John Hoey

Clinical Trial Registration: A Statement from the International Committee of Medical Journal Editors

Altruism and trust lie at the heart of research on human subjects. Altruistic individuals volunteer for research because they trust that their participation will contribute to improved health for others and that researchers will minimize risks to participants. In return for the altruism and trust that make clinical research possible, the research enterprise has an obligation to conduct research ethically and to report it honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavorably on a research sponsors product. Unfortunately, selective reporting of trials does occur, and it distorts the body of evidence available for clinical decision making. Researchers (and journal editors) are generally most enthusiastic about the publication of trials that show either a large effect of a new treatment (positive trials) or equivalence of two approaches to treatment (noninferiority trials). Researchers (and journals) typically are less excited about trials that show that a new treatment is inferior to standard treatment (negative trials) and even less interested in trials that are neither clearly positive nor clearly negative, since inconclusive trials will not in themselves change practice. Irrespective of their scientific interest, trial results that place financial interests at risk are particularly likely to remain unpublished and hidden from public view. The interests of the sponsor or authors notwithstanding, anyone should be able to learn of any trials existence and its important characteristics. The case against selective reporting is particularly compelling for research that tests interventions that could enter mainstream clinical practice. Rather than a single trial, it is usually a body of evidence, consisting of many studies, that changes medical practice. When research sponsors or investigators conceal the presence of selected trials, these studies cannot influence the thinking of patients, clinicians, other researchers, and experts who write practice guidelines or decide on insurance-coverage policy. If all trials are registered in a public repository at their inception, every trials existence is part of the public record and the many stakeholders in clinical research can explore the full range of clinical evidence. We are far from this ideal at present, since trial registration is largely voluntary, registry data sets and public access to them vary, and registries contain only a small proportion of trials. In this editorial, published simultaneously in all member journals, the International Committee of Medical Journal Editors (ICMJE) proposes comprehensive trials registration as a solution to the problem of selective awareness and announces that all 11 ICMJE member journals will adopt a trials-registration policy to promote this goal. The ICMJE member journals will require, as a condition of consideration for publication, registration in a public trials registry. Trials must register at or before the onset of patient enrollment. This policy applies to any clinical trial starting enrollment after July 1, 2005. For trials that began enrollment prior to this date, the ICMJE member journals will require registration by September 13, 2005, before considering the trial for publication. We speak only for ourselves, but we encourage editors of other biomedical journals to adopt similar policies. For this purpose, the ICMJE defines a clinical trial as any research project that prospectively assigns human subjects to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome. Studies designed for other purposes, such as to study pharmacokinetics or major toxicity (for example, phase I trials), would be exempt. The ICMJE does not advocate one particular registry, but its member journals will require authors to register their trial in a registry that meets several criteria. The registry must be accessible to the public at no charge. It must be open to all prospective registrants and managed by a not-for-profit organization. There must be a mechanism to ensure the validity of the registration data, and the registry should be electronically searchable. An acceptable registry must include at minimum the following information: a unique identifying number, a statement of the intervention (or interventions) and comparison (or comparisons) studied, a statement of the study hypothesis, definitions of the primary and secondary outcome measures, eligibility criteria, key trial dates (registration date, anticipated or actual start date, anticipated or actual date of last follow-up, planned or actual date of closure to data entry, and date trial data considered complete), target number of subjects, funding source, and contact information for the principal investigator. To our knowledge, at present, only www.clinicaltrials.gov, sponsored by the United States National Library of Medicine, meets these requirements; there may be other registries, now or in the future, that meet all these requirements. Registration is only part of the means to an end; that end is full transparency with respect to performance and reporting of clinical trials. Research sponsors may argue that public registration of clinical trials will result in unnecessary bureaucratic delays and destroy their competitive edge by allowing competitors full access to their research plans. We argue that enhanced public confidence in the research enterprise will compensate for the costs of full disclosure. Patients who volunteer to participate in clinical trials deserve to know that their contribution to improving human health will be available to inform health care decisions. The knowledge made possible by their collective altruism must be accessible to everyone. Required trial registration will advance this goal. Catherine De Angelis, MD, MPH, Editor-in-Chief, Journal of the American Medical Association Jeffrey M. Drazen, MD, Editor-in-Chief, The New England Journal of Medicine Professor Frank A. Frizelle, MBChB, MMedSc, FRACS, Editor, The New Zealand Medical Journal Charlotte Haug, MD, PhD, MSc, Editor-in-Chief, Norwegian Medical Journal John Hoey, MD, Editor, Canadian Medical Association Journal Richard Horton, FRCP, Editor, The Lancet Sheldon Kotzin, MLS, Executive Editor, MEDLINE; National Library of Medicine Christine Laine, MD, MPH, Senior Deputy Editor, Annals of Internal Medicine Ana Marusic, MD, PhD, Editor, Croatian Medical Journal A. John P.M. Overbeke, MD, PhD, Executive Editor, Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine) Torben V. Schroeder, MD, DMSc, Editor, Journal of the Danish Medical Association Harold C. Sox, MD, Editor, Annals of Internal Medicine Martin B. Van Der Weyden, MD, Editor, The Medical Journal of Australia

