Systematic reviews which, here, include meta-analyses, synthesise research results to produce a pooled effects estimate. Well conducted reviews of randomised controlled trials receive preferential consideration when anaesthesiology treatment guidelines are being developed. The American Society of Anesthesiologists, for example, classifies literature containing multiple randomised controlled trials and aggregate findings by meta-analysis as Category A Level 1 scientific evidence.1 One notable concern with such reviews is that, because of publication bias, statistically significant outcomes are over represented in estimating the pooled summary effect. Publication bias occurs as a result of studies with statistically nonsignificant results not being published, either because authors do not submit the studies or peer reviewers and journal editors reject them.2 Publication bias is a known problem in the anaesthesiology literature.3 Including nonsignificant, unpublished data in a systematic review may alter conclusions regarding an intervention's effectiveness and, in extreme cases, even show an intervention to be harmful to patients.4
Although many solutions have been proposed to ameliorate publication bias in systematic reviews, the most promising may be for authors of systematic reviews to search clinical trials registries for unpublished trial data and include this in their statistical calculations. Such clinical trial registry searches are supported by authoritative bodies of systematic review methodology. The Institute of Medicine of the National Academy of Sciences states in its Standards for Systematic Reviews that action should be taken to ‘address potentially biased reporting of research results’ such as ‘search[ing] grey literature databases, clinical trials registries and other sources of unpublished information about studies’.5 The Cochrane Collaboration's Handbook for Systematic Reviews of Interventions also recommends searching trials registries for unpublished studies.6 Several key events have transpired to promote the registration of clinical trials and other types of studies involving humans. In 2005, the International Committee of Medical Journal Editors began to require that any journal participating in its vast network make study inclusion in a recognised clinical trials registry prior to the start of a trial as a precondition for publication.7 About 2 years later, the US Food and Drug Administration mandated that all clinical trials involving humans be registered in ClinicalTrials.gov, the US Trials registry platform.8 The WHO released a position statement encouraging registration of clinical trials in a freely searchable, public clinical trials registry.9 The Report of the United Nations Secretary General's High-Level Panel on Access to Medicines recently called for governments across the globe to enact legislation requiring clinical trial registration, which should include availability of study protocols and trial data (regardless of the nature of findings).10 Positions favouring trial registration have also been expressed in anaesthesiology,11 and some anaesthesiology journals, including the European Journal of Anaesthesiology, now require trial registration before enrolment of the first patient as a condition for publication. A cursory search of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (WHO ICTRP) for the search term ‘anaesthesia’ yielded 13 676 registered trials, suggesting that trial registries may be a viable source of additional anaesthesiology studies.
In a recent study, Hedin et al.12 evaluated high-impact factor anaesthesiology journals for systematic reviews that omitted publication bias evaluations. These authors12 conducted analyses to evaluate the likely extent of publication bias for those reviews that did not evaluate for publication bias. The authors12 found possible publication bias in several meta-analyses, including Zhang et al.13 In this latter study,12 it was found that after accounting for publication bias the original result13 overestimated the effectiveness of pregabalin in acute postoperative pain management by 582%. Using date criteria reported in the meta-analysis of Zhang et al.13 and the help of an information specialist, we conducted a search of ClinicalTrials.gov and WHO ICTRP for registered trials evaluating the efficacy of pregabalin for postoperative pain management. Our search resulted in four completed registered trials,14,15 not included in the meta-analysis,13 lending support for using clinical trial registries during the search process. We decided to investigate the use of trial registry data in publications specific to systematic reviews in anaesthesiology.
The specific aims of this study were to examine the rate of clinical trial registry searches reported in systematic reviews published in high-yield anaesthesiology journals and whether these reviews found eligible trials (or trial data) for inclusion; to compare rates of registry searches between these published reviews and the Cochrane Anaesthesia, Critical and Emergency Care Group's (ACE) reviews; to conduct our own trial registry searches for a subset of reviews that omitted these searches to determine whether eligible studies may have been overlooked and to investigate the percentage of completed anaesthesia trials in ClinicalTrials.gov that reported results.
The study did not meet the regulatory definition of human study participants research as defined in 45 code of federal regulations (CFR) 46.102(d) and (f) of the Department of Health and Human Services’ CFR and, therefore, was not subject to Institutional Review Board oversight. We applied relevant Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines16 for reporting our findings and Statistical Analyses and Methods in the Published Literature guidelines17 to ensure best practice in reporting our study results.
