest sample size used.

    “For trials with more than one primary outcome, a separate calculation can be performed for each, and the largest sample size used.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The sample size calculation is generally based on one primary outcome.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    Successful randomisation in practice depends on two interrelated factors: the adequate generation of an unpredictable allocation sequence and the concealment of that sequence until assignment occurs.

    “Successful randomisation in practice depends on two interrelated factors the adequate generation of an unpredictable allocation sequence and the concealment of that sequence until assignment occurs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Blinding the interventions, using larger block sizes, and randomly varying the block size helps to avoid the problem of deducing next allocations from block size.

    “Blinding the interventions, using larger block sizes, and randomly varying the block size helps to avoid this problem.321”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [321] Schulz KF Grimes DA . Essential Concepts in Clinical Research: randomized controlled trials and observational epidemiology. 2nd ed. Elsevier, 2019.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisereasoning

    Knowledge of restricted randomisation details might undermine randomisation by facilitating deciphering of the allocation sequence.

    “Knowledge of these details might undermine randomisation by facilitating deciphering of the allocation sequence.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Use of terms such as randomisation without further elaboration in the protocol is not sufficient to describe the allocation process, as these terms have been used inappropriately to describe non-random, deterministic allocation methods such as alternation or allocation by date of birth.

    “Use of terms such as randomisation without further elaboration in the protocol is not sufficient to describe the allocation process, as these terms have been used inappropriately to describe non-random, deterministic allocation methods such as alternation or allocation by date of birth.322”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [322] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Stratification requires some form of restriction (eg, blocking within strata) to be effective.

    “Stratification requires some form of restriction (eg, blocking within strata) to be effective.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In general, non-random allocation methods introduce selection bias and biased estimates of an intervention's effect size.

    “In general, these non-random allocation methods introduce selection bias and biased estimates of an intervention’s effect size.323 324 325 326 327 328”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [323] source

      Not checked in the free run.

    • cites [324] source

      Not checked in the free run.

    • cites [325] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The allocation concealment mechanism aims to prevent participants and recruiters from knowing the study group to which the next participant will be assigned.

    “The allocation concealment mechanism aims to prevent participants and recruiters from knowing the study group to which the next participant will be assigned.336 346”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [336] source

      Not checked in the free run.

    • cites [346] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although most trials will use strategies to promote enrolment of participants, this information is often incompletely reported in trial protocols.

    “Although most trials will use strategies to promote enrolment of participants, this information is often incompletely reported in trial protocols.9 10 317”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [9] source

      Not checked in the free run.

    • cites [10] source

      Not checked in the free run.

    • cites [317] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Design issues such as the number and stringency of eligibility criteria will also directly affect the number of eligible trial participants.

    “Design issues such as the number and stringency of eligibility criteria will also directly affect the number of eligible trial participants.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    Without stratification, study groups might not be well matched for baseline characteristics, such as age and stage of disease, especially in small trials.

    “Without stratification, study groups might not be well matched for baseline characteristics, such as age and stage of disease, especially in small trials.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Simple randomisation is perfectly unpredictable.

    “However, simple randomisation procedures could be reported in detail in the protocol because simple randomisation is perfectly unpredictable.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Stratification is used to ensure a good balance in characteristics of participants between each group.

    “Stratification is used to ensure a good balance in characteristics of participants between each group.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Selection bias can also be a problem in trials where everyone is supposedly blinded (masked), but the blinding is ineffective, or the harms from the intervention provide clues such that treatments can be guessed.

    “It can also be a problem in trials where everyone is supposedly blinded (masked), but the blinding is ineffective, or the harms from the intervention provide clues such that treatments can be guessed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Selection bias is mainly a problem in open label trials where everyone becomes aware of the intervention after assignment.

    “Selection bias is mainly a problem in open label trials where everyone becomes aware of the intervention after assignment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Blocked randomisation assures that study groups of about the same size will be generated when an allocation ratio of 1:1 is used.

    “Blocked randomisation (also called permuted block randomisation) assures that study groups of about the same size will be generated when an allocation ratio of 1:1 is used.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Bias presumably arises from the inability to adequately conceal these more predictable, non-random sequence generation systems.

    “Bias presumably arises from the inability to adequately conceal (item 22) these more predictable, non-random sequence generation systems.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Additional elements for trial designs other than parallel group superiority trials are often not described in final trial reports and are infrequently specified in the protocol.

    “Such elements are often not described in final trial reports,299 300 301 302 and they are infrequently specified in the protocol.303”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [299] source

      Not checked in the free run.

    • cites [300] source

      Not checked in the free run.

    • cites [301] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reviews of two samples of 108 and 292 trial protocols from 2016 found that 99% reported the estimated sample size but only 57% to 78%, respectively, reported the assumed outcome values involved.

    “Reviews of two samples of 108 and 292 trial protocols from 2016 found that 99% reported the estimated sample size but only 57% to 78%, respectively, reported the assumed outcome values involved.9 10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] source

      Not checked in the free run.

    • cites [10] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Randomisation decreases selection bias in allocation, helps to facilitate blinding after allocation, and enables the use of probability theory to test whether any difference in outcome between trial groups reflects chance.

    “Randomisation decreases selection bias in allocation, helps to facilitate blinding after allocation, and enables the use of probability theory to test whether any difference in outcome between trial groups reflects chance.321”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [321] Schulz KF Grimes DA . Essential Concepts in Clinical Research: randomized controlled trials and observational epidemiology. 2nd ed. Elsevier, 2019.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Minimisation lacks the theoretical basis for eliminating bias on all known and unknown factors.

    “Conversely, minimisation lacks the theoretical basis for eliminating bias on all known and unknown factors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Successful randomisation in practice depends on two interrelated factors: generation of an unpredictable allocation sequence and concealment of that sequence until assignment irreversibly occurs.

    “Successful randomisation in practice depends on two interrelated factors: generation of an unpredictable allocation sequence (item 21), and concealment of that sequence until assignment irreversibly occurs.336 346”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [336] source

      Not checked in the free run.

    • cites [346] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Different recruitment methods can substantially affect the number and type of trial participants recruited and can incur different costs.

    “Different recruitment methods can substantially affect the number and type of trial participants recruited206 309 312 313 and can incur different costs.314 315 316”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [206] source

      Not checked in the free run.