EQUATOR: reporting guidelines for health research

Despite the effort of researchers, editors and peer reviewers, the quality of health-research reporting in journal articles is unsatisfactory.1-6 Guidelines that specify a minimum set of items for reporting can improve the accuracy and transparency of publications, thus facilitating easier and more reliable appraisal of quality and relevance. During the past 10 years several internationally respected guidelines for the reporting of health research have been developed.7-10 However, those guidelines are still not widely supported by medical journals11, 12 or adhered to by researchers, and thus their potential impact is lessened. To remedy this situation the UK National Knowledge Service provided funding to start the EQUATOR project (Enhancing the QUAlity and Transparency Of health Research). This initiative seeks to improve the reliability of medical publications by promoting transparent and accurate reporting of health research. This movement grew out of the work of CONSORT9 and other groups. EQUATOR is an umbrella for all areas of health-research reporting. The network aims to become a global centre that provides resources and training, and which assists in the development, dissemination, and implementation of robust reporting guidelines. EQUATORs strategic plan reflects the needs of its major stakeholders: developers of reporting guidelines, researchers, journal editors, peer-reviewers, and research-funding bodies. One of the first activities was to identify existing reporting guidelines to see how they were developed. The development methods of most guidelines were broadly similar, but with wide variation in important details. Development usually took a long time and only half the groups had strategies for dissemination and implementation of their guidelines. The difficulty of securing sufficient funding to develop, assess, and disseminate guidelines was widely acknowledged as a major problem. The initial survey and discussions with the main stakeholders helped us to prioritise future activities. First, we developed an internet-based resource centre, which can be freely accessed on our website.13 At present, it provides a collection of available reporting guidelines. In the future, the website will also host other resources for authors of research articles, editors, peer-reviewers, and developers of guidelines, including a comprehensive digital library for health-research reporting, guidance for the development of robust reporting guidelines, tools to facilitate their use, and educational materials. The availability of good reporting guidelines is not sufficient for the improvement of the quality of reporting. Our second priority will be active promotion of such guidelines and their use, by developing and running training for editors, peer-reviewers, and authors. The courses will concentrate on the important factors of research reporting and the efficient use of reporting guidelines. Figure 1 EQUATOR Network logo Poor reporting reflects a collective failure of those involved. Collaboration with and the support of influential medical journals are vital for the success of this project. Benefits will be equally split between both communities—users will benefit from improved reliability of scientific information and journals will benefit from increased loyalty of their readers attracted by improved accuracy and reliability of reports. The EQUATOR network will regularly monitor how journals implement reporting guidelines. We will annually audit the quality of reporting across the health-research literature and hope to document gradual improvements. Sufficient funding is a necessary requirement for the development and implementation of robust reporting guidelines and widespread promotion of good reporting of research. In view of how much money funding agencies spend on health research, their lack of interest in ensuring that this research is reported accurately is deeply disappointing. Good reporting is not an optional extra; it is an essential component of research. Funding bodies should recognise this and support initiatives such as EQUATOR that aim to improve the current situation. The EQUATOR Network will hold its official launch meeting on June 26, 2008, in London, UK. The meeting will focus on better understanding of problems associated with health-research reporting and use of reporting guidelines, and on finding potential solutions to improve the health-research literature.

