Guidelines for Reporting Trial Protocols and Completed Trials Modified Due to the COVID-19 Pandemic and Other Extenuating Circumstances: The CONSERVE 2021 Statement

May combine two claims.

Responses were received from 198 professionals from 34 countries, including 61 respondents from low- and middle-income countries.

“Responses were received from 198 professionals from 34 countries”

• Also stated in: § Global Survey of Trials Community · plain

  “Responses were received from 198 professionals from 34 countries, including 61 respondents from low-and middle-income countries.”

May combine two claims.

Feedback from survey respondents was used to finalize the guideline and confirm that the core concepts were suited for widespread implementation.

“Feedback from survey respondents was used to finalize the guideline and confirm that the guideline's core concepts were applicable and had utility for the trial community.”

• Also stated in: § Global Survey of Trials Community · plain

  “Feedback from survey respondents was used to finalize the guideline and confirm that the core concepts were suited for widespread implementation.”

May combine two claims.

The rapid review yielded 41,673 citations, of which 38 titles were relevant.

“The rapid review yielded 41 673 citations, of which 38 titles were relevant”

• Also stated in: § Rapid Review · plain

  “The search yielded 41 673 citations, of which 3735 were duplicates, and panelists conducted independent and dupli- cate screening of titles and abstracts using Covidence software, yield- ing 38 relevant titles”

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

The James et al investigators' mitigating strategies included new exclusion criteria for patients with contraindications to celecoxib use, changes in the intervention duration, and revisions to the consent materials.

“The investigators' mitigating strategies included new exclusion criteria for patients with contraindications to celecoxib use (SPIRIT item 10; CONSORT item 4), changes in the intervention duration (SPIRIT item 11; CONSORT item 5), and revisions to the consent materials (SPIRIT item 26).”

• cites [23] sourceNot checked yet

  Not checked in the free run.

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

The CONSERVE implementation tool provides a pathway to determine when CONSERVE should be used to report on trials and trial protocols and provides guidance for its application.

“The CONSERVE implementation tool (Figure ) provides a pathway to determine when CONSERVE should be used to report on trials and trial protocols and provides guidance for its application.”

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

In one reported case, the extenuating circumstance was terrorism, which affected the outcomes, data collection methods, and participant flow.

“In this case, the extenuating circumstance was terrorism, which affected the outcomes, data collection methods, and participant flow (SPIRIT items 12 and 18; CONSORT items 13 and 17).”

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

CONSERVE provides 2 checklists: CONSERVE-CONSORT for completed trial results and CONSERVE-SPIRIT for trial protocols.

“CONSERVE provides 2 checklists to support authors in reporting how their trial addressed important modifications in extenuating circumstances.CONSERVE-CONSORT is designed for reporting completed trial results, while CONSERVE-SPIRIT is for reporting trial protocols.”

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

The trial was reported without these details.

“The trial was reported without these details.”

• cites [22] sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

CONSERVE is designed to guide reporting for trials that have undergone important modifications in extenuating circumstances.

“CONSERVE is designed to guide reporting for trials that have undergone important modifications in extenuating circumstances (Figure).”

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

The CONSERVE checklists consist of 4 sections: (1) extenuating circumstances, (2) important modifications including impacts and mitigating strategies, (3) responsible parties, and (4) interim data.

“The checklists include 4 sections capturing extenuating circumstances, important modifications, responsible parties, and interim data analyses.”

• Also stated in: § CONSERVE Checklists · plain

  “The CONSERVE checklists consist of 4 sections: (1) extenuating circumstances, (2) important modifications including impacts and mitigating strategies, (3) responsible parties, and (4) interim data.”

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

In a trial by James et al involving celecoxib for hormone-sensitive prostate cancer, investigators were unable to implement the intended intervention because of unanticipated regulatory changes concerning the use of celecoxib in trials.

“In a trial by James et al 23 involving celecoxib for hormone-sensitive prostate cancer, investigators were unable to implement the intended intervention because of unanticipated regulatory changes concerning the use of celecoxib in trials (Table).”

• cites [23] sourceNot checked yet

  Not checked in the free run.

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

In the Vaillancourt example, the extenuating circumstance was regional policy change, and the impacts affected both the interventions and the numbers analyzed.

“In this example, the extenuating circumstance was regional policy change, and the impacts affected both the interventions (SPIRIT item 11; CONSORT item 5) and the numbers analyzed (SPIRIT item 20; CONSORT item 16).”

