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      The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta‐analyses

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          Abstract

          Policy Points:

          • Currently, there is massive production of unnecessary, misleading, and conflicted systematic reviews and meta‐analyses. Instead of promoting evidence‐based medicine and health care, these instruments often serve mostly as easily produced publishable units or marketing tools.

          • Suboptimal systematic reviews and meta‐analyses can be harmful given the major prestige and influence these types of studies have acquired.

          • The publication of systematic reviews and meta‐analyses should be realigned to remove biases and vested interests and to integrate them better with the primary production of evidence.

          Context

          Currently, most systematic reviews and meta‐analyses are done retrospectively with fragmented published information. This article aims to explore the growth of published systematic reviews and meta‐analyses and to estimate how often they are redundant, misleading, or serving conflicted interests.

          Methods

          Data included information from PubMed surveys and from empirical evaluations of meta‐analyses.

          Findings

          Publication of systematic reviews and meta‐analyses has increased rapidly. In the period January 1, 1986, to December 4, 2015, PubMed tags 266,782 items as “systematic reviews” and 58,611 as “meta‐analyses.” Annual publications between 1991 and 2014 increased 2,728% for systematic reviews and 2,635% for meta‐analyses versus only 153% for all PubMed‐indexed items. Currently, probably more systematic reviews of trials than new randomized trials are published annually. Most topics addressed by meta‐analyses of randomized trials have overlapping, redundant meta‐analyses; same‐topic meta‐analyses may exceed 20 sometimes. Some fields produce massive numbers of meta‐analyses; for example, 185 meta‐analyses of antidepressants for depression were published between 2007 and 2014. These meta‐analyses are often produced either by industry employees or by authors with industry ties and results are aligned with sponsor interests. China has rapidly become the most prolific producer of English‐language, PubMed‐indexed meta‐analyses. The most massive presence of Chinese meta‐analyses is on genetic associations (63% of global production in 2014), where almost all results are misleading since they combine fragmented information from mostly abandoned era of candidate genes. Furthermore, many contracting companies working on evidence synthesis receive industry contracts to produce meta‐analyses, many of which probably remain unpublished. Many other meta‐analyses have serious flaws. Of the remaining, most have weak or insufficient evidence to inform decision making. Few systematic reviews and meta‐analyses are both non‐misleading and useful.

          Conclusions

          The production of systematic reviews and meta‐analyses has reached epidemic proportions. Possibly, the large majority of produced systematic reviews and meta‐analyses are unnecessary, misleading, and/or conflicted.

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          Most cited references70

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          The nuts and bolts of PROSPERO: an international prospective register of systematic reviews

          Background Following publication of the PRISMA statement, the UK Centre for Reviews and Dissemination (CRD) at the University of York in England began to develop an international prospective register of systematic reviews with health-related outcomes. The objectives were to reduce unplanned duplication of reviews and provide transparency in the review process, with the aim of minimizing reporting bias. Methods An international advisory group was formed and a consultation undertaken to establish the key items necessary for inclusion in the register and to gather views on various aspects of functionality. This article describes the development of the register, now called PROSPERO, and the process of registration. Results PROSPERO offers free registration and free public access to a unique prospective register of systematic reviews across all areas of health from all around the world. The dedicated web-based interface is electronically searchable and available to all prospective registrants. At the moment, inclusion in PROSPERO is restricted to systematic reviews of the effects of interventions and strategies to prevent, diagnose, treat, and monitor health conditions, for which there is a health-related outcome. Ideally, registration should take place before the researchers have started formal screening against inclusion criteria but reviews are eligible as long as they have not progressed beyond the point of completing data extraction. The required dataset captures the key attributes of review design as well as the administrative details necessary for registration. Submitted registration forms are checked against the scope for inclusion in PROSPERO and for clarity of content before being made publicly available on the register, rejected, or returned to the applicant for clarification. The public records include an audit trail of major changes to planned methods, details of when the review has been completed, and links to resulting publications when provided by the authors. Conclusions There has been international support and an enthusiastic response to the principle of prospective registration of protocols for systematic reviews and to the development of PROSPERO. In October 2011, PROSPERO contained 200 records of systematic reviews being undertaken in 26 countries around the world on a diverse range of interventions.
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            Cumulative meta-analysis of therapeutic trials for myocardial infarction.

