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Clinical study reports of randomised controlled trials: an exploratory review of previously confidential industry reports.

ABSTRACT: To explore the structure and content of a non-random sample of clinical study reports (CSRs) to guide clinicians and systematic reviewers.We searched public sources and lodged Freedom of Information requests for previously confidential CSRs primarily written by the industry for regulators.CSRs reporting sufficient information for extraction ('adequate').Presence and length of essential elements of trial design and reporting and compression factor (ratio of page length for CSRs compared to its published counterpart in a scientific journal).Data were extracted on standard forms and crosschecked for accuracy.We assembled a population of 78 CSRs (covering 90 randomised controlled trials; 144 610 pages total) dated 1991-2011 of 14 pharmaceuticals. Report synopses had a median length of 5 pages, efficacy evaluation 13.5 pages, safety evaluation 17 pages, attached tables 337 pages, trial protocol 62 pages, statistical analysis plan 15 pages and individual efficacy and safety listings had a median length of 447 and 109.5 pages, respectively. While 16 (21%) of CSRs contained completed case report forms, these were accessible to us in only one case (765 pages representing 16 individuals). Compression factors ranged between 1 and 8805.Clinical study reports represent a hitherto mostly hidden and untapped source of detailed and exhaustive data on each trial. They should be consulted by independent parties interested in a detailed record of a clinical trial, and should form the basic unit for evidence synthesis as their use is likely to minimise the problem of reporting bias. We cannot say whether our sample is representative and whether our conclusions are generalisable to an undefined and undefinable population of CSRs.

SUBMITTER: Doshi P

PROVIDER: S-EPMC3586134 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Clinical study reports of randomised controlled trials: an exploratory review of previously confidential industry reports.

Doshi Peter P Jefferson Tom T

BMJ open 20130226 2

<h4>Objective</h4>To explore the structure and content of a non-random sample of clinical study reports (CSRs) to guide clinicians and systematic reviewers.<h4>Search strategy</h4>We searched public sources and lodged Freedom of Information requests for previously confidential CSRs primarily written by the industry for regulators.<h4>Selection criteria</h4>CSRs reporting sufficient information for extraction ('adequate').<h4>Primary outcome measures</h4>Presence and length of essential elements ...[more]

PMID: 23447465

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Project description:Trial registries were established to combat publication bias by creating a comprehensive and unambiguous record of initiated clinical trials. However, the proliferation of registries and registration policies means that a single trial may be registered multiple times (i.e., "duplicates"). Because unidentified duplicates threaten our ability to identify trials unambiguously, we investigate to what degree duplicates have been identified across registries globally.We retrieved all records from the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal and made a list of all records identified as duplicates by the ICTRP. To investigate how to discriminate duplicates from non-duplicates, we applied text-based similarity scoring to various registration fields of both ICTRP-identified duplicates and arbitrary pairs of trials. We then used the best similarity measure to identify the most similar pairs of records and manually assessed a random sample of pairs not identified as duplicates by the ICTRP to estimate the number of previously unidentified (or "hidden") duplicates.Two hundred eighty-five thousand unique records, or 271 thousand unique trials after accounting for known duplicates, were retrieved from the ICTRP portal in April 2015. We found that the title field best discriminated duplicates from non-duplicates. Out of 41 billion total pair-wise comparisons, we identified the 474,000 pairs of titles with the highest similarity scores (>0.5). After manually assessing a random sample of 434 pairs, we estimated that 45 % of all duplicate registrations currently go undetected and remain to be identified and confirmed as duplicates. Thus, the actual number of unique trials represented in this dataset is estimated to be approximately 258,000 (5 % less).The ICTRP portal does not currently enable the unambiguous identification of trials across registries. Further research is needed to identify and verify the duplicates that currently go undetected. Sponsors, registries, and the ICTRP should consider actions to ensure duplicate registrations are easily identifiable.

Project description:BackgroundHealthcare decisions are ideally based on clinical trial results, published in study registries, as journal articles or summarized in secondary research articles. In this research project, we investigated the impact of academically and commercially sponsored clinical trials on medical practice by measuring the proportion of trials published and cited by systematic reviews and clinical guidelines.MethodsWe examined 691 multicenter, randomized controlled trials that started in 2005 or later and were completed by the end of 2016. To determine whether sponsorship/funding and place of conduct influence a trial's impact, we created four sub-cohorts of investigator initiated trials (IITs) and industry sponsored trials (ISTs): 120 IITs and 171 ISTs with German contribution compared to 200 IITs and 200 ISTs without German contribution. We balanced the groups for study phase and place of conduct. German IITs were funded by the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), or by another non-commercial research organization. All other trials were drawn from the German Clinical Trials Register or ClinicalTrials.gov. We investigated, to what extent study characteristics were associated with publication and impact using multivariable logistic regressions.ResultsFor 80% of the 691 trials, results were published as result articles in a medical journal and/or study registry, 52% were cited by a systematic review, and 26% reached impact in a clinical guideline. Drug trials and larger trials were associated with a higher probability to be published and to have an impact than non-drug trials and smaller trials. Results of IITs were more often published as a journal article while results of ISTs were more often published in study registries. International ISTs less often gained impact by inclusion in systematic reviews or guidelines than IITs.ConclusionAn encouraging high proportion of the clinical trials were published, and a considerable proportion gained impact on clinical practice. However, there is still room for improvement. For publishing study results, study registries have become an alternative or complement to journal articles, especially for ISTs. IITs funded by governmental bodies in Germany reached an impact that is comparable to international IITs and ISTs.

