This article has Open Peer Review reports available.
A systematic review of the processes used to link clinical trial registrations to their published results
- Rabia Bashir1Email author,
- Florence T. Bourgeois2, 3 and
- Adam G. Dunn1
Received: 28 November 2016
Accepted: 9 June 2017
Published: 3 July 2017
Abstract
Background
Studies measuring the completeness and consistency of trial registration and reporting rely on linking registries with bibliographic databases. In this systematic review, we quantified the processes used to identify these links.
Methods
PubMed and Embase databases were searched from inception to May 2016 for studies linking trial registries with bibliographic databases. The processes used to establish these links were categorised as automatic when the registration identifier was available in the bibliographic database or publication, or manual when linkage required inference or contacting of trial investigators. The number of links identified by each process was extracted where available. Linear regression was used to determine whether the proportions of links available via automatic processes had increased over time.
Results
In 43 studies that examined cohorts of registry entries, 24 used automatic and manual processes to find articles; 3 only automatic; and 11 only manual (5 did not specify). Twelve studies reported results for both manual and automatic processes and showed that a median of 23% (range from 13 to 42%) included automatic links to articles, while 17% (range from 5 to 42%) of registry entries required manual processes to find articles. There was no evidence that the proportion of registry entries with automatic links had increased (R 2 = 0.02, p = 0.36). In 39 studies that examined cohorts of articles, 21 used automatic and manual processes; 9 only automatic; and 2 only manual (7 did not specify). Sixteen studies reported numbers for automatic and manual processes and indicated that a median of 49% (range from 8 to 97%) of articles had automatic links to registry entries, and 10% (range from 0 to 28%) required manual processes to find registry entries. There was no evidence that the proportion of articles with automatic links to registry entries had increased (R 2 = 0.01, p = 0.73).
Conclusions
The linkage of trial registries to their corresponding publications continues to require extensive manual processes. We did not find that the use of automatic linkage has increased over time. Further investigation is needed to inform approaches that will ensure publications are properly linked to trial registrations, thus enabling efficient monitoring of trial reporting.
Keywords
Background
Clinical trial registries were established to improve transparency and completeness in the reporting of clinical trials [1–6]. Since they were established, a number of policies have been implemented to encourage or mandate their use, and this has led to substantial growth in the number of trials that have been registered [7–11]. For example, since 2005, prospective trial registration has been a condition for publication in member journals of the International Committee of Medical Journal Editors (ICMJE) [1, 12]. The European Union and USA have also passed legislation requiring prospective registration of clinical trials involving drugs or devices [13].
Clinical trial registries provide the ability to measure biases in the reporting of clinical trials that arise due to non-publication, delayed publication, or incomplete publication of results [14]. Studies examining these issues rely on the ability to establish a link between the original trial registration and subsequent published article. These links can be established in an automatic fashion if the publication abstract or metadata includes the registry identifier [15, 16]. However, if this identifier is not included by trial investigators or added by journals, manual processes are needed to create these links, either through searches and inference or through direct contact with investigators. Despite the number of studies that have examined reporting biases by linking trial registry entries and publications, the processes for linking are variable and poorly described.
Clinical trial registries are a critical source of information for systematic reviewers who use these registries to augment bibliographic database searches when compiling relevant evidence from clinical trials [17–19]. Systematic reviewers may seek to identify links from published trial reports to their respective registry entries to fill in gaps for information that is missing or incompletely reported. They may also independently search trial registries to identify additional trials [20, 21] and follow links from the registry to reports of the trials.
Our aim was to quantify the processes that have been used to link clinical trial registries with published results and to examine the use and utility of automatic linkage over time. To do this, we conducted a systematic review of all studies examining a cohort of clinical trials to identify links from clinical trial registries to bibliographic databases and from bibliographic databases to clinical trial registries, following a published systematic review protocol [22].
Methods
Inclusion criteria and search strategy
We identified all primary studies that examined links between any of the registries in the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and published articles in bibliographic databases. Studies were excluded if there was no English-language version, if they did not unambiguously report the total number of clinical trials for which links were identified, if they were reporting on a specific clinical trial, or if the identification of links was not the primary focus of the study. Studies that did not unambiguously report the processes used to identify links were included in the review but excluded from the analyses.
