Evidence for the Selective Reporting of Analyses and Discrepancies in Clinical Trials: A Systematic Review of Cohort Studies of Clinical Trials

Most publications about selective reporting in clinical trials have focussed on outcomes. However, selective reporting of analyses for a given outcome may also affect the validity of findings. If analyses are selected on the basis of the results, reporting bias may occur. The aims of this study were to review and summarise the evidence from empirical cohort studies that assessed discrepant or selective reporting of analyses in randomised controlled trials (RCTs).

Methods and Findings

A systematic review was conducted and included cohort studies that assessed any aspect of the reporting of analyses of RCTs by comparing different trial documents, e.g., protocol compared to trial report, or different sections within a trial publication. The Cochrane Methodology Register, Medline (Ovid), PsycInfo (Ovid), and PubMed were searched on 5 February 2014. Two authors independently selected studies, performed data extraction, and assessed the methodological quality of the eligible studies. Twenty-two studies (containing 3,140 RCTs) published between 2000 and 2013 were included. Twenty-two studies reported on discrepancies between information given in different sources. Discrepancies were found in statistical analyses (eight studies), composite outcomes (one study), the handling of missing data (three studies), unadjusted versus adjusted analyses (three studies), handling of continuous data (three studies), and subgroup analyses (12 studies). Discrepancy rates varied, ranging from 7% (3/42) to 88% (7/8) in statistical analyses, 46% (36/79) to 82% (23/28) in adjusted versus unadjusted analyses, and 61% (11/18) to 100% (25/25) in subgroup analyses. This review is limited in that none of the included studies investigated the evidence for bias resulting from selective reporting of analyses. It was not possible to combine studies to provide overall summary estimates, and so the results of studies are discussed narratively.

Conclusions

Discrepancies in analyses between publications and other study documentation were common, but reasons for these discrepancies were not discussed in the trial reports. To ensure transparency, protocols and statistical analysis plans need to be published, and investigators should adhere to these or explain discrepancies.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

In the past, clinicians relied on their own experience when choosing the best treatment for their patients. Nowadays, they turn to evidence-based medicine—the systematic review and appraisal of trials, studies that investigate the benefits and harms of medical treatments in patients. However, evidence-based medicine can guide clinicians only if all the results from clinical trials are published in an unbiased and timely manner. Unfortunately, the results of trials in which a new drug performs better than existing drugs are more likely to be published than those in which the new drug performs badly or has unwanted side effects (publication bias). Moreover, trial outcomes that support the use of a new treatment are more likely to be published than those that do not support its use (outcome reporting bias). Recent initiatives—such as making registration of clinical trials in a trial registry (for example, ClinicalTrials.gov) a prerequisite for publication in medical journals—aim to prevent these biases, which pose a threat to informed medical decision-making.

Why Was This Study Done?

Selective reporting of analyses of outcomes may also affect the validity of clinical trial findings. Sometimes, for example, a trial publication will include a per protocol analysis (which considers only the outcomes of patients who received their assigned treatment) rather than a pre-planned intention-to-treat analysis (which considers the outcomes of all the patients regardless of whether they received their assigned treatment). If the decision to publish the per protocol analysis is based on the results of this analysis being more favorable than those of the intention-to-treat analysis (which more closely resembles “real” life), then “analysis reporting bias” has occurred. In this systematic review, the researchers investigate the selective reporting of analyses and discrepancies in randomized controlled trials (RCTs) by reviewing published studies that assessed selective reporting of analyses in groups (cohorts) of RCTs and discrepancies in analyses of RCTs between different sources (for example, between the protocol in a trial registry and the journal publication) or different sections of a source. A systematic review uses predefined criteria to identify all the research on a given topic.

What Did the Researchers Do and Find?