The study was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000021932).
The study was designed as a cross-sectional study of systematic reviews published in both anaesthesiology journals and the Cochrane Library.
Screening and data extraction
One author (MV) identified the top 10 anaesthesiology journals (between 2007 and 2015) according to the 2014 h5-index of Google Scholar Metrics: Anaesthesiology subcategory. The h5-index is a journal-level metric based on the Hirsch index for authors, and it uses an algorithm to determine journal influence based on the number of citations received from articles published in the journal. Additionally, MV searched for systematic reviews produced by the Cochrane ACE Group using the Cochrane Database of Systematic Reviews. All searches for systematic reviews occurred on 15 July 2016, in PubMed and the Cochrane Database of Systematic Reviews (Appendix 1, http://links.lww.com/EJA/A123). This search strategy was adapted from a previously published approach sensitive to identify systematic reviews and meta-analyses.18
Two investigators (BAU and MTS) screened PubMed records of retrieved systematic reviews based on their title and abstract. To qualify as a systematic review, articles had to summarise evidence across multiple primary studies and provide information on search strategy, such as search terms, databases or inclusion/exclusion criteria. Meta-analyses were considered studies that applied a quantitative synthesis of results across multiple primary studies.19 We included systematic reviews of clinical trials and observational studies because both are found in trial registries. All reviews from the Cochrane ACE Group were screened (by BND) to ensure that they focused on anaesthesia-relevant topics.
Variables and data extraction
After title and abstract screening, systematic reviews were subject to full-text screening and data extraction (BND). All investigators were involved in the design of an extraction guideline to ensure consistent and accurate application of the process. The guideline was piloted on 15 systematic reviews, and a meeting followed to reaffirm the intent of each data element. Consistent with previous studies,20–22 the WHO ICTRP (Version 2.1) was used to determine qualified clinical trial registries.23 ClinicalTrials.gov was also considered a qualified registry.
For each systematic review, MTS and MV extracted the following information: title; author(s); review's country of origin (based on first author's published address); whether a clinical trial registry had been searched by reviewers; if yes, the registry or registries searched; whether relevant unpublished data were found. During extraction, BND searched keywords using EndNote's search feature. The EndNote library contained all reviews identified by PubMed and Cochrane ACE Group searches. BND searched this library using keywords selected based on careful consideration of ways that authors referenced trial registries in the pilot test (see Appendix 2 for all keywords, http://links.lww.com/EJA/A123). MTS and MV followed these searches with a full-text review to ensure that keyword searches correctly identified a registry search reported in a review's methods section rather than a reference to a trial registry or a registered trial cited in the reference list.
Also, BND searched ClinicalTrials.gov to identify completed primary studies that may have been overlooked by systematic reviewers who omitted registry searches. We randomly sampled 30 systematic reviews, retrieved during the PubMed (MEDLINE) search, that did not report trial registry searches. With the help of an information specialist, we identified keywords and search parameters (including date ranges) from the original Methods sections of these reviews and adapted them to the search capabilities of ClinicalTrials.gov. Searches occurred between 12 and 16 September 2016 (Table 1). Some reviews did not provide a date limiter. For these, we limited search results to the date that review was accepted for publication. For each review, we noted the number of studies that were possible candidates for inclusion.
Finally, on 29 August 2016, BND searched ClinicalTrials.gov for completed clinical trials using the keywords ‘anaesthesia’ and ‘anesthesia’. The search was limited to the same date range as our searches in PubMed and the Cochrane Database of Systematic Reviews (1 January 2007 to 31 December 2015). BND then conducted the same search, limited to completed trials with results.
To estimate the compliance rate of results reporting in anaesthesia trials, we compared the total number of completed trials with the numbers of trials with reported results. In addition, we examined the reporting of trial results to clinical trial registries by country.
We attempted to eliminate bias in several ways. First, in efforts to minimise selection bias, we conducted our MEDLINE search using a validated search strategy found to be sensitive to the identification of systematic reviews. Second, standardised extraction forms were additional methods used to reduce bias and improve the validity and reliability of study data.
Our primary endpoint was the frequency of clinical trial registry searches reported in systematic reviews. We also measured the number of trials catalogued in clinical trial registries that were possible candidates for inclusion in a subset of systematic reviews from our sample.