PubMed and Embase were searched from inception to May 27, 2016, [23, 24]. The search strategy was developed with the assistance of a medical research librarian with details described in a previously published protocol [22]. The full version of the search strategy for both databases is provided in additional files (see Additional files 1 and 2). This strategy included searching of all study references to identify any other relevant articles not captured in the original search. Duplicate studies were removed using digital object identifiers and manually comparing titles, authors, publication dates, and article metadata. All identified studies were screened individually by two reviewers for inclusion, and disagreement was resolved through discussion.
Data extraction
Two reviewers evaluated all the included studies to extract relevant information from the studies and resolved ambiguities by discussion. For each study, the following information was extracted: (a) number of reported clinical trials, (b) number of published articles, (c) trial registries used, (d) the study purpose (such as publication bias, outcome reporting bias, or assessing the publication rate of registered trials), (e) application domain (any constraints such as journal lists, conditions, or specialties), (f) processes for identifying links, and (g) proportions of links found using each process.
The processes used to identify links were categorised as one of three types: automatic, inferred, and inquired. Automatic links were defined by any process that used the unique registry identifier to reconcile the link into or from a bibliographic database without the need for a search or inquiry. This included searching PubMed for registry identifiers to find published articles in cohorts of registry entries or using identifiers in the metadata, abstract, or full text of published articles to find registry entries in cohorts of published articles. Inferred links were defined by any manual processes in which investigators searched for matches across databases using characteristics of the trial such as the names of the investigators, titles, and acronyms associated with the trial, location, sample size, or the population, intervention, or measurable outcome information to find a match in a bibliographic database or trial registry. Inquired links were defined by any manual process where the study authors attempted to contact the investigators or authors of a trial to request or confirm the presence or absence of a registry entry or a published article for each included trial.
Data synthesis and analysis
We examined the proportions of links that were identified through each of these three processes. Using the publication year of the studies that used both automatic and manual processes, we applied linear regression to determine whether the utility of the automatic processes—the proportion that were found automatically compared to the proportion that required manual processes—had increased over time. We did not undertake a pooled analysis of the utility of automatic links because many studies did not specify proportions found by each process used and because of the heterogeneity in the study designs. All statistical analyses were conducted using SPSS statistical software version 24.0 (IBM, Armonk, NY).
The protocol for this systematic review was published in 2016 [22] (see Additional file 3). We did not register the systematic review with PROSPERO because it does not directly examine at least one outcome of direct patient or clinical relevance.
Results
PRISMA flow diagram of study selection for a search and screening process that resulted in the inclusion of 81 studies
Studies identifying published articles from cohorts of registry entries
Characteristics of 43 analyses identifying published articles from cohorts of trial registry entries
Study | Registry entry cohort | Published articles found | Trial registries included | Study purpose | Study publication year | Application domain | Proportion of links by process |
|---|---|---|---|---|---|---|---|
Hartung [70] | 305 | 110 | ClinicalTrials.gov | To determine consistency between registered trials and their publication | 2014 | Phase III or IV trials | Automatic = 95 Inferred = 15 |