            The large volume of published randomized, controlled trials has led to a need for meta-analyses to track therapeutic advances. Performing a new meta-analysis whenever the results of a new trial of a particular therapy are published permits the study of trends in efficacy and makes it possible to determine when a new treatment appears to be significantly effective or deleterious. We describe the use of such a procedure, cumulative meta-analysis, to assess therapeutic trials among patients with myocardial infarction. We performed cumulative meta-analyses of clinical trials that evaluated 15 treatments and preventive measures for acute myocardial infarction. An example of this method is its application to the use of intravenous streptokinase as thrombolytic therapy for acute infarction. Thirty-three trials evaluating this therapy were performed between 1959 and 1988. We found that a consistent, statistically significant reduction in total mortality (odds ratios, 0.74; 95 percent confidence interval, 0.59 to 0.92) was achieved in 1973, after only eight trials involving 2432 patients had been completed. The results of the 25 subsequent trials, which enrolled an additional 34,542 patients through 1988, had little or no effect on the odds ratio establishing efficacy, but simply narrowed the 95 percent confidence interval. In particular, two very large trials, the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico trial in 1986 (11,712 patients) and the Second International Study of Infarct Survival trial in 1988 (17,187 patients) did not modify the already established evidence of efficacy. We used a similar approach to study the accumulating evidence of efficacy (or lack of efficacy) of 14 other therapies and preventive measures for myocardial infarction. Cumulative meta-analysis of therapeutic trials facilitates the determination of clinical efficacy and harm and may be helpful in tracking trials, planning future trials, and making clinical recommendations for therapy.
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              Is Open Access

              Publication of NIH funded trials registered in ClinicalTrials.gov: cross sectional analysis

              Objective To review patterns of publication of clinical trials funded by US National Institutes of Health (NIH) in peer reviewed biomedical journals indexed by Medline. Design Cross sectional analysis. Setting Clinical trials funded by NIH and registered within ClinicalTrials.gov (clinicaltrials.gov), a trial registry and results database maintained by the US National Library of Medicine, after 30 September 2005 and updated as having been completed by 31 December 2008, allowing at least 30 months for publication after completion of the trial. Main outcome measures Publication and time to publication in the biomedical literature, as determined through Medline searches, the last of which was performed in June 2011. Results Among 635 clinical trials completed by 31 December 2008, 294 (46%) were published in a peer reviewed biomedical journal, indexed by Medline, within 30 months of trial completion. The median period of follow-up after trial completion was 51 months (25th-75th centiles 40-68 months), and 432 (68%) were published overall. Among published trials, the median time to publication was 23 months (14-36 months). Trials completed in either 2007 or 2008 were more likely to be published within 30 months of study completion compared with trials completed before 2007 (54% (196/366) v 36% (98/269); P<0.001). Conclusions Despite recent improvement in timely publication, fewer than half of trials funded by NIH are published in a peer reviewed biomedical journal indexed by Medline within 30 months of trial completion. Moreover, after a median of 51 months after trial completion, a third of trials remained unpublished.
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                Author and article information

                Contributors
                jioannid@stanford.edu
                Journal
                Milbank Q
                Milbank Q
                10.1111/(ISSN)1468-0009
                MILQ
                The Milbank Quarterly
                John Wiley and Sons Inc. (Hoboken )
                0887-378X
                1468-0009
                13 September 2016
                September 2016
                : 94
                : 3 ( doiID: 10.1111/milq.2016.94.issue-3 )
                : 485-514
                Affiliations
                [ 1 ] Stanford University School of Medicine Stanford University School of Humanities and Sciences Meta‐Research Innovation Center at Stanford (METRICS) Stanford University
                Author notes
                [*] [* ] Address correspondence to: John P.A. Ioannidis, Meta‐Research Innovation Center at Stanford, 1265 Welch Rd, MSOB X306, Stanford, CA 94305 (email: jioannid@ 123456stanford.edu ).
                Article
                PMC5020151 PMC5020151 5020151 MILQ12210
                10.1111/1468-0009.12210
                5020151
                27620683
                999c4dbe-3e8c-40b8-bd0f-862513fed974
                © 2016 Milbank Memorial Fund
                History
                Page count
                Figures: 4, Tables: 0, Pages: 30, Words: 8964
                Categories
                Original Investigation
                Original Investigation
                Custom metadata
                2.0
                milq12210
                September 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:13.09.2016

                conflicts of interest,industry,evidence‐based medicine,China,bias,meta‐analyses,systematic reviews

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