Nonregistration, discontinuation, and nonpublication of randomized trials: A repeated metaresearch analysis

BACKGROUND We previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs. METHODS AND FINDINGS We included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment. Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%). The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations. CONCLUSIONS We have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research

Creation of Matrix Protein Gene Variants of Two Serotypes of VSV as Prime-Boost Vaccine Vectors Downloaded from 2

Abstract 33 To take advantage of live rVSVs as vaccine vectors for their high yield and for their 34 induction of strong and long-lasting immune responses, it is necessary to make live 35 vaccine vectors safe for use without losing their immunogenicity. We have generated 36 safer and highly efficient recombinant VSV vaccine vectors by combining the M51R 37 mutation in the M gene of VSV Ind with a temperature sensitive mutation of the VSV Ind 38 Orsay tsO23. In addition, we have also generated two new VSV NJ vaccine vectors by 39 combining M48R/M51R mutations with G22E and L110F mutations in the M gene, 4

Creation of Matrix Protein Gene Variants of Two Serotypes of Vesicular Stomatitis Virus as Prime-Boost Vaccine Vectors

Interstate 25, Colorado Springs, CO 80840general vie

Reporting of Imaging Diagnostic Accuracy Studies With Focus on MRI Subgroup: Adherence to STARD 2015

Purpose: To evaluate adherence of diagnostic accuracy studies in imaging journals to the STAndards for Reporting of Diagnostic accuracy studies (STARD) 2015. The secondary objective was to identify differences in reporting for magnetic resonance imaging (MRI) studies. Materials and Methods: MEDLINE was searched for diagnostic accuracy studies published in imaging journals in 2016. Studies were evaluated for adherence to STARD 2015 (30 items, including expanded imaging specific subitems). Evaluation for differences in STARD adherence based on modality, impact factor, journal STARD adoption, country, subspecialty area, study design, and journal was performed. Results: Adherence (n = 142 studies) was 55% (16.6/30 items, SD = 2.2). Index test description (including imaging-specific subitems) and interpretation were frequently reported (>66% of studies); no important differences in reporting of individual items were identified for studies on MRI. Infrequently reported items ( <33% of studies) included some critical to generalizability (study setting and location) and assessment of bias (blinding of assessor of reference standard). New STARD 2015 items: sample size calculation, protocol reporting, and registration were infrequently reported. Higher impact factor (IF) journals reported more items than lower IF journals (17.2 vs. 16 items; P = 0.001). STARD adopter journals reported more items than nonadopters (17.5 vs. 16.4 items; P = 0.01). Adherence varied between journals (P = 0.003). No variability for study design (P = 0.32), subspecialty area (P = 0.75), country (P = 0.28), or imaging modality (P = 0.80) was identified. Conclusion: Imaging accuracy studies show moderate adherence to STARD 2015, with only minor differences for studies evaluating MRI. This baseline evaluation will guide targeted interventions towards identified deficiencies and help track progress in reportin

Treatment of multiple test readers in diagnostic accuracy systematic reviews-meta-analyses of imaging studies

Objective: To evaluate the handling of multiple readers in imaging diagnostic accuracy systematic reviews-metaanalyses. Methods: Search was performed for imaging diagnostic accuracy systematic reviews that performed metaanalysis from 2005-2015. Handling of multiple readers was classified as: 1) averaged; 2) `best' reader; 3) `most experienced' reader; 4) each reader counted individually; 5) random; 6) other; 7) not specified. Incidence and reporting of multiple reader data was assessed in primary diagnostic accuracy studies that were included in a random sample of reviews. Results: Only 28/296 (9.5%) meta-analyses specified how multiple readers were handled: 7/28 averaged results, 2/28 included the best reader, 14/28 treated each reader as a separate data set, 1/28 randomly selected a reader, 4/28 used other methods. Sample of 27/268 ` not specified' reviews generated 442 primary studies. 270/442 (61%) primary studies had multiple readers: 164/442 (37%) reported consensus reading, 87/442 (20%) reported inter-observer variability, 9/442 (2%) reported independent datasets for each reader. 26/27 (96%) meta-analyses contained at least one primary study with multiple readers. Conclusions: Reporting how multiple readers were treated in imaging systematic reviews-meta-analyses is uncommon and method used varied widely. This may result from a lack of guidance, unavailability of appropriate statistical methods for handling multiple readers in meta-analysis, and sub-optimal primary study reportin