Ross [51] | 677 | 315 | ClinicalTrials.gov | To assess the publication of registered trials in ClinicalTrials.gov | 2009 | Completed trials of phase II or higher | Automatic = 96 Inferred = 215 Inquired = 4 (contact = 117, responded = 44, published = 4) |
Bourgeois [71] | 546 | 362 | ClinicalTrials.gov | To determine whether funding source of these trials is associated with favorable published outcomes | 2010 | Anticholesteremics, antidepressants, antipsychotics, proton-pump inhibitors, and vasodilators | Inferred = unknown Inquired = unknown |
Liu [72] | 443 | 156 | ANZCTR, ISRCTN, ChiCTR, IRCT, DRKS, NTR, JPRN, SLCTR, CTRI, PACTR, Clinicaltrials.gov. | Publication rate of Chinese Trials in WHO Registries | 2010 | Trials sponsored by China | Automatic = 103 Inferred = 40 Inquired = 13 (contact = 54, responded = all, published = 1) |
Prenner [73] | 64 | 35 | Clinicaltrials.gov | To evaluate the rate of publication of registered clinical trials concerning age-related macular degeneration | 2009 | Muscular degeneration | Automatic = 8 Inferred = 27 |
Wildt [74] | 105 | 66 | ClinicalTrials.gov | To evaluate the adequacy of reporting of protocols for on diseases of the digestive system | 2011 | Gastrointestinal diseases | Inferred = 66 |
Gandhi [75] | 37 | 20 | ClinicalTrials.gov | To compare the published orthopaedic trauma trials following registration in ClinicalTrials.gov | 2011 | Orthopaedic trauma | Automatic and Inferred = unknown |
Ross [53] | 635 | 432 | ClinicalTrials.gov | To review patterns of publication of clinical trials funded by NIH in peer reviewed biomedical journals | 2012 | NIH-funded trials in biomedical journals | Automatic and Inferred = unknown |
Shamliyan [76] | 758 | 212 | ClinicalTrials.gov | To examine registration, completeness and publication of children studies | 2012 | Children studies funded by NIH | Inferred = 212 |
Vawdrey [77] | 62 | 47 | ClinicalTrials.gov | To measure the rate of non-publication and assess possible publication bias in clinical trials of electronic health records | 2012 | Electronic health record registered in clinicaltrials.gov | Automatic, inferred, and inquired = unknown |
Chapman [55] | 314 | 208 | ClinicalTrials.gov | To determine the rate of early discontinuation and non-publication of RCTs | 2014 | Surgery | Inferred = 192 Inquired = 16 (contact = 101, responded = 25, published = 16) |
Liu [52] | 505 | 115 | All 14 registries in ICTRP and ClinicalTrials.gov | To estimate bias risk and outcome-reporting bias in RCTs of traditional Chinese medicine | 2013 | Traditional Chinese medicines | Unknown |
van de Wetering [26] | 599 | 312 | NTR | To evaluate the reporting of trial registration numbers in biomedical publications | 2012 | Biomedical publications | Automatic and inferred = unknown Inquired = 0 (contact = 42, responded = 9, published = 0) |
Huser [15] | 8907 | 885 | ClinicalTrials.gov | Linking ClinicalTrials.gov with PubMed | 2013 | Interventional phase II or higher clinical trials | Automatic = 885 |
Stockmann [78] | 108 | 65 | ClinicalTrials.gov | To evaluate the publication patterns of obstetric studies registered in ClinicalTrials.gov | 2014 | Obstetric studies | Automatic = 45 Inferred = 20 |
Jones [79] | 585 | 414 | ClinicalTrials.gov | To estimate the frequency with which results of large randomized clinical trials registered with ClinicalTrials.gov are not available to the public | 2013 | Interventional RCTs with more than one arm | Automatic and inferred = unknown Inquired = 4 |
Riveros [80] | 594 | 297 | ClinicalTrials.gov | To assess timing and completeness of trial results posted at ClinicalTrials.gov and published in journals | 2013 | Interventional studies of phase III and IV | Unknown |
Korevaar [81] | 418 | 224 | ClinicalTrials.gov | To assess publication and reporting of test accuracy studies registered in ClinicalTrials.gov | 2014 | Test accuracy studies | Automatic = 154 Inferred = 64 Inquired = 6 (contact = 175, responded = 119, published = 6) |
Munch [82] | 391 | 118 | ICTRP, ClinicalTrials.gov | To analyse the perils and pitfalls of constructing a global open-access database of registered analgesic clinical trials | 2014 | Analgesic clinical trials | Inferred = 118 |
