Non-publication is more common among industry-funded trials, study finds
CHAPEL HILL, N.C. – A new analysis of 585 large, randomized clinical trials registered with ClinicalTrials.gov finds that 29 percent have not been published in scientific journals. In addition, nearly 78 percent of the unpublished trials had no results available on the website, either.
As a result, nearly 300,000 people who were enrolled in the 171 unpublished trials “were exposed to the risks of trial participation without the societal benefits which accompany the dissemination of trial results,” said Christopher W. Jones, MD, a former resident physician at University of North Carolina School of Medicine who is now an attending physician at Cooper Medical School of Rowan University in Camden, N.J. and lead author of the study published in the Oct. 29, 2013 issue of the British Medical Journal.
Contact: Stephanie Burns
BMJ-British Medical Journal
Study finds almost 1 in 3 large clinical trials still not published 5 years after completion
Almost one in three (29%) large clinical trials remain unpublished five years after completion. And of these, 78% have no results publicly available, finds a study published on bmj.com today.
This means that an estimated 250,000 people have been exposed to the risks of trial participation without the societal benefits that accompany the dissemination of their results, say the authors.
They argue that this “violates an ethical obligation that investigators have towards study participants” and call for additional safeguards “to ensure timely public dissemination of trial data.”
Randomized clinical trials are a critical means of advancing medical knowledge. They depend on the willingness of people to expose themselves to risks, but the ethical justification for these risks is that society will eventually benefit from the knowledge gained from the trial.
But when trial data remain unpublished, the societal benefit that may have motivated someone to enrol in a study remains unrealized.
US law requires that many trials involving human participants be registered – and their results posted – on the largest clinical trial website ClinicalTrials.gov. But evidence suggests that this legislation has been largely ignored.
So a team of US-based researchers set out to estimate the frequency of non-publication of trial results and, among unpublished studies, the frequency with which results are unavailable in the ClinicalTrials.gov database.
They searched scientific literature databases and identified 585 trials with at least 500 participants that were registered with ClinicalTrials.gov and completed prior to January 2009. The average time between study completion and the final literature search (November 2012) was 60 months for unpublished trials.
Registry entries for unpublished trials were then reviewed to determine whether results for these studies were available in the ClinicalTrials.gov results database.
Of 585 registered trials, 171 (29%) remained unpublished. Of these, 133 (78%) had no results available in ClinicalTrials.gov. Non-publication was more common among trials that received industry funding (32%) than those that did not (18%).
“Our results add to existing work by showing that non-publication is an important problem even among large randomized trials,” say the authors. Furthermore, the sponsors and investigators of these unpublished trials infrequently utilize the ClinicalTrials.gov results database.
The lack of availability of results from these trials “contributes to publication bias and also constitutes a failure to honor the ethical contract that is the basis for exposing study participants to the risks inherent in trial participation,” they add. “Additional safeguards are needed to ensure timely public dissemination of trial data,” they conclude.
Amsterdam, The Netherlands,Thursday 25 April 2013: Probiotics could emerge as a treatment plan to manage hepatic encephalopathy (HE) therapy after a new study announced at the International Liver Congress™ 2013 found they significantly reduced development of the notoriously difficult-to-treat disease.
The study analysed the efficacy of probiotics in preventing the development of HE in 160 cirrhotic patients over a period of approximately nine months and found significant improvements in reducing patients’ arterial ammonia levels after three months of treatment with probiotics.
Ammonia, produced by gut bacteria, is thought to be one of the main mediators of cerebral dysfunction in HE. Probiotics work by enriching the gut flora with a non-urease producing microorganisms, which decrease ammonia production. Probiotics are live microorganisms (mostly bacteria) that produce a health benefit on the host when administered in adequate amounts.
Twice as many patients taking a placebo developed overt HE (the study’s primary endpoint) compared to patients taking probiotics in the form of a capsule.
EASL’s Treasurer, Prof. Mauro Bernardi welcomed the findings and said they would provide a positive impact for cirrhotic patients at risk of developing HE for whom the prognosis is typically very poor.
Prof. Bernardi said: “Hepatic encephalopathy is an insidious disease that’s caused by an accumulation of toxins in the blood that are normally removed by the liver. Treatment normally involves the use of antibiotics or laxatives to suppress the production of toxic substances in the intestine but there is still a great deal of room for improvement so it will be exciting to see the results of further studies to determine if clinicians have a new form of treatment on the cards.”
Hepatic encephalopathy is a spectrum of neuropsychiatric abnormalities including personality changes, intellectual impairment and reduced levels of consciousness in patients with liver failure, after exclusion of other known brain disease.
Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2013.
Notes to Editors
EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.