Rationale and design of repeated cross-sectional studies to evaluate the reporting quality of trial protocols: the Adherence to SPIrit REcommendations (ASPIRE) study and associated projects

BACKGROUND Clearly structured and comprehensive protocols are an essential component to ensure safety of participants, data validity, successful conduct, and credibility of results of randomized clinical trials (RCTs). Funding agencies, research ethics committees (RECs), regulatory agencies, medical journals, systematic reviewers, and other stakeholders rely on protocols to appraise the conduct and reporting of RCTs. In response to evidence of poor protocol quality, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline was published in 2013 to improve the accuracy and completeness of clinical trial protocols. The impact of these recommendations on protocol completeness and associations between protocol completeness and successful RCT conduct and publication remain uncertain. OBJECTIVES AND METHODS Aims of the Adherence to SPIrit REcommendations (ASPIRE) study are to investigate adherence to SPIRIT checklist items of RCT protocols approved by RECs in the UK, Switzerland, Germany, and Canada before (2012) and after (2016) the publication of the SPIRIT guidelines; determine protocol features associated with non-adherence to SPIRIT checklist items; and assess potential differences in adherence across countries. We assembled an international cohort of RCTs based on 450 protocols approved in 2012 and 402 protocols approved in 2016 by RECs in Switzerland, the UK, Germany, and Canada. We will extract data on RCT characteristics and adherence to SPIRIT for all included protocols. We will use multivariable regression models to investigate temporal changes in SPIRIT adherence, differences across countries, and associations between SPIRIT adherence of protocols with RCT registration, completion, and publication of results. We plan substudies to examine the registration, premature discontinuation, and non-publication of RCTs; the use of patient-reported outcomes in RCT protocols; SPIRIT adherence of RCT protocols with non-regulated interventions; the planning of RCT subgroup analyses; and the use of routinely collected data for RCTs. DISCUSSION The ASPIRE study and associated substudies will provide important information on the impact of measures to improve the reporting of RCT protocols and on multiple aspects of RCT design, trial registration, premature discontinuation, and non-publication of RCTs observing potential changes over time

Reporting quality of trial protocols improved for non-regulated interventions but not regulated interventions: A repeated cross-sectional study

To investigate the adherence of randomised controlled trial (RCT) protocols evaluating non-regulated interventions (including dietary interventions, surgical procedures, behavioural and lifestyle interventions, and exercise programmes) in comparison with regulated interventions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement.; We conducted a repeated cross-sectional investigation in a random sample of RCT protocols approved in 2012 (n = 257) or 2016 (n = 292) by research ethics committees in Switzerland, Germany, or Canada. We investigated the proportion of accurately reported SPIRIT checklist items in protocols of trials with non-regulated as compared to regulated interventions.; Overall, 131 (24%) of trial protocols tested non-regulated interventions. In 2012, the median proportion of SPIRIT items reported in these protocols (59%, interquartile range [IQR], 53%-69%) was lower than in protocols with regulated interventions (median, 74%, IQR, 66%-80%). In 2016, the reporting quality of protocols with non-regulated interventions (median, 75%, IQR, 62%-83%) improved to the level of regulated intervention protocols, which had not changed on average.; Reporting of RCT protocols evaluating non-regulated interventions improved between 2012 and 2016, although remained suboptimal. SPIRIT recommendations need to be further endorsed by researchers, ethics committees, funding agencies, and journals to optimize reporting of RCT protocols

Nonregistration, discontinuation, and nonpublication of randomized trials: A repeated metaresearch analysis.

BackgroundWe previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs.Methods and findingsWe included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment. Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%). The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations.ConclusionsWe have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research