    • cites [309] source

      Not checked in the free run.

    • cites [312] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    When uncertainty about a sample size estimate is acknowledged, there are methods to re-estimate sample size.

    “When uncertainty about a sample size estimate is acknowledged, there are methods to re-estimate sample size.296”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [296] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Inadequate enrolment reduces statistical power and can lead to early trial stoppage or to extensions resulting in delayed results and greater costs.

    “Inadequate enrolment reduces statistical power and can lead to early trial stoppage or to extensions resulting in delayed results and greater costs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In general, trials that use minimisation are usually considered methodologically similar to randomised trials, even when a random element is not incorporated.

    “Nevertheless, in general, trials that use minimisation are usually considered methodologically similar to randomised trials, even when a random element is not incorporated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The method of sequence generation was not described in three quarters of randomised trial protocols approved by a research ethics committee in Denmark in 1994-95, and a US cooperative cancer research group in 1968-2006.

    “The method of sequence generation was not described in three quarters of randomised trial protocols approved by a research ethics committee in Denmark in 1994-95, and a US cooperative cancer research group in 1968-2006.329 330”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [329] source

      Not checked in the free run.

    • cites [330] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Standard processes are often implemented by local study staff to enhance data quality and reduce bias by detecting and reducing missing or incomplete data, inaccuracies, and excessive variability in measurements.

    “Standard processes are often implemented by local study staff to enhance data quality and reduce bias by detecting and reducing the amount of missing or incomplete data, inaccuracies, and excessive variability in measurements.390”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [390] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Modified versions of validated instruments might no longer be considered validated, and use of unpublished measurement scales can introduce bias and inflate treatment effect sizes.

    “Modified versions of validated instruments might no longer be considered validated, and use of unpublished measurement scales can introduce bias and inflate treatment effect sizes.388”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [388] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compared with paper based data collection, use of mobile devices and electronic data capture systems has the potential to improve protocol adherence, data accuracy, user acceptability, and timeliness of receiving data.

    “Also, when compared with paper based data collection, the use of mobile devices and electronic data capture systems has the potential to improve protocol adherence, data accuracy, user acceptability, and timeliness of receiving data.385”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [385] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reviews of two samples of 108 and 292 trial protocols from 2016 found that 82% to 94% of protocols addressed the blinding status of participants and care providers, and 68% to 70% reported the blinding status of outcome assessors.

    “Yet, reviews of two samples of 108 and 292 trial protocols from 2016 found that 82% to 94% of protocols addressed the blinding status of participants and care providers, and 68% to 70% reported the blinding status of outcome assessors.9 10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 9 10

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a sample of protocols from 1994, out of 55 protocols of trials planned as double blind, five (9%) provided no information beyond double blind, 25 (45%) reported a double dummy procedure, and 32 (58%) reported the compared interventions as being similar.

    “The reporting in trial protocols of plans for inducing and maintaining blinding was studied in a sample of protocols from 1994.5 Out of 55 protocols of trials planned as double blind, five (9%) provided no information beyond double blind, 25 (45%) reported a double dummy procedure, and 32 (58%) reported the compared interventions as being similar.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Blinding of data monitoring committee members is generally discouraged.

    “Blinding of data monitoring committee members is generally discouraged.363”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [363] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The exception to blinding outcome assessors is in trials with patient or participant reported outcomes where the patient is the outcome assessor.

    “The exception is in trials with patient or participant reported outcomes (eg, pain) where the patient is the outcome assessor.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Instruments with low interrater reliability will reduce statistical power, whereas those with low validity will not accurately measure the intended outcome variable.

    “Instruments with low interrater reliability will reduce statistical power, whereas those with low validity will not accurately measure the intended outcome variable.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    Allocation concealment helps to ensure that a participant's decision to provide informed consent, or a recruiter's decision to enrol a participant, is not influenced by knowledge of the group to which they will be allocated if they join the trial.

    “Allocation concealment helps to ensure that a participant’s decision to provide informed consent, or a recruiter’s decision to enrol a participant, is not influenced by knowledge of the group to which they will be allocated if they join the trial.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Routinely collected data, such as from administrative databases, are increasingly used for data collection in randomised trials, although they may be associated with reduced effect estimates.

    “Routinely collected data, such as from administrative databases, are increasingly used for data collection in randomised trials, although they may be associated with reduced effect estimates.389”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [389] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    It is important that emergency unblinding procedures are constrained to a single participant and that unblinding of additional participants is avoided.

    “It is important that emergency unblinding procedures are constrained to a single participant and that unblinding of additional participants is avoided (item 24b).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Emergency unblinding reveals the assigned intervention of a trial participant, typically when the participant experiences potential harm from the intervention.

    “Emergency unblinding reveals the assigned intervention of a trial participant, typically when the participant experiences potential harm from the intervention.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Many groups can be blinded: trial participants, care providers, data collectors, outcome assessors, data analysts, and manuscript writers.

    “Many groups can be blinded: trial participants, care providers, data collectors, outcome assessors, data analysts,362 and manuscript writers.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [362] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Achieving blinding of trial participants or staff requires adequate procedures for both induction and maintenance of blinding.

    “Achieving blinding of trial participants or staff requires adequate procedures for both induction and maintenance of blinding.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Participant retention can be improved, such as by financial reimbursement, systematic methods and reminders for contacting patients, scheduling appointments, and monitoring retention, as well as limiting participant burden related to follow-up visits and procedures.

    “Participant retention can be improved,205 235 395 such as by financial reimbursement, systematic methods and reminders for contacting patients, scheduling appointments, and monitoring retention, as well as limiting participant burden related to follow-up visits and procedures (item 18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 205 235 395

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Blinding is commonly used to reduce the risk of bias in randomised trials.

    “Blinding (masking)—the process of keeping the study group assignment hidden after allocation—is commonly used to reduce the risk of bias in randomised trials.355 356”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 355 356

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most trials will have some degree of non-retention, and the number of off-study participants usually increases with the duration of follow-up.

    “Most trials will have some degree of non-retention, and the number of these off-study participants usually increases with the duration of follow-up.394”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [394] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    An individual who generated the allocation sequence will likely have access to a copy of the sequence list and could consult it if enrolling and assigning participants, and thus could bias the enrolment or assignment process.

