Transparency and reporting characteristics of COVID-19 randomized controlled trials.

BACKGROUND: In the context of the COVID-19 pandemic, randomized controlled trials (RCTs) are essential to support clinical decision-making. We aimed (1) to assess and compare the reporting characteristics of RCTs between preprints and peer-reviewed publications and (2) to assess whether reporting improves after the peer review process for all preprints subsequently published in peer-reviewed journals. METHODS: We searched the Cochrane COVID-19 Study Register and L·OVE COVID-19 platform to identify all reports of RCTs assessing pharmacological treatments of COVID-19, up to May 2021. We extracted indicators of transparency (e.g., trial registration, data sharing intentions) and assessed the completeness of reporting (i.e., some important CONSORT items, conflict of interest, ethical approval) using a standardized data extraction form. We also identified paired reports published in preprint and peer-reviewed publications. RESULTS: We identified 251 trial reports: 121 (48%) were first published in peer-reviewed journals, and 130 (52%) were first published as preprints. Transparency was poor. About half of trials were prospectively registered (n = 140, 56%); 38% (n = 95) made their full protocols available, and 29% (n = 72) provided access to their statistical analysis plan report. A data sharing statement was reported in 68% (n = 170) of the reports of which 91% stated their willingness to share. Completeness of reporting was low: only 32% (n = 81) of trials completely defined the pre-specified primary outcome measures; 57% (n = 143) reported the process of allocation concealment. Overall, 51% (n = 127) adequately reported the results for the primary outcomes while only 14% (n = 36) of trials adequately described harms. Primary outcome(s) reported in trial registries and published reports were inconsistent in 49% (n = 104) of trials; of them, only 15% (n = 16) disclosed outcome switching in the report. There were no major differences between preprints and peer-reviewed publications. Of the 130 RCTs published as preprints, 78 were subsequently published in a peer-reviewed journal. There was no major improvement after the journal peer review process for most items. CONCLUSIONS: Transparency, completeness, and consistency of reporting of COVID-19 clinical trials were insufficient both in preprints and peer-reviewed publications. A comparison of paired reports published in preprint and peer-reviewed publication did not indicate major improvement.

Registration and primary outcome reporting in behavioral health trials.

BACKGROUND: Registration of research studies is designed to lock investigators into a data collection and analysis plan before a study starts and thereby limit their ability to engage in flexible data analysis and selective outcome reporting. Studies of registered clinical trials show that one- to two-thirds are registered after the study has started and that non-adherence to important design and analytic features, such as reporting data pertaining to all primary outcomes, remains high. Less is known about the effects of registration on research transparency and integrity outside of clinical trials. To address this gap in knowledge, the current study examined the effects of registration on the reporting of research findings in a sample of behavioral health trials published in BMC Public Health. METHODS: Registered trials published in the BMC Public Health section "Health Behavior, Health Promotion and Society" between 2011 and 2015 were included in the study. For each trial, we reviewed associated online submissions from 13 different registration sites. For those determined to have been prospectively registered, we used the trial registry, MEDLINE (Pubmed), PsychINFO, Web of Science and e-mails to investigators to identify subsequent publications from the study that reported results pertaining to primary outcomes. The two investigators then independently reviewed the outcome publication(s) and compared the primary outcomes reported in these to the registered primary outcomes. RESULTS: The final analytic sample comprised 136 locatable, registered trials with an identifiable start date. Sixty-eight of the 136 were prospectively registered. Among these prospectively registered trials, only 16 published manuscripts reported outcomes and methods that were concordant with their registrations. CONCLUSIONS: Retrospective submission of protocols for publication and retrospective registration remain common in public health research, and adherence to prespecified outcomes is rare. In its current form, registration of behavioral and health promotion trials is likely to have minimal effect on preventing selective outcome reporting in publications, and the pervasiveness of vague and incomplete registry entries means that registries will have limited utility in terms of facilitating replication studies.

ROB-MEN: a tool to assess risk of bias due to missing evidence in network meta-analysis.