May combine two claims.

Although some health regulatory agencies released guidance on trial modifications due to the COVID-19 pandemic, no consensus exists on how such changes and their implications should be reported.

“Although some health regulatory agencies released guidance on trial modifications due to the COVID-19 pandemic, no consensus exists on how such changes and their implications should be reported.”

• cites [5] sourceNot checked yet

  Not checked in the free run.

• cites [6] sourceNot checked yet

  Not checked in the free run.

• cites [7] sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The CONSERVE approach is applicable to other extenuating circumstances that result in important modifications to a trial, such as natural disaster, strikes and other personnel disruptions, regulatory changes, or changes to the clinical standard of care.

“Although the COVID-19 pandemic is the exemplar that prompted the development of CONSERVE, the approach is applicable to other extenuating circumstances that result in important modifications to a trial, such as natural disaster, strikes and other personnel disruptions, regulatory changes, or changes to the clinical standard of care.”

May combine two claims.

As of January 29, 2021, 2043 trials registered with ClinicalTrials.gov had been terminated, withdrawn, or suspended because of COVID-19, affecting more than 129,000 participants and interrupting plans to recruit more than 4 million future participants.

“As of January 29, 2021, 2043 trials registered with ClinicalTrials.govhad been terminated, withdrawn, or suspended because of COVID-19, affecting more than 129 000 participants and interrupting plans to recruit more than 4 million future participants.”

• cites [4] sourceNot checked yet

  Not checked in the free run.

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

Panelists conducted independent and duplicate screening of titles and abstracts using Covidence software.

“panelists conducted independent and dupli- cate screening of titles and abstracts using Covidence software”

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

The panel wrote and registered a protocol for the guideline development process involving 3 main elements: (1) rapid review, (2) consensus-based meetings and surveys, and (3) a global survey of the trials community.

“The panel wrote and registered a protocol (available through the Open Science Framework at https://osf.io/ms8bz) 12 for the guideline development process involving 3 main elements: (1) rapid review, (2) consensus-based meetings and surveys, and (3) a global survey of the trials community.”

• cites [12] sourceNot checked yet

  Not checked in the free run.

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

A review protocol and search strategy was registered through the Open Science Framework.

“A review protocol and search strategy was registered through the Open Science Framework.”

• cites [15] sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Amendments to trial procedures are common, and circumstances such as new safety or efficacy information, regulatory requirements, or changes in the standard of care can make those changes unavoidable.

“Amendments to trial procedures are common, and circumstances such as new safety or efficacy information, regulatory requirements, or changes in the standard of care can make those changes unavoidable.”

• cites [1]Not checked yet

  Not checked in the free run.

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

Through a fourth, final meeting, the panel refined the resulting guideline and checklists by incorporating the results of the rapid literature review and survey of the global trials community.

“Through a fourth, final meeting, the panel refined the resulting guideline and checklists by incorporating the results of the rapid literature review and survey of the global trials community.”

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

Searches were conducted by a health research librarian and peer reviewed using the Peer Review of Electronic Search Strategies (PRESS) guideline.

“Searches were conducted by a health research librarian and peer reviewed using the Peer Review of Electronic Search Strategies (PRESS) guideline.”

• cites [16] sourceNot checked yet

  Not checked in the free run.

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

Panelists were recruited through professional networks to ensure global and interprofessional representation.

“Panelists were recruited through professional networks to ensure global and interprofessional representation.”

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

The CONSERVE panel achieved consensus following 3 meetings.

“The panel achieved consensus following 3 meetings.”

May combine two claims.

Modifications to trial procedures can introduce biases, raising doubts about the validity of the conclusion of a clinical trial.

“Modifications can also introduce biases, raising doubts about the validity of the conclusion of a clinical trial.”

• cites [2] sourceNot checked yet

  Not checked in the free run.

• cites [3] sourceNot checked yet

  Not checked in the free run.

May combine two claims.

CONSERVE is based on the observations that protocol amendments are common and that in some circumstances important modifications can be necessary, unavoidable, or beneficial.

“CONSERVE is based on the observations that protocol amendments are common and that in some circumstances important modifications can be necessary, unavoidable, or beneficial.”

• cites [1]Not checked yet

  Not checked in the free run.

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

Although the guideline development timeline was extended, the guideline development process proceeded per protocol.