EASL’s main focus on education and research is delivered through numerous events and initiatives, including:
- The International Liver CongressTM which is the main scientific and professional event in hepatology worldwide
- Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year
- Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology
- Journal of Hepatology published monthly
- Participation in a number of policy initiatives at European levelM.
About The International Liver CongressTM 2013
The International Liver Congress™ 2013, the 48th annual meeting of the European Association for the study of the Liver, is being held at the RAI Convention Centre in Amsterdam from April 24 – 28, 2013.
The congress annually attracts in excess of 9,000 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.
1 M.K Lunia, AN OPEN LABEL RANDOMISED CONTROLLED TRIAL OF PROBIOTICS FOR PRIMARY PROPHYLAXIS OF HEPATIC ENCEPHALOPATHY IN PATIENTS WITH CIRRHOSIS. Presented at the International Liver CongressTM 2013
2 A. Agrawal, Secondary Prophylaxis of Hepatic Encephalopathy in Cirrhosis, An Open-Label, Randomized Controlled Trial of Lactulose, Probiotics, and No Therapy. Available http://www.medscape.com/viewarticle/767674_3 [Accessed 9/4/13]
3 World Health Organization and Food and Agriculture Organizationof the United Nations. Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria. Ava http://www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf [Accessed 9/4/13]
Special edition to mark World TB day maps new issues and approaches to curbing spread of infection
During the 1930s, dedicated sanitaria and invasive surgery were commonly prescribed for those with the infection – usually caused by Mycobacterium tuberculosis, which the editors describe as “the most successful human pathogen of all time.”
TB often lies dormant with no symptoms, but in a proportion of cases, becomes active, predominantly attacking the lungs. But it can also affect the bones and nervous system, and if left untreated can be fatal.
The infection is developing increasing resistance around the world to the powerful drugs currently used to treat it.
“Whatever we may have once optimistically thought, TB remains with death, taxes and political chicanery as being inevitable, unavoidable and deeply unpleasant,” write the joint editors, Andy Bush and Ian Pavord.
“It shows every sign of weathering the storm and superb randomised controlled trials, to emerge in ever-increasingly drug-resistant forms, potentially turning the clock back to the 1930s,” they say.
“This edition of Thorax, coinciding with world TB day, is themed to recognise the ongoing sinister successes of Mycobacterium tuberculosis, unarguably the most successful human pathogen of all time,” they conclude.
The issue contains international research papers, looking at a broad range of issues, from the risk of TB after seroconversion to HIV infection, to the impact of ethnicity on the pattern of disease.
2009 study posted for filing
This release is available in Chinese.
Randomised Controlled Trials (RCTs) are considered the ‘gold standard’ research method for assessing new medical treatments. But research published in BioMed Central’s open access journal Trials shows that the design of a remarkable 93 percent of 2235 so-called RCTs published in some Chinese medical journals during 1994 to 2005 was flawed, casting doubt on the reliability of research that is likely to influence medical decision-makers.
Researchers led by Taixiang Wu of the Chinese Cochrane Centre at Sichuan University, China and Ottawa Hospital Research Institute investigated clinical trials published in China between 1994 and 2005, searching the China National Knowledge Infrastructure (CNKI) electronic database for RCTs on 20 common diseases. To determine how many of these met recognised standards for randomly allocating participants to treatment groups, trained investigators interviewed the first or co-authors of 2235 trial reports by phone.
Less than seven percent of self-described RCTs published in some Chinese medical journals meet criteria for authentic randomisation. The researchers looked at both conventional and traditional Chinese medicine trials, but there was no difference between these in terms of study authenticity rates. However, all RCTs of pre-market drug clinical trial were authentic, and RCTs conducted at hospitals affiliated with medical universities were more likely to be authentic than trials conducted at lower tier level three and level two hospitals. More than half of the trials at university-affiliated hospitals met RCT criteria, which means lower-tier hospital research is the least rigorous in design terms.
“The fact that so many non-RCTs were published as RCTs reflected that peer-review needs to be improved and a Good Practice of Peer Review, including how to identify the authenticity of the study, urgently needs to be developed,” says Wu.
Misleading reporting of medical research is not unique to China. Studies labelled as RCTs are more likely to influence health policy-makers meaning falsely reported RCTs have the potential to mislead health care providers, consumers and policy-makers. The results of this study suggest authors of systematic reviews – articles that combine the results of multiple RCTs – need to be aware that RCTs in some Chinese journals may not be RCTs at all.
The approximately 1100 medical journals now active in China are rapidly increasing their output of research reports, including many identified by their authors as RCTs. But these trials present mostly positive results (they favour the treatment being investigated), which can be influenced by inadequate randomisation of patients when designing the study.
