Blog
About

44
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Timing and Completeness of Trial Results Posted at ClinicalTrials.gov and Published in Journals

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Agnes Dechartres and colleagues searched ClinicalTrials.gov for completed drug RCTs with results reported and then searched for corresponding studies in PubMed to evaluate timeliness and completeness of reporting.

          Please see later in the article for the Editors' Summary

          Abstract

          Background

          The US Food and Drug Administration Amendments Act requires results from clinical trials of Food and Drug Administration–approved drugs to be posted at ClinicalTrials.gov within 1 y after trial completion. We compared the timing and completeness of results of drug trials posted at ClinicalTrials.gov and published in journals.

          Methods and Findings

          We searched ClinicalTrials.gov on March 27, 2012, for randomized controlled trials of drugs with posted results. For a random sample of these trials, we searched PubMed for corresponding publications. Data were extracted independently from ClinicalTrials.gov and from the published articles for trials with results both posted and published. We assessed the time to first public posting or publishing of results and compared the completeness of results posted at ClinicalTrials.gov versus published in journal articles. Completeness was defined as the reporting of all key elements, according to three experts, for the flow of participants, efficacy results, adverse events, and serious adverse events (e.g., for adverse events, reporting of the number of adverse events per arm, without restriction to statistically significant differences between arms for all randomized patients or for those who received at least one treatment dose).

          From the 600 trials with results posted at ClinicalTrials.gov, we randomly sampled 50% ( n = 297) had no corresponding published article. For trials with both posted and published results ( n = 202), the median time between primary completion date and first results publicly posted was 19 mo (first quartile = 14, third quartile = 30 mo), and the median time between primary completion date and journal publication was 21 mo (first quartile = 14, third quartile = 28 mo). Reporting was significantly more complete at ClinicalTrials.gov than in the published article for the flow of participants (64% versus 48% of trials, p<0.001), efficacy results (79% versus 69%, p = 0.02), adverse events (73% versus 45%, p<0.001), and serious adverse events (99% versus 63%, p<0.001).

          The main study limitation was that we considered only the publication describing the results for the primary outcomes.

          Conclusions

          Our results highlight the need to search ClinicalTrials.gov for both unpublished and published trials. Trial results, especially serious adverse events, are more completely reported at ClinicalTrials.gov than in the published article.

          Please see later in the article for the Editors' Summary

          Editors' Summary

          Background

          When patients consult a doctor, they expect to be recommended what their doctor believes is the most effective treatment with the fewest adverse effects. To determine which treatment to recommend, clinicians rely on sources that include research studies. Among studies, the best evidence is generally agreed to come from systematic reviews and randomized controlled clinical trials (RCTs), studies that test the efficacy and safety of medical interventions by comparing clinical outcomes in groups of patients randomly chosen to receive different interventions. Decision-making based on the best available evidence is called evidence-based medicine. However, evidence-based medicine can only guide clinicians if trial results are published in a timely and complete manner. Unfortunately, underreporting of trials is common. For example, an RCT in which a new drug performs better than existing drugs is more likely to be published than one in which the new drug performs badly or has unwanted adverse effects (publication bias). There can also be a delay in publishing the results of negative trials (time-lag bias) or a failure to publish complete results for all the prespecified outcomes of a trial (reporting bias). All three types of bias threaten informed medical decision-making and the health of patients.

          Why Was This Study Done?

          One initiative that aims to prevent these biases was included in the 2007 US Food and Drug Administration Amendments Act (FDAAA). The Food and Drug Administration (FDA) is responsible for approving drugs and devices that are marketed in the US. The FDAAA requires that results from clinical trials of FDA-approved drugs and devices conducted in the United States be made publicly available at ClinicalTrials.gov within one year of trial completion. ClinicalTrials.gov—a web-based registry that includes US and international clinical trials—was established in 2000 in response to the 1997 FDA Modernization Act, which required mandatory registration of trial titles and designs and of the conditions and interventions under study. The FDAAA expanded these mandatory requirements by requiring researchers studying FDA-approved drugs and devices to report additional information such as the baseline characteristics of the participants in each arm of the trial and the results of primary and secondary outcome measures (the effects of the intervention on predefined clinical measurements) and their statistical significance (an indication of whether differences in outcomes might have happened by chance). Researchers of other trials registered in ClinicalTrials.gov are welcome to post trial results as well. Here, the researchers compare the timing and completeness (i.e., whether all relevant information was fully reported) of results of drug trials posted at ClinicalTrials.gov with those published in medical journals.

          What Did the Researchers Do and Find?

