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1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up.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 One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered.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.

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 reporting. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:523-544.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Long-term outcomes in syncope patients presenting to the emergency department: A systematic review.

INTRODUCTION: Long-term outcomes among syncope patients are not well studied to guide physicians regarding outpatient testing and follow-up. The objective of this study was to conduct a systematic review for outcomes at 1-year or later among ED syncope patients. METHODS: We searched Cochrane Central, Medline, Medline in Process, PubMed, Embase, and the Cumulative Index to Nursing databases from inception to December 2018. We included studies that reported long-term outcomes among ED syncope patients. We excluded studies on patients <16 years old, studies that included syncope mimickers (pre-syncope, seizure, intoxication, loss of consciousness after head trauma), case reports, letters to the editor, non-English and review articles. Outcomes included death, syncope recurrence requiring hospitalization, arrhythmias and procedural interventions for arrhythmias. Meta-analysis was performed by pooling the outcomes using random effects model. RESULTS: Initial literature search generated 2,094 articles duplicate removal. Of the 50 articles selected for full-text review, 19 articles with 98,211 patients were included in this review: of which 12 were included in the 1-year outcome meta-analysis. Pooled analysis showed : 7.0% mortality; 16.0% syncope recurrence requiring hospitalization; 6.0% with device insertion. 1-year arrhythmias reported in two studies were 1.1 and 26.4%. Pooled analysis for outcome at 31 to 365 days showed: 5.0% mortality and 1% device insertion. Two studies reported 4.9% and 21% mortality at 30 months and 4.2 years follow-up. CONCLUSIONS: An important proportion of ED syncope patients suffer long-term morbidity and mortality. Appropriate follow-up is needed and future research to identify patients at risk is needed.

Systematic review of patient-oriented interventions to reduce unnecessary use of antibiotics for upper respiratory tract infections.

BACKGROUND: Antibiotics are prescribed frequently for upper respiratory tract infections (URTIs) even though most URTIs do not require antibiotics. This over-prescription contributes to antibiotic resistance which is a major health problem globally. As physicians' prescribing behaviour is influenced by patients' expectations, there may be some opportunities to reduce antibiotic prescribing using patient-oriented interventions. We aimed to identify these interventions and to understand which ones are more effective in reducing unnecessary use of antibiotics for URTIs. METHODS: We conducted a systematic review by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), EMBASE (OVID), CINAHL, and the Web of Science. We included English language randomized controlled trials (RCTs), quasi-RCTs, controlled before and after studies, and interrupted time series (ITS) studies. Two authors screened the abstract/titles and full texts, extracted data, and assessed study risk of bias. Where pooling was appropriate, a meta-analysis was performed by using a random-effects model. Where pooling of the data was not possible, a narrative synthesis of results was conducted. RESULTS: We included 13 studies (one ITS, one cluster RCTs, and eleven RCTs). All interventions could be classified into two major categories: delayed prescriptions (seven studies) and patient/public information and education interventions (six studies). Our meta-analysis of delayed prescription studies observed significant reductions in the use of antibiotics for URTIs (OR = 0.09, CI 0.03 to 0.23; six studies). A subgroup analysis showed that prescriptions that were given at a later time and prescriptions that were given at the index consultation had similar effects. The studies in the patient/public information and education group varied according to their methods of delivery. Since only one or two studies were included for each method, we could not make a definite conclusion on their effectiveness. In general, booklets or pamphlets demonstrated promising effects on antibiotic prescription, if discussed by a practitioner. CONCLUSIONS: Patient-oriented interventions (especially delayed prescriptions) may be effective in reducing antibiotic prescription for URTIs. Further research is needed to investigate the costs and feasibility of implementing these interventions as part of routine clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016048007.

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.

Evaluating Progression-Free Survival as a Surrogate Outcome for Health-Related Quality of Life in Oncology: A Systematic Review and Quantitative Analysis.

Importance: Progression-free survival (PFS) has become a commonly used outcome to assess the efficacy of new cancer drugs. However, it is not clear if delay in progression leads to improved quality of life with or without overall survival benefit. Objective: To evaluate the association between PFS and health-related quality of life (HRQoL) in oncology through a systematic review and quantitative analysis of published randomized clinical trials. Eligible trials addressed oral, intravenous, intraperitoneal, or intrapleural chemotherapy or biological treatments, and reported PFS or health-related quality of life. Data Sources: For this systematic review and quantitative analysis of randomized clinical trials of patients with cancer, we searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from January 1, 2000, through May 4, 2016. Study Selection: Paired reviewers independently screened citations, extracted data, and assessed risk of bias of included studies. Data Extraction and Synthesis: We examined the association of difference in median PFS duration (in months) between treatment groups with difference in global, physical, and emotional HRQoL scores between groups (standardized to a range of 0-100, with higher scores representing better HRQoL) using weighted simple regressions. Main Outcome and Measure: The association between PFS duration and HRQoL. Results: Of 35 960 records screened, 52 articles reporting on 38 randomized clinical trials involving 13 979 patients across 12 cancer types using 6 different HRQoL instruments were included. The mean (SD) difference in median PFS between the intervention and the control arms was 1.91 (3.35) months. The mean (SD) differences in change of HRQoL adjusted to per-month values were -0.39 (3.59) for the global domain, 0.26 (5.56) for the physical domain, and 1.08 (3.49) for the emotional domain. The slope of the association between the difference in median PFS and the difference in change for global HRQoL (n = 30 trials) was 0.12 (95% CI, -0.27 to 0.52); for physical HRQoL (n = 20 trials) it was -0.20 (95% CI, -0.62 to 0.23); and for emotional HRQoL (n = 13 trials) it was 0.78 (95% CI, -0.05 to 1.60). Conclusions and Relevance: We failed to find a significant association between PFS and HRQoL in cancer clinical trials. These findings raise questions regarding the assumption that interventions prolonging PFS also improve HRQoL in patients with cancer. Therefore, to ensure that patients are truly obtaining important benefit from cancer therapies, clinical trial investigators should measure HRQoL directly and accurately, ensuring adequate duration and follow-up.