    “For example, the individual who generated the allocation sequence will likely have access to a copy of the sequence list and could consult it if they were enrolling and assigning participants in a trial. Thus, that individual could bias the enrolment or assignment process.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The validity and reliability of trial data depend on the quality of the data collection methods.

    “The validity and reliability of trial data depend on the quality of the data collection methods.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Premisenone given

    Although independent double data entry is performed to detect data entry errors, the time and costs need to be weighed against the magnitude of reduction in error rates compared with single data entry.

    “Although independent double data entry is performed to detect data entry errors, the time and costs need to be weighed against the magnitude of reduction in error rates compared with single data entry.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Differences in data entry methods can affect the trial in terms of data accuracy, cost, and efficiency.

    “Differences in data entry methods can affect the trial in terms of data accuracy, cost, and efficiency.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisenone given

    Plans to handle the data collected from trial participants helps to promote data validity and integrity.

    “Plans to handle the data collected from trial participants helps to promote data validity and integrity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisenone given

    A clear and comprehensive account of the planned statistical methods for a trial facilitates implementation, replication, and critical assessment.

    “A clear and comprehensive account of the planned statistical methods for a trial facilitates implementation, replication, and critical assessment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Details of all statistical analyses are often reported in a full statistical analysis plan-a document that accompanies a trial protocol.

    “Details of all statistical analyses are often reported in a full statistical analysis plan—a document that accompanies a trial protocol.71”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Standard processes are often implemented to improve the accuracy of data entry and coding.

    “Standard processes are often implemented to improve the accuracy of data entry and coding.390 404”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 390 404

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Because missing data can be a major threat to trial validity and statistical power, data collection is often continued until a participant withdraws from the study.

    “Because missing data can be a major threat to trial validity and statistical power, data collection is often continued until a participant withdraws from the study.396”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [396] PRincipleS for handling end-of-participation EVEnts in clinical trials REsearch: the PeRSEVERE principles. https://persevereprinciples.org/the-persevere-principles/ [Accessed 8 Nov 2023].

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Local data entry can enable fast correction of missing or inaccurate data, whereas central data entry facilitates blinding, standardisation, and training of a core group of data entry staff.

    “Local data entry can enable fast correction of missing or inaccurate data, whereas central data entry facilitates blinding (masking), standardisation, and training of a core group of data entry staff.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    When compared with paper case report forms, electronic data capture can reduce the time required for data entry and allow for efficient data validation, resolution of queries, and database release by combining data entry with data collection.

    “For example, when compared with paper case report forms, electronic data capture can reduce the time required for data entry and allow for efficient data validation, resolution of queries, and database release by combining data entry with data collection (item 25a).385 403”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 385 403

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Guidance is available on key problems to consider for dealing with multiplicity.

    “Although no standardised rules exist for dealing with multiplicity, guidance is available on key problems to consider.411 412”
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    • cites [411] source

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    • cites [412] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Planning a prospective meta-analysis can in some situations help achieve sufficient power by pooling the results from multiple trials.

    “Furthermore, planning a prospective meta-analysis can in some situations help achieve sufficient power by pooling the results from multiple trials.414”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [414] source

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  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisecitation

    An intention-to-treat analysis population is widely recommended as the preferred analysis population.

    “An intention-to-treat analysis population is defined by the inclusion of outcome data from all participants in their originally allocated group—this is widely recommended as the preferred analysis population.360 419 420”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [360] source

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    • cites [419] source

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    • cites [420] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some trials are designed based on bayesian methods.

    “Some trials are designed based on bayesian methods.416 417”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [416] source

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    • cites [417] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Among protocols for randomised trials approved in 2016, 87% detailed the main analysis plan for the primary outcome.

    “Among protocols for randomised trials approved in 2016, 87% detailed the main analysis plan for the primary outcome.9 10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] source

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    • cites [10] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reviews of two samples of 108 and 292 trial protocols from 2016 reported that 69% and 74%, respectively, specified the analysis population.

    “Reviews of two samples of 108 and 292 trial protocols from 2016 reported that 69% and 74%, respectively, specified the analysis population.9 10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] source

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    • cites [10] source

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  • May combine two claims.

    Premisecitation

    Simple imputation methods (eg, last observation carried forward) introduce bias and ignore the uncertainty induced by missing data, leading to confidence intervals that are too narrow.

    “Simple imputation methods (eg, last observation carried forward) may seem appealing but are not advisable as they introduce bias and ignore the uncertainty induced by missing data, leading to confidence intervals that are too narrow.433”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [433] source

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  • May combine two claims.

    Premisecitation

    The mechanism resulting in missing data affects the risk of bias and decisions on how best to handle the missing data.

    “The mechanism resulting in missing data affects the risk of bias and decisions on how best to handle the missing data.428 429”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [428] source

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    • cites [429] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Some reasons for missingness could be related to the treatment allocation, prognostic factors, or a particular adverse event or health outcome.

    “Some reasons for missingness could be related to the treatment allocation, prognostic factors, or a particular adverse event or health outcome.427”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [427] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Multiple imputation is often recommended for participants with missing data, wherein missing outcomes or covariates are estimated using other variables.

    “It is often recommended that participants with missing data be included in the analysis using multiple imputation, wherein the missing outcomes or covariates are estimated using other variables.432”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [432] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Examining differences in subgroups involves assessing the statistical interaction between a variable and the intervention effect.

    “Examining differences in subgroups involves assessing the statistical interaction between a variable and the intervention effect.438”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [438] source

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  • May combine two claims.

    Premisecitation

    Missing data negatively affect trials by reducing statistical power and introducing potential bias.

    “Missing data negatively affect trials by reducing statistical power and introducing potential bias.426”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [426] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Protocol authors have a choice between various methods for handling anticipated missing data, including imputing data, fitting a mixed effects model to repeated measures data, or omitting participants.

    “When planning to handle anticipated missing data, protocol authors have a choice between various methods, including imputing data, fitting a mixed effects model to repeated measures data, or omitting participants.428 429”
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    • cites [428] source

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    • cites [429] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Many trials do not need a formal data monitoring committee; typically trials with a short duration or known minimal risks.