“Although the guideline development timeline was extended, the guideline development process proceeded per protocol.”

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

The CONSERVE Panel that convened to develop the guideline was composed of 37 trial investigators, trial methodologists, patient representatives, ethicists, funders, regulators, and journal editors, including CONSORT and SPIRIT executive committee members.

“The CONSERVE Panel that convened to develop the guideline was composed of 37 trial investigators, trial methodologists, patient representatives, ethicists, funders, regulators, and journal editors, including CONSORT and SPIRIT executive committee members.”

May combine two claims.

While CONSORT 2010 and SPIRIT 2013 guide reporting for completed trials and trial protocols, respectively, there is limited guidance for reporting trial modifications.

“While CONSORT (Consolidated Standards of Reporting Trials) 2010 and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 guide reporting for completed trials and trial protocols, respectively, there is limited guidance for reporting trial modifications.”

• cites [9] sourceNot checked yet

  Not checked in the free run.

• cites [10] sourceNot checked yet

  Not checked in the free run.

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

Extenuating circumstances share elements with the contract law concept of force majeure, referring to external events such as wars, strikes, riots, or epidemics that prevent parties from fulfilling their contractual obligations.

“Extenuating circumstances share elements with the contract law concept of force majeure, referring to external events such as wars, strikes, riots, or epidemics that prevent parties from fulfilling their contractual obligations.”

• cites [8] sourceNot checked yet

  Not checked in the free run.

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

The entire CONSERVE panel convened through a series of 4 virtual meetings to revise the prototype and build consensus.

“The entire CONSERVE panel convened through a series of 4 virtual meetings to revise this prototype and build consensus.”

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

CONSERVE was developed between June 2020 and February 2021 following a process adapted from the reporting guideline development procedure of Moher et al, modified to replace face-to-face meetings with virtual meetings and emphasizing rapid completion given the unprecedented disruption of trials in the context of the COVID-19 pandemic.

“CONSERVE was developed between June 2020 and February 2021 following a process adapted from the reporting guideline development procedure of Moher et al, 11 modified to replace face-to-face meetings with virtual meetings and emphasizing rapid completion given the unprecedented disruption of trials in the context of the COVID-19 pandemic.”

• cites [11] sourceNot checked yet

  Not checked in the free run.

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

Thorough and consistent reporting of trials that undergo modifications could enhance trial interpretation and transparency, reduce research waste, and facilitate understanding of how trialists respond and adjust to unforeseen circumstances related to major disruptions, such as the COVID-19 pandemic.

“Thorough and consistent reporting of trials that undergo modifications could enhance trial interpretation and transparency, reduce research waste, and facilitate understanding of how trialists respond and adjust to unforeseen circumstances related to major disruptions, such as the COVID-19 pandemic.”

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

The guideline development process did not involve human subjects research as defined by the Tri-Council Policy Statement (Canada) and therefore was outside the scope of research ethics committee review.

“The guideline development process did not involve human subjects research as defined by the Tri-Council Policy Statement (Canada) and therefore was outside the scope of research ethics committee review.”

• cites [13] sourceNot checked yet

  Not checked in the free run.

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

Participants were listed as lost to follow-up because they could not access outcome assessment facilities per protocol.

“Participants were listed as lost to follow-up because they could not access outcome assessment facilities per protocol.”

• cites [22] sourceNot checked yet

  Not checked in the free run.

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

The overall implications for the trial were that recruitment was likely slowed by the highly publicized safety concerns and the shortened intervention duration may not have been sufficiently long to show benefit.

“The overall implications for the trial were that recruitment was likely slowed by the highly publicized safety concerns and the shortened intervention duration may not have been sufficiently long to show benefit.”

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

A 2-group multisite trial was conducted in rural Niger to assess the effect of a low-cost, heat-stable rotavirus vaccine compared with placebo to prevent laboratory-confirmed severe rotavirus gastroenteritis.

“A 2-group multisite trial was conducted in rural Niger to assess the effect of a low-cost, heat-stable rotavirus vaccine compared with placebo to prevent laboratory-confirmed severe rotavirus gastroenteritis.”

• cites [22] sourceNot checked yet

  Not checked in the free run.

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

Prior to beginning recruitment in 2004, rofecoxib was withdrawn from the market by the manufacturer for safety concerns about cardiovascular toxicity, and regulatory agencies stopped all trials involving cyclooxygenase 2 inhibitors.