          The researchers searched ClinicalTrials.gov for reports of completed phase III and IV (late-stage) RCTs of drugs with posted results. For a random sample of 600 eligible trials, they searched PubMed (a database of biomedical publications) for corresponding publications. Only 50% of trials with results posted at ClinicalTrials.gov had a matching published article. For 202 trials with both posted and published results, the researchers compared the timing and completeness of the results posted at ClinicalTrials.gov and of results reported in the corresponding journal publication. The median time between the study completion date and the first results being publicly posted at ClinicalTrials.gov was 19 months, whereas the time between completion and publication in a journal was 21 months. The flow of participants through trials was completely reported in 64% of the ClinicalTrials.gov postings but in only 48% of the corresponding publications. Results for the primary outcome measure were completely reported in 79% and 69% of the ClinicalTrials.gov postings and corresponding publications, respectively. Finally, adverse events were completely reported in 73% of the ClinicalTrials.gov postings but in only 45% of the corresponding publications, and serious adverse events were reported in 99% and 63% of the ClinicalTrials.gov postings and corresponding publications, respectively.

          What Do These Findings Mean?

          These findings suggest that the reporting of trial results is significantly more complete at ClinicalTrials.gov than in published journal articles reporting the main trial results. Certain aspects of this study may affect the accuracy of this conclusion. For example, the researchers compared the results posted at ClinicalTrials.gov only with the results in the publication that described the primary outcome of each trial, even though some trials had multiple publications. Importantly, these findings suggest that, to enable patients and physicians to make informed treatment decisions, experts undertaking assessments of drugs should consider seeking efficacy and safety data posted at ClinicalTrials.gov, both for trials whose results are not published yet and for trials whose results are published. Moreover, they suggest that the use of templates to guide standardized reporting of trial results in journals and broader mandatory posting of results may help to improve the reporting and transparency of clinical trials and, consequently, the evidence available to inform treatment of patients.

          Additional Information

          Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001566.

          Related collections

          Most cited references 22

          • Record: found
          • Abstract: found
          • Article: not found

          CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials.

          The CONSORT (Consolidated Standards of Reporting Trials) statement is used worldwide to improve the reporting of randomized, controlled trials. Schulz and colleagues describe the latest version, CONSORT 2010, which updates the reporting guideline based on new methodological evidence and accumulating experience.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Identifying outcome reporting bias in randomised trials on PubMed: review of publications and survey of authors.

            To examine the extent and nature of outcome reporting bias in a broad cohort of published randomised trials. Retrospective review of publications and follow up survey of authors. Cohort All journal articles of randomised trials indexed in PubMed whose primary publication appeared in December 2000. Prevalence of incompletely reported outcomes per trial; reasons for not reporting outcomes; association between completeness of reporting and statistical significance. 519 trials with 553 publications and 10,557 outcomes were identified. Survey responders (response rate 69%) provided information on unreported outcomes but were often unreliable--for 32% of those who denied the existence of such outcomes there was evidence to the contrary in their publications. On average, over 20% of the outcomes measured in a parallel group trial were incompletely reported. Within a trial, such outcomes had a higher odds of being statistically non-significant compared with fully reported outcomes (odds ratio 2.0 (95% confidence interval 1.6 to 2.7) for efficacy outcomes; 1.9 (1.1 to 3.5) for harm outcomes). The most commonly reported reasons for omitting efficacy outcomes included space constraints, lack of clinical importance, and lack of statistical significance. Incomplete reporting of outcomes within published articles of randomised trials is common and is associated with statistical non-significance. The medical literature therefore represents a selective and biased subset of study outcomes, and trial protocols should be made publicly available.
              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              Bias in location and selection of studies.

                Bookmark

                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                PLoS
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                December 2013
                December 2013
                3 December 2013
                : 10
                : 12
                Affiliations
                [1 ]INSERM U738, Paris, France
                [2 ]Université Paris Descartes—Sorbonne Paris Cité, Paris, France
                [3 ]Centre d'Épidémiologie Clinique, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France
                [4 ]French Cochrane Centre, Paris, France
                [5 ]Mailman School of Public Health, Columbia University, New York, New York, United States of America
                Center for Clinical Trials, United States of America
                Author notes

                IB is a member of the Editorial Board of PLOS Medicine. All other authors have declared that no competing interests exist.

                Conceived and designed the experiments: AD IB PR. Performed the experiments: CR RH. Analyzed the data: CR AD EP. Contributed reagents/materials/analysis tools: CR AD EP. Wrote the first draft of the manuscript: CR AD. Contributed to the writing of the manuscript: CR AD EP RH IB PR. ICMJE criteria for authorship read and met: CR AD EP RH IB PR. Agree with manuscript results and conclusions: CR AD EP RH IB PR.

                Article
                PMEDICINE-D-13-01170
                10.1371/journal.pmed.1001566
                3849189
                24311990

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 12
                Funding
                Our team is supported by Grant No. DEQ20101221475, academic grant, program “Equipe espoir de la Recherche”, Fondation pour la Recherche Médicale (FRM), Paris, France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article

                Medicine

                Comments

                Comment on this article