Study size and statistical analysis
Our sample was composed of systematic reviews published between 2007 and 2015. This date range was selected because of the 2007 passage of the food and drug administration (FDA) Amendments Act requiring applicable clinical trials involving humans be registered on ClinicalTrials.gov prior to patient enrollment.8
Descriptive statistics were used to summarise data. A χ2 test was used to examine percentage differences between Cochrane systematic reviews and journal-published systematic reviews reporting having searched for unpublished trials. All analyses were conducted using STATA 13.1 (College Station, Texas, USA).
Included systematic reviews
The initial search of PubMed and the Cochrane Database of Systematic Reviews returned 507 and 73 systematic reviews, respectively. Figure 1 shows the subsequent screening and fate of these 580 systematic reviews to leave 415 from the PubMed search and 73 from the Cochrane database.
Of the 415 systematic reviews included from PubMed, 49 (11.8%) reported a search of at least one clinical trial registry for unpublished studies with ClinicalTrials.gov being searched in the majority of these cases (n = 40). In total, 14 reviews searched the international standard registered clinical/social study number (ISRCTN) Registry (controlled-trials.com). The WHO ITCRP was searched in six reviews. Two reviews cited a search of both CenterWatch Clinical Trials Listing Service and controlled-trials.com in addition to a search of ClinicalTrials.gov. Another systematic review reported a search of the UMIN Clinical Trials Registry, and another searched the National Research Register. These four (CenterWatch, controlled-trials.com, UMIN and the National Research Register) are not listed within the WHO registry platform. The British Journal of Anaesthesia had the highest percentage of systematic reviews that included trial registry searches (18.9%, 17/90), followed by the Canadian Journal of Anaesthesia (17.6%, 6/34) and Acta Anaesthesiologica Scandinavica (17.3%, 9/52). Complete results are displayed in Table 2.
Within the sample of 49 PubMed reviews that included a search of clinical trials registries, 12 found potentially usable unpublished data but only five of the reviews included this unpublished data in the final data synthesis. For 19 systematic reviews, we could not determine the extent to which unpublished data was found or incorporated.
We also investigated the frequency of trial registry searches by country. In the PubMed sample, reviews from the United Kingdom contained the largest number of registry searches (31.0%, 15/47). Only 5.6% (4/71) of the reviews from the United States and 9.2% (6/65) of the reviews from Canada reported registry searches. Both reviews from Taiwan and one of the two reviews from Korea reported registry searches. None of the reviews from Germany (22), the Netherlands (14), South Africa (10) and India (5) reported clinical trial registry searches (Fig. 2).
Cochrane Anaesthesia, Critical and Emergency Care Group care group
Reviews conducted by the Cochrane ACE Group featured clinical trial registry searches with greater consistency than reviews published in journals. Of the 73 Cochrane reviews, 43 (58.9%) reported searching registries (Table 2). Of these, 26 found unpublished data and 20 used the unpublished data (Table 2). Most (36 of the 43) searched ClinicalTrials.gov, and 29 searched multiple registries. In total, 29 reported searches of ISRCTN (controlled-trials.com), and eight reported searches of WHO ICTRP. The Cochrane reviews from the United Kingdom and the United States had higher rates of registry searches (10/17 and 5/7, respectively) than reviews published in journals from these countries. χ2 analysis indicated a significant difference between Cochrane reviews and journal-published reviews on the use of trials registries during the search process [P < 0.0001, % difference (95% confidence interval) = 47.1 (34.5 to 58.9)%].
Studies identified via ClinicalTrials.gov
Searches of ClinicalTrials.gov using search terms and date limiters from 30 randomly selected reviews that did not report clinical trial registry searches indicated that many could have located additional studies for consideration had these searches been performed. Although three of these searches did not return any relevant clinical trials, 11 (36.7%) returned more than 100 search results each, with one returning 938.51 These search results were screened and many appeared to be directly applicable to the reviews whose respective search terms retrieved the record (Table 1). The number of potentially relevant studies which could have been considered ranged from 0 to 43 with a median of 3 (IQR: 1 to 8).
