Impact of inclusion of industry trial results registries as an information source for systematic reviews.

BACKGROUND: Clinical trial results registries may contain relevant unpublished information. Our main aim was to investigate the potential impact of the inclusion of reports from industry results registries on systematic reviews (SRs). METHODS: We identified a sample of 150 eligible SRs in PubMed via backward selection. Eligible SRs investigated randomized controlled trials of drugs and included at least 2 bibliographic databases (original search date: 11/2009). We checked whether results registries of manufacturers and/or industry associations had also been searched. If not, we searched these registries for additional trials not considered in the SRs, as well as for additional data on trials already considered. We reanalysed the primary outcome and harm outcomes reported in the SRs and determined whether results had changed. A "change" was defined as either a new relevant result or a change in the statistical significance of an existing result. We performed a search update in 8/2013 and identified a sample of 20 eligible SRs to determine whether mandatory results registration from 9/2008 onwards in the public trial and results registry ClinicalTrials.gov had led to its inclusion as a standard information source in SRs, and whether the inclusion rate of industry results registries had changed. RESULTS: 133 of the 150 SRs (89%) in the original analysis did not search industry results registries. For 23 (17%) of these SRs we found 25 additional trials and additional data on 31 trials already included in the SRs. This additional information was found for more than twice as many SRs of drugs approved from 2000 as approved beforehand. The inclusion of the additional trials and data yielded changes in existing results or the addition of new results for 6 of the 23 SRs. Of the 20 SRs retrieved in the search update, 8 considered ClinicalTrials.gov or a meta-registry linking to ClinicalTrials.gov, and 1 considered an industry results registry. CONCLUSION: The inclusion of industry and public results registries as an information source in SRs is still insufficient and may result in publication and outcome reporting bias. In addition to an essential search in ClinicalTrials.gov, authors of SRs should consider searching industry results registries.

Completeness of reporting of patient-relevant clinical trial outcomes: comparison of unpublished clinical study reports with publicly available data.

BACKGROUND: Access to unpublished clinical study reports (CSRs) is currently being discussed as a means to allow unbiased evaluation of clinical research. The Institute for Quality and Efficiency in Health Care (IQWiG) routinely requests CSRs from manufacturers for its drug assessments. Our objective was to determine the information gain from CSRs compared to publicly available sources (journal publications and registry reports) for patient-relevant outcomes included in IQWiG health technology assessments (HTAs) of drugs. METHODS AND FINDINGS: We used a sample of 101 trials with full CSRs received for 16 HTAs of drugs completed by IQWiG between 15 January 2006 and 14 February 2011, and analyzed the CSRs and the publicly available sources of these trials. For each document type we assessed the completeness of information on all patient-relevant outcomes included in the HTAs (benefit outcomes, e.g., mortality, symptoms, and health-related quality of life; harm outcomes, e.g., adverse events). We dichotomized the outcomes as "completely reported" or "incompletely reported." For each document type, we calculated the proportion of outcomes with complete information per outcome category and overall. We analyzed 101 trials with CSRs; 86 had at least one publicly available source, 65 at least one journal publication, and 50 a registry report. The trials included 1,080 patient-relevant outcomes. The CSRs provided complete information on a considerably higher proportion of outcomes (86%) than the combined publicly available sources (39%). With the exception of health-related quality of life (57%), CSRs provided complete information on 78% to 100% of the various benefit outcomes (combined publicly available sources: 20% to 53%). CSRs also provided considerably more information on harms. The differences in completeness of information for patient-relevant outcomes between CSRs and journal publications or registry reports (or a combination of both) were statistically significant for all types of outcomes. The main limitation of our study is that our sample is not representative because only CSRs provided voluntarily by pharmaceutical companies upon request could be assessed. In addition, the sample covered only a limited number of therapeutic areas and was restricted to randomized controlled trials investigating drugs. CONCLUSIONS: In contrast to CSRs, publicly available sources provide insufficient information on patient-relevant outcomes of clinical trials. CSRs should therefore be made publicly available. Please see later in the article for the Editors' Summary.

Access to regulatory data from the European Medicines Agency: the times they are a-changing.