BACKGROUND: Selective outcome reporting and publication bias threaten the validity of systematic reviews and meta-analyses and can affect clinical decision-making. A rigorous method to evaluate the impact of this bias on the results of network meta-analyses of interventions is lacking. We present a tool to assess the Risk Of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN). METHODS: ROB-MEN first evaluates the risk of bias due to missing evidence for each of the possible pairwise comparison that can be made between the interventions in the network. This step considers possible bias due to the presence of studies with unavailable results (within-study assessment of bias) and the potential for unpublished studies (across-study assessment of bias). The second step combines the judgements about the risk of bias due to missing evidence in pairwise comparisons with (i) the contribution of direct comparisons to the network meta-analysis estimates, (ii) possible small-study effects evaluated by network meta-regression, and (iii) any bias from unobserved comparisons. Then, a level of "low risk", "some concerns", or "high risk" for the bias due to missing evidence is assigned to each estimate, which is our tool's final output. RESULTS: We describe the methodology of ROB-MEN step-by-step using an illustrative example from a published NMA of non-diagnostic modalities for the detection of coronary artery disease in patients with low risk acute coronary syndrome. We also report a full application of the tool on a larger and more complex published network of 18 drugs from head-to-head studies for the acute treatment of adults with major depressive disorder. CONCLUSIONS: ROB-MEN is the first tool for evaluating the risk of bias due to missing evidence in network meta-analysis and applies to networks of all sizes and geometry. The use of ROB-MEN is facilitated by an R Shiny web application that produces the Pairwise Comparisons and ROB-MEN Table and is incorporated in the reporting bias domain of the CINeMA framework and software.

Trial registration and selective outcome reporting in 585 clinical trials investigating drugs for prevention of postoperative nausea and vomiting.

BACKGROUND: Selective outcome reporting in clinical trials introduces bias in the body of evidence distorting clinical decision making. Trial registration aims to prevent this bias and is suggested by the International Committee of Medical Journal Editors (ICMJE) since 2004. METHODS: The 585 randomized controlled trials (RCTs) published between 1965 and 2017 that were included in a recently published Cochrane review on antiemetic drugs for prevention of postoperative nausea and vomiting were selected. In a retrospective study, we assessed trial registration and selective outcome reporting by comparing study publications with their registered protocols according to the 'Cochrane Risk of bias' assessment tool 1.0. RESULTS: In the Cochrane review, the first study which referred to a registered trial protocol was published in 2004. Of all 585 trials included in the Cochrane review, 334 RCTs were published in 2004 or later, of which only 22% (75/334) were registered. Among the registered trials, 36% (27/75) were pro- and 64% (48/75) were retrospectively registered. 41% (11/27) of the prospectively registered trials were free of selective outcome reporting bias, 22% (6/27) were incompletely registered and assessed as unclear risk, and 37% (10/27) were assessed as high risk. Major outcome discrepancies between registered and published high risk trials were a change from the registered primary to a published secondary outcome (32%), a new primary outcome (26%), and different outcome assessment times (26%). Among trials with high risk of selective outcome reporting 80% favoured at least one statistically significant result. Registered trials were assessed more often as 'overall low risk of bias' compared to non-registered trials (64% vs 28%). CONCLUSIONS: In 2017, 13 years after the ICMJE declared prospective protocol registration a necessity for reliable clinical studies, the frequency and quality of trial registration in the field of PONV is very poor. Selective outcome reporting reduces trustworthiness in findings of clinical trials. Investigators and clinicians should be aware that only following a properly registered protocol and transparently reporting of predefined outcomes, regardless of the direction and significance of the result, will ultimately strengthen the body of evidence in the field of PONV research in the future.

Trial registration and selective outcome reporting in Endodontic Research: Evidence over a 5-year period.

