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Trials 2010, 11:43 TRIALS Gibson et al. Trials 2010, 11:43 http://www.trialsjournal.com/content/11/1/43 TRIALS RESEARCH Open Access AResearch systematic review of clinical trials of pharmacological interventions for acute ischaemic stroke (1955-2008) that were completed, but not published in full Lorna M Gibson1, Miriam Brazzelli2, Brenda M Thomas2 and Peter AG Sandercock*2 Abstract Background: We assessed the prevalence, and potential impact of, trials of pharmacological agents for acute stroke that were completed but not published in full. Failure to publish trial data is to be deprecated as it sets aside the altruism of participants' consent to be exposed to the risks of experimental interventions, potentially biases the assessment of the effects of therapies, and may lead to premature discontinuation of research into promising treatments. Methods: We searched the Cochrane Stroke Group's Specialised Register of Trials in June 2008 for completed trials of pharmacological interventions for acute ischaemic stroke, and searched MEDLINE and EMBASE (January 2007 - March 2009) for references to recent full publications. We assessed trial completion status from trial reports, online trials registers and correspondence with experts. Results: We identified 940 trials. Of these, 125 (19.6%, 95% confidence interval 16.5-22.6) were completed but not published in full by the point prevalence date. They included 16,058 participants (16 trials had over 300 participants each) and tested 89 different interventions. Twenty-two trials with a total of 4,251 participants reported the number of deaths. In these trials, 636/4251 (15.0%) died. Conclusions: Our data suggest that, at the point prevalence date, a substantial body of evidence that was of relevance both to clinical practice in acute stroke and future research in the field was not published in full. Over 16,000 patients had given informed consent and were exposed to the risks of therapy. Responsibility for non-publication lies with investigators, but pharmaceutical companies, research ethics committees, journals and governments can all encourage the timely publication of trial data. Background Previous studies of unpublished clinical trials used Completing but not publishing clinical trials in full can be small samples of clinical trials to estimate the prevalence unethical[1]. Well designed clinical trials should be pub- of non-publication, including trial abstracts which were lished because their results can benefit patients, justifying submitted to one conference over three years [4-6], trials the risk to trial participants from experimental treat- submitted to a single research ethics committee[7,8] or a ments[1]. Failing to publish clinical trials can bias the single country's drug regulatory agency[9]. Limiting findings of systematic reviews and meta-analyses if their searches for published trials to databases[4,8] may have findings differ from published results[2] which may lead missed full trial reports in non-indexed journals and to inappropriate treatment decisions and health care pol- books, leading such trials to be misclassified as unpub- icies[3]. lished. Also ongoing trials may have been misclassified as * Correspondence: [email protected] unpublished by failing to determine the status of clinical 2 Department of Clinical Neurosciences, University of Edinburgh, Western trials[4,6,9]. A systematic review which identified trials of General Hospital, Edinburgh, UK acute ischaemic stroke only through reference lists of Full list of author information is available at the end of the article © 2010 Gibson et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons BioMed Central Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gibson et al. Trials 2010, 11:43 Page 2 of 12 http://www.trialsjournal.com/content/11/1/43 published Cochrane Stroke Group reviews found that www.controlled-trials.com. Trials were classified as com- 11% (19/178) had not been published in full as of Decem- plete or ongoing depending on the status described by ber 31, 1999, although the trials had been reported in these databases. If completion status remained unknown, abstracts between two and 17 years before this date[10]. we attempted to contact investigators at least twice. If The Cochrane Stroke Group's Specialised Register of investigators did not reply by 31st December 2008, the Trials is a very comprehensive database[11] which trial completion status was classified as unclear. includes over 12,000 reports relating to around 6,000 stroke trials (Brenda Thomas, personal communication, Inclusion criteria June 2008). We used this register to perform a systematic We included all completed randomised controlled trials review of clinical trials of pharmacological interventions (RCTs) and controlled clinical trials (CCTs) of pharmaco- for acute ischaemic stroke. We aimed to determine the logical interventions for acute ischaemic stroke which prevalence of and characteristics of completed but were unpublished as of March 2009. Trials were labelled unpublished trials. as RCTs if they stated that participants or groups of par- ticipants were randomly assigned to treatments. We Methods assumed that trials that were described as either double- Definition of 'unpublished' blind or placebo-controlled or both were randomised. We classified trials as unpublished if detailed methods Trials were labelled as CCTs if they stated that partici- and results were not reported in either a peer-reviewed pants or groups of participants were allocated prospec- journal article [8] or book chapter, i.e. not published in tively to different interventions using either a quasi- full. We considered forms of written information includ- random method, or if no method was described[13]. We ing abstracts, drug company reports, letters, literature defined 'acute stroke' as a stroke assessed within 30 days reviews, and online trials registers to be less than full of symptom onset. We excluded trials which included publications, which we term 'sources.' If it was unclear mixed populations of patients with acute and non-acute whether a trial had or had not been published from the stroke unless they reported results for patients with acute titles of references, the trial source(s) were retrieved. We stroke separately. Similarly, we excluded trials which considered a study in the trials register to be unpublished included mixed populations of patients with ischaemic if we could not match the details of study methods and and haemorrhagic stroke unless they reported results for results to any subsequent full publication. patients with ischaemic stroke separately. We excluded trials which did not describe a control group. Search strategy One author (BT) searched the Cochrane Stroke Group's Data extraction Specialised Register of Trials[12] on June 19th 2008 for tri- One author (LG) extracted data on trial designs, meth- als of pharmacological interventions for acute ischaemic ods, and results. We recorded sample size, number of stroke. Another author (LG) screened the titles of refer- centres, type of intervention, comparison groups, method ences identified from the search of the register to select of randomisation, blinding procedures, and allocation trials which appeared to be unpublished. We searched concealment for each trial. If details were unclear, trial MEDLINE and EMBASE from January 2007 to March sources were referred to a second author (PS and/or MB). 2009 to check for recent publications of any trials which We classified trials as single or multi-centre according to initially appeared to be unpublished. Duplicate trials were descriptions provided by investigators. If such descrip- removed. There were no language restrictions. tions were not available, we noted investigators' institu- tional affiliations and arbitrarily classified trials with one Classification of trial completion status affiliated hospital or clinic as single centre, and trials with We assigned a completion status of complete, ongoing, more than one affiliated hospital or clinic as multi-centre, temporarily suspended, planned, never started or unclear accepting that in rare instances, investigators from multi- to unpublished trials. We classified trials as complete if ple hospitals or clinics would participate but only one the most recent source reported results and gave no indi- centre would be responsible for recruiting patients. cation that these results were either interim or prelimi- We extracted all available data on treatment effects on nary, or that patient recruitment or data analysis would clinical outcomes (e.g. death, death or dependency and continue. If the trial could not be classified as complete adverse effects) and on non-clinical outcomes (e.g. physi- after reviewing the most recent source, we searched for ological variables or laboratory measures of uncertain the trial using the acronym or intervention on three clinical significance). We classified results as qualitative online databases (Clinical trials.gov http://www.clinical- or quantitative and noted whether statistical significance trials.gov, The Internet Stroke Center http://www.stroke- was reported. We extracted data on the most important center.org and Current Controlled Trials http:// clinical outcome reported, such as death or functional Gibson et al. Trials 2010, 11:43 Page 3 of 12 http://www.trialsjournal.com/content/11/1/43
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