Helping editors, peer reviewers and authors improve the clarity, completeness and transparency of reporting health research

Inadequate reporting is problematic for several reasons. If authors do not provide sufficient details concerning the conduct of their study, readers are left with an incomplete picture of what was done. As such, they are not able to judge the merits of the results and interpret them. The EQUATOR Network is a new initiative aimed at improving the clarity and transparency of reporting health research.

Describing reporting guidelines for health research: a systematic review

OBJECTIVE To describe the process of development, content, and methods of implementation of reporting guidelines for health research. STUDY DESIGN AND SETTING A systematic review of publications describing health research reporting guidelines developed using consensus. RESULTS Eighty-one reporting guidelines for health research were included in the review. The largest number of guidelines do not focus on a specific study type (n=35; 43%), whereas those that do primarily refer to reporting of randomized controlled trials (n=16; 35%). Most of the guidelines (n=76; 94%) include a checklist of recommended reporting items, with a median of 21 checklist items (range: 5-64 items). Forty-seven (58%) reporting guidelines were classified as new guidance. Explanation documents were developed for 11 (14%) reporting guidelines. Reporting-guideline developers provided little information about the guideline development process. Developers of 50 (62%) reporting guidelines encouraged endorsement, most commonly by including guidelines in journal instructions to authors (n=18; 36%). CONCLUSIONS Reporting-guideline developers need to endeavor to maximize the quality of their product. Recently developed guidance is likely to facilitate more robust guideline development. Journal editors can be more confident in endorsing reporting guidelines that have followed these approaches.

Relation of completeness of reporting of health research to journals' endorsement of reporting guidelines: systematic review.

Objective To assess whether the completeness of reporting of health research is related to journals’ endorsement of reporting guidelines. Design Systematic review. Data sources Reporting guidelines from a published systematic review and the EQUATOR Network (October 2011). Studies assessing the completeness of reporting by using an included reporting guideline (termed “evaluations”) (1990 to October 2011; addendum searches in January 2012) from searches of either Medline, Embase, and the Cochrane Methodology Register or Scopus, depending on reporting guideline name. Study selection English language reporting guidelines that provided explicit guidance for reporting, described the guidance development process, and indicated use of a consensus development process were included. The CONSORT statement was excluded, as evaluations of adherence to CONSORT had previously been reviewed. English or French language evaluations of included reporting guidelines were eligible if they assessed the completeness of reporting of studies as a primary intent and those included studies enabled the comparisons of interest (that is, after versus before journal endorsement and/or endorsing versus non-endorsing journals). Data extraction Potentially eligible evaluations of included guidelines were screened initially by title and abstract and then as full text reports. If eligibility was unclear, authors of evaluations were contacted; journals’ websites were consulted for endorsement information where needed. The completeness of reporting of reporting guidelines was analyzed in relation to endorsement by item and, where consistent with the authors’ analysis, a mean summed score. Results 101 reporting guidelines were included. Of 15 249 records retrieved from the search for evaluations, 26 evaluations that assessed completeness of reporting in relation to endorsement for nine reporting guidelines were identified. Of those, 13 evaluations assessing seven reporting guidelines (BMJ economic checklist, CONSORT for harms, PRISMA, QUOROM, STARD, STRICTA, and STROBE) could be analyzed. Reporting guideline items were assessed by few evaluations. Conclusions The completeness of reporting of only nine of 101 health research reporting guidelines (excluding CONSORT) has been evaluated in relation to journals’ endorsement. Items from seven reporting guidelines were quantitatively analyzed, by few evaluations each. Insufficient evidence exists to determine the relation between journals’ endorsement of reporting guidelines and the completeness of reporting of published health research reports. Journal editors and researchers should consider collaborative prospectively designed, controlled studies to provide more robust evidence. Systematic review registration Not registered; no known register currently accepts protocols for methodology systematic reviews.