AIM: To assess the prevalence of registration of clinical trials in endodontic research and to identify outcome reporting discrepancies between trial registration entries and respective final publications. Associations with publication characteristics, such as journal, year of publication, origin, number of centres and authors, funding and statistical significance of the findings, were also sought. METHODOLOGY: All reports of endodontic randomized controlled trials (RCTs) published in 4 endodontic specialty and 4 general dental journals from 1 January 2016 to 31 December 2020 were identified. Trial registration frequency patterns were assessed for the included RCTs, whilst for the ones registered, outcome reporting discrepancies were recorded. Article characteristics such as year of publication, geographic region, number of centres, authors participating in the publication, funding, type of registration and others were identified. Descriptive statistics and univariable/multivariable logistic regression were performed to examine the effect of study characteristics on identified registration practices. RESULTS: One hundred and fifty-five RCTs were included, with the majority published in specialty journals (121/155; 78.1%). A total of 42.6% of the identified RCTs was registered (66/155), mostly retrospectively (38/66; 57.6%). There was strong evidence that each additional year for more recent publication accounted for 1.42 times higher odds of being registered (adjusted Odds Ratio = 1.42; 95%CI: 1.11, 1.80; p = .004). More than 1/3 of registered RCTs presented outcome reporting discrepancies (24/66; 36.4%), whilst such inconsistencies were almost evenly distributed between primary and secondary outcomes. CONCLUSIONS: Trial registration policies in endodontic research should be reviewed and active endorsement of prospective registration practices should be prioritized for better clarity and transparency of the disseminated research. Outcome reporting discrepancies shall thus be eliminated, offering increased credibility in research findings and eliminating bias in this respect.

Published intimate partner violence studies often differ from their trial registration records.

INTRODUCTION: Registering study protocols in a trial registry is important for methodologic transparency and reducing selective reporting bias. The objective of this investigation was to determine whether published studies of intimate partner violence (IPV) that had been registered matched the registration record on key study design elements. METHODS: We systematically searched three trial registries to identify registered IPV studies and the published literature for the associated publication. Two authors independently determined for each study whether key study elements in the registry matched those in the published paper. RESULTS: We included 66 studies published between 2006 and 2017. Nearly half (29/66, 44%) were registered after study completion. Many (26/66, 39%) had discrepancies regarding the primary outcome, and nearly two-thirds (42/66, 64%) had discrepancies in secondary outcomes. Discrepancies in study design were less frequent (13/66, 20%). However, large changes in sample size (26/66, 39%) and discrepancies in funding source (28/66, 42%) were frequently observed. CONCLUSIONS: Trial registries are important tools for research transparency and identifying and preventing outcome switching and selective outcome reporting bias. Published IPV studies often differ from their records in trial registries. Researchers should pay close attention to the accuracy of trial registry records.

Selective outcome reporting and sponsorship in randomized controlled trials in IVF and ICSI.

STUDY QUESTION: Are randomized controlled trials (RCTs) on IVF and ICSI subject to selective outcome reporting and is this related to sponsorship? SUMMARY ANSWER: There are inconsistencies, independent from sponsorship, in the reporting of primary outcome measures in the majority of IVF and ICSI trials, indicating selective outcome reporting. WHAT IS KNOWN ALREADY: RCTs are subject to bias at various levels. Of these biases, selective outcome reporting is particularly relevant to IVF and ICSI trials since there is a wide variety of outcome measures to choose from. An established cause of reporting bias is sponsorship. It is, at present, unknown whether RCTs in IVF/ICSI are subject to selective outcome reporting and whether this is related with sponsorship. STUDY DESIGN, SIZE, DURATION: We systematically searched RCTs on IVF and ICSI published between January 2009 and March 2016 in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the publisher subset of PubMed. We analysed 415 RCTs. PARTICIPANTS/MATERIALS, SETTING, METHODS: Per included RCT, we extracted data on impact factor of the journal, sample size, power calculation, and trial registry and thereafter data on primary outcome measure, the direction of trial results and sponsorship. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 415 identified RCTs, 235 were excluded for our primary analysis, because the sponsorship was not reported. Of the 180 RCTs included in our analysis, 7 trials did not report on any primary outcome measure and 107 of the remaining 173 trials (62%) reported on surrogate primary outcome measures. Of the 114 registered trials, 21 trials (18%) provided primary outcomes in their manuscript that were different from those in the trial registry. This indicates selective outcome reporting. We found no association between selective outcome reporting and sponsorship. We ran additional analyses to include the trials that had not reported sponsorship and found no outcomes that differed from our primary analysis. LIMITATIONS, REASONS FOR CAUTION: Since the majority of the trials did not report on sponsorship, there is a risk on sampling bias. WIDER IMPLICATIONS OF THE FINDINGS: IVF and ICSI trials are subject, to a large extent, to selective outcome reporting. Readers should be aware of this to avoid implementation of false or misleading results in clinical practice. STUDY FUNDING/COMPETING INTERESTS: No funding received and there are no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Selective outcome reporting in randomized clinical trials using the third molar surgery model.