    “Many trials do not, however, need a formal data monitoring committee450; typically trials with a short duration or known minimal risks.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [450] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    When the findings from a sensitivity analysis are consistent with the primary results, confidence that the primary results are valid can be increased.

    “When the findings from a sensitivity analysis are consistent with the primary results, confidence that the primary results are valid can be increased.445 447”
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    • cites [445] source

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    • cites [447] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A data monitoring committee will often comprise members from a variety of disciplines.

    “A data monitoring committee will often comprise members from a variety of disciplines.363 451 452”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [363] source

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    • cites [451] source

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    • cites [452] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The use of a data monitoring committee was reported for 29% of trial protocols approved from 2000 to 2003 in Switzerland, Germany, and Canada, and for about 40% of trials registered on ClinicalTrials.gov from 2007 to 2010.

    “The use of a data monitoring committee was reported for 29% of trial protocols approved from 2000 to 2003 in Switzerland, Germany, and Canada,453 454 and for about 40% of trials registered on ClinicalTrials.gov from 2007 to 2010.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [453] source

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    • cites [454] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Independence, particularly from the sponsor and trial investigators, is a key characteristic of the data monitoring committee.

    “Independence, particularly from the sponsor and trial investigators, is a key characteristic of the data monitoring committee and can be broadly defined as the committee comprising members who are “completely uninvolved in the running of the trial and who cannot be unfairly influenced (either directly or indirectly) by people, or institutions, involved in the trial.”363 452”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [363] source

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    • cites [452] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Criteria for stopping for harm are often different from those for benefit and may or may not employ a formal statistical criterion.

    “Criteria for stopping for harm are often different from those for benefit and may or may not employ a formal statistical criterion.458”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [458] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Prespecified interim analyses can be used for other trial adaptations such as sample size re-estimation, alteration of the proportion of participants allocated to each study group, and changes to eligibility criteria.

    “Aside from informing stopping guidelines, prespecified interim analyses can be used for other trial adaptations such as sample size re-estimation, alteration of the proportion of participants allocated to each study group, and changes to eligibility criteria.460”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [460] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A third of protocols for industry initiated randomised trials that received ethics approval in Denmark in 1994-95 stated that the sponsor had access to accumulating trial data, which can introduce potential bias due to conflicts of interests.

    “A third of protocols for industry initiated randomised trials that received ethics approval in Denmark in 1994-95 stated that the sponsor had access to accumulating trial data, which can introduce potential bias due to conflicts of interests.38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The results of interim analyses, along with non-statistical criteria, can be part of a stopping guideline that helps inform whether the trial should be continued, modified, or halted earlier than intended for benefit, harm, or futility.

    “The results of these analyses, along with non-statistical criteria, can be part of a stopping guideline that helps inform whether the trial should be continued, modified, or halted earlier than intended for benefit, harm, or futility.457”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [457] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Interim analyses were described in a third of 894 trial protocols approved from 2000 to 2003 in Switzerland, Germany, and Canada.

    “Interim analyses were described in a third of 894 trial protocols approved from 2000 to 2003 in Switzerland, Germany, and Canada.454”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [454] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reviews of two samples of 108 and 292 trial protocols from 2016 found that 58% reported whether a data monitoring committee would or would not be planned.

    “Reviews of two samples of 108 and 292 trial protocols from 2016 found that 58% reported whether a data monitoring committee would or would not be planned.9 10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] source

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    • cites [10] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Various statistical strategies have been developed to compensate for the inflated risk from multiple analyses of accumulating data.

    “Multiple analyses of the accumulating data increase the risk of a false positive (type I error), and various statistical strategies have been developed to compensate for this inflated risk.459”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [459] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Such analyses were reported in 71% (106/150) of cancer trial protocols with time-to-event outcomes in Italy from 2000 to 2005; among 86 protocols with plans for efficacy interim analyses, 100% reported the timing of the analyses, 90% specified the overall reason for stopping, and 94% detailed the statistical approach.

    “Such analyses were also reported in 71% (106/150) of cancer trial protocols with time-to-event outcomes in Italy from 2000 to 2005461; among 86 protocols with plans for efficacy interim analyses, 100% reported the timing of the analyses, 90% specified the overall reason for stopping (eg, superiority, futility), and 94% detailed the statistical approach.461”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [461] source

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  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    It is widely recommended that trials adopt a risk based approach to monitoring that focuses on the trial data and processes that are critical to study integrity, data validity, and the wellbeing of participants.

    “Rather than reviewing 100% of accumulating data and processes, it is widely recommended that trials adopt a risk based approach to monitoring that focuses on the trial data and processes that are critical to study integrity, data validity, and the wellbeing of participants.46 467”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Integrated addendum to ICH E6(R1): guideline for good clinical practice E6(R2). Step 4 version dated 9 November 2016. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf.

      Not checked in the free run.

    • cites [467] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    New, decentralised monitoring options are becoming more widely available.

    “New, decentralised monitoring options are also becoming more widely available.468”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [468] source

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  • May combine two claims.

    Premisecitation

    The implementation and communication of amendments is burdensome and potentially costly.

    “The implementation and communication of amendments is also burdensome and potentially costly.474”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [474] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Before participants are enrolled, a universal requirement for the ethical conduct of clinical trials is the review and approval of the protocol by qualified individuals who are not associated with the research team and have no disqualifying conflicts of interest as reviewers.

    “Before participants are enrolled, a universal requirement for the ethical conduct of clinical trials is the review and approval of the protocol by qualified individuals who are not associated with the research team and have no disqualifying conflicts of interest as reviewers.46 471”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Integrated addendum to ICH E6(R1): guideline for good clinical practice E6(R2). Step 4 version dated 9 November 2016. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf.

      Not checked in the free run.

    • cites [471] World Medical Association. WMA Declaration of Helsinki - ethical principles for medical research involving human subjects. 2022. https://www.wma.net/policies-post/wma-declaration-of-helsinki/

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reviews of two samples of 108 and 292 trial protocols from 2016 found that 15% to 18% of trial protocols approved in 2016 did not describe the process of obtaining informed consent.

    “Reviews of two samples of 108 and 292 trial protocols from 2016 found that 15% to 18% of trials protocols approved in 2016 did not describe the process of obtaining informed consent.9 10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] source

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    • cites [10] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    It is generally agreed that trial sponsors and investigators have an ethical obligation to plan to provide care for participants' healthcare needs that arise as a direct consequence of participation in a trial.