“Prior to beginning recruitment in 2004, rofecoxib was withdrawn from the market by the manufacturer for safety concerns about cardiovascular toxicity, and regulatory agencies stopped all trials involving cyclooxygenase 2 inhibitors.”

• cites [23] sourceNot checked yet

  Not checked in the free run.

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

These are important modifications because they affected the study's ethical acceptability and feasibility.

“These are important modifications because they affected the study's ethical acceptability and feasibility.”

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

The authors determined that a sufficient number of clusters had completed implementation of the planned intervention to allow analysis of the primary outcome but were unable to use the final 3 months of the stepped-wedge design (after the policy change) for the planned analysis.

“The authors determined that a sufficient number of clusters had completed implementation of the planned intervention to allow analysis of the primary outcome but were unable to use the final 3 months of the stepped-wedge design (after the policy change) for the planned analysis.”

• cites [20] sourceNot checked yet

  Not checked in the free run.

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

A planned comparison was celecoxib plus hormone therapy vs hormone therapy alone.

“A planned comparison was celecoxib plus hormone therapy vs hormone therapy alone.”

• cites [23] sourceNot checked yet

  Not checked in the free run.

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

The STAMPEDE investigators could not recruit to the celecoxib group and had to reassess the risk-benefit balance of the intervention.

“The STAMPEDE investigators could not recruit to the celecoxib group and had to reassess the risk-benefit balance of the intervention.”

• cites [23] sourceNot checked yet

  Not checked in the free run.

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

The trialists identified this policy change as an extenuating circumstance leading to a premature and unanticipated modification to the implementation schedule at 9 months, before the planned completion at 12 months.

“The trialists identified this policy change as an extenuating circumstance leading to a premature and unanticipated modification to the implementation schedule at 9 months, before the planned completion at 12 months.”

• cites [20] sourceNot checked yet

  Not checked in the free run.

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

This could represent an important modification to trials conducted in critical care settings regardless of whether such a change triggered an amendment to the study protocol.

“This could represent an important modification to trials conducted in critical care settings regardless of whether such a change triggered an amendment to the study protocol.”

Classified as probably not a substantial claim.

These are important modifications that had implications for study feasibility and analytical methods in this trial.

“These are important modifications that had implications for study feasibility and analytical methods in this trial.”

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

CONSERVE is not a mechanism to redress poor trial design, and it does not encourage unwarranted trial modifications, especially post hoc changes to favor positive results based on accumulating trial data.

“CONSERVE is not a mechanism to redress poor trial design, and it does not encourage unwarranted trial modifications, especially post hoc changes to favor positive results based on accumulating trial data.”

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

This introduced ethical challenges as study staff and participants worked to continue study operations despite the security threat.

“This introduced ethical challenges as study staff and participants worked to continue study operations despite the security threat.”

• cites [22] sourceNot checked yet

  Not checked in the free run.

May combine two claims.

There is a gap in existing trial reporting guidance that predates the COVID-19 pandemic and will persist beyond the pandemic.

“This could help address a gap in existing trial reporting guidance that predates the COVID-19 pandemic and will persist beyond the pandemic.”

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

The investigators' mitigating strategies included omission of the final study period from the randomized clinical trial analysis, an extended observational data collection period for 3 months beyond the anticipated stop date, and a revised design and analysis plan to include 3 conditions: usual care, planned intervention, and an uncontrolled modified intervention condition.

“The investigators' mitigating strategies included omission of the final study period from the randomized clinical trial analysis, an extended observational data collection period for 3 months beyond the anticipated stop date, and a revised design and analysis plan to include 3 conditions: usual care, planned intervention, and an uncontrolled modified intervention condition.”

• cites [20] sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The prevalence of other underlying conditions leading to critical care unit admissions also changed in unanticipated ways.

“The prevalence of other underlying conditions leading to critical care unit admissions also changed in unanticipated ways.”

• cites [21] sourceNot checked yet

  Not checked in the free run.

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

By promoting complete and transparent reporting of trial modifications, CONSERVE allows the research community to learn from how extenuating circumstances have been managed, examine the overall impact of those circumstances, and take modifications into account when interpreting trial results.

“By promoting complete and transparent reporting of trial modifications, CONSERVE also allows the research community to learn from how extenuating circumstances have been managed, examine the overall impact of those circumstances, and take modifications into account when interpreting trial results.”