Notes to Editors
1. Randomized trials published in some Chinese journals: How many are randomized? Taixiang Wu, Youping Li, Zhaoxiang Bian, Guanjian Liu and David Moher Trials (in press)
During embargo, article available here: http://www.trialsjournal.com/imedia/1756122426222937_article.pdf?random=263457
After the embargo, article available at the journal website: http://www.trialsjournal.com/
Please name the journal in any story you write. If you are writing for the web, please link to the article. All articles are available free of charge, according to BioMed Central’s open access policy.
Article citation and URL available on request at email@example.com on the day of publication.
2. This study was funded by the Chinese Medical Board of New York.
3. Trials is an open access, peer-reviewed, online journal that will encompass all aspects of the performance and findings of randomized controlled trials. Trials will experiment with, and then refine, innovative approaches to improving communication about trials. We are keen to move beyond publishing traditional trial results articles (although these will be included). We believe this represents an exciting opportunity to advance the science and reporting of trials. Prior to 2006, Trials was published as Current Controlled Trials in Cardiovascular Medicine (CCTCVM). All published CCTCVM articles are available via the Trials website and citations to CCTCVM article URLs will continue to be supported.
4. BioMed Central (http://www.biomedcentral.com/) is an STM (Science, Technology and Medicine) publisher which has pioneered the open access publishing model. All peer-reviewed research articles published by BioMed Central are made immediately and freely accessible online, and are licensed to allow redistribution and reuse. BioMed Central is part of Springer Science+Business Media, a leading global publisher in the STM sector.
Press release from PLOS Medicine
Despite previous studies suggesting the contrary, statins (cholesterol-lowering drugs) may not prevent blood clots (venous thrombo-embolism) in adults, according to a large analysis by international researchers published in this week’s PLOS Medicine.
In 2009, an additional analysis of data from a randomized controlled trial called the JUPITER trial reported that the statin rosuvastatin halved the risk of venous thromboembolic events among apparently healthy adults. However, this finding was based on a small number of patients who had thromboembolic events (34 vs 60). To gather more evidence about the possible benefits of statins, a group of international researchers led by Kazem Rahimi from the George Centre for Healthcare Innovation at the University of Oxford in the UK, combined the results (performed a meta-analysis) of 29 suitable published and unpublished randomised controlled trials of the effects of statins involving over 100 000 participants and more than 1000 events: Only two studies presented venous thrombotic events in the published report, but such events had been recorded as adverse events in all of the included trials, which the authors were able to include in their analysis.
In the combined analysis, the authors found that venous thrombosis occurred in 0.9% of people taking statins compared to 1% of people not taking statins, which suggests that statins have a very small, if any, effect. These results did not change when the authors excluded the findings of the JUPITER trial. The authors also found that there was no effect at all in people taking high doses and low doses of statins.
The authors conclude: “this study provides a more detailed assessment of the potential effects of statins (or higher dose statins) on venous thromboembolic events than has previously been possible. We were unable to confirm the large proportional reduction in risk suggested by some previous studies.”
The authors add: “However, a more modest but perhaps clinically worthwhile reduction in venous thromboembolic events in some or all types of patient cannot be ruled out.”
In an accompanying Perspective article, Frits Rosendaal from the Leiden University Medical Center in The Netherlands (uninvolved in the study) argues that even if the study cannot provide definite answers to the statin question, some tentative conclusions can be drawn. He says: “Firstly, that for the association between statins and venous thrombosis the methodologically strongest analysis shows at most a very small effect. Secondly, if we do not wish to discard the possibility of a beneficial effect for the whole class, any such effects are limited to rosuvastatin.”
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. No funding bodies played any role in the design, data collection and analysis, writing or decision to publish this manuscript. KR is supported by the Oxford Martin School and the Oxford NIHR Biomedical Research Centre. NB is supported by a MRC Health of the Public Research Fellowship.
Competing Interests: NB is a member of the secretariat of the Cholesterol Treatment Trialists’ (CTT) Collaboration. VK is a member of the steering committee of the SHARP trial (Study of Heart and Renal Protection), and was involved in the 4D Study (German Diabetes and Dialysis Study) as clinical coordinator. JM is supported by the University of Glasgow. MR is a member of the PLOS Medicine Editorial Board. All other authors have declared that no competing interests exist.
Citation: Rahimi K, Bhala N, Kamphuisen P, Emberson J, Biere-Rafi S, et al. (2012) Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials. PLoS Med 9(9): e1001310. doi:10.1371/journal.pmed.1001310
George Centre for Healthcare Innovation
University of Oxford,
Oxford, United Kingdom
+44 (0)1865 617201
Funding: No specific funding was received for writing this article.