    “It is generally agreed that trial sponsors and investigators have an ethical obligation to plan to provide care for participants’ healthcare needs that arise as a direct consequence of participation in a trial.2 501 502”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] source

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    • cites [501] source

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    • cites [502] source

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  • May combine two claims.

    Premisecitation

    The content, quantity, and mode of delivery of consent information can affect trial recruitment; participant comprehension, anxiety, and retention rates; and costs.

    “The content, quantity, and mode of delivery of consent information can affect trial recruitment; participant comprehension, anxiety, and retention rates; and costs.207 486 487 488 489”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [207] source

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    • cites [486] source

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    • cites [487] Fayter D, McDaid C, Ritchie G, Stirk L, Eastwood A. Systematic review of barriers, modifiers and benefits involved in participation in cancer trials. Centre for Reviews and Dissemination report 31. University of York; 2006. Report No 31.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reviews of two samples of 108 and 292 trial protocols approved in 2016 found that 76% and 88%, respectively, considered confidentiality of data.

    “Reviews of two samples of 108 and 292 trial protocols approved in 2016 found that 76% and 88%, respectively, considered confidentiality of data.9 10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] source

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    • cites [10] source

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205 of 205

  • The paper relies on this without support.

    Funding agencies, research ethics committees or institutional review boards, regulatory agencies, medical journals, systematic reviewers, and others rely on protocols to appraise the conduct and reporting of clinical trials.

    “Funding agencies, research ethics committees or institutional review boards, regulatory agencies, medical journals, systematic reviewers, and others rely on protocols to appraise the conduct and reporting of clinical trials.”

  • The paper relies on this without support.

    The usefulness of trial results to patients, healthcare providers, and policy makers depends on how well the trial was planned.

    “The usefulness of trial results to patients, healthcare providers, and policy makers depends on how well the trial was planned.”

  • The paper relies on this without support.

    Adequate reporting of a trial protocol conveys that the core methodological and logistical challenges of running the trial have been considered, and possibly dealt with, before the trial commences.

    “Adequate reporting of a trial protocol conveys that the core methodological and logistical challenges of running the trial have been considered, and possibly dealt with, before the trial commences.”

  • The paper relies on this without support.

    Trials are typically funded by drug or device companies or by scientific, private, or governmental foundations or organisations.

    “Trials are typically funded by drug or device companies (ie, industry funded) or by scientific, private, or governmental foundations or organisations (ie, non-industry funded).”

  • The paper relies on this without support.

    The various types of funders differ in their overall agenda, reasons for funding a trial, and propensity to influence the trial.

    “The various types of funders differ in their overall agenda, reasons for funding a trial, and propensity to influence the trial.”

  • The paper relies on this without support.

    A funder will typically provide direct monetary support for a trial, but funding may also be provided indirectly, such as through free trial drugs, equipment, or services.

    “A funder will typically provide direct monitory support for a trial, but funding may also be provided indirectly, such as through free trial drugs, equipment, or services (eg, statistical analysis or use of medical writers) (item 7a).”

  • The paper relies on this without support.

    The more direct the influence a trial funder with a strong interest in a specific study result has on the design, conduct, analysis, and reporting of a trial, the higher is the risk that their interests interfere with the scientific purpose of the trial.

    “The more direct the influence a trial funder (or sponsor) with a strong interest in a specific study result has on the design, conduct, analysis, and reporting of a trial, the higher is the risk that their interests interfere with the scientific purpose of the trial.”

  • The paper relies on this without support.

    Undue influence can result in methodological problems and bias.

    “Undue influence can result in methodological problems (eg, inappropriate comparator group or narrow patient eligibility criteria) and bias.”

  • The paper relies on this without support.

    Information on the types, conduct, and membership of committees helps ensure roles and responsibilities are clearly understood at the onset of the trial and facilitates communication from external parties about the trial.

    “Information on the types, conduct, and membership of such committees helps to ensure that roles and responsibilities are clearly understood at the onset of the trial and facilitates communication from external parties about the trial.”

  • The paper relies on this without support.

    Information on committees enables readers to understand the mandate and expertise of those responsible for overseeing participant safety, trial design, database integrity, and study conduct.

    “Information also enables readers to understand the mandate and expertise of those responsible for overseeing participant safety, trial design, database integrity, and study conduct.”

  • The paper relies on this without support.

    The complexity of a trial, and the need for a clear division of responsibilities and a transparent organisational structure, increase with the number of included sites and participants.

    “The complexity of a trial, and the need for a clear division of responsibilities and a transparent organisational structure, increase with the number of included sites and participants.”

  • The paper relies on this without support.

    Most trial registries allow the full protocol and statistical analysis plan to be included along with the trial’s registration record.

    “Most trial registries allow the full protocol and statistical analysis plan to be included along with the trial’s registration record.”

  • The paper relies on this without support.

    Data sharing increases transparency, facilitates reproducibility, reduces research waste, and provides data for additional exploration.

    “Data sharing increases transparency, facilitates reproducibility, reduces research waste, and provides data for additional exploration.”

  • The paper relies on this without support.

    Access to trial data is sometimes restricted for trial investigators, and not only for individuals outside the trial.

    “Access to the trial data is also sometimes restricted for trial investigators, and not only for individuals outside the trial.”

  • The paper relies on this without support.

    Results from randomised trials might be more reproducible and trustworthy when the complete final dataset can be accessed by multiple investigators who contributed the data.

    “Results from randomised trials might be more reproducible and trustworthy when the complete final dataset can be accessed by multiple investigators who contributed the data.”

  • The paper relies on this without support.

    For some multicentre trials, only the trial steering committee has access to the full trial dataset.

    “For some multicentre trials, only the trial steering committee has access to the full trial dataset.”

  • The paper relies on this without support.

    Many of these trials will allow site investigators to access the full dataset if the steering committee approves a formal request describing their plans.

    “Many of these trials will allow site investigators to access the full dataset if the steering committee approves a formal request describing their plans.”

  • The paper relies on this without support.

    Various types of funders differ in their overall agenda, reasons for funding a trial, and propensity to influence the trial.