ClinicalTrials.gov registry data reporting for anaesthesia
The search of ClinicalTrials.gov for completed clinical trials in anaesthesia from 1 January 2007 to 31 December 2015, yielded 4712 studies. Of these, 727 (15.4%) reported trial results. North American (USA, Canada, Mexico) anaesthesia trials as a whole had results with a reporting rate of 29.4% (459/1563) in ClinicalTrials.gov, with the USA in isolation achieving a rate of 34.5% (439/1274). Trial results reporting, was much lower in other regions: Africa 15% (16/107), East Asia 13.9% (84/603), The Middle East 8.0% (21/263) and Europe 7.3% (111/1524).
Historically, some high-impact factor journals have marginalised studies with nonsignificant or unimportant findings as a credible source of evidence by omitting them from publication. This issue has also been perpetuated by investigators who are more likely to abandon such studies. As the vast physician readership and journal subscribers tend to incorporate published study findings into their decision-making process,3 these omissions may misdirect clinical decision-making and patient care. Such omissions also limit the availability of primary studies for systematic reviews. For the clinical implications of a specific intervention to be accurately assessed, trials with sound methodology should be published regardless of the statistical significance of results.
The real-life consequences of publication bias have been noted to have severe and possibly lethal outcomes for patients. One example discussed by Sutton,54 involved a trial in 1980 in which lorcainide (a Class 1C antiarrhythmic drug) was compared with a placebo in patients with myocardial infarction. The pharmaceutical company that produced the drug halted the trial after nine deaths occurred from the 49 patients in the treatment group and the trial data was never published. Almost a decade later, two trials conducted for related compounds, encainide and flecainide, also resulted in excess patient deaths in the treatment groups. Had the lorcainide trial data been published, these deaths may have been prevented. Although other examples may have less serious implications, the role publication bias plays in understanding the effectiveness of clinical interventions is nonetheless concerning. Systematic reviews, which summarise an intervention's effectiveness, should make use of all available resources to mitigate this form of bias.
Clinical trial registries are a promising source of unpublished data that, placed in the context of a body of literature, may yield a more accurate representation of clinical interventions. The majority of the 415 anaesthesiology systematic reviews neglected to search clinical trial registries. Specifically, only 11.8% of the reviews published in anaesthesiology journals contained searches of clinical trial registries. This proportion is higher than in the clinical neurology literature (6%) reported by Sinnett et al.20, but lower than in the emergency medicine literature (19%).21 The variability of registry searches ranges from 6 in clinical neurology to 35% in general medicine.22 Compared to anaesthesiology journals, systematic reviews reporting the use of a clinical trial registry search in their methodology, as published in high-impact factor general medical journals, was nearly three times greater.12 Among systematic reviews that reported registry searches, many found potentially usable data to consider for inclusion. However, few reviewers used data from registries in the final analysis. Nonetheless, we see promise in searching these registries because other studies have reported inclusion of registry data in systematic reviews.20 Our sample of Cochrane ACE reviews showed a much higher reported rate of trial registry searches than other anaesthesiology reviews. Many sources indicate that Cochrane reviews are held to stricter methodology and are thus better quality,55–58 a finding supported by our results.
We investigated whether it was likely that systematic reviews which did not report trial registry searches would have located additional studies for consideration had such searches been performed. Overall, we found many possible studies that could have been considered for inclusion. The Cochrane Collaboration59 and others60 advocate trial registry searching, yet our results suggest that despite the suggestions from these authoritative groups, authors of systematic reviews often do not perform registry searches as a means to limit publication bias in anaesthesiology reviews.
The compliance rate for reporting results of anaesthesia studies to clinical trials registries was only 15.4%. This finding is consistent with previous research: a 2011 investigation of ClinicalTrials.gov registrations found that 22% of clinical trials had reported results within the 1-year timeline mandated by the US Food and Drug Administration Amendments Act. Phase II trials had lower compliance rates compared with phase III and phase IV trials. Industry-funded trials were more likely to report results than trials funded by other sources.61 A second study of trials completed by September 2008 found that 7.6% of trials posted results on ClinicalTrials.gov by 31 May 2010, with industry-funded trials being three times more likely to postresults.62 A cumulative proportion analysis by days following study completion suggested that 1 year after completion, only 12% of all trials and 14.1% of phase IV trials had reported results.62 More recent evidence suggests that only 13.4% of trials reported summary results within 12 months following trial completion, and of the trials reporting results, median time for reporting trial results was 17 months.63
Given that each year thousands of patients agree to participate in trials that place them at risk, such data matters. It is imperative that, regardless of outcomes, data from trials contribute to the body of evidence. Trial registration promotes greater transparency, which likely improves attitudes toward clinical research. Ultimately, positive perceptions may lead to higher rates of patient participation in trials.64 Clinical trial registration is on the rise globally, increasing exponentially in countries with established registries.65 Recommendations have been made to increase registrations through the development of more geographically available registries and incorporation of these within the WHOs ICTRP.66 However, trial registration must be accompanied by results reporting,62 which we find to be lacking in many countries. Anaesthesia trial results reporting in ClinicalTrials.gov is low: United States (34.4%), Africa (15.0%), East Asia (13.9%), the Middle East (8.0%) and Europe (7.3%).