Selective outcome reporting (SOR) can threaten the validity of results found in clinical trials. Some studies in the literature have analyzed SOR in dentistry, but there is no study that has observed SOR in clinical trials in oral and maxillofacial surgery. Impacted third molar surgery is one of the most used models in clinical trials to study mainly analgesic and anti-inflammatory drug interventions. Our study aimed to evaluate the prevalence of SOR in publications employing the third molar extraction clinical trial model, and to verify whether there was an association between the statistical significance of outcomes and other characteristics that could lead to SOR. A systematic search was performed on the ClinicialTrials.gov platform for randomized clinical trial protocols, using the condition of third molar extraction. The corresponding published articles were sourced in PubMed, Scopus, and Embase databases, and compared with the registered protocols regarding the methodological data, in terms of: sample calculation, primary outcome identification, end-point periods, insertion of new outcomes in the publication, and results of outcomes. 358 protocol records were retrieved; 87 presented their corresponding articles. SOR was identified in 28.74% of the publications, and had a significant relationship with changes in the protocol, insertions of new outcomes, and discrepancies in the types of study. General risk of bias was found to be low. There were associations between SOR and the discrepancies in terms of the type of study, the choice of new outcome, and changes in the history of protocol records. The prevalence of SOR in clinical research using the third molar extraction surgery model is moderate. The quality of the scientific reporting of the results and, consequently, the certainty of evidence relating to the intervention tested can be overstated, increasing the chances of misinterpretation by health professionals.

Misleading presentations in functional food trials led by contract research organizations were frequently observed in Japan: meta-epidemiological study.

OBJECTIVES: The functional food market has experienced significant growth, leading to an uptick in clinical trials conducted by contract research organizations (CROs). Research focusing on CRO-managed trials and the communication of trial outcomes to the consumer market remains underexplored. This metaepidemiological study aims to evaluate the quality of randomized controlled trials (RCTs) facilitated by prominent CROs in Japan and to examine the quality of the representations used to convey their results to consumers. STUDY DESIGN AND SETTING: This study focused on the food trials that were registered in the University Hospital Medical Information Network Clinical Trial Registry or the International Clinical Trials Registry Platform by the top 5 CROs. Press releases of study results or advertisements of food products based on the study results were identified by conducting a Google search. The risk of bias in the RCT publications was independently assessed by 2 reviewers, who also evaluated the presence of "spin" in the abstracts and full texts. An assessment of "spin" in press releases/advertisements was undertaken. RESULTS: A total of 76 RCT registrations, 32 RCT publications, and 11 press releases/advertisements were included. Approximately 72% of the RCT publications exhibited a high risk of bias due to selective outcome reporting. "Spin" was present in the results of the abstract (72%), abstract conclusion (81%), full-text results (44%), and full-text conclusion (84%). "Spin" appeared in 73% of press releases/advertisements due to the selective outcome reporting. CONCLUSION: Functional food presentations in Japan frequently contained "spin." The Japanese government should more rigorously check whether food manufacturers report outcomes selectively.

Selective outcome reporting in trials of behavioural health interventions in health psychology and behavioural medicine journals: a review.