    “The various types of funders differ in their overall agenda, reasons for funding a trial, and propensity to influence the trial.”

  • The paper relies on this without support.

    There is no clear consensus on a threshold for when funding from a source with conflicting interests becomes problematic, nor on the characteristics of a possible dose-response association.

    “There is no clear consensus on a threshold for when funding from a source with conflicting interests becomes problematic, nor on the characteristics of a possible dose-response association.”

  • The paper relies on this without support.

    Indirect financial support, such as provision of various medical services, will impact differently on various stages of a trial.

    “Indirect financial support, such as provision of various medical services, will impact differently on various stages of a trial.”

  • The paper relies on this without support.

    Reporting the funding source and the role of the trial funder provides important context for readers of a protocol when ascertaining the feasibility of the trial as well as its overall methodological quality and risk of bias.

    “Reporting the funding source and the role of the trial funder (item 3c) provides important context for readers of a protocol when ascertaining the feasibility of the trial as well as its overall methodological quality (for example, the relevance of the type of comparator intervention and eligibility criteria for patients) and risk of bias (for example, the risk of selective reporting of favourable”

  • The paper relies on this without support.

    Disclosure of interests enables a management plan to be developed and implemented and facilitates full ascertainment of conflicts of interest, risk of bias, and overall methodological quality.

    “Disclosure of interests enables a management plan to be developed and implemented and facilitates full ascertainment of conflicts of interest, risk of bias, and overall methodological quality—for example, the relevance of the type of comparator intervention.”

  • The paper relies on this without support.

    Journal publication remains a key means of reporting trial results.

    “Journal publication remains a key means of reporting trial results.”

  • The paper relies on this without support.

    Open access publishing provides patients, the public, and other interested parties with immediate and free access to read the trial’s results, with reduced copyright barriers.

    “Open access publishing provides patients, the public, and other interested parties with immediate and free access to read the trial’s results, with reduced copyright barriers.”

  • The paper relies on this without support.

    Trials would not be possible without the voluntary contributions of participants.

    “Trials would not be possible without the voluntary contributions of participants.”

  • The paper relies on this without support.

    The ethical and scientific justification for a trial depends on the uncertainty of the benefit or harm of the intervention to be tested, which depends on what is known on the topic before the trial commences.

    “The ethical and scientific justification for a trial depends on the uncertainty of the benefit or harm of the intervention to be tested. This uncertainty depends in turn on what is known on the topic before the trial commences.”

  • The paper relies on this without support.

    Background information is relevant to funders, research ethics committees or institutional review boards, and other groups who evaluate the scientific and ethical basis for trial approval.

    “It is also relevant to funders, research ethics committees or institutional review boards, and other groups who evaluate the scientific and ethical basis for trial approval.”

  • The paper relies on this without support.

    What constitutes usual care differs substantially across clinical settings.

    “What constitutes usual care differs substantially across clinical settings.”

  • The paper relies on this without support.

    The environment in which a trial will be conducted may differ considerably from the setting in which the trial’s results are later used to guide practice and policy.

    “The environment in which the trial will be conducted may differ considerably from the setting in which the trial’s results are later used to guide practice and policy.”

  • The paper relies on this without support.

    The appropriateness of restrictive participant selection depends on the objectives of the trial.

    “The appropriateness of restrictive participant selection depends on the objectives of the trial.218”

  • The paper relies on this without support.

    Composite outcomes increase event rates and statistical power.

    “Although composite outcomes increase event rates and statistical power, their relevance and interpretation can be unclear if the individual component outcomes vary greatly for event rates, direction of effect, importance to patients, or amount of missing data.”

  • The paper relies on this without support.

    The relevance and interpretation of composite outcomes can be unclear if the individual component outcomes vary greatly for event rates, direction of effect, importance to patients, or amount of missing data.

    “Although composite outcomes increase event rates and statistical power, their relevance and interpretation can be unclear if the individual component outcomes vary greatly for event rates, direction of effect, importance to patients, or amount of missing data.”

  • The paper relies on this without support.

    In explanatory randomised trials, the intervention is usually highly standardised, with close monitoring of fidelity and adherence and use of strategies to increase them.

    “In explanatory randomised trials, where the aim is to determine the treatment effect under ideal circumstances, the intervention is usually highly standardised, with close monitoring of fidelity and adherence and use of strategies to increase them.”

  • The paper relies on this without support.

    Low fidelity and adherence can have a substantial effect on statistical power and interpretation of results.

    “Although no consensus exists on the acceptable minimum fidelity and adherence level in explanatory randomised trials, low fidelity and adherence can have a substantial effect on statistical power and interpretation of results.”

  • The paper relies on this without support.

    In pragmatic randomised trials, interventions are usually highly flexible, with less focus on measuring fidelity and adherence and less use of strategies to maintain or improve them.

    “In pragmatic randomised trials, which aim to determine the treatment effect in typical clinical settings, interventions are usually highly flexible, with less focus on measuring fidelity and adherence and less use of strategies to maintain or improve them.”

  • The paper relies on this without support.

    In a randomised trial, a key goal is to have comparable study groups that differ only by the intervention being evaluated.

    “In a randomised trial, a key goal is to have comparable study groups that differ only by the intervention being evaluated.”

  • The paper relies on this without support.

    Assessing fidelity and adherence to the intervention or comparator, or at least recording the most important components, is necessary to understand what was administered to participants.

    “Nevertheless, assessing fidelity and adherence to the intervention or comparator, or at least recording the most important components, is necessary to understand what was administered to participants.”

  • The paper relies on this without support.

    Assessing fidelity and adherence is particularly important for complex interventions when diversity in the implementation of the intervention or comparator is expected.

    “This is particularly important for complex interventions when diversity in the implementation of the intervention or comparator is expected.”

  • The paper relies on this without support.

    Recording key elements of the intervention is essential to provide a relevant description of the intervention that was provided when the trial was completed.

    “This information is essential to provide a relevant description of the intervention that was provided when the trial was completed.”

  • The paper relies on this without support.

    Trials may differ in what is meant by the intervention being evaluated.

    “Trials may differ in what is meant by the intervention being evaluated.”

  • The paper relies on this without support.

    In some trials with a marked explanatory approach, the intervention might be defined narrowly as the experimental intervention tested.