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

The STAMPEDE trial was a multicenter, multigroup, multistage platform trial evaluating the efficacy and safety of multiple novel systemic therapies compared with standard care for hormone-sensitive prostate cancer.

“The STAMPEDE trial was a multicenter, multigroup, multistage platform trial evaluating the efficacy and safety of multiple novel systemic therapies compared with standard care for hormone-sensitive prostate cancer.”

• cites [23] sourceNot checked yet

  Not checked in the free run.

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

The intervention duration was also reduced, and cardiovascular risks were added to the consent materials.

“The intervention duration was also reduced, and cardiovascular risks were added to the consent materials.”

• cites [23] sourceNot checked yet

  Not checked in the free run.

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

Investigators evaluated the effect of small-volume blood collection tubes vs standard tubes to reduce red blood cell transfusion in critical care patients in a pragmatic multicenter, stepped-wedge cluster trial at 25 sites in Canada.

“Investigators evaluated the effect of small-volume blood collection tubes vs standard tubes to reduce red blood cell transfusion in critical care patients in a pragmatic multicenter, stepped-wedge cluster trial at 25 sites in Canada.”

• cites [21] sourceNot checked yet

  Not checked in the free run.

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

They modified the eligibility criteria to exclude any potential participants who had substantial cardiovascular disease, and the start of recruitment to the celecoxib group was delayed by 1 year.

“They modified the eligibility criteria to exclude any potential participants who had substantial cardiovascular disease, and the start of recruitment to the celecoxib group was delayed by 1 year.”

• cites [23] sourceNot checked yet

  Not checked in the free run.

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

These are important modifications because they had meaningful effects for the study's ethical acceptability, analytical methods, and statistical power.

“These are important modifications because they had meaningful effects for the study's ethical acceptability, analytical methods, and statistical power.”

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

The authors interpreted this extenuating circumstance as a threat to the study's ethical foundations and analysis plan.

“The authors interpreted this extenuating circumstance as a threat to the study's ethical foundations and analysis plan.”

• cites [22] sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Examining interim outcome data can bias trial results and interpretation and introduce analytical and ethical challenges when interim analyses are not prespecified or lead to early study termination.

“Examining interim outcome data can bias trial results and interpretation and introduce analytical and ethical challenges when interim analyses are not prespecified or lead to early study termination.”

• cites [27] sourceNot checked yet

  Not checked in the free run.

• cites [28] sourceNot checked yet

  Not checked in the free run.

• cites [29] sourceNot checked yet

  Not checked in the free run.

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

The investigators modified their analysis plan to mitigate the effect of these changes.

“The investigators modified their analysis plan to mitigate the effect of these changes (Table).”

• cites [21] sourceNot checked yet

  Not checked in the free run.

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

Using data concerning recruitment rate or adherence would not generally introduce bias, whereas using outcome data by study group would have a greater potential to bias the choice of mitigating strategies used to respond to extenuating circumstances.

“For example, using data concerning recruitment rate or adherence would not generally introduce bias, whereas using outcome data by study group would have a greater potential to bias the choice of mitigating strategies used to respond to extenuating circumstances.”

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

When trials are affected by extenuating circumstances, it may be reasonable in some instances to use outcome data to plan and implement mitigating strategies.

“When trials are affected by extenuating circumstances, however, it may be reasonable in some instances to use outcome data to plan and implement mitigating strategies.”

Classified as probably not a substantial claim.

Trialists can reduce the chance of introducing bias by creating a plan for interim analyses a priori and detailing how the findings will inform further decisions.

“Rather than conducting ad hoc interim analyses in a fully ad hoc manner, trialists can reduce the chance of introducing bias by creating a plan for these interim analyses a priori and detailing how the findings will inform further decisions.”

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

The authors interpreted these as extenuating circumstances and implemented mitigating strategies including changes to the statistical analysis plan to mitigate the effects of these changes in the patient population.

“The authors interpreted these as extenuating circumstances and implemented mitigating strategies including changes to the statistical analysis plan to mitigate the effects of these changes in the patient population.”

• cites [21] sourceNot checked yet

  Not checked in the free run.

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

The types of patients admitted to the critical care units (and their corresponding prognoses) may have changed substantially after the start of the COVID-19 pandemic, with variable proportions of COVID-19 and elective surgery patients across sites.