Competing Interests: The author reports no competing interests in relation to statins. The author is named on several patents for prothrombotic gene variants (such as Factor V Leiden) but does not benefit personally from royalties on these.
Citation: Rosendaal FR (2012) Statins and Venous Thrombosis: A Story Too Good to Be True? PLoS Med 9(9): e1001311. doi:10.1371/journal.pmed.1001311
Frits R. Rosendaal
Department of Clinical Epidemiology and Department of Thrombosis and Haemostasis
Leiden University Medical Center
Leiden, The Netherlands
Press releases and news stories reporting the results of randomized controlled trials often contain “spin”—specific reporting strategies (intentional or unintentional) emphasizing the beneficial effect of the experimental treatment—but such “spin” frequently comes from the abstract (summary) of the actual study published in a scientific journal, rather than being related to misinterpretation by the media, according to French researchers writing in this week’s PLOS Medicine.
“Spinning” the reporting of clinical trials could give physicians and patients unrealistic expectations about new treatments. It is important to know the source of “spin” and so French researchers, led by Isabelle Boutron from the Université Paris Descartes, looked for the presence of “spin” in a sample of 70 press releases, and 41 associated news stories, of randomized controlled trials and investigated the source of the “spin”.
The authors found that 33 (47%) of press releases contained “spin” and also identified “spin” in the conclusions of 28 (40%) study abstracts published in scientific journals. Furthermore, 21 (51%) of the associated news stories were reported with “spin”, mainly the same type of ‘”spin”‘ as those identified in the press release and article abstract conclusions. Importantly, “spin” could lead readers to overestimate the benefits of the treatment.
The authors conclude: “Our results highlight a tendency for press releases and the associated media coverage of randomized controlled trials to place emphasis on the beneficial effects of experimental treatments. This tendency is probably related to the presence of “spin” in conclusions of the scientific article’s abstract. ”
They continue: “Our work highlights that this inappropriate reporting could bias readers’ interpretation of research results.”
The authors add: “Consequently, reviewers and editors of published articles have an important role to play in the dissemination of research findings and should be particularly aware of the need to ensure that the conclusions reported are an appropriate reflection of the trial findings and do not overinterpret or misinterpret the results.”
Funding: No direct funding was received for this study. The authors were personally salaried by their institutions during the period of writing (though no specific salary was set aside or given for the writing of this paper). No funding bodies had any role in the study design, data collection, analysis, decision to publish or preparation of the manuscript.
Competing Interests: Isabelle Boutron is a member of PLOS Medicine Editorial Board. The authors have declared that no other competing interests exist.
Citation: Yavchitz A, Boutron I, Bafeta A, Marroun I, Charles P, et al. (2012) Misrepresentation of Randomized Controlled Trials in Press Releases and News Coverage: A Cohort Study. PLoS Med 9(9): e1001308. doi:10.1371/journal.pmed.1001308
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Assistance Publique Hopitaux de Paris, Paris Descartes University, PRES Sorbonne Paris Cité, INSERM U738, Paris, France
INDIANAPOLIS – Previous explorations of a link between statins, a cholesterol lowering medication, and cognitive decline have produced inconsistent results. New research reveals that the relationship between statin use and cognitive decline appears even more complex than had been thought.
In a three year epidemiological study, researchers from the Indiana University School of Medicine and the Regenstrief Institute, Inc. have found an association of statin use with less cognitive decline in elderly African Americans and report that, surprisingly, the association is even stronger for those who had discontinued use than for continuous users. Their findings are published in the Nov. 6 issue of Neurology.
In 2001 and again in 2004, the IU School of Medicine researchers evaluated 1146 African Americans aged 70 and older living in Indianapolis testing them in various cognitive areas including language, attention and calculation, memory and orientation. The researchers also compared use of statins and whether, if used, they were taken consistently. While cognitive decline in statin users was less than those who did not take statins, those who continued to take statins from 2001 to 2004 had greater cognitive decline than those who were taking statins in 2001 but were no longer taking them in 2004. Study participants who discontinued statin use did not differ from those who continued to use statins in any other health, demographic, clinical or biochemical characteristics.
If statin use were directly associated with a reduction in cognitive decline, continuously taking statins would presumably produce the greatest effect. The study authors say that in light of their findings that the association between statins and decreased cognitive decline is more complex than previously realized, carefully designed randomized clinical trials of statins are needed to provide definitive answers to their potential role in dementia prevention.
***Ralph’s note- It appears that initial use of statins had some benefit on cognitive ability, but then had a negative rebound effect. The wording here is difficult so those in the initial study up to 2001 had an advantage. However, that same group when re analyzed from 2001 to 2004. The Statin users fared much worse than those who stopped after 2001.
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