Does journal endorsement of reporting guidelines influence the completeness of reporting of health research? A systematic review protocol

BackgroundReporting of health research is often inadequate and incomplete. Complete and transparent reporting is imperative to enable readers to assess the validity of research findings for use in healthcare and policy decision-making. To this end, many guidelines, aimed at improving the quality of health research reports, have been developed for reporting a variety of research types. Despite efforts, many reporting guidelines are underused. In order to increase their uptake, evidence of their effectiveness is important and will provide authors, peer reviewers and editors with an important resource for use and implementation of pertinent guidance. The objective of this study was to assess whether endorsement of reporting guidelines by journals influences the completeness of reporting of health studies.MethodsGuidelines providing a minimum set of items to guide authors in reporting a specific type of research, developed with explicit methodology, and using a consensus process will be identified from an earlier systematic review and from the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network’s reporting guidelines library. MEDLINE, EMBASE, the Cochrane Methodology Register and Scopus will be searched for evaluations of those reporting guidelines; relevant evaluations from the recently conducted CONSORT systematic review will also be included. Single data extraction with 10% verification of study characteristics, 20% of outcomes and complete verification of aspects of study validity will be carried out. We will include evaluations of reporting guidelines that assess the completeness of reporting: (1) before and after journal endorsement, and/or (2) between endorsing and non-endorsing journals. For a given guideline, analyses will be conducted for individual and the total sum of items. When possible, standard, pooled effects with 99% confidence intervals using random effects models will be calculated.DiscussionEvidence on which guidelines have been evaluated and which are associated with improved completeness of reporting is important for various stakeholders, including editors who consider which guidelines to endorse in their journal editorial policies.

Open Medicine is indexed in PubMed

Editors’ note: This corrected editorial replaces the version published on 5 January 2010, which stated that Open Medicine is indexed in MEDLINE, when in fact it is indexed in PubMed (of which MEDLINE is a subset). Open Medicine currently has an application under review for indexing in MEDLINE. The Open Medicine team is pleased to announce our recent acceptance for indexing in PubMed—an official stamp of approval from the US National Library of Medicine (NLM) for the scientific and technical quality of articles published in our journal. Why is this development such an important milestone? PubMed indexing ensures that new and previously published articles in Open Medicine are searchable online (http://www.ncbi.nlm.nih.gov/sites/entrez) and are archived on PubMed Central, the NLM’s comprehensive online archive of nearly 2 million full-text articles. The ability to find Open Medicine’s articles through PubMed literature searches will make it easier for both researchers and readers to find, assess and download them.1 Indexing by the NLM and accessibility through PubMed Central ensures, in addition to enhanced visibility, the permanence of our publishing record for years to come. As a result of PubMed indexing, we anticipate an increase in article submissions. To date, we have managed the journal with mostly volunteer input—despite some logistical challenges in doing so. We remain committed to maintaining a medical journal based on editorial independence, open-source publishing and open access.2,3 To sustain this while managing the expected increase in workflow, we are introducing a publication charge for articles accepted by Open Medicine. This fee will be C

Clinical Trial Registration

1200 for research and review articles and C

Sponsorship, authorship, and accountability.

