Reporting Discrepancies between the ClinicalTrials.gov Results Database and Peer Reviewed Publications

BACKGROUND: Result summaries are now required to be reported in ClinicalTrials.gov for many 1 trials of drugs and devices. PURPOSE: To evaluate the consistency of reporting in trials that are both registered in the ClinicalTrials.gov results database and published in the literature. DATA SOURCES: ClinicalTrials.gov results database, matched publications identified through both ClinicalTrials.gov and a manual search of two electronic databases. STUDY SELECTION: 10% random sample of Phase III or IV trials with results in the ClinicalTrials.gov results database, completed before January 1, 2009, with two or more arms. DATA EXTRACTION: One reviewer extracted data from ClinicalTrials.gov results database and matching publications. A subsample was independently verified. Basic design features and results were compared between reporting sources and discrepancies were summarized. DATA SYNTHESIS: Of 110 reviewed trials with results, most were industry-sponsored, parallel design, drug studies. The most common inconsistency was the number of secondary outcome measures reported (80%). There were 16 trials (15%) that reported the primary outcome description inconsistently and 22 (20%) in which the primary outcome value was reported inconsistently. A total of 38 trials inconsistently reported the number of individuals with a serious adverse event (SAE), of which 33 (87%) reported more SAEs in ClinicalTrials.gov. Among the 84 trials that reported SAEs in ClinicalTrials.gov, 11 publications did not mention SAEs, 5 reported SAEs as zero or not occurring, and 21 reported a different number of SAEs. In 29 trials that reported deaths in ClinicalTrials.gov, 28% differed with the matched publication. LIMITATIONS: Small sample that includes earliest results posted to the database and therefore may reflect inexperience with the submission process. CONCLUSIONS: Reporting discrepancies between the ClinicalTrials.gov results database and matching publications are common. It is unclear which reporting source contains the most accurate account of trial results. ClinicalTrials.gov may provide a more comprehensive description of trial adverse events than the publication.This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American College of Physicians and can be found at: http://annals.org/

Methods for the Drug Effectiveness Review Project

Abstract The Drug Effectiveness Review Project was initiated in 2003 in response to dramatic increases in the cost of pharmaceuticals, which lessened the purchasing power of state Medicaid budgets. A collaborative group of state Medicaid agencies and other organizations formed to commission high-quality comparative effectiveness reviews to inform evidence-based decisions about drugs that would be available to Medicaid recipients. The Project is coordinated by the Center for Evidence-based Policy (CEbP) at Oregon Health & Science University (OHSU), and the systematic reviews are undertaken by the Evidence-based Practice Centers (EPCs) at OHSU and at the University of North Carolina. The reviews adhere to high standards for comparative effectiveness reviews. Because the investigators have direct, regular communication with policy-makers, the reports have direct impact on policy and decision-making, unlike many systematic reviews. The Project was an innovator of methods to involve stakeholders and continues to develop its methods in conducting reviews that are highly relevant to policy-makers. The methods used for selecting topics, developing key questions, searching, determining eligibility of studies, assessing study quality, conducting qualitative and quantitative syntheses, rating the strength of evidence, and summarizing findings are described. In addition, our on-going interactions with the policy-makers that use the reports are described

Association of Down's syndrome and water fluoride level: a systematic review of the evidence

BACKGROUND: A review of the safety and efficacy of drinking water fluoridation was commissioned by the UK Department of Health to investigate whether the evidence supported a beneficial effect of water fluoridation and whether there was any evidence of adverse effects. Down's syndrome was one of the adverse effects reported. The aim of this review is to examine the evidence for an association between water fluoride level and Down's syndrome. METHODS: A systematic review of research. Studies were identified through a comprehensive literature search, scanning citations and online requests for papers. Studies in all languages which investigated the incidence of Down's syndrome in areas with different levels of fluoride in their water supplies were included. Study inclusion and quality was assessed independently by 2 reviewers. A qualitative analysis was conducted. RESULTS: Six studies were included. All were ecological in design and scored poorly on the validity assessment. The estimates of the crude relative risk ranged from 0.84 to 3.0. Four studies showed no significant associations between the incidence of Down's syndrome and water fluoride level and two studies by the same author found a significant (p < 0.05) positive association (increased Down's syndrome incidence with increased water fluoride level). Only two of the studies controlled for confounding factors and only one of these presented summary outcome measures. CONCLUSIONS: The evidence of an association between water fluoride level and Down's syndrome incidence is inconclusive

Uterine Rupture by Intended Mode of Delivery in the UK: A National Case-Control Study

A case-control study using UK data estimates the risk of uterine rupture in subsequent deliveries amongst women who have had a previous caesarean section

Aggregator: a machine learning approach to identifying MEDLINE articles that derive from the same underlying clinical trial

Objective It is important to identify separate publications that report outcomes from the same underlying clinical trial, in order to avoid over-counting these as independent pieces of evidence. Methods We created positive and negative training sets (comprised of pairs of articles reporting on the same condition and intervention) that were, or were not, linked to the same clinicaltrials.gov trial registry number. Features were extracted from MEDLINE and PubMed metadata; pairwise similarity scores were modeled using logistic regression. Results Article pairs from the same trial were identified with high accuracy (F1 score = 0.843). We also created a clustering tool, Aggregator, that takes as input a PubMed user query for RCTs on a given topic, and returns article clusters predicted to arise from the same clinical trial. Discussion Although painstaking examination of full-text may be needed to be conclusive, metadata are surprisingly accurate in predicting when two articles derive from the same underlying clinical trial

A study of the value of requesting information from drug manufacturers for systematic reviews; 9 years of experience from the drug effectiveness review project

Abstract Background Systematic reviews (SRs) depend on comprehensive searches for evidence to provide balanced, accurate results. Requesting published and unpublished studies from pharmaceutical manufacturers has been proposed as a method to engage industry stakeholders and potentially reduce reporting bias. The Drug Effectiveness Review Project (DERP) has been requesting such evidence since 2003; the purpose of this study was to retrospectively evaluate the type and impact of the evidence received. Methods Data from “dossiers” submitted by pharmaceutical manufacturers for a set of 40 SRs conducted for DERP from July 2006 to June 2015 were retrospectively evaluated. Characteristics of data submitted in dossiers, including numbers, types, and characteristics of studies submitted and then included in DERP SRs, were abstracted. Time trends, study quality, publication status, and whether the submission represented a unique study or supplemental data to a published study were assessed. The impact of this evidence on SR conclusions was assessed using dual review. Differences were resolved through a consensus. Results Over 9 years, 160 dossiers were received, relating to 40 DERP SRs. Out of 7360 studies/datasets submitted, 2.2% (160) were included in a SR. The ratio of submitted-to-included increased over time. Most were unique studies (23% were supplemental data sets), and almost 42% of the studies were unpublished. The majority of the studies were rated fair quality, with 7.3% rated good and 14% rated poor quality by the original SR authors. Considering all literature search sources, 7.2% of all studies included in the 40 SRs came from a dossier, and 16% of dossier studies were included in a meta-analysis. The dossier studies resulted in changes to conclusions in 42% of the SRs. Out of 46 unpublished unique studies included in a SR, 25 (54%) influenced the conclusions in favor of the manufacturers drug, 8% favored a competitor drug, and 40% favored neither. In 92% of cases favoring the manufacturer’s drug, the dossier study was the only evidence for that drug in a specific population or outcome. Conclusions In SRs conducted for DERP, few studies submitted by pharmaceutical manufacturers were ultimately included in a SR. The included data helped to reduce reporting and publication bias by filling important gaps and in some cases led to altered conclusions