Selective outcome reporting can result in overestimation of treatment effects, research waste, and reduced openness and transparency. This review aimed to examine selective outcome reporting in trials of behavioural health interventions and determine potential outcome reporting bias. A review of nine health psychology and behavioural medicine journals was conducted to identify randomised controlled trials of behavioural health interventions published since 2019. Discrepancies in outcome reporting were observed in 90% of the 29 trials with corresponding registrations/protocols. Discrepancies included 72% of trials omitting prespecified outcomes; 55% of trials introduced new outcomes. Thirty-eight percent of trials omitted prespecified and introduced new outcomes. Three trials (10%) downgraded primary outcomes in registrations/protocols to secondary outcomes in final reports; downgraded outcomes were not statistically significant in two trials. Five trials (17%) upgraded secondary outcomes to primary outcomes; upgraded outcomes were statistically significant in all trials. In final reports, three trials (7%) omitted outcomes from the methods section; three trials (7%) introduced new outcomes in results that were not in the methods. These findings indicate that selective outcome reporting is a problem in behavioural health intervention trials. Journal- and trialist-level approaches are needed to minimise selective outcome reporting in health psychology and behavioural medicine.

Selective outcome reporting in randomised controlled trials including participants with stroke or transient ischaemic attack: A systematic review.

INTRODUCTION: The prevalence of outcome reporting bias (ORB, i.e. selective reporting according to the results observed) across primary outcomes in randomised controlled trials (RCTs) including participants with stroke or transient ischaemic attack (TIA) is unknown. MATERIALS AND METHODS: We searched the Cochrane Database of Systematic Reviews on 3 February 2021 for reviews published 2008-2020 with at least one RCT of a therapeutic intervention, for participants with stroke or TIA, and a safety or efficacy outcome. We took a random sample of these RCTs and included those with a trial registry record or protocol published before reporting results. Two reviewers assessed discrepancies in outcome reporting across the trial registry record, protocol, statistical analysis plan, and publication for each RCT, using the classification system designed by the Outcome Reporting Bias in Trials group. RESULTS: Of 600 RCTs, we identified a trial registry record in 120 (20%), a protocol in 28 (5%), and a statistical analysis plan in 5 (1%) with 123 (21%) distinct RCTs being eligible for assessment: 110 (89%, 95% CI 83-94) were at no risk, 7 (6%, 95% CI 3-11) RCTs were at low risk, and 6 (5%, 95% CI 2-10) were at high risk of ORB. DISCUSSION: The prevalence of ORB in primary outcomes was low in stroke/TIA RCTs that were included in Cochrane reviews and had an identifiable trial registry record or protocol. Concerningly, we were unable to identify a trial registry record or protocol in most of our sample. CONCLUSION: Work is needed to further reduce ORB in stroke/TIA RCTs and explore the generalisability of these findings to RCTs outside of Cochrane reviews or without a registry record or protocol, as well as to secondary outcomes.

Selective outcome reporting across psychopharmacotherapy randomized controlled trials.

OBJECTIVE: Selective reporting impairs the valid interpretation of trials and leads to bias with regards to the clinical evidence. We aimed to examine factors associated with selective reporting in psychopharmacotherapy trials and thus enable solutions to prevent such selective reporting in the future. METHODS: We retrieved all registry records of trials investigating medication for depressive, bipolar and psychotic disorders. Multivariate logistic regression was performed with selective reporting as outcome, and funding source, psychiatric disorder, year of study start date, participating centers, and anticipated sample size as explanatory variables, after testing for multicollinearity. Adjusted odds ratios (AOR) were calculated. Two-sided Fisher exact test was used to compare the proportions of newly added positive primary outcomes with the proportions of positive results in the overall group of primary outcomes. RESULTS: Of 151 included trials (N = 94,303 participants), 21 (14%) showed irregularities between registered and published primary outcomes. Higher odds of such irregularities were associated with non-industry-funded RCTs (AOR 5.3; p = 0.014) and trials investigating major depressive disorder (AOR 12.7; p = 0.024) or schizophrenia (AOR 14.5; p = 0.016; Table 1). CONCLUSION: We demonstrate discrepancies between trial registrations and publications across RCTs investigating debilitating psychiatric disorders, especially in non-industry funded RCTs.

How prospective trial registration can prevent selective outcome reporting and salami slicing?