“The types of patients admitted to the critical care units (and their corresponding prognoses) may have changed substantially after the start of the COVID-19 pandemic, with variable proportions of COVID-19 and elective surgery patients across sites.”

• cites [21] sourceNot checked yet

  Not checked in the free run.

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

Terrorism in the region inhibited access to some areas, affecting outcome assessments and access to the laboratory.

“Terrorism in the region inhibited access to some areas, affecting outcome assessments and access to the laboratory.”

• cites [22] sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

These are important modifications because the change in standards of care could have effects on the study's ability to address its objectives, analytical methods, and statistical power.

“These are important modifications because the change in standards of care could have effects on the study's ability to address its objectives, analytical methods, and statistical power.”

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

Previously unanticipated analyses can be conducted in a planned manner by documenting the intended analysis in the protocol and determining a priori how those analyses will inform modifications.

“These previously unanticipated analyses can be conducted in a planned manner by documenting the intended analysis in the protocol and determining how those analyses will inform modifications a priori.”

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

The COVID-19 pandemic delayed implementation of the intervention at some sites due to clinical workload, pandemic preparedness activities, and infection control precautions, but the trial was ultimately completed.

“The COVID-19 pandemic delayed implementation of the intervention at some sites due to clinical workload, pandemic preparedness activities, and infection control precautions, but the trial was ultimately completed.”

• cites [21] sourceNot checked yet

  Not checked in the free run.

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

In a multicenter stepped-wedge cluster randomized pragmatic trial, regional government enacted a policy change partway through the rollout that mandated widespread use of a modified version of the experimental intervention as the new standard of care.

“In a multicenter stepped-wedge cluster randomized pragmatic trial, regional government enacted a policy change partway through the rollout that mandated widespread use of a modified version of the experimental intervention as the new standard of care.”

• cites [20] sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The CONSERVE development process adapted the conventional Delphi process and incorporated several steps to solicit detailed feedback and achieve consensus with a large group of trial professionals and public representatives who refined the process, substituting virtual meetings for in-person discussions to ensure that dissenting views could be addressed.

“Unlike prior reporting guidelines, this process adapted the conventional Delphi process and incorporated several steps to solicit detailed feedback and achieve consensus with a large group of trial professionals and public representatives who refined the process, but substituted in-person discussions with virtual meetings to ensure that dissenting views could be addressed.”

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

By supporting transparency, CONSERVE may also promote public trust in science when studies encounter unanticipated circumstances.

“By supporting transparency, CONSERVE may also promote public trust in science when studies encounter unanticipated circumstances.”

• cites [38] sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The global survey sought to capture a large, international body of interdisciplinary persons working on and with trials, and those respondents provided examples and feedback about how CONSERVE could be used.

“Third, the global survey sought to capture a large, international body of interdisciplinary persons working on and with trials, and those respondents provided examples and feedback about how CONSERVE could be used.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

Consistent reporting of trials that encounter extenuating circumstances could prompt trialists to develop plans for a wider range of potential disruptions in trial protocols.

“Consistent reporting of trials that encounter extenuating circumstances could also prompt trialists to develop plans for a wider range of potential disruptions in trial protocols.”

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

The EMA guidance outlined the importance of describing specific dates and durations of issues external to the trial and discussed when data review may be warranted to inform study decisions.

“The EMA guidance outlined the importance of describing specific dates and durations of issues external to the trial (eg, lockdowns and travel restrictions) and discussed when data review may be warranted to inform study decisions.”

• cites [8] sourceNot checked yet

  Not checked in the free run.

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

Clinical and research specialty societies have provided guidance on conducting trials during the pandemic, including in oncology, cardiovascular disease and heart failure, and hepatology.

“Clinical and research specialty societies have also provided guidance on conducting trials during the pandemic, including in oncology, cardiovascular disease and heart failure, and hepatology.”

• cites [46]Not checked yet

  Not checked in the free run.

• cites [47]Not checked yet

  Not checked in the free run.

• cites [48]Not checked yet

  Not checked in the free run.

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

Other reports have provided analyses on the management of missing data in trials due to COVID-19, the ethical dimensions of conducting trials during public health emergencies, and the challenges of trial sponsorship during a pandemic.

“Other reports have provided analyses on the management of missing data in trials due to COVID-19, 41 ethical dimensions of conducting trials during public health emergencies, 33,42,43 and the challenges of trial sponsorship during a pandemic.”