300 for commentary and analysis pieces that meet our author guidelines in format and word count. The fee will allow us to continue publishing articles 3 to 4 months after acceptance and eventually to improve turnaround times. We will implement the publication charge for all articles submitted on or after March 1, 2010 that we subsequently accept. Maintaining high standards and making improvements to a high-quality medical journal takes expertise and considerable resources. These new fees represent a small proportion of the funds required to produce the journal; Table 1 shows some of our major operating costs. Considerable value is added during the editorial process, which makes articles more readable and absolutely clear in purpose.4 The modest fee covers most of the copyediting costs as well as the production and layout costs required to meet NLM standards; the remaining costs are covered by our editorial team of volunteers. Table 1 Time spent processing research articles at Open Medicine For funded research, we expect that this new fee will not limit an author’s ability to publish in the journal. Increasingly, granting agencies such as CIHR (the Canadian Institutes of Health Research) permit funds to cover any reasonable fee that an open access journal charges for the publication of accepted articles.5 In addition, partial or complete fee waivers will be available to authors with little or no means to pay, as is done at other open access journals.6 We believe this may be important for our growing authorship in low- and middle-income countries. Much has been made of publishers’ recent attempts to use questionable methods to increase revenue.7 The misuse of publishing platforms for self-interest, whether through advertising revenue or charges for services, is a serious problem in biomedical publishing. Open Medicine will never use fees to solicit manuscripts, and we will uphold our peer review and editorial policies rigorously. Since publication charges will apply only after an article is accepted, the fees will not influence our editorial decisions at either the review or the editing stages. Although many medical journals do not charge fees, they nonetheless incur costs through the publication cycle. How do publishers usually absorb these costs? Typically, they are met through pharmaceutical advertising, post-publication marketing reprint fees, subscriptions fees for individuals and university libraries and sponsorship by professional societies. Traditional publishing models are superficially convenient for authors, but we believe they are fundamentally flawed.8 Editors face pressures to publish research that supports the sale of specific products and devices, and to accept advertising revenue and reprint profits.9 Authors may be required to sign over their copyright as well as any revenue resulting from the sale of their intellectual work, a practice that is equally pernicious. Finally, access to a journal’s full text is limited to those who are able to pay. The need to re-purpose biomedical publishing for greater academic freedom and editorial independence is one of our reasons for being.8 Put simply, instituting publication charges is the price that academics, granting agencies, research institutes and medical schools must be prepared to pay to move toward more equitable publishing models. We call for greater leadership from academic institutions to “walk the walk” by covering publication charges for faculty. As a result, biomedical research can be placed into as many capable hands as possible, thereby releasing its true potential. Although publishing in indexed journals such as Open Medicine is important, we also encourage all authors to “self-archive” articles at their local digital libraries and institutional repositories. Self-archiving adds a second layer of openness to published medical research because web search engines typically scour these repositories. If you are unsure about how to deposit your research in this manner, speak to your local open access librarian for more information. The growth of Open Medicine — and its recognition by NLM — would never have been possible without the enthusiastic support of many people. We want to thank our board of directors, editorial board, authors, reviewers, university libraries, and our readers, who have supported Open Medicine and given their time throughout our development.

The EQUATOR Network: facilitating transparent and accurate reporting of health research

We, the Editors and the Scientific Publishing Committee of the American Heart Association journals, support the principles enunciated in the editorial “Clinical Trial Registration: A Statement From the International Committee of Medical Journal Editors.” We look forward to working together in addressing the details of their implementation. Donald Heistad, MD, Editor-in-Chief, Arteriosclerosis, Thrombosis, and Vascular Biology Joseph Loscalzo, MD, PhD, Editor-in-Chief, Circulation Eduardo Marban, MD, PhD, Editor, Circulation Research John E. Hall, PhD, Editor-in-Chief, Hypertension Vladimir Hachinski, MD, Editor-in-Chief, Stroke Ivor J. Benjamin, MD, FAHA, Chair, American Heart Association Scientific Publishing Committee Altruism and trust lie at the heart of research on human subjects. Altruistic individuals volunteer for research because they trust that their participation will contribute to improved health for others and that researchers will minimize risks to participants. In return for the altruism and trust that make clinical research possible, the research enterprise has an obligation to conduct research ethically and to report it honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavorably on a research sponsor’s product. Unfortunately, selective reporting of trials does occur, and it distorts the body of evidence available for clinical decision-making. …