Hill [54] | 90 | 66 | ClinicalTrials.gov | To assess the characteristics of paediatric cardiovascular clinical trials registered on ClinicalTrials.gov | 2014 | Pediatric cardiovascular clinical trials | Unknown |
Khan [83] | 143 | 95 | ClinicalTrials.gov | To examine characteristics associated with the publication and timeliness of publication of RCTs of treatment of rheumatoid arthritis | 2014 | Rheumatoid Arthritis | Automatic and inferred = unknown Inquired = 1 (contact = 58, responded = 28, published = 1) |
Su [84] | 239 | 88 | All 14 registries in ICTRP and ClinicalTrials.gov | Outcome reporting bias | 2015 | Acupuncture | Automatic and inferred = unknown |
Hakala [85] | 177 | 102 | ClinicalTrials.gov | To quantify the proportion of trials for unsuccessfully licensed drugs that are not published | 2015 | Stalled drugs | Automatic = unknown Inferred = unknown Inquired = 0 (emails or calls = 42, responded = 9, published = 0) |
Pranic [50] | 81 | 21 | ClinicalTrials.gov | Outcome reporting bias | 2016 | Completed RCTs | Inferred = 21 |
Tang [86] | 300 | 222 | ClinicalTrials.gov | Outcome reporting bias | 2015 | Random sample of phase II or IV trials | Automatic and inferred = unknown |
Boccia [87] | 1109 | 120 | ClinicalTrials.gov | To assess the status of registration of observational studies | 2015 | Cancer | Inferred = 120 |
Saito [88] | 400 | 229 | ClinicalTrials.gov | To determine publication rates of completed US trials | 2014 | Interventional studies | Automatic = 126 Inferred = 103 |
Son [89] | 161 | 62 | ClinicalTrials.gov | To assess whether there is publication bias in industry funded clinical trials of degenerative diseases of the spine | 2015 | Diseases of the spine | Inferred = 62 |
Baudart [90] | 489 | 189 | ClinicalTrials.gov | To evaluate the publication rate of observational studies for intervention | 2016 | Observational studies with safety outcomes | Automatic = 75 Inferred = 99 Inquired = 15 (contact = 241, responded = 52, published = 15) |
Chahal [91] | 34 | 20 | ClinicalTrials.gov | To determine publication rates of RCTs in sports medicine | 2012 | Sports medicine | Automatic and Inferred = unknown |
Manzoli [92] | 355 | 176 | ClinicalTrials.gov, ICTRP, ANZCTR, ChiCTR, Current Control Trails, Clinical Study Register or Indian | To evaluate the extent of non-publication or delayed publication of registered RCTs on vaccines | 2014 | Vaccines | Automatic = 132 Inferred = 44 Inquired = 0, (contact = 24, responded = 0, published = unknown) |
Lebensburger [93] | 147 | 52 | ClinicalTrials.gov | To analyse ClinicalTrials.gov for registered sickle cell trials | 2015 | Sickle cells | Automatic = 28 Inferred = 24 |
Smith [94] | 101 | 25 | ClinicalTrials.gov | Outcome reporting bias | 2012 | Arthroplasty | Automatic = 10 Inferred = 15 |
Guo [95] | 35 | 11 | ClinicalTrials.gov | To estimate patterns of publication of clinical trials of endometriosis registered in ClinicalTrials.gov | 2013 | Endometriosis | Inquired = 8 Inferred = 3 |
Tsikkinis [96] | 333 | 141 | ClinicalTrials.gov | To identify all phase III prostate cancer trials in ClinicalTrials.gov with pending results | 2015 | Prostate cancer | Inferred = 141 |
Chen [97] | 4347 | 2458 | ClinicalTrials.gov | To assess publication rate and reporting of results for completed trials | 2016 | Interventional clinical trials | Automatic and inferred = unknown |
Ramsey [98] | 2028 | 357 | ClinicalTrials.gov | To assess the proportion of registered trials that are published | 2008 | Oncology | Automatic = 357 |
Hurley [99] | 142 | 62 | ClinicalTrials.gov | To assess the delayed publication of clinical trials | 2012 | Cystic fibrosis | Inferred = 59 Inquired = 3 (contact = 83, responded = 29, published = 3) |
Ioannidis [100] | 73 | 21 | Cochrane Controlled Clinical Trial Register, ISRCTN, ClinicalTrials.gov, ICTRP, GSK Clinical Study Register, and Indian, ANZCTR, and Chinese Clinical Trial Registries) | To assess publication delay | 2011 | Influenza A (H1N1) vaccination | Unknown |
Ohnmeiss [101] | 72 | 28 | ClinicalTrials.gov | To assess the publication of the studies registered on ClinicalTrials.gov. | 2015 | Spine studies | Automatic and inferred = unknown |