BACKGROUND: Pre-registration of a clinical trial before the first participant is recruited can help to prevent selective outcome reporting and salami-slicing that can distort the evidence base for an intervention and result in people being offered care or treatment that is not effective. Rates of clinical trial registration in nursing and midwifery are low. AIM: To use a hypothetical example from midwifery practice to illustrate how selective outcome reporting and salami-slicing can distort the evidence base. FINDINGS: A trial of immersion in water during labour and birth is used to consider issues in outcome selection and how researchers may be drawn to switch primary outcomes or report different outcomes across multiple papers. DISCUSSION: In nursing and midwifery science, selective outcome and salami reporting are seemingly common. Prospective trial registration is intended to prevent these practices, enhancing the quality and integrity of the work. CONCLUSION: Clinical trials are a robust form of primary research evidence and directly impact clinical practice. Researchers must ensure their trials are correctly registered and editors need to reconcile submitted papers and registration entries as part of the review process.

Around ten percent of most recent Cochrane reviews included outcomes in their literature search strategy and were associated with potentially exaggerated results: A research-on-research study.

OBJECTIVES: To assess the proportion of the recent Cochrane reviews that included outcomes in their literature search strategy, how often they acknowledged these limitations, and how qualitatively different the results of outcomes included and not included in the search strategy were. DESIGN AND SETTING: We identified all the Cochrane reviews of the interventions published in 2020 that used a search strategy connecting outcome terms with "AND." Reviews were defined as acknowledging the limitations of searching for outcomes if they mentioned them in the discussion. We compared the characteristics of outcomes included and not included in the search strategy. RESULTS: Of the 523 Cochrane reviews published in 2020, 51 (9.8%) included outcomes in their search strategy. Only one review acknowledged it as a limitation. Forty-seven (92%) assessed outcomes not included in the search strategy. Outcomes included in the search strategies tended to include a larger number of studies and show their effects in favor of the intervention. CONCLUSIONS: Around ten percent of the recent Cochrane reviews included outcomes in their search, which may have resulted in more outcomes significantly in favor of the intervention. Reviewers should be more explicit in acknowledging the potential implications of searching for outcomes.

The Campbell Collaboration's systematic review of school-based anti-bullying interventions does not meet mandatory methodological standards.

BACKGROUND: Many published reviews do not meet the widely accepted PRISMA standards for systematic reviews and meta-analysis. Campbell Collaboration and Cochrane reviews are expected to meet even more rigorous standards, but their adherence to these standards is uneven. For example, a newly updated Campbell systematic review of school-based anti-bullying interventions does not appear to meet many of the Campbell Collaboration's mandatory methodological standards. ISSUES: In this commentary, we document methodological problems in the Campbell Collaboration's new school-based anti-bullying interventions review, including (1) unexplained deviations from the protocol; (2) inadequate documentation of search strategies; (3) inconsistent reports on the number of included studies; (4) undocumented risk of bias ratings; (5) assessments of selective outcome reporting bias that are not transparent, not replicable, and appear to systematically underestimate risk of bias; (6) unreliable assessments of risk of publication bias; (7) use of a composite scale that conflates distinct risks of bias; and (8) failure to consider issues related to the strength of the evidence and risks of bias in interpreting results and drawing conclusions. Readers who are unaware of these problems may place more confidence in this review than is warranted. Campbell Collaboration editors declined to publish our comments and declined to issue a public statement of concern about this review. CONCLUSIONS: Systematic reviews are expected to use transparent methods and follow relevant methodological standards. Readers should be concerned when these expectations are not met, because transparency and rigor enhance the trustworthiness of results and conclusions. In the tradition of Donald T. Campbell, there is need for more public debate about the methods and conclusions of systematic reviews, and greater clarity regarding applications of (and adherence to) published standards for systematic reviews.

Evaluation of selective outcome reporting and trial registration practices among addiction clinical trials.