• cites [41] sourceNot checked yet

  Not checked in the free run.

• cites [33] sourceNot checked yet

  Not checked in the free run.

• cites [44]Not checked yet

  Not checked in the free run.

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

Despite its international representation, including respondents from low- and middle-income countries, CONSERVE may not have captured all relevant perspectives.

“Despite its international representation, including respondents from low-and middle-income countries, CONSERVE may not have captured all relevant perspectives.”

Classified as probably not a substantial claim.

CONSERVE complements regulatory guidance on modifying trials in the context of the COVID-19 pandemic.

“CONSERVE complements regulatory guidance on modifying trials in the context of the COVID-19 pandemic.”

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

Drs Orkin and Gill had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

“Author Contributions: Drs Orkin and Gill had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.”

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

Guidance from the FDA also addressed statistical methodology as it relates to meeting trial objectives during the pandemic.

“Guidance from the FDA also addressed statistical methodology as it relates to meeting trial objectives during the pandemic.”

• cites [40] sourceNot checked yet

  Not checked in the free run.

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

The UK Medicines and Healthcare Products Regulatory Agency set guidance for trial investigators to assess the risks and benefits of ongoing trials during COVID-19 and to consider options including halting recruitment, adapting delivery processes, stopping or suspending the trial, or mitigating risks as the trial proceeds.

“For example, the UK Medicines and Healthcare Products Regulatory Agency set guidance for trial investigators to assess the risks and benefits of ongoing trials during COVID-19 and to consider options including halting recruitment, adapting delivery processes, stopping or suspending the trial, or mitigating risks as the trial proceeds.”

• cites [39] sourceNot checked yet

  Not checked in the free run.

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

Editorials have called on trial authors to describe pandemic-related issues in the methods sections of articles, including changes in study protocol, trial delays or interruptions, issues with missing data, and effects on statistical power.

“Editorials have called on trial authors to describe pandemic-related issues in the methods sections of articles, including changes in study protocol, trial delays or interruptions, issues with missing data, and effects on statistical power.”

• cites [51]Not checked yet

  Not checked in the free run.

• cites [52] sourceNot checked yet

  Not checked in the free run.

• cites [53]Not checked yet

  Not checked in the free run.

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

The Norwegian Medicines Agency and the South African Health Products Regulatory Authority made similar recommendations, while the European Medicines Agency provided guidance on the methodological aspects of ongoing clinical trials.

“Similar recommendations were made by the Norwegian Medicines Agency and the South African Health Products Regulatory Authority, while the European Medicines Agency (EMA) provided guidance on the methodological aspects of ongoing clinical trials.”

• cites [6] sourceNot checked yet

  Not checked in the free run.

• cites [7] sourceNot checked yet

  Not checked in the free run.

• cites [8] sourceNot checked yet

  Not checked in the free run.

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

CONSERVE was developed rapidly using a modified process to engage rapidly with a global community of trial investigators, methodologists, ethicists, funders, regulators, journal editors, and patient representatives.

“First, CONSERVE was developed rapidly using a modified process to engage rapidly with a global community of trial investigators, methodologists, ethicists, funders, regulators, journal editors, and patient representatives.”

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

These existing resources provide methodological guidance, while CONSERVE delivers a framework for reporting what decisions were made, why they were made, and the corresponding impact.

“These resources provide methodological guidance, while CONSERVE delivers a framework for reporting what decisions were made, why they were made, and the corresponding impact.”

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

Guidance from the FDA on trials during the COVID-19 pandemic recommended that trialists describe the contingency measures implemented, list how and which participants were affected including how participation was altered, and provide analyses and discussions that address the effect on safety and efficacy.

“Guidance from the FDA on trials during the COVID-19 pandemic recommended that trialists describe the contingency measures implemented, list how and which participants were affected including how participation was altered, and provide analyses and discussions that address the effect on safety and efficacy.”

• cites [5] sourceNot checked yet

  Not checked in the free run.

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

The supporting organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

“Role of the Funder/Sponsor: The supporting organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.”

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

Because many ongoing trials affected by the pandemic have not yet been published, only a few reports have described how investigators have responded to the extenuating circumstances, limiting the examples available about COVID-19.

“Second, given that many ongoing trials affected by the pandemic have not yet been published, only a few reports have described how investigators have responded to the extenuating circumstances, limiting the examples available about COVID-19.”