    “In some trials (with a marked explanatory approach), the intervention might be defined narrowly as the experimental intervention tested.”

  • The paper relies on this without support.

    In other trials with a more pragmatic approach, the intervention might be defined as the experimental intervention plus allowed concomitant interventions and procedures, such as rescue interventions.

    “In other trials (with a more pragmatic approach), the intervention might be defined as the experimental intervention plus allowed concomitant interventions and procedures, such as rescue interventions.”

  • The paper relies on this without support.

    In some multicentre trials an intervention could be added to usual care that might differ considerably in content between centres.

    “Also, in some multicentre trials an intervention could be added to usual care that might differ considerably in content between centres (item 15a).”

  • The paper relies on this without support.

    To increase statistical power, harms outcomes are sometimes grouped in a composite outcome.

    “To increase statistical power, harms outcomes are sometimes grouped in a composite outcome (eg, cardiovascular events).”

  • The paper relies on this without support.

    Assessing the risk of bias domain for deviations from the intended intervention requires a clear understanding of deviations that occur as planned in the protocol and deviations that arise owing to the experimental context.

    “Assessing this domain requires a clear understanding of deviations that occur as planned in the protocol and deviations that arise owing to the experimental context.”

  • The paper relies on this without support.

    Key considerations determining the need to report an adverse event to external groups include severity, potential causality, and whether the adverse event represents an unexpected event.

    “Key considerations determining the need to report an adverse event to external groups include severity, potential causality, and whether the adverse event represents an unexpected event.”

  • The paper relies on this without support.

    The sample size calculation is generally based on one primary outcome.

    “The sample size calculation is generally based on one primary outcome.”

  • The paper relies on this without support.

    The results for primary and secondary outcomes can be substantially affected by the choice of methods used for analysis.

    “The results for the primary and secondary outcomes can be substantially affected by the choice of methods used for analysis, which should align with the trial objectives, and, if used, the estimands framework (item 10).”

  • The paper relies on this without support.

    When more than one analysis method is applied to an outcome, there is potential for inappropriately selecting the approach that leads to the most “interesting” finding.

    “When more than one analysis method is applied to an outcome, there is potential for inappropriately selecting the approach that leads to the most “interesting” finding.”

  • The paper relies on this without support.

    Attrition bias can be avoided when outcome data are obtained from all participants and included in the analysis, regardless of adherence to the protocol.

    “Attrition bias can be avoided when outcome data are obtained from all participants and included in the analysis, regardless of adherence to the protocol.”

  • The paper relies on this without support.

    Imputation of missing outcomes does not guarantee avoidance of bias except under strong assumptions about the missing data.

    “Although imputation of missing outcomes would allow an intention-to-treat analysis, it does not guarantee avoidance of bias except under strong assumptions about the missing data.”

  • The paper relies on this without support.

    Methods for handling missing data (including analysis of complete cases only) typically rely on unverifiable assumptions.

    “Methods for handling missing data (including analysis of complete cases only) typically rely on unverifiable assumptions.”

  • The paper relies on this without support.

    If randomised participants with missing data are omitted (a complete case analysis), then the analysis deviates from the intention-to-treat principle and can introduce bias depending on the amount of missing data and the mechanism resulting in the missing data.

    “If randomised participants with missing data are omitted (a complete case analysis), then the analysis deviates from the intention-to-treat principle and can introduce bias (item 27b) depending on the amount of missing data and the mechanism resulting in the missing data.”

  • The paper relies on this without support.

    A complete case analysis diminishes statistical power by reducing the sample size.

    “A complete case analysis also diminishes statistical power by reducing the sample size.”

  • The paper relies on this without support.

    Categorisation of continuous variables to define subgroups leads to loss of information and a reduction of statistical power.

    “Categorisation also leads to the loss of information and a reduction of statistical power.”

  • The paper relies on this without support.

    Cut-off points to define subgroups are often arbitrarily chosen without clinical or biological rationale.

    “Cut-off points to define subgroups are often arbitrarily chosen without clinical or biological rationale.”

  • The paper relies on this without support.

    Personal information about trial participants is acquired during the process of recruitment, eligibility screening, and data collection.

    “Personal information about trial participants is acquired during the process of recruitment, eligibility screening, and data collection.”

  • The paper relies on this without support.

    Much of the personal information collected consists of private details of which many people wish to maintain control, such as health status, personal genotype, and social and family history.

    “Much of this information consists of private details of which many people wish to maintain control, such as their health status, personal genotype, and social and family history.”

  • The paper relies on this without support.

    Provision of care for ancillary needs reflects the fact that participants implicitly, but unavoidably, entrust certain aspects of their health to the research team.

    “Provision of care for ancillary needs reflects the fact that participants implicitly, but unavoidably, entrust certain aspects of their health to the research team.”

  • The paper relies on this without support.

    The scope of entrustment varies depending on the nature of the trial (eg, setting, health condition under study, investigations performed).

    “The scope of entrustment will vary depending on the nature of the trial (eg, setting, health condition under study, investigations performed).”

  • The paper relies on this without support.

    Additional factors that influence the strength of the responsibility to provide ancillary care include participants’ vulnerabilities, uncompensated burdens and harms, the intensity and duration of the participant-researcher relationship, and the degree to which participants are uniquely dependent on the research team for healthcare.

    “Additional factors that influence the strength of the responsibility to provide ancillary care include participants’ vulnerabilities, uncompensated burdens and harms, the intensity and duration of the participant-researcher relationship, and the degree to which participants are uniquely dependent on the research team for healthcare.”

  • The paper relies on this without support.

    Public access to trial protocols enables readers to compare what was planned in a protocol with what was reported in a publication.

    “Public access to trial protocols (in addition to trial publications) enables readers (eg, patients, peer reviewers, editors, healthcare providers, funders, researchers conducting systematic reviews, and guideline developers) to compare what was planned in a protocol with what was reported in a publication.”

  • The paper relies on this without support.

    The review of a clinical trial protocol is typically conducted by a formal research ethics board or committee in accordance with jurisdictional policy.

    “The review is typically conducted by a formal research ethics board or committee (also called an institutional review board) in accordance with jurisdictional policy.”

  • The paper relies on this without support.

