NEWS - NEJM - Clinical Trial Registration: A Statement from the ICMJE

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The New England Journal of Medicine

Editorial

September 8, 2004

Clinical Trial Registration: A Statement from the International

Committee of Medical Journal Editors

De Angelis, M.D., M.P.H., M. Drazen, M.D., A.

Frizelle, M.B., Ch.B., M.Med.Sc., F.R.A.C.S., Charlotte Haug, M.D.,

Ph.D., M.Sc., Hoey, M.D., Horton, F.R.C.P., Sheldon Kotzin,

M.L.S., Laine, M.D., M.P.H., Ana Marusic, M.D., Ph.D., A.

P.M. Overbeke, M.D., Ph.D., V. Schroeder, M.D., D.M.Sc., Hal C.

Sox, M.D., and B. Van Der Weyden, M.D.

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interests at risk are particularly likely to remain unpublished and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 before 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 (e.g., phase 1 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.

De Angelis, M.D., M.P.H.

Editor-in-Chief, JAMA

M. Drazen, M.D.

Editor-in-Chief, New England Journal of Medicine

Prof. A. Frizelle, M.B., Ch.B., M.Med.Sc., F.R.A.C.S.

Editor, The New Zealand Medical Journal

Charlotte Haug, M.D., Ph.D., M.Sc.

Editor-in-Chief, Norwegian Medical Journal

Hoey, M.D.

Editor, CMAJ

Horton, F.R.C.P.

Editor, The Lancet

Sheldon Kotzin, M.L.S.

Executive Editor, MEDLINE

National Library of Medicine

Laine, M.D., M.P.H.

Senior Deputy Editor, ls of Internal Medicine

Ana Marusic, M.D., Ph.D.

Editor, Croatian Medical Journal

A. P.M. Overbeke, M.D., Ph.D.

Executive Editor, Nederlands Tijdschrift voor Geneeskunde

(Dutch Journal of Medicine)

V. Schroeder, M.D., D.M.Sc.

Editor, Journal of the Danish Medical Association

Hal C. Sox, M.D.

Editor, ls of Internal Medicine

B. Van Der Weyden, M.D.

Editor, The Medical Journal of Australia

http://content.nejm.org/cgi/content/full/NEJMe048225

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org