ARVO Statement on Registering Clinical Trials

Introduction

The editors of several leading journals of internal medicine have recently adopted a policy, originally proposed by the International Committee of Medical Journal Editors (ICMJE), that controlled clinical trials must be registered in a publicly available database or these journals will not publish manuscripts based on the results of these trials. These standards were published simultaneously in four leading journals of internal medicine, ^{1 2 3 4} but they have subsequently appeared in numerous other journals and in several languages. The editors of several leading peer-reviewed ophthalmic journals have subsequently published a joint editorial endorsing this policy, ⁵ as has the Association of American Medical Colleges, ⁶ and editorial and reader commentaries in numerous publications have strongly endorsed it. ARVO completely agrees with the principles of clinical trial registration put forth by the ICMJE and endorsed by numerous other journals. 

Why should clinical trials be registered?

Clinical trials are investigations involving human subjects that test prospective new methods of treatment for diseases, and which involve a simultaneous comparison group, or groups, that are either untreated, placebo-treated or treated using an alternative therapy. If they demonstrate a sufficient benefit in treating the disease under investigation [usually by showing a statistically significant difference in achieving the primary endpoint, stated in the initial protocol, by comparison with the control group(s)], and if there is an acceptable minimum of adverse effects, then a clinical trial can change the standards of medical therapy. However, clinical trials can also have negative outcomes. Results of a clinical trial can show no statistically significant benefit of a new therapy over the previous standard or even a statistically significant worsening. Or, and this may only be apparent after a very large number of subjects have been exposed to the therapy, the new therapy may produce serious adverse effects in a small number of subjects, insufficient to halt its prescription for specifically indicated conditions, but sufficient to place substantial caution on its more indiscriminate use. It is evident that investigators will want the positive results of their clinical trials to be widely announced. However, past experience has shown that sponsors of clinical trials, whether they are corporations, other institutions, or individual investigators, may not wish to make public the negative or harmful results of their clinical trials. ^{7 8 9} It is because biomedical investigators and clinicians, as well as the public, should have a right to know both the positive and negative results of clinical trials, that registration of clinical trials before they begin recruiting subjects should be required. Such registration ensures that all clinical trials that are being conducted are in the public domain, although it does not guarantee that sponsors will publish their results in a publicly available site, or that published results are complete and accurate. However, public knowledge that a trial is being conducted should engender interest in its eventual results. Thus, at the least, it will be much more difficult for results of unsuccessful trials, or of trials with harmful results, to be hidden. 

What kinds of clinical studies need not be registered?

These include: (a) “Phase 1” pharmaceutical trials to determine effective dose of a drug or biological agent and its lack of complications; preliminary tests by an investigator of a new surgical therapy, since such studies typically do not involve a control group or groups and are usually conducted in order to determine optimal doses and possible complications; (b) Individual case reports or observational case series; (c) Retrospective analyses of historical cases, e.g., “chart reviews” (these are typically, but not always, single-institutional); and (d) Experimental treatments that are compared to non-simultaneous (e.g. “historical”) control groups. 

Does registration of clinical trials add an extra administrative burden to investigators and institutions?

Registration of a clinical trial on one of the sites given below is a relatively straightforward process that is not excessively time-consuming. The World Health Organization (WHO) registration advisory group, cited in a recent editorial in the New England Journal of Medicine, ¹⁰ and on line at http://www.lillytrials.com/docs/ictrp_sag_meeting_april2005_conclusions.pdf listed a series of 20 items that investigators should be able to provide easily, as requirements for the registration process. Registration of a clinical trial could be one of the items required by Institutional Review Boards (IRBs) for approval before an investigator can begin recruitment and treatment of subjects in a clinical trial. 

Who has responsibility for registering clinical trials?

The principal investigator of a trial is responsible for registering the trial. In a multi-institutional trial, the PI at each institution should register through a specified joint registration site, and should so indicate on the application form in order to be approved through his/her IRB. Beginning July 1, 2007, all ARVO publications will require that submitted manuscripts dealing with clinical trials state that the trial was registered and provide the publicly available registration site so that information about registration can be accessed by reviewers, and readers (if the manuscript is published). 

What happens if an investigator is unaware of the requirement? How will failure to register a clinical trial affect its publication in ARVO journals and abstracts?

Failure to register a clinical trial by the target dates cited below will exclude a manuscript dealing with that trial from consideration for publication, or an abstract from consideration for presentation at the annual ARVO meeting. “Ignorance of the law is not an excuse.” The ARVO policy will be added to the Instructions for Authors for articles submitted, and a notice to authors to read and adhere to the policy will be printed on the Table of Contents page of each issue, and on the Internet Home Pages of all journals and of ARVO. Although we announce here an initial starting date for this new policy, we intend to make its enforcement flexible for a period that may extend for several years after the startup date. Investigators, particularly those who have initiated smaller trials at their own institutions, and who feel that their unregistered studies are being unfairly penalized may appeal to the Editors of ARVO journals, or if appropriate, to the Program Committee for abstract selection for their section of ARVO. 

Will requiring registration of clinical trials make the reporting of data from such trials more transparent?

That, of course, is our hope. No set of regulations is flawless, but we strongly believe that by making the conduct of clinical trials and the reporting of their results available to the public we will reduce the possibility that negative and harmful results will remain hidden, to the detriment of all. 

Guidelines on Clinical Trials Registration

1.  
   Beginning July 1, 2006, ARVO will no longer consider abstracts or articles dealing with clinical trials that were not registered before the first subject was enrolled. Trials that began before this date and were not registered must be registered by July 1, 2006. The letter accompanying manuscript submission must state the beginning date of the trial, and the date of registration.
2.  
   The registration requirement will apply to abstracts submitted for presentation at the ARVO Meeting beginning in 2007. Investigators will be prompted to include the registration number on the online abstract form.
3.  
   Registration must be done on a publicly available database. At present, the only databases that are satisfactory are the NIH’s registry, http://www.clinicaltrials.gov, and the International Standard Randomized Controlled Trials Number (http://isrctn.com). Further information about these sites can be obtained through http://prsinfo.clinicaltrials.gov and http://www.controlled-trials.com. The ICMJE standards can be obtained at http://www.icmje.org/faq.pdf. Registration must include completion of all 20 items on the list recommended by the WHO advisory group (Ref. ¹⁰ and see below).
4.  
   For the purposes of this policy, a “clinical trial” consists of any study involving a new therapy of any kind, whether medical, surgical, psychological or sociological, in which subjects are concurrently divided into one or more treatment or control groups. Several treatments may be compared simultaneously, or one or more treatment groups may be compared to a simultaneous, untreated control group. Although the division into such groups in most such trials is presently by random assignment, randomization is not a part of the requirement for registration but only the evaluation, in the trial, of concurrent control groups.
5.  
   The size of a clinical trial is not a relevant consideration as to whether it must be registered. This policy applies not only to large, multi-institutional clinical trials sponsored by pharmaceutical companies or other organizations, but also to individual investigators at a single institution who are conducting their own trials. The only consideration is whether the trial is comparing an experimental therapy, or therapies with a simultaneous control group, or groups.

Approved: Board of Trustees, October 29, 2005 

 The Policy Adopted by the ARVO Board of Trustees is shown below, and is available online at http://www.arvo.org/clinicaltrials