Clinical Trials Registry

You may have already read the editorial on registering clinical trials from the 11 International Committee of Medical Journal Editors (ICMJE) but here it is in full for those who may have not yet seen it. I hope you will find it relevant for your journal and its editorial policies.

Ana Marusic, MD, PhD
Editor-in-Chief, Croatian Medical Journal
Zagreb University School of Medicine

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 sponsor's 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 (non-inferiority 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of their scientific interest, trial results that place financial interests at risk are particularly likely to remain unpublished and hidden from public view.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 trial's 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 trial's 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 varies, 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 eleven 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 (eg, 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 (1), 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 DeAngelis
Editor-in-Chief, JAMA

Jeffrey M. Drazen
Editor-in-Chief, New England Journal of Medicine

Frank A. Frizelle
Editor, The New Zealand Medical Journal

Charlotte Haug
Editor-in-Chief, Norwegian Medical Journal

John Hoey
Editor, Canadian Medical Association Journal

Richard Horton
Editor, The Lancet

Sheldon Kotzin
Executive Editor, MEDLINE

Christine Laine
Senior Deputy Editor, Annals of Internal Medicine

Ana Marusic
Editor, Croatian Medical Journal

A. John P.M. Overbeke
Executive Editor, Nederlands Tijdschrift voor
Geneeskunde (Dutch Journal of Medicine)

Torben V. Schroeder
Editor, Journal of the Danish Medical Association

Hal C. Sox
Editor, Annals of Internal Medicine

Martin B. Van Der Weyden
Editor, The Medical Journal of Australia

Reference

1. A service of the national institutes of health developed by the National Library of Medicine. Available from: www.clinicaltrials.gov

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The statement from the ICMJE on the need for registering clinical trials is to be welcomed. I however share the reservations expressed by other editors on the list regarding the prequalification of a sole registry. Previous mails have pointed out the problems with this approach. WHO will be promoting the global registration of clinical trials at the Ministerial Summit on Health Research to be held in Mexico City, 16-20 November 2004. WHO is working with a number of organizations including www.clinicaltrials.gov and ISRCTN (where WHO is registering its own trials) on this project. In this context the recommendation in the ICMJE statement of a preferred registry is unhelpful and I would call on ICMJE to modify their statement.

Hooman Momen
Editor, Bulletin of the World Health Organization
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People may have noticed the absence of the BMJ from the list signatories to the recent ICMJE statement on trial registration. The BMJ's position is clarified in the note below.

Doug Altman

"We didn't sign the ICMJE editorial because we did not attend the meeting where the policy was discussed and we do not agree that the NIH register should be recommended above others. We expected the ICMJE editorial to be released next week but it has obviously been published earlier than planned.

We will state our policy (which will also require trial registration) in an editorial in next week's BMJ and I hope that this editorial will be available on our website early next week.

I'm happy for you to post this response on the WAME website.

Best wishes,
Kamran Abbasi
Acting editor, BMJ
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We are writing in response to the statement from the International Committee of Medical Journal Editors regarding clinical trial registration which has been forwarded to the WAME list by Dr Marusic, Editor-in-Chief of the Croatian Medical Journal.

Current Controlled Trials fully support the requirement that trials must be registered in a public trials registry as a condition of consideration for publication in all ICMJE member journal. Indeed, our website was set up in October 1998 in order to respond to the growing demand for more openness about clinical trials. However, the main requirements demanded by the ICMJE member journals that the registry must meet certain criteria effectively means that no register currently exists that fulfils these requirements.

Current Controlled Trials maintain the only international trial register, which is open to randomised controlled trials in all areas of healthcare and in all countries of the world—the International Standard Randomised Controlled Trial Number (ISRCTN) Register (http://controlled-trials.com/isrctn). Our register is accessible to the public at no charge, is open to all prospective registrants but is managed by a commercial company—Current Controlled Trials Ltd. The US National Library of Medicine website http://clinicaltrials.gov has been set up to capture trials that comply with the FDA 1997 Modernization Act. It is accessible to the public at no charge, is managed by a not-for-profit organisation but is NOT open to all prospective registrants (see http://prsinfo.clinicaltrials.gov/).

This could leave trialists who wish to publish in ICMJE member journals with a real dilemma. The fact that Current Controlled Trials is a commercial company seems to be a strange reason for disqualifying the ISRCTN Register. No reasons for this disqualification are given, and no viable alternative is proposed. In fact, the history of the ISBN scheme (for the unique numbering of books) provides a good comparison with the current trial situation. The ISBN system was started by 2 commercial companies—Whittakers in the UK and Bowkers in the USA. This system has since become adopted by the International Standards Agency and is the numbering scheme used by all publishers. It works efficiently, provides the appropriate service to all who need it, and the commercial structure did not damage the service.

Because the availability of trial information requires perhaps some additional level of security, Current Controlled Trials now plan to appoint an independent Board of Trustees, similar to the one that is guiding the open access publishing activities of our sister company, BioMed Central (http://www.biomedcentral.com/info/about/trustees). This Board of Trustees will be appointed to ensure the mode of function of the ISRCTN scheme, and if necessary have the power to implement appropriate responses to any possible change in the circumstances of the service, including the ability to take over the database if circumstance require this.

The ISRCTN Register is used and supported by several major trial funding organisations: the World Health Organisation, the Wellcome Trust, the Canadian Institutes of Health Research, the UK Medical Research Council, the Department of Health in England, the European Science Foundation and a number of other international organisations and journals.

We hope that the ICMJE will reconsider their position regarding the ISRCTN Register, or provide clear reasons why our efforts over the past number of years are to be considered inappropriate for the task.

Anne Greenwood
Managing Director, Current Controlled Trials Ltd

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I am very pleased indeed that the International Committee of Medical Journal Editors has now shown the leadership for which some of us have been calling for many years. I am surprised, however, that an international committee should single out for special mention a national trials register that restricts categories of potential registrants to "federal agencies sponsoring or supporting clinical research, sponsors of clinical trials that have been submitted to the FDA under IND regulations, or organizations representing IND sponsors," and which cannot, therefore, meet the requirements set out in the ICMJE statement. Is this yet another example of the current trend among powerful nations—like mine—to jettison internationalist principles?

Iain Chalmers
Editor, James Lind Library

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Ed Note: Please see the ICMJE Update on Trials Registration: October 2004.