Anette Blümle

Prevalence, Characteristics, and Publication of Discontinued Randomized Trials

IMPORTANCE The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear. OBJECTIVES To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. DESIGN AND SETTING Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013. MAIN OUTCOMES AND MEASURES Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys. RESULTS After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43]; P < .001) and a larger planned sample size in increments of 100 (-0.7%; OR, 0.96 [95% CI, 0.92-1.00]; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P < .001). CONCLUSIONS AND RELEVANCE In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials.

Evidence of effectiveness of herbal medicinal products in the treatment of arthritis. Part 2: Rheumatoid arthritis

Herbal medicinal products (HMPs) are used in a variety of oral and topical forms for the treatment of osteoarthritis. The aim of this study was to update a previous systematic review published in 2000. We searched electronic databases (MEDLINE, EMBASE, CISCOM, AMED, CINAHL, Cochrane registers) to June 2007, unrestricted by date or language, and included randomized controlled trials that compared HMPs with inert (placebo) or active controls in patients with osteoarthritis. Five reviewers contributed to data extraction. Disagreements were discussed and resolved by consensus with reference to Cochrane guidelines and advice from the Cochrane Collaboration.

Evidence of Effectiveness of Herbal Medicinal Products in the Treatment of Arthritis

Herbal medicinal products (HMPs) that interact with the mediators of inflammation are used in the treatment of rheumatoid arthritis (RA). The aim of this study was to update a previous systematic review published in 2000. We searched electronic databases (MEDLINE, EMBASE, CISCOM, AMED, CINAHL, Cochrane registers) to June 2007, unrestricted by date or language, and included randomized controlled trials that compared HMPs with inert (placebo) or active controls in patients with rheumatoid arthritis. Five reviewers contributed to data extraction. Disagreements were discussed and resolved by consensus with reference to Cochrane guidelines and advice from the Cochrane Collaboration.

Clinical research projects at a German medical faculty: follow-up from ethical approval to publication and citation by others

Background: Only data of published study results are available to the scientific community for further use such as informing future research and synthesis of available evidence. If study results are reported selectively, reporting bias and distortion of summarised estimates of effect or harm of treatments can occur. The publication and citation of results of clinical research conducted in Germany was studied. Methods: The protocols of clinical research projects submitted to the research ethics committee of the University of Freiburg (Germany) in 2000 were analysed. Published full articles in several databases were searched and investigators contacted. Data on study and publication characteristics were extracted from protocols and corresponding publications. Results: 299 study protocols were included. The most frequent study design was randomised controlled trial (141; 47%), followed by uncontrolled studies (61; 20%), laboratory studies (30; 10%) and non-randomised studies (29; 10%). 182 (61%) were multicentre studies including 97 (53%) international collaborations. 152 of 299 (51%) had commercial (co-)funding and 46 (15%) non-commercial funding. 109 of the 225 completed protocols corresponded to at least one full publication (total 210 articles); the publication rate was 48%. 168 of 210 identified publications (80%) were cited in articles indexed in the ISI Web of Science. The median was 11 citations per publication (range 0–1151). Conclusions: Results of German clinical research projects conducted are largely underreported. Barriers to successful publication need to be identified and appropriate measures taken. Close monitoring of projects until publication and adequate support provided to investigators may help remedy the prevailing underreporting of research.

Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications

Objective To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. Design Cohort of protocols of randomised controlled trial and subsequent full journal publications. Setting Six research ethics committees in Switzerland, Germany, and Canada. Data sources 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. Results Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. Conclusions Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.

Reporting of eligibility criteria of randomised trials: cohort study comparing trial protocols with subsequent articles

Objective To determine whether and how eligibility criteria of participants prespecified in protocols of randomised trials are reported in subsequent articles. Design Cohort study. Setting Protocols submitted to the ethics committee of a German medical faculty. Data sources 52 trial protocols and 78 subsequent publications published between 2000 and 2006. Main outcome measure Proportion of matching, missing, modified, or newly added eligibility criteria between trial protocols and subsequent publications. Results Differences were found between protocols and subsequent publications for all 52 trials. Information on eligibility criteria was missing in the publications for all 52 trials (100%, 95% confidence interval 93% to 100%), modified for 44 (85%, 72% to 93%), and newly added for 21 (41%, 27% to 55%). The mean number of eligibility criteria for each trial was 25 (range 7-43) and the mean proportion of matching eligibility criteria per trial was 50% (95% confidence interval 44% to 55%, range 13-93). Of 1248 eligibility criteria prespecified in the protocols, 606 (49%, 46% to 51%) were matching in subsequent publications, 479 (38%, 36% to 41%) were missing, and 163 (13%, 11% to 15%) were modified. 51 eligibility criteria were added to publications. Most prespecified eligibility criteria were about comorbidity (42%, 39% to 45%), treatment (20%, 18% to 22%), or type or severity of illness (17%, 15% to 19%). Most of the missing eligibility criteria (96%, 94% to 97%) and modified eligibility criteria (54%, 46% to 62%) suggested broader study populations and most of the added eligibility criteria (86%, 74% to 94%) suggested narrower study populations. Conclusions Many users of trial information rely on published journal articles. These articles generally do not reflect the exact definition of the study population as prespecified in the protocol. Incomplete or inadequate reporting of eligibility criteria hampers a proper assessment of the applicability of trial results.