BACKGROUND AND AIMS: Selective outcome reporting occurs when trialists pre-specify primary and secondary outcomes during trial planning but alter the definitions in the published report. Here, we investigate selective outcome reporting in published addiction randomized controlled trials (RCTs) and evaluate whether particular funding sources are associated with an increased likelihood of selective outcome reporting. DESIGN: We conducted a cross-sectional study of published addiction clinical trials. A PubMed search was performed to identify RCTs in addiction journals from 2013 to 2017. Included studies used a randomized design to address one of the following topics: (1) drug, alcohol and tobacco addiction prevention, (2) stabilization following excessive use of a substance, (3) relapse prevention or (4) recovery maintenance. SETTING: Single-center, medical research institution. PARTICIPANTS: Our sample included 162 RCTs that were prospectively registered with a clearly defined primary outcome. MEASUREMENT: We extracted the following items from addiction RCTs: journal, funding source, trial registry number (if included), sample size, dates of subject enrollment, whether primary and secondary outcomes were denoted, all published outcomes, P-value for all outcomes and whether authors mentioned any deviations from the trial protocol as it related to RCT outcomes. FINDINGS: In total, 47 of 162 RCTs (29.0%) had at least one major discrepancy between the trial registry and published RCT. Overall, these 47 RCTs included 54 major discrepancies. The most common major discrepancy was demotion of a primary registered outcome (19/54, 35.2%). The majority of RCTs (132/162, 81.5%) were funded from public sources. Additionally, 166 RCTs were excluded from our sample because registration could not be confirmed. CONCLUSIONS: There is evidence suggestive of selective outcome reporting in addiction randomized controlled trials (RCTs). The most common major discrepancies pertained to the primary outcome.

Opportunities for selective reporting of harms in randomized clinical trials: Selection criteria for non-systematic adverse events.

BACKGROUND: Adverse events (AEs) in clinical trials may be reported in multiple sources. Different methods for reporting adverse events across trials or across sources for a single trial may produce inconsistent information about the adverse events associated with interventions. METHODS: We compared the methods authors use to decide which AEs to include in a particular source (i.e., "selection criteria"), including the number of different types of AEs reported (i.e., rather than the number of events). We compared sources (e.g., journal articles, clinical study reports (CSRs)) of trials for two drug-indications-gabapentin for neuropathic pain and quetiapine for bipolar depression. Electronic searches were completed in 2015. We identified selection criteria and assessed how criteria affected AE reporting. RESULTS: We identified 21 gabapentin and 7 quetiapine trials. We found 6 gabapentin CSRs and 2 quetiapine CSRs, all written by drug manufacturers. All CSRs reported all AEs without applying selection criteria; by comparison, no other source reported all AEs, and 15/68 (22%) gabapentin sources and 19/48 (40%) quetiapine sources reported using selection criteria. Selection criteria greatly affected the number of AEs reported. For example, 67/316 (21%) AEs in one quetiapine trial met the criterion "occurring in ≥2% of participants in any treatment group," while only 5/316 (2%) AEs met the criterion "occurring in ≥10% of quetiapine-treated patients and twice as frequent in the quetiapine group as the placebo group." CONCLUSIONS: Selection criteria for reporting AEs vary across trials and across sources for individual trials. If investigators do not pre-specify selection criteria, they might "cherry-pick" AEs based on results. Even if investigators pre-specify selection criteria, selective reporting will produce biased meta-analyses and clinical practice guidelines. Data about all AEs identified in clinical trials should be publicly available; however, sharing data will not solve all the problems identified in this study.

Influence of peer review on the reporting of primary outcome(s) and statistical analyses of randomised trials.