Several proposals to improve the compliance of results reporting have been discussed.67 The International Committee of Medical Journal Editors has considered mandating data sharing as a precondition for publication among member journals.68 Others have suggested linking mandatory results reporting to funding requirements.69 Doernberg and Wendler67 make a persuasive argument for Institutional Review Boards to take an active role in ensuring trialists comply with reporting results. They recommend that during initial protocol submission, trialists submit a data-sharing plan that includes the nature of results, location or registry where results will be posted, timeline for sharing results and the party responsible for reporting results. Such proposals, if implemented, are likely to have a positive effect on results reporting.
Our study has limitations in both design and execution. First, although we took care in developing a search strategy for systematic reviews, it is possible that some systematic reviews were not retrieved during the search. It is also possible that the inclusion of other databases (e.g. Embase) during the search might have generated additional returns. Our results are also limited to the sample of the included journals and the timeframe of our study, and should not be generalised more broadly. In our screening of potentially eligible trials from registry searches, we may have identified trials that, even if discovered by the authors of original systematic reviews, would not have been included in the data analyses for various reasons; inclusion of such data is a judgement call by the authors of systematic reviews. In some cases, it would have been necessary to contact trialists for additional study details to make more sound determinations. Therefore, our results should be regarded as tentative more than absolute, as the intent was to show the possibility of missed trials rather than the exact number of them. We only searched ClinicalTrials.gov, and it is possible that the WHO ICTRP may have yielded additional studies. Finally, in our analysis of results reporting on ClinicalTrials.gov, we did not take into account the FDA Amendments Act definition of ‘applicable clinical trial’. At present, only applicable clinical trials are required by law to report trial data to ClinicalTrials.gov 1 year after completion. Generally defined, applicable clinical trials include phase II, III or IV trials which used an FDA approved drug, device or biologic, and involved at least one study site in the United States. Ambiguity in the Act, such as statutory terms not being fully defined, has made it difficult to determine whether a trial falls within this definition.70 To address this limitation, the Department of Health and Human Services issued the Notice of Proposed Rulemaking in November 2014 for public comment and reviewed almost 900 comments from individuals and organisations. The Final Rule was made available in September 2016 in the hope of increasing results reporting to ClinicalTrials.gov.70 A more thorough investigation of compliance of applicable trials reporting results to ClinicalTrials.gov would be a welcomed addition to the anaesthesiology literature.
Many choices are available when conducting literature searches for reviews. As well as traditional databases other resources, including trials registries, should be considered to improve the likelihood of identifying all pertinent studies. Current search practices in anaesthesiology reviews should be reevaluated. A better understanding of the extent to which reviewers make use of other possibilities for limiting publication bias would be helpful. Within the anaesthesiology literature, future research could be conducted to determine the extent to which summary effect sizes from systematic reviews are altered when unpublished studies are included. It has been argued that publication bias should not only be evaluated in systematic reviews but also the degree of publication bias in such reviews.71 If only negligible publication bias is found, such that inclusion of unpublished data would not considerably alter outcomes, it would be reasonable to conclude that publication bias is not a cause for concern. However, if the inclusion of unpublished data suggests the intervention is not effective then publication bias should be taken seriously. Such a lack of effect might suggest a reversal of any clinical decisions based on the previously incomplete data analysis. Our results should be interpreted in the context of the specific journals and time frame used in this study, and results may not generalise to all anaesthesia journals.
Acknowledgements relating to this article
Assistance with the analyses: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
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