Dataset Information

Comparison of primary endpoints between publications, registries, and protocols of phase III cancer clinical trials.

ABSTRACT:

Background

Decisions by leading journals to require trial registration and to make protocols of phase III randomized clinical trials (RCTs) publicly accessible were landmark events in clinical trial reporting.

Materials and methods

We identified phase III cancer RCTs published between 2013 and 2015 in New England Journal of Medicine (NEJM), The Lancet, The lancet Oncology, JAMA and Journal of Clinical Oncology (JCO).

Results

We identified 345 reports of phase III RCTs of which 217 (62.9%) had available protocols. The availability rates for NEJM, The Lancet, The Lancet Oncology, JAMA and JCO were 98.0%, 33.3%, 22.7%, 55.6% and 88.3%, respectively. Journal and publication year were significantly associated with protocol availability. Eight of 215 trials (3.7%) with English language protocols had a discrepancy in primary endpoints between publication and protocol. Discrepancies of primary endpoints between protocol and registration existed in 16 (7.7%) of 209 trials.

Conclusions

The policy of providing protocols with articles reporting RCTs has not been enforced rigorously. Selective reporting of primary endpoints only remains in a small fraction of phase III trials. Further improvement in consistency between primary endpoints registered and that in protocol is necessary.

SUBMITTER: Liang F

PROVIDER: S-EPMC5722592 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Publications

Comparison of primary endpoints between publications, registries, and protocols of phase III cancer clinical trials.

Liang Fei F Guo Xinmei X Zhang Sheng S Xue Hongxi H Chen Qiang Q Hu Xichun X

Oncotarget 20171003 57

<h4>Background</h4>Decisions by leading journals to require trial registration and to make protocols of phase III randomized clinical trials (RCTs) publicly accessible were landmark events in clinical trial reporting.<h4>Materials and methods</h4>We identified phase III cancer RCTs published between 2013 and 2015 in New England Journal of Medicine (<i>NEJM</i>), The Lancet, The lancet Oncology, <i>JAMA</i> and Journal of Clinical Oncology (JCO).<h4>Results</h4>We identified 345 reports of phase ...[more]

PMID: 29228640

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Project description:Objectives: We aimed to study the prevalence of selective reporting of primary and secondary outcomes in tinnitus trials and to examine if selective reporting of outcome measures is influenced by the nature and direction of its results. Background: Selective reporting of outcome measures has been reported in several biomedical fields and can influence the clinical usefulness and implementation of outcomes of clinical trials. It is reported as one of the obstacles in finding an effective intervention for tinnitus. Methods: ClinicalTrials.gov (CT.gov) was used to identify all registered interventional tinnitus trials up to December 2015. A standardized search was used to find corresponding publications up to March 2018. The prespecified outcomes in CT.gov were compared with the outcomes reported in corresponding publication(s). The effects of the (lack of) statistical significance of trial results and the effects of funding source on record adherence were evaluated. Changes in registration elements were assessed with the Archive site of CT.gov. Results: We found corresponding publications for 60 (64.5%) of 93 eligible tinnitus trials registered in CT.gov. Of all the publications, five (7.5%) fully reported outcome measures entirely in line with the prespecified outcome measures. Discrepancies between the prespecified and reported outcomes were found in a total of 51 (76.1%) of the studies for primary outcomes, whereas 62 (92.5%) of the studies had discrepancies in secondary outcomes. In secondary outcomes, statistical significance of trial results influenced CT.gov record adherence. In addition, there was a statistically significant difference in the rate of discrepancy in industry-funded [n = 98 (87.5%) discrepant outcomes] and non-industry funded trials [n = 172 (74.5%) discrepant outcomes] (p = 0.01). Finally, 15 (25.9%) trialists made modifications in registered outcome measures during or after the trial period. Conclusion: Tinnitus trials suffer from substantial outcome reporting bias. Awareness of its presence must be raised to limit the obstacles of finding an effective intervention for tinnitus.

Project description:ImportanceClinical trial registries are intended to increase clinical research transparency by nonselectively identifying and documenting clinical trial designs and outcomes. Inconsistencies in reported data undermine the utility of such registries and have previously been noted in general medical literature.ObjectiveTo assess whether inconsistencies in reported data exist between ophthalmic literature and clinical trial registries.Design, setting, and participantsIn this retrospective, cross-sectional study, interventional clinical trials published from January 1, 2014, to December 31, 2014, in the American Journal of Ophthalmology, JAMA Ophthalmology, and Ophthalmology were reviewed. Observational, retrospective, uncontrolled, and post hoc reports were excluded, yielding a sample size of 106 articles. Data collection was performed from January through September 2016. Data review and adjudication continued through January 2017.Main outcomes and measuresIf possible, articles were matched to registry entries listed in the ClinicalTrials.gov database or in 1 of 16 international registries indexed by the World Health Organization International Clinical Trials Registry Platform version 3.2 search engine. Each article-registry pair was assessed for inconsistencies in design, results, and funding (each of which was further divided into subcategories) by 2 reviewers and adjudicated by a third.ResultsOf 106 trials that met the study criteria, matching registry entries were found for 68 (64.2%), whereas no matching registry entries were found for 38 (35.8%). Inconsistencies were identified in study design, study results, and funding sources, including specific interventions in 8 (11.8%), primary outcome measure (POM) designs in 32 (47.1%), and POM results in 48 (70.6%). In addition, numerous data pieces were unreported, including analysis methods in 52 (76.5%) and POM results in 38 (55.9%).Conclusions and relevanceClinical trial registries were underused in this sample of ophthalmology clinical trials. For studies with registry data, inconsistency rates between published and registered data were similar to those previously reported for general medical literature. In most cases, inconsistencies involved missing data, but explicit discrepancies in methods and/or data were also found. Transparency and credibility of published trials may be improved by closer attention to their registration and reporting.