Systematic reviewers are increasingly trying to obtain regulatory clinical study reports (CSRs) to correct for publication bias. For instance, our organization, the Institute for Quality and Efficiency in Health Care, routinely asks drug manufacturers to provide full CSRs of studies considered in health technology assessments. However, since cooperation is voluntary, CSRs are available only for a subset of studies analysed. In the case of the inhaled insulin Exubera, the manufacturer refused to cooperate and in 2007 we asked the European Medicines Agency (EMA) to provide the relevant CSRs, but EMA denied access. Other researchers have reported similar experiences.In 2010 EMA introduced a new policy on access to regulatory documents, including CSRs, and has also undertaken further steps. The new policy has already borne fruit: in 2011, by providing additional sections of relevant CSRs, EMA made an important contribution to a review of oseltamivir (Tamiflu).Unfortunately, speedy implementation of the new policy may be endangered. We define a CSR following the International Conference on Harmonisation (ICH) E3 guideline. Although this guideline requires individual patient data listings, it does not necessarily require that these listings be made available in a computer-readable format, as proposed by some regulators from EMA and other agencies. However, access to raw data in a computer-readable format poses additional problems; merging this issue with that of access to CSRs could hamper the relatively simple implementation of the EMA policy. Moreover, EMA plans to release CSRs only on request; we suggest making these documents routinely available on the EMA website.Public access to regulatory data also carries potential risks. In our view, the issue of patient confidentiality has been largely resolved by current European legislation. The risk of other problems, such as conflicts of interest (CoIs) of independent researchers or quality issues can be reduced by transparency measures, such as the implementation of processes to evaluate CoIs and the publication of methods and protocols.In conclusion, regulatory data are an indispensable source for systematic reviews. Because of EMA's policy change, a milestone for data transparency in clinical research is within reach; let's hope it is not unnecessarily delayed.

Impact of document type on reporting quality of clinical drug trials: a comparison of registry reports, clinical study reports, and journal publications.

OBJECTIVE: To investigate to what extent three types of documents for reporting clinical trials provide sufficient information for trial evaluation. DESIGN: Retrospective analysis DATA SOURCES: Primary studies and corresponding documents (registry reports, clinical study reports, journal publications) from 16 health technology assessments of drugs conducted by the German Institute for Quality and Efficiency in Health Care between 2006 and February 2011. Data analysis We assessed reporting quality for each study and each available document for six items on methods and six on outcomes, and dichotomised them as "completely reported" or "incompletely reported." For each document type, we calculated the proportion of studies with complete reporting for methods and outcomes, per item and overall, and compared the findings. RESULTS: We identified 268 studies. Publications, study reports and registry reports were available for 192 (72%), 101 (38%), and 78 (29%) studies, respectively. Reporting quality was highest in study reports, which overall provided complete information for 90% of items (1086/1212). Registry reports provided more complete information on outcomes than on methods (overall 330/468 (71%) v 147/468 (31%)); the same applied to publications (594/1152 (52%) v 458/1152 (40%)). In the matched pairs analysis, reporting quality was poorer in registry reports than in study reports for overall methods and outcomes (P<0.001 in each case). Compared with publications, reporting quality was poorer in registry reports for overall methods (P<0.001), but better for outcomes (P=0.005). CONCLUSION: Registry reports and publications insufficiently report clinical trials but may supplement each other. Measures to improve reporting include the mandatory worldwide implementation of adequate standards for results registration.

Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials.

OBJECTIVES: To assess the benefits and harms of reboxetine versus placebo or selective serotonin reuptake inhibitors (SSRIs) in the acute treatment of depression, and to measure the impact of potential publication bias in trials of reboxetine. DESIGN: Systematic review and meta-analysis including unpublished data. DATA SOURCES: Bibliographic databases (Medline, Embase, PsycINFO, BIOSIS, and Cochrane Library), clinical trial registries, trial results databases, and regulatory authority websites up until February 2009, as well as unpublished data from the manufacturer of reboxetine (Pfizer, Berlin). ELIGIBILITY CRITERIA: Double blind, randomised, controlled trials of acute treatment (six weeks or more) with reboxetine versus placebo or SSRIs in adults with major depression. OUTCOME MEASURES: Remission and response rates (benefit outcomes), as well as rates of patients with at least one adverse event and withdrawals owing to adverse events (harm outcomes). DATA EXTRACTION AND DATA SYNTHESIS: The procedures for data extraction and assessment of risk of bias were always conducted by one person and checked by another. If feasible, data were pooled by meta-analyses (random effects model). Publication bias was measured by comparing results of published and unpublished trials. RESULTS: We analysed 13 acute treatment trials that were placebo controlled, SSRI controlled, or both, which included 4098 patients. Data on 74% (3033/4098) of these patients were unpublished. In the reboxetine versus placebo comparison, no significant differences in remission rates were shown (odds ratio 1.17, 95% confidence interval 0.91 to 1.51; P=0.216). Substantial heterogeneity (I(2)=67.3%) was shown in the meta-analysis of the eight trials that investigated response rates for reboxetine versus placebo. A sensitivity analysis that excluded a small inpatient trial showed no significant difference in response rates between patients receiving reboxetine and those receiving placebo (OR 1.24, 95% CI 0.98 to 1.56; P=0.071; I(2)=42.1%). Reboxetine was inferior to SSRIs (fluoxetine, paroxetine, and citalopram) for remission rates (OR 0.80, 95% CI 0.67 to 0.96; P=0.015) and response rates (OR 0.80, 95% CI 0.67 to 0.95; P=0.01). Reboxetine was inferior to placebo for both harm outcomes (P<0.001 for both), and to fluoxetine for withdrawals owing to adverse events (OR 1.79, 95% CI 1.06 to 3.05; P=0.031). Published data overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm. CONCLUSIONS: Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published evidence is affected by publication bias, underlining the urgent need for mandatory publication of trial data.