The researchers identified 22 cohort studies (containing 3,140 RCTs) that were eligible for inclusion in their systematic review. All of these studies reported on discrepancies between the information provided by the RCTs in different places, but none investigated the evidence for analysis reporting bias. Several of the cohort studies reported, for example, that there were discrepancies in the statistical analyses included in the different documents associated with the RCTs included in their analysis. Other types of discrepancies reported by the cohort studies included discrepancies in the reporting of composite outcomes (an outcome in which multiple end points are combined) and in the reporting of subgroup analyses (investigations of outcomes in subgroups of patients that should be predefined in the trial protocol to avoid bias). Discrepancy rates varied among the RCTs according to the types of analyses and cohort studies considered. Thus, whereas in one cohort study discrepancies were present in the statistical test used for the analysis of the primary outcome in only 7% of the included studies, they were present in the subgroup analyses of all the included studies.

What Do These Findings Mean?

These findings indicate that discrepancies in analyses between publications and other study documents such as protocols in trial registries are common. The reasons for these discrepancies in analyses were not discussed in trial reports but may be the result of reporting bias, errors, or legitimate departures from a pre-specified protocol. For example, a statistical analysis that is not specified in the trial protocol may sometimes appear in a publication because the journal requested its inclusion as a condition of publication. The researchers suggest that it may be impossible for systematic reviewers to distinguish between these possibilities simply by looking at the source documentation. Instead, they suggest, it may be necessary for reviewers to contact the trial authors. However, to make selective reporting of analyses more easily detectable, they suggest that protocols and analysis plans should be published and that investigators should be required to stick to these plans or explain any discrepancies when they publish their trial results. Together with other initiatives, this approach should help improve the quality of evidence-based medicine and, as a result, the treatment of patients.

Additional Information

Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001666.

Citation: Dwan K, Altman DG, Clarke M, Gamble C, Higgins JPT, Sterne JAC, et al. (2014) Evidence for the Selective Reporting of Analyses and Discrepancies in Clinical Trials: A Systematic Review of Cohort Studies of Clinical Trials. PLoS Med 11(6): e1001666. https://doi.org/10.1371/journal.pmed.1001666

Academic Editor: Adriane J. Fugh-Berman, Georgetown University Medical Center, United States of America

Received: November 21, 2013; Accepted: May 8, 2014; Published: June 24, 2014

Copyright: © 2014 Dwan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. Data is included within the tables included in the manuscript.

Funding: This review was funded by the MRC Hub for Trials Methodology Research Network (Grant Number: R18). DGA is supported by a Cancer Research UK programme grant (C5529). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: Three of the authors (KD, PRW and DGA) are authors on four of the included studies [6],[15],[17],[29].

Abbreviations: RCT, randomised controlled trial

Introduction

Selective reporting in clinical trial reports has been described mainly with respect to the reporting of a subset of the originally recorded outcome variables in the final trial report. Selective outcome reporting can create outcome reporting bias, if reporting is driven by the statistical significance or direction of the estimated effect (e.g., outcomes where the results are not statistically significant are suppressed or reported only as p>0.05) [1]. A recent review showed that statistically significant outcomes were more likely to be fully reported than non-significant outcomes (range of odds ratios: 2.2 to 4.7). In 40% to 62% of studies at least one primary outcome was changed, introduced, or omitted between the protocol and the trial publication [2]. Another review reached similar conclusions and also found that studies with significant results tended to be published earlier than studies with non-significant results [3].

Other types of selective reporting may also affect the validity of reported findings from clinical trials. Discrepancies can occur in analyses, if data for a given outcome are analysed and reported differently from the trial protocol or statistical analysis plan. For example, a trial's publication may report a per protocol analysis rather than a pre-planned intention-to-treat analysis, or report on an unadjusted analysis rather than a pre-specified adjusted analysis. In the latter example, discrepancies in analyses may also occur if adjustment covariates are used that are different to those originally planned. If analyses are selected for inclusion in a trial report based on the results being more favourable than those obtained by following the analysis plan, then analysis reporting bias occurs in a similar way to outcome reporting bias.