Project description:IntroductionSystematic reviews collate trial data to provide evidence to support clinical decision-making. For effective synthesis, there must be consistency in outcome reporting. There is no agreed set of outcomes for reporting the effect of burn care interventions. Issues with outcome reporting have been identified, although not systematically investigated. This study gathers empirical evidence on any variation in outcome reporting and assesses the need for a core outcome set for burn care research.MethodsElectronic searches of four search engines were undertaken from January 2012 to December 2016 for randomised controlled trials (RCTs), using medical subject headings and free text terms including 'burn', 'scald' 'thermal injury' and 'RCT'. Two authors independently screened papers, extracted outcomes verbatim and recorded the timing of outcome measurement. Duplicate outcomes (exact wording ± different?spelling), similar outcomes (albumin in blood, serum albumin) and identical outcomes measured at different times were removed. Variation in outcome reporting was determined by assessing the number of unique outcomes reported across all included trials. Outcomes were classified into domains. Bias was reduced using five researchers and a patient working independently and together.Results147 trials were included, of which 127 (86.4%) were RCTs, 13 (8.8%) pilot studies and 7 (4.8%) RCT protocols. 1494 verbatim clinical outcomes were reported; 955 were unique. 76.8% of outcomes were measured within 6?months of injury. Commonly reported outcomes were defined differently. Numbers of unique outcomes per trial varied from one to 37 (median 9; IQR 5,13). No single outcome was reported across all studies demonstrating inconsistency of reporting. Outcomes were classified into 54 domains. Numbers of outcomes per domain ranged from 1 to 166 (median 11; IQR 3,24).ConclusionsThis review has demonstrated heterogeneity in outcome reporting in burn care research which will hinder amalgamation of study data. We recommend the development of a Core Outcome Set.Prospero registration numberCRD42017060908.

Project description:OBJECTIVE:Randomised controlled trials (RCT) are the gold standard to provide unbiased data. However, when patients have a treatment preference, randomisation may influence participation and outcomes (eg, external and internal validity). The aim of this study was to assess the influence of patients' preference in RCTs by analysing partially randomised patient preference trials (RPPT); an RCT and preference cohort combined. DESIGN:Systematic review and meta-analyses. DATA SOURCES:MEDLINE, Embase, PsycINFO and the Cochrane Library. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:RPPTs published between January 2005 and October 2018 reporting on allocation of patients to randomised and preference cohorts were included. DATA EXTRACTION AND SYNTHESIS:Two independent reviewers extracted data. The main outcomes were the difference in external validity (participation and baseline characteristics) and internal validity (lost to follow-up, crossover and the primary outcome) between the randomised and the preference cohort within each RPPT, compared in a meta-regression using a Wald test. Risk of bias was not assessed, as no quality assessment for RPPTs has yet been developed. RESULTS:In total, 117 of 3734 identified articles met screening criteria and 44 were eligible (24 873 patients). The participation rate in RPPTs was >95% in 14 trials (range: 48%-100%) and the randomisation refusal rate was >50% in 26 trials (range: 19%-99%). Higher education, female, older age, race and prior experience with one treatment arm were characteristics of patients declining randomisation. The lost to follow-up and cross-over rate were significantly higher in the randomised cohort compared with the preference cohort. Following the meta-analysis, the reported primary outcomes were comparable between both cohorts of the RPPTs, mean difference 0.093 (95% CI -0.178 to 0.364, p=0.502). CONCLUSIONS:Patients' preference led to a substantial proportion of a specific patient group refusing randomisation, while it did not influence the primary outcome within an RPPT. Therefore, RPPTs could increase external validity without compromising the internal validity compared with RCTs. PROSPERO REGISTRATION NUMBER:CRD42019094438.