BACKGROUND: Selective reporting of outcomes in clinical trials is a serious problem. We aimed to investigate the influence of the peer review process within biomedical journals on reporting of primary outcome(s) and statistical analyses within reports of randomised trials. METHODS: Each month, PubMed (May 2014 to April 2015) was searched to identify primary reports of randomised trials published in six high-impact general and 12 high-impact specialty journals. The corresponding author of each trial was invited to complete an online survey asking authors about changes made to their manuscript as part of the peer review process. Our main outcomes were to assess: (1) the nature and extent of changes as part of the peer review process, in relation to reporting of the primary outcome(s) and/or primary statistical analysis; (2) how often authors followed these requests; and (3) whether this was related to specific journal or trial characteristics. RESULTS: Of 893 corresponding authors who were invited to take part in the online survey 258 (29%) responded. The majority of trials were multicentre (n = 191; 74%); median sample size 325 (IQR 138 to 1010). The primary outcome was clearly defined in 92% (n = 238), of which the direction of treatment effect was statistically significant in 49%. The majority responded (1-10 Likert scale) they were satisfied with the overall handling (mean 8.6, SD 1.5) and quality of peer review (mean 8.5, SD 1.5) of their manuscript. Only 3% (n = 8) said that the editor or peer reviewers had asked them to change or clarify the trial's primary outcome. However, 27% (n = 69) reported they were asked to change or clarify the statistical analysis of the primary outcome; most had fulfilled the request, the main motivation being to improve the statistical methods (n = 38; 55%) or avoid rejection (n = 30; 44%). Overall, there was little association between authors being asked to make this change and the type of journal, intervention, significance of the primary outcome, or funding source. Thirty-six percent (n = 94) of authors had been asked to include additional analyses that had not been included in the original manuscript; in 77% (n = 72) these were not pre-specified in the protocol. Twenty-three percent (n = 60) had been asked to modify their overall conclusion, usually (n = 53; 88%) to provide a more cautious conclusion. CONCLUSION: Overall, most changes, as a result of the peer review process, resulted in improvements to the published manuscript; there was little evidence of a negative impact in terms of post hoc changes of the primary outcome. However, some suggested changes might be considered inappropriate, such as unplanned additional analyses, and should be discouraged.

Outcome pre-specification requires sufficient detail to guard against outcome switching in clinical trials: a case study.

BACKGROUND: Pre-specification of outcomes is an important tool to guard against outcome switching in clinical trials. However, if the outcome is not sufficiently clearly defined, then different definitions could be applied and analysed, with only the most favourable result reported. METHODS: In order to assess the impact that differing outcome definitions could have on treatment effect estimates, we re-analysed data from TRIGGER, a cluster randomised trial comparing two red blood cell transfusion strategies for patients with acute upper gastrointestinal bleeding. We varied several aspects of the definition of further bleeding: (1) the criteria for what constitutes a further bleeding episode; (2) how further bleeding is assessed; and (3) the time-point at which further bleeding is measured. RESULTS: There were marked discrepancies in the estimated odds ratios (OR) (range 0.23-0.94) and corresponding P values (range < 0.001-0.89) between different outcome definitions. At the extremes, differing outcome definitions led to markedly different conclusions; one definition led to very little evidence of a treatment effect (OR = 0.94, 95% confidence interval [CI] = 0.37-2.40, P = 0.89), while another led to very strong evidence of a treatment effect (OR = 0.23, 95% CI = 0.11-0.50, P < 0.001). CONCLUSIONS: Outcomes should be pre-specified in sufficient detail to avoid differing definitions being analysed and only the most favourable result being reported. TRIAL REGISTRATION: Clinical Trials.gov, NCT02105532 . Registered on 7 April 2014.

Making protocols available with the article improved evaluation of selective outcome reporting.

OBJECTIVE: To compare primary outcomes reported in publications, protocols and registries and to evaluate the contribution of available protocols to assess selective outcome reporting (SOR) as compared with registration alone. STUDY DESIGN AND SETTING: We included all randomized controlled trials (RCTs) published in 2015 and 2016 in the five leading general medical journals. For each RCT, we evaluated whether the protocol was available and searched for registration. We extracted all primary outcomes reported in publications, registries, and protocols. We evaluated whether SOR was suspected (i.e., at least one discrepancy in primary outcomes), unclear, or not suspected based on comparisons of publications and (1) trial registration alone or (2) protocols in addition to registration. RESULTS: Selective outcome reporting was suspected for 77/274 (28.1%), unclear for 30 (10.9%), and not suspected for 167 (60.9%) when comparing publications and trial registration alone. With protocols available, the classification changed for 38 RCTs (13.9%): 11 not suspected of SOR based on registration became suspected of SOR with protocols available, and 27 with unclear assessment based on registration became suspected of SOR (n = 7) and not suspected of SOR (n = 20) with protocols available. CONCLUSIONS: Compared to registration alone, making protocols available allows for a more precise evaluation of SOR.