Examples of the various ways in which selective reporting can occur in randomised controlled trials (RCTs) have previously been described [4]. Furthermore, a systematic review of cohorts of RCTs comparing protocols or trial registry entries with corresponding publications found that discrepancies in methodological details, outcomes, and analyses were common [5]. However, no study to our knowledge has yet systematically reviewed the empirical evidence for the selective reporting of analyses in clinical trials or examined discrepancies with documents apart from the protocol or trial registry entry.

This study aimed to fill this gap by reviewing and summarising the evidence from empirical cohort studies that have assessed (1) selective reporting of analyses in RCTs and (2) discrepancies in analyses of RCTs between different sources (i.e., grant proposal, protocol, trial registry entry, information submitted to regulatory authorities, and the publication of the trial's findings), or between sections within a publication.

Methods

Study Inclusion Criteria

We included research that compared different sources of information when assessing any aspect of the analysis of outcome data in RCTs.

Cohorts containing RCTs alone, or a mixture of RCTs and non-RCTs were eligible. For those cohorts where it was not possible to identify the study type (i.e., to determine whether any RCTs were included), we sought clarification from the authors of the cohort study. Studies were excluded where inclusion of RCTs could not be confirmed, or where only non-RCTs had been included.

Search Strategy

The search was conducted without language restrictions. In May 2013, the Cochrane Methodology Register, Medline (Ovid), PsycInfo (Ovid), and PubMed were searched (Text S2). These searches were updated on 5 February 2014, except for the search of the Cochrane Methodology Register, which has been unchanged since July 2012. Cochrane Colloquium conference proceedings from 2011, 2012, and 2013 were hand-searched, noting that abstracts from previous Cochrane Colloquia had already been included in the Cochrane Methodology Register. A citation search of a key article [1] was also performed. The lead or contact authors of all identified studies and other experts in this area were asked to identify further studies.

Two authors independently applied the inclusion criteria to the studies identified. Any discrepancies between the authors were resolved through discussion, until consensus was reached.

Data Extraction

One author extracted details of the characteristics and results of the empirical cohort studies. Information on the main objectives of each empirical study was also extracted, and the studies were separated according to whether they related to selective reporting or discrepancies between sources. Selective reporting of analyses was defined as when the reported analyses had been selected from multiple analyses of the same data for a given outcome. A discrepancy was defined as when information was absent in one source but reported in another, or when the information given in two sources was contradictory. If selective reporting bias was studied, the definition of “significance” used in each cohort was noted (i.e., direction of results or whether the study used a particular p-value [e.g., p

Data extraction was checked by another author. No masking was used, and disagreements were resolved through discussion.

Methodological Quality

In the absence of a recognised tool to evaluate the methodological quality of the empirical studies eligible for this review, we developed and used three criteria to assess methodological quality:

  1. Independent data extraction by at least two people
    1. High quality: data extraction completed independently by at least two people.
    2. Methodological concerns: data extraction not completed independently by at least two people.
    3. Uncertain quality: not stated.
    1. High quality: clearly defined.
    2. Methodological concerns: not clearly defined.
    3. Not applicable: this was not included in the objectives of the study.
    1. High quality: all comparisons and outcomes mentioned in the methods section of the empirical study report are fully reported in the results section of the publication.
    2. Methodological concerns: not all comparisons and outcomes mentioned in the methods section of the empirical study report are fully reported in the results section of the publication.

    Two authors independently assessed these items for all studies. An independent assessor (Matthew Page) was invited to assess one study [6] because the first author was directly involved in its design. Any discrepancies were resolved through a consensus discussion with a third reviewer not involved with the included studies.

    Data Analysis

    This review provides a descriptive summary of the included empirical cohort studies. We refrained from any statistical combination of the results from the different cohorts because of the differences in their design.

    Results

    Search Results

    The search strategy identified 600 records. After duplicates were removed, 446 records were screened, and 390 were excluded. Full texts were accessed for 56 articles.

    The PRISMA flow diagram is shown in Figure 1.