    The acquisition and storage of data and biological specimens for ancillary studies are increasingly common in the context of clinical trials.

    “The acquisition and storage of data and biological specimens for ancillary studies are increasingly common in the context of clinical trials.”
64 of 64

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 item.

    “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 item.28”

    From SPIRIT 2025 statement: updated guideline for protocols of randomised trials (2025) · cites this paper as [28]

  • The accompanying SPIRIT 2025 explanation and elaboration document provides background and context for each checklist item along with examples of good reporting.

    “An accompanying SPIRIT 2025 explanation and elaboration document provides background and context for each checklist item along with examples of good reporting.28”

    From SPIRIT 2025 statement: updated guideline for protocols of randomised trials (2025) · cites this paper as [28]

  • The expanded checklist comprises an abridged version of elements presented in the SPIRIT 2025 explanation and elaboration document, with examples and references removed.

    “The expanded checklist comprises an abridged version of elements presented in the SPIRIT 2025 explanation and elaboration document,28 with examples and references removed.”

    From SPIRIT 2025 statement: updated guideline for protocols of randomised trials (2025) · cites this paper as [28]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Diluted event rate does not follow from the stated subgroup effect

    Major

    If one third of participants have cardiac dysfunction and their event rate falls from 15% to 7.5%, while the other two thirds remain at 15%, the overall rate is 12.5%, not 9%. The stated 9% rate is used for the sample-size calculation.

    Reported 9 · recomputed 12.5

  • Four milestones are described as five

    Minor

    The example says there are five predetermined review milestones but lists only four enrolment counts.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 8

  1. JAMA Network. JAMA Instructions for Authors: authorship and disclosures. 2024. https://jamanetwork.com/journals/jama/pages/instructions-for-authors#SecAuthorshipandDisclosures.
  2. Institute of Medicine . Conflict of interest in medical research, education, and practice. National Academies Press, 2009.
  3. ASAPbio. Preprint resource centre. https://asapbio.org/preprint-info [Accessed 8 Nov 2023].
  4. Schulz KF Grimes DA . Essential Concepts in Clinical Research: randomized controlled trials and observational epidemiology. 2nd ed. Elsevier, 2019.
  5. 10.7326/0003-4819-144-4-200602210-00007 · DOI · Paper page
  6. Chappell L, Alfirevich Z, Chien P, Jarvis S, Thornton JG. A comparison of the published version of randomized controlled trials in a specialist clinical journal with the original trial protocols [abstract]. International Congress on Peer Review and Biomedical Publication; 16-18 Sept 2005; Chicago, Illinois, USA. 2005:27.
  7. European Commission. Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1) (2010/C 82/01). Official Journal of the European Union. 2010.
  8. Fayter D, McDaid C, Ritchie G, Stirk L, Eastwood A. Systematic review of barriers, modifiers and benefits involved in participation in cancer trials. Centre for Reviews and Dissemination report 31. University of York; 2006. Report No 31.

Cited by

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Related

Authors
Hróbjartsson, A., Boutron, I., Hopewell, S., Moher, D., Schulz, K. F., Collins, G. S., Tunn, R., Aggarwal, R., Berkwits, M., Berlin, J. A., Bhandari, N., Butcher, N. J., Campbell, M. K., Chidebe, R. C. W., Elbourne, D. R., Farmer, A. J., Fergusson, D. A., Golub, R. M., Goodman, S. N., Hoffmann, T. C., Ioannidis, J. P. A., Kahan, B. C., Knowles, R. L., Lamb, S. E., Lewis, S., Loder, E., Offringa, M., Ravaud, P., Richards, D. P., Rockhold, F. W., Schriger, D. L., Siegfried, N. L., Staniszewska, S., Taylor, R. S., Thabane, L., Torgerson, D. J., Vohra, S., White, I. R., & Chan, A.-W.
Affiliations
  • University of Southern Denmark (DK)
  • Inserm (FR)
  • University of Oxford (GB)
  • Ottawa Hospital Research Institute (CA)
  • University of North Carolina at Chapel Hill (US)
  • Jawaharlal Institute of Post Graduate Medical Education and Research (IN)
  • Rutgers, The State University of New Jersey (US)
  • Society for Applied Studies (IN)
  • University of Toronto (CA)
  • University of Aberdeen (GB)
  • Miami University (US)
  • London School of Hygiene & Tropical Medicine (GB)
  • Northwestern University (US)
  • Stanford University (US)
  • Bond University (AU)
  • MRC Clinical Trials Unit at UCL (GB)
  • University College London (GB)
  • University of Exeter (GB)
  • University of Edinburgh (GB)
  • Brigham and Women's Hospital (US)
  • Hospital for Sick Children (CA)
  • MaRS (CA)
  • Duke University (US)
  • University of California, Los Angeles (US)
  • South African Medical Research Council (ZA)
  • University of Warwick (GB)
  • MRC/CSO Social and Public Health Sciences Unit (GB)
  • St. Joseph’s Healthcare Hamilton (CA)
  • University of York (GB)
  • University of Alberta (CA)
Corresponding author
Hróbjartsson, Asbjørn
ORCID
Venue
BMJ
Publisher
BMJ
Published
2025-04-28
Volume
389
Pages
e081660
ISSN
1756-1833 (ISSN-L)
DOI
10.1136/bmj-2024-081660
PMC
PMC12128891
OpenAlex
W4409954495
Semantic Scholar
b8007d80648965edd52f9adabbed370abea54993
Cited by
171
References
469
Citations by year
2026: 140 · 2025: 31
FWCI
109.37
Type
journal article
Language
en
Open access
Licence
Locations
  • BMJ (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (publishedVersion, cc-by)
  • Pure Amsterdam UMC (acceptedVersion, cc-by)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • Aberdeen University Research Archive (Aberdeen University) (submittedVersion, cc-by)
  • Bond University Research Portal (Bond University) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by)
Funders
  • Pfizer (GA6120A8)
  • National Institute for Health and Care Research
  • Department of Health and Social Care
  • University of Queensland
  • Medical Research Council (MC_UU_00004/09)
  • National Health and Medical Research Council (1140756, 1037220)
Topics
  • Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
  • Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Clinical practice guidelines implementation
Keywords
trial protocol reporting, reporting guidelines, randomised trials, trial planning, reporting quality

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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