Gopal [102] | 6251 | 818 | ClinicalTrials.gov | To evaluated the rate of compliance with the FDA mandatory results reporting in clinicaltrials.gov | 2012 | Interventional studies | Automatic = 818 |
Lampert [103] | 76 | 40 | ClinicalTrials.gov | To determine selective outcome reporting and delay of publication | 2015 | Epilepsy | Automatic = 32 Inferred = 7 Inquired = 1 |
Gandhi [104] | 46 | 2 | ISRCTN, ClinicalTrials.gov, ANZCTR | To determine the extent to which ongoing and future RCTs in diabetes will ascertain patient-important outcomes | 2008 | Diabetes | Unknown |
The processes used to identify links in 81 included studies, including studies that examined automatic links only (red), both automatic and manual processes (purple), manual processes only (blue), and studies that did not report the processes used (grey)
The proportions of published articles identified in cohorts of registry entries (top, 43 studies, ranging from 34 to 8907 registry entries) and the proportions of registry entries found in cohorts of published articles (bottom, 39 studies, ranging from 54 to 698 articles), with studies that only considered automatic links (red) and all other studies (blue). The circle areas are proportional to the study size
The proportions of published articles found in cohorts of registry entries (12 studies, top) and the proportions of registry entries found in cohorts of published articles (16 studies, bottom), by automatic links (grey) and manual processes (blue)
We found no evidence of a change in the overall proportion of publications that could be found via automatic links. A linear regression over the 12 studies—using the publication year as the independent variable—indicated no significant trend in the proportion of available links that can be identified by automatic processes (R 2 = 0.02, p = 0.36, β = 1.28% increase per year).
Studies identifying registry entries from cohorts of publications
Characteristics of 39 analyses identifying trial registry entries from cohorts of published articles
Study | Published article cohort | Registry entries found | Trial registries included | Study purpose | Study publication year | Application domain | Proportion of links by process |
|---|---|---|---|---|---|---|---|
Mathieu [59] | 234 | 323 | ClinicalTrials.gov, ISRCTN, ICTRP, national register based on country of first author | Outcome reporting bias | 2009 | Cardiology, rheumatology, gastroenterology | Automatic = 205 Inferred = 6 Inquired = 23 |
Chowers [105] | 49 | 60 | Unknown | Outcome reporting bias | 2009 | Anti-retroviral therapy | Unknown |
Rasmussen [60] | 54 | 137 | ClinicalTrials.gov, ISRCTN, ICTRP, NCI-PDQ | To determine association of trial registration with the results and conclusions of published trials | 2009 | Oncology drugs | Inferred = 54 |
Kunath [58] | 63 | 106 | ICTRP | To observe trial registration in urology journals | 2011 | Urology | Automatic = 48 Inferred = 15 |
Ewart [56] | 135 | 124 | ISRCTN, ClinicalTrials.gov, ANZCTR, EU-CTR, National Research Register | Outcome reporting bias | 2009 | RCTs in five high-impact factor journals | Unknown |
You [106] | 215 | 366 | ClinicalTrials.gov, ISRCTN | Outcome reporting bias | 2011 | Oncology drugs | Unknown |
Reveiz [109] | 89 | 526 | ICTRP | Outcome reporting bias | 2012 | RCT from Latin America and Caribbean | Unknown |
Nankervis [108] | 37 | 109 | ICTRP | Outcome reporting bias | 2012 | Eczema treatment | Automatic = 20 Inferred = 17 |
Pinto [107] | 67 | 200 | ClinicalTrials.gov, ISRCTN, ANZCTR, national register based on country of first author | Completeness of clinical trial registration and the extent of selective reporting of outcomes in published trials | 2013 | Physical therapy | Automatic = 48 Inferred = 2 Inquired = 17 |
van de Wetering [26] | 185 | 302 | ClinicalTrials.gov, ISRCTN, ICTRP, national register based on country of first author | To determine reporting of trial registration numbers in biomedical publications | 2012 | RCT from core clinical journals | Automatic = 166 Inquired = 19 (contact = 136, responded = 51, published = 19) |