Completion and publication rates of randomized controlled trials in surgery: an empirical study

OBJECTIVE To investigate the prevalence of discontinuation and nonpublication of surgical versus medical randomized controlled trials (RCTs) and to explore risk factors for discontinuation and nonpublication of surgical RCTs. BACKGROUND Trial discontinuation has significant scientific, ethical, and economic implications. To date, the prevalence of discontinuation of surgical RCTs is unknown. METHODS All RCT protocols approved between 2000 and 2003 by 6 ethics committees in Canada, Germany, and Switzerland were screened. Baseline characteristics were collected and, if published, full reports retrieved. Risk factors for early discontinuation for slow recruitment and nonpublication were explored using multivariable logistic regression analyses. RESULTS In total, 863 RCT protocols involving adult patients were identified, 127 in surgery (15%) and 736 in medicine (85%). Surgical trials were discontinued for any reason more often than medical trials [43% vs 27%, risk difference 16% (95% confidence interval [CI]: 5%-26%); P = 0.001] and more often discontinued for slow recruitment [18% vs 11%, risk difference 8% (95% CI: 0.1%-16%); P = 0.020]. The percentage of trials not published as full journal article was similar in surgical and medical trials (44% vs 40%, risk difference 4% (95% CI: -5% to 14%); P = 0.373). Discontinuation of surgical trials was a strong risk factor for nonpublication (odds ratio = 4.18, 95% CI: 1.45-12.06; P = 0.008). CONCLUSIONS Discontinuation and nonpublication rates were substantial in surgical RCTs and trial discontinuation was strongly associated with nonpublication. These findings need to be taken into account when interpreting surgical literature. Surgical trialists should consider feasibility studies before embarking on full-scale trials.

Fate of Clinical Research Studies After Ethical Approval—Follow-Up of Study Protocols Until Publication

Background Many clinical studies are ultimately not fully published in peer-reviewed journals. Underreporting of clinical research is wasteful and can result in biased estimates of treatment effect or harm, leading to recommendations that are inappropriate or even dangerous. Methods We assembled a cohort of clinical studies approved 2000–2002 by the Research Ethics Committee of the University of Freiburg, Germany. Published full articles were searched in electronic databases and investigators contacted. Data on study characteristics were extracted from protocols and corresponding publications. We characterized the cohort, quantified its publication outcome and compared protocols and publications for selected aspects. Results Of 917 approved studies, 807 were started and 110 were not, either locally or as a whole. Of the started studies, 576 (71%) were completed according to protocol, 128 (16%) discontinued and 42 (5%) are still ongoing; for 61 (8%) there was no information about their course. We identified 782 full publications corresponding to 419 of the 807 initiated studies; the publication proportion was 52% (95% CI: 0.48–0.55). Study design was not significantly associated with subsequent publication. Multicentre status, international collaboration, large sample size and commercial or non-commercial funding were positively associated with subsequent publication. Commercial funding was mentioned in 203 (48%) protocols and in 205 (49%) of the publications. In most published studies (339; 81%) this information corresponded between protocol and publication. Most studies were published in English (367; 88%); some in German (25; 6%) or both languages (27; 6%). The local investigators were listed as (co-)authors in the publications corresponding to 259 (62%) studies. Conclusion Half of the clinical research conducted at a large German university medical centre remains unpublished; future research is built on an incomplete database. Research resources are likely wasted as neither health care professionals nor patients nor policy makers can use the results when making decisions.

Learning from failure - rationale and design for a study about discontinuation of randomized trials (DISCO study)

BackgroundRandomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs.Methods/DesignOur aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs.We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment.DiscussionOur study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

Systematic review finds that study data not published in full text articles have unclear impact on meta-analyses results in medical research.

Background A meta-analysis as part of a systematic review aims to provide a thorough, comprehensive and unbiased statistical summary of data from the literature. However, relevant study results could be missing from a meta-analysis because of selective publication and inadequate dissemination. If missing outcome data differ systematically from published ones, a meta-analysis will be biased with an inaccurate assessment of the intervention effect. As part of the EU-funded OPEN project (www.open-project.eu) we conducted a systematic review that assessed whether the inclusion of data that were not published at all and/or published only in the grey literature influences pooled effect estimates in meta-analyses and leads to different interpretation. Methods and findings Systematic review of published literature (methodological research projects). Four bibliographic databases were searched up to February 2016 without restriction of publication year or language. Methodological research projects were considered eligible for inclusion if they reviewed a cohort of meta-analyses which (i) compared pooled effect estimates of meta-analyses of health care interventions according to publication status of data or (ii) examined whether the inclusion of unpublished or grey literature data impacts the result of a meta-analysis. Seven methodological research projects including 187 meta-analyses comparing pooled treatment effect estimates according to different publication status were identified. Two research projects showed that published data showed larger pooled treatment effects in favour of the intervention than unpublished or grey literature data (Ratio of ORs 1.15, 95% CI 1.04–1.28 and 1.34, 95% CI 1.09–1.66). In the remaining research projects pooled effect estimates and/or overall findings were not significantly changed by the inclusion of unpublished and/or grey literature data. The precision of the pooled estimate was increased with narrower 95% confidence interval. Conclusions Although we may anticipate that systematic reviews and meta-analyses not including unpublished or grey literature study results are likely to overestimate the treatment effects, current empirical research shows that this is only the case in a minority of reviews. Therefore, currently, a meta-analyst should particularly consider time, effort and costs when adding such data to their analysis. Future research is needed to identify which reviews may benefit most from including unpublished or grey data.