Project description:BackgroundMapping the international landscape of clinical trials may inform global health research governance, but no large-scale data are available. Industry or non-industry sponsorship may have a major influence in this mapping. We aimed to map the global landscape of industry- and non-industry-sponsored clinical trials and its evolution over time.MethodsWe analyzed clinical trials initiated between 2006 and 2013 and registered in the WHO International Clinical Trials Registry Platform (ICTRP). We mapped single-country and international trials by World Bank's income groups and by sponsorship (industry- vs. non- industry), including its evolution over time from 2006 to 2012. We identified clusters of countries that collaborated significantly more than expected in industry- and non-industry-sponsored international trials.Results119,679 clinical trials conducted in 177 countries were analysed. The median number of trials per million inhabitants in high-income countries was 100 times that in low-income countries (116.0 vs. 1.1). Industry sponsors were involved in three times more trials per million inhabitants than non-industry sponsors in high-income countries (75.0 vs. 24.5) and in ten times fewer trials in low- income countries (0.08 vs. 1.08). Among industry- and non-industry-sponsored trials, 30.3% and 3.2% were international, respectively. In the industry-sponsored network of collaboration, Eastern European and South American countries collaborated more than expected; in the non-industry-sponsored network, collaboration among Scandinavian countries was overrepresented. Industry-sponsored international trials became more inter-continental with time between 2006 and 2012 (from 54.8% to 67.3%) as compared with non-industry-sponsored trials (from 42.4% to 37.2%).ConclusionsBased on trials registered in the WHO ICTRP we documented a substantial gap between the globalization of industry- and non-industry-sponsored clinical research. Only 3% of academic trials but 30% of industry trials are international. The latter appeared to be conducted in preferentially selected countries.

Project description:To evaluate the clinical and cost-effectiveness of non-medical prescribing (NMP).Systematic review. Two reviewers independently completed searches, eligibility assessment and assessment of risk of bias.Pre-defined search terms/combinations were utilised to search electronic databases. In addition, hand searches of reference lists, key journals and grey literature were employed alongside consultation with authors/experts.Randomised controlled trials (RCTs) evaluating clinical or cost-effectiveness of NMP. Measurements reported on one or more outcome(s) of: pain, function, disability, health, social impact, patient-safety, costs-analysis, quality adjusted life years (QALYs), patient satisfaction, clinician perception of clinical and functional outcomes.Three RCTs from two countries were included (n = 932 participants) across primary and tertiary care settings. One RCT was assessed as low risk of bias, one as high risk of bias and one as unclear risk of bias. All RCTs evaluated clinical effectiveness with one also evaluating cost-effectiveness. Clinical effectiveness was evaluated using a range of safety and patient-reported outcome measures. Participants demonstrated significant improvement in outcomes when receiving NMP compared to treatment as usual (TAU) in all RCTs. An associated cost analysis showed NMP to be more expensive than TAU (regression coefficient p = 0.0000), however experimental groups generated increased QALYs compared to TAU.Limited evidence with overall unclear risk of bias exists evaluating clinical and cost-effectiveness of NMP across all professions and clinical settings. GRADE assessment revealed moderate quality evidence. Evidence suggests that NMP is safe and can provide beneficial clinical outcomes. Benefits to the health economy remain unclear, with the cost-effectiveness of NMP assessed by a single pilot RCT of low risk of bias. Adequately powered low risk of bias RCTs evaluating clinical and cost effectiveness are required to evaluate NMP across clinical specialities, professions and settings.PROSPERO (CRD42015017212).

Project description:BackgroundTrial design plays a key role in clinical trials. Traditional group sequential design has been used in cardiovascular clinical trials over decades as the trials can potentially be stopped early, therefore, it can reduce pre-planned sample size and trial resources. In contrast, trials with adoptive designs provide greater flexibility and are more efficient due to the ability to modify trial design according to the interim analysis results. In this systematic review, we aim to explore characteristics of adaptive and traditional group sequential trials in practice and to gain an understanding how these trial designs are currently being reported in cardiology.MethodsPubMed, Embase and Cochrane Central Register of Controlled Trials database were searched from January 1980 to June 2022. Randomised controlled phase 2/3 trials with either adaptive or traditional group sequential design in patients with cardiovascular disease were included. Descriptive statistics were used to present the collected data.ResultsOf 456 articles found in the initial search, 56 were identified including 43 (76.8%) trials with traditional group sequential design and 13 (23.2%) with adaptive. Most trials were large, multicentre, led by the USA (50%) and Europe (28.6%), and were funded by companies (78.6%). For trials with group sequential design, frequency of interim analyses was determined mainly by the number of events (47%). 67% of the trials stopped early, in which 14 (32.6%) were due to efficacy, and 5 (11.6%) for futility. The commonly used stopping rule to terminate trials was O'Brien- Fleming-type alpha spending function (10 (23.3%)). For trials with adaptive designs, 54% of the trials stopped early, in which 4 (30.8%) were due to futility, and 2 (15.4%) for efficacy. Sample size re-estimation was commonly used (8 (61.5%)). In 69% of the trials, simulation including Bayesian approach was used to define the statistical stopping rules. The adaptive designs have been increasingly used (from 0 to 1999 to 38.6% after 2015 amongst adaptive trials). 25% of the trials reported "adaptive" in abstract or title of the studies.ConclusionsThe application of adaptive trials is increasingly popular in cardiovascular clinical trials. The reporting of adaptive design needs improving.

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Clinical study reports of randomised controlled trials: an exploratory review of previously confidential industry reports.

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Clinical study reports of randomised controlled trials: an exploratory review of previously confidential industry reports.

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