Hannink [110] | 218 | 327 | ClinicalTrials.gov, ISRCTN, ANZCTR and others | Outcome reporting bias | 2013 | Surgical interventions | Automatic = 218 |
Huser [16] | 661 | 698 | ClinicalTrials.gov.gov, ISRCTN | Evaluating adherence to ICMJE policy of mandatory and timely clinical trial registration | 2013 | Trials published in five ICMJE journals | Automatic = 661 |
Rosenthal [111] | 51 | 55 | ClinicalTrials.gov, ISRCTN, ANZCTR, ChiCTR, UMIN | Outcome reporting bias | 2013 | Surgery | Automatic, inferred, and inquired = unknown |
Hopewell [112] | 30 | 69 | Unknown | To observe reporting characteristics of non-primary publications of results of RCTs | 2013 | RCTs from National Library of Medicine’s set of 121 core clinical journals | Automatic = 30 |
Babu [113] | 121 | 417 | Unknown | To observe clinical trial registration in physical therapy journals | 2014 | Physical therapy journals | Automatic = 121 |
Lee [114] | 8 | 83 | Unknown | Assessment of compliance of randomized controlled trials in trauma surgery with the CONSORT statement | 2013 | Trauma surgery | Automatic = 8 |
Li [115] | 252 | 305 | ClinicalTrials.gov, Current Controlled Trials, NTR, ANZCTR, UMIN CTR | Outcome reporting bias | 2013 | Gastroenterology and herpetology | Automatic = 212 Inferred = 40 |
Norris [116] | 50 | 107 | ICTRP | To determine selective outcome reporting | 2013 | Pharmacotherapy | Automatic = 30 Inferred = 20 |
Hardt [117] | 85 | 103 | ICTRP(ClinicalTrials.gov, ISRCTN, EU-CTR, NTR, ANZCTR, DRKS, JPRNUMIN, ChiCTR, CTRI), Belgian register | To determine whether the results of registered surgical RCTs are published in journals requiring registration | 2013 | Ten highest rank surgery journals | Automatic = 68 Inferred = 17 |
Anand [118] | 133 | 197 | ClinicalTrials.gov, ISRCTN, ANZCTR | To determine the registration and design alterations of clinical trials in clinical care | 2014 | RCT in clinical care medicine | Automatic = 105 Inferred = 28 |
Mann [119] | 140 | 220 | ICTRP | To assess the registration status of RCTs and analyse the correspondence of registered outcomes with published outcomes | 2014 | Clinical geriatrics | Unknown |
Walker [120] | 75 | 76 | ISRCTN, ClinicalTrials.gov, national register based on country of first author | Outcome reporting bias | 2014 | RCTs published in British Medical Journal and the Journal of American Medical Association | Automatic and inferred = unknown |
Dekkers [121] | 29 | 54 | ICTRP | To compare non-inferiority margins defined in study protocols and trial registry records with margins reported in subsequent publications | 2015 | Non-inferiority trials submitted 2001–2005 to ethics committees in Switzerland and Netherlands | Automatic and inferred = unknown |
Østervig [122] | 85 | 200 | ISRCTN, IRCT, EU-CTR, ChiCTR, CRiS, UMIN CTR, ClinicalTrials.gov | To check registration of randomized clinical trials | 2015 | Trials in Acta Anaesthesiologica Scandinavica | Automatic = 85 |
Scott [62] | 160 | 181 | ISRCTN, NTR, ANZCTR, ClinicalTrials.gov, national register based on country of first author | Selective outcome reporting | 2015 | Psychiatry journals | Automatic = 150 Inferred = 6 Inquired = 4 |
De Oliveira [123] | 107 | 201 | ISRCTN, ClinicalTrials.gov, ICTRP | Outcome reporting bias | 2015 | Anaesthesiology | Automatic, inferred, and inquired = unknown |
Rayhill [61] | 58 | 225 | ClinicalTrials.gov and others | To assess the registration status of RCTs and analyse the correspondence of registered outcomes with published outcomes | 2015 | Core headache medicine journals | Automatic = 58 |
Dal-Ré [124] | 175 | 178 | ClinicalTrials.gov, ISRCTN, ANZCTR, NTR, EU-CTR, CTRI, DRKS | To evaluate adherence to ICMJE policy on prospective trial registration | 2016 | Trials in high-impact journals | Unknown |
Reveiz [125] | 52 | 144 | Registered in any international clinical trial registry | To evaluate the influence of trial registration on reporting quality of RCTs | 2010 | Highest rank journals | Unknown |
Rongen [126] | 90 | 362 | ClinicalTrials.gov, ISRCTN, ANZCTR, NTR and others | Outcome reporting bias | 2016 | Orthopedic surgical interventions | Automatic = 90 |