Project description:BackgroundLittle is known about publication agreements between industry and academic investigators in trial protocols and the consistency of these agreements with corresponding statements in publications. We aimed to investigate (i) the existence and types of publication agreements in trial protocols, (ii) the completeness and consistency of the reporting of these agreements in subsequent publications, and (iii) the frequency of co-authorship by industry employees.Methods and findingsWe used a retrospective cohort of randomized clinical trials (RCTs) based on archived protocols approved by six research ethics committees between 13 January 2000 and 25 November 2003. Only RCTs with industry involvement were eligible. We investigated the documentation of publication agreements in RCT protocols and statements in corresponding journal publications. Of 647 eligible RCT protocols, 456 (70.5%) mentioned an agreement regarding publication of results. Of these 456, 393 (86.2%) documented an industry partner's right to disapprove or at least review proposed manuscripts; 39 (8.6%) agreements were without constraints of publication. The remaining 24 (5.3%) protocols referred to separate agreement documents not accessible to us. Of those 432 protocols with an accessible publication agreement, 268 (62.0%) trials were published. Most agreements documented in the protocol were not reported in the subsequent publication (197/268 [73.5%]). Of 71 agreements reported in publications, 52 (73.2%) were concordant with those documented in the protocol. In 14 of 37 (37.8%) publications in which statements suggested unrestricted publication rights, at least one co-author was an industry employee. In 25 protocol-publication pairs, author statements in publications suggested no constraints, but 18 corresponding protocols documented restricting agreements.ConclusionsPublication agreements constraining academic authors' independence are common. Journal articles seldom report on publication agreements, and, if they do, statements can be discrepant with the trial protocol.

Project description:ObjectiveTo determine, using research on duloxetine for major depressive disorder as an example, if there are inconsistencies between protocols, clinical study reports, and main publicly available sources (journal articles and trial registries), and within clinical study reports themselves, with respect to benefits and major harms.DesignData on primary efficacy analysis and major harms extracted from each data source and compared.SettingNine randomised placebo controlled trials of duloxetine (total 2878 patients) submitted to the European Medicines Agency (EMA) for marketing approval for major depressive disorder.Data sourcesClinical study reports, including protocols as appendices (total 13,729 pages), were obtained from the EMA in May 2011. Journal articles were identified through relevant literature databases and contacting the manufacturer, Eli Lilly. Clinicaltrials.gov and the manufacturer's online clinical trial registry were searched for trial results.ResultsClinical study reports fully described the primary efficacy analysis and major harms (deaths (including suicides), suicide attempts, serious adverse events, and discontinuations because of adverse events). There were minor inconsistencies in the population in the primary efficacy analysis between the protocol and clinical study report and within the clinical study report for one trial. Furthermore, we found contradictory information within the reports for seven serious adverse events and eight adverse events that led to discontinuation but with no apparent bias. In each trial, a median of 406 (range 177-645) and 166 (100-241) treatment emergent adverse events (adverse events that emerged or worsened after study drug was started) in the randomised phase were not reported in journal articles and Lilly trial registry reports, respectively. We also found publication bias in relation to beneficial effects.ConclusionClinical study reports contained extensive data on major harms that were unavailable in journal articles and in trial registry reports. There were inconsistencies between protocols and clinical study reports and within clinical study reports. Clinical study reports should be used as the data source for systematic reviews of drugs, but they should first be checked against protocols and within themselves for accuracy and consistency.

Project description:BackgroundGiven the inherent challenges of conducting randomized phase III trials in older cancer patients, single-arm phase II trials which assess the feasibility of a treatment that has already been shown to be effective in a younger population may provide a compelling alternative. Such an approach would need to evaluate treatment feasibility based on a composite endpoint that combines multiple clinical dimensions and to stratify older patients as fit or frail to account for the heterogeneity of the study population to recommend an appropriate treatment approach. In this context, stratified adaptive two-stage designs for binary or composite endpoints, initially developed for biomarker studies, allow to include two subgroups whilst maintaining competitive statistical performances. In practice, heterogeneity may indeed affect more than one dimension and incorporating co-primary endpoints, which independently assess each individual clinical dimension, would therefore appear quite pertinent. The current paper presents a novel phase II design for co-primary endpoints which takes into account the heterogeneity of a population. METHODS: We developed a stratified adaptive Bryant & Day design based on the Jones et al. and Parashar et al. algorithm. This two-stage design allows to jointly assess two dimensions (e.g. activity and toxicity) in two different subgroups. The operating characteristics of this new design were evaluated using examples and simulation comparisons with the Bryant & Day design in the context where the study population is stratified according to a pre-defined criterion.ResultsSimulation results demonstrated that the new design minimized the expected and maximum sample sizes as compared to parallel Bryant & Day designs (one in each subgroup), whilst controlling type I error rates and maintaining a competitive statistical power as well as a high probability of detecting heterogeneity.ConclusionsIn a heterogeneous population, this two-stage stratified adaptive phase II design provides a useful alternative to classical one and allows to identify a subgroup of interest without dramatically increasing sample size. As heterogeneity is not limited to older populations, this new design may also be relevant to other study populations such as children or adolescents and young adults or the development of targeted therapies based on a biomarker.

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Dataset Information

Comparison of primary endpoints between publications, registries, and protocols of phase III cancer clinical trials.

Background

Materials and methods

Results

Conclusions

Publications

Comparison of primary endpoints between publications, registries, and protocols of phase III cancer clinical trials.

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