Harriman [57] | 105 | 108 | ClinicalTrials.gov, ISRCTN, ANZCTR, UMIN CTR, NTR, ChiCTR, IRCT | To assess trial registration, analysis of prospective versus retrospective registration | 2016 | Clinical trials published in the BMC series | Automatic = 105 Inquired = 0 |
Vera-Badillo [129] | 30 | 164 | ClinicalTrials.gov | Outcome reporting bias | 2013 | Breast cancer | Automatic and inferred = unknown |
McGee [128] | 74 | 307 | ICTRP | To determine whether trial is registered and declared registration in the publication | 2016 | Kidney transplantation | Automatic = 44 Inferred = 30 |
Huić [127] | 149 | 152 | ClinicalTrials.gov | To determine completeness and outcome reporting bias | 2011 | RCTs published in ICMJE journals | Automatic = 149 |
Chan [34] | 519 | 553 | Unknown | Outcome reporting bias | 2005 | RCTs indexed in PubMed | Inferred and inquired = unknown |
Korevaar [130] | 52 | 351 | ClinicalTrials.gov, ISRCTN, national register based on country of first author | To identify the proportion of articles for which the corresponding study had been registered | 2014 | Test accuracy studies | Automatic = 27 Inferred = 11 Inquired = 14 (contact = 324, responded = 187, published = 14) |
Jones [131] | 57 | 123 | ClinicalTrials.gov, ISRCTN, ICTRP, national register based on country of first author | Outcome reporting bias | 2012 | Emergency | Automatic = 23 Inferred = 34 |
Smaïl-Faugeron [132] | 73 | 317 | ICTRP | To assess the registration rate of RCTs | 2015 | Oral health | Automatic = 50 Inferred = 23 |
Riehm [133] | 40 | 76 | ISRCTN, ClinicalTrials.gov, ICTRP | Outcome reporting bias | 2015 | Psychosomatic and behavioral health | Automatic = 33 Inferred = 7 |
The processes used to identify links between clinical trial registries and published articles varied across the set of studies (Figs. 2 and 3). The most common process was to use a combination of automatic and manual processes (21/39, 54%), followed by automatic processes only (9/39, 23%), and manual processes only (2/39, 5%). There were 7 studies for which the processes used to identify registry entries were not clear or not provided.
Of the 21 studies that looked for registry entries among a cohort of published articles and used both manual and automatic processes, 16 reported the number of registry entries found using each process (Fig. 4). Among these studies, automatic links identified between 8 and 97% (median 49%) of registry entries and the manual processes identified between 0 and 28% (median 10%) additional entries.
We found no evidence of a change in the overall proportion of published articles for which registry entries could be found via automatic links. A linear regression over the 16 studies—using the publication year as the independent variable—indicated no significant trend in the proportion of links that can be identified via automatic processes (R 2 = 0.01, p = 0.73, β = 1.40% increase per year).
Discussion
In this systematic review, we found that investigators use both automatic and manual processes to link registry entries and publications and that automatic links could be used to identify some but not all links between registry entries and published articles. We found no evidence that the utility of automatic processes had increased over time.
To the best of our knowledge, no other systematic review has examined the utility of automatic links between trial registries and bibliographic databases. Previous studies that examined the availability of automatic links provided a broad analysis of automatic links made available through ClinicalTrials.gov and PubMed but did not systematically evaluate the proportion of links that could additionally be resolved using manual processes [15, 16, 63]. Other systematic reviews have examined reporting biases as a topic and included subsets of the studies we included [14, 64], but focused on publication rates and the completeness and consistency of outcome reporting, which we did not evaluate here. Our review adds to this area of research by compiling information about a broader group of studies and synthesising what is known about the utility of automatic links, and the need for supplementing automatic processes with manual processes, in studies that rely on links between trial registries and bibliographic databases.
Implications
Our results indicate that automatic links alone are a useful but not sufficient process for measuring rates of registration and publication or associated biases. Relying on automatic links to draw conclusions about the rate of non-publication will likely over-estimate the rate of non-publication. When aiming to monitor compliance with prospective registration of clinical trials, or monitoring publication practices and patterns, the limits of automatic links should be considered.
In general, the proportion of links identified by automatic processes was lower in studies that started with a cohort of registry entries and aimed to identify published articles, compared to studies that started with a cohort of published articles, and aimed to identify registrations. This may be a consequence of journals that have not yet established standards for registration [65] or have not implemented standards for incorporating registry identifiers in the information they pass to bibliographic databases.
The results also have implications for systematic reviews. Systematic review technologies for automating or supporting reviewers rarely consider information from clinical trial registries to improve the searching or screening processes [66] or the prioritisation or scheduling of systematic review updates. Because systematic reviews are already time-consuming [67, 68], the need for additional manual effort in the linking of trial registry entries with their published results may have hindered the development of tools based on this linkage. Areas for development include processes where systematic reviewers compare published reports with information in a registry or use trial registries to identify trials not found in bibliographic databases. By removing these barriers, machine-readable information linking all published studies with all registry entries may provide the catalyst for the increased use of registries in the searching, screening, and prioritising of systematic reviews.
Recommendations
We recommend continued pressure to ensure that journals and publishers adhere to standards of reporting that require unique trial identifiers to be specified in the abstract of the article and reported as part of the metadata provided to bibliographic databases. Trial investigators should also be encouraged to update registry entries with links to published results when journals do not provide the information to bibliographic databases. As we move into an era where the structured reporting of clinical trial results and individual participant data become the standard for responsible clinical trial reporting [69], the inability to automatically identify all sources of information about a clinical trial hinders our ability to reuse and synthesise results across trials. Given the number of extra links that could be identified by examining the full text of articles, we also recommend that journals ensure that clinical trial identifiers are included in the abstract or metadata provided to bibliographic databases.
We additionally recommend a standardised method for identifying links between registry entries and published articles that, for the time being, includes manual validation and checking and avoids drawing conclusions based only on automatic links. A standardised method should include details about what elements of a registry entry should be used to search for published articles and a standard definition for what constitutes published results. Standard reporting for these studies should include the number of registry entries for which searches were performed, the proportion that were identified by automatic links, by inference or by inquiry, and the full details of the dates of trial completion and the length of follow-up. Presenting studies in terms of the time to publication rather than the presence or absence of publication would make a greater proportion of the studies comparable and amenable to meta-analysis.
Limitations
There are two limitations to this review. First, the exclusion of studies for which there was no English language version available meant that we may have missed some studies examining WHO ICTRP registries from countries where English is not the primary language. Second, we used the publication year of the studies as a proxy for estimating changes in the proportions of links identified by each process without considering the period of study that each of the studies covered. This was necessary because a substantial proportion of studies did not report the range and distribution of publication and registration dates in the cohorts they examined, and this may have influenced our analysis of the trends in the utility of the automatic processes.
Conclusions
In this systematic review, we have quantified the use and utility of the processes that are used to link trial registries to bibliographic databases. The results indicate that manual processes are still used extensively and that the gap between what can be identified via automatic processes and what must be identified via manual processes persists. Future improvements in the quality of automatic linking between clinical trial registries and bibliographic databases should come from continued pressure on journals to enforce policies and practices to consistently include registry identifiers in published reports.
Abbreviations
- ICTRP:
-
International Clinical Trial Registry Platform
- WHO:
-
World Health Organization
Declarations
Acknowledgements
Not applicable.
Funding
RB is supported by a Macquarie University Postgraduate Scholarship. AD and FB report funding from the Agency for Healthcare Research and Quality (R03HS024798).
Availability of data and materials
All data generated or analysed during this study are included in this published article and its Additional files 1, 2, and 3.
Authors’ contributions
RB and AD drafted the manuscript, conducted the review, critically revised the manuscript, and approved the final version. FB critically revised the manuscript and approved the final version. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Not applicable.
Ethics approval and consent to participate
Not applicable.
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