Trial Registration in Rheumatology: The Next Step

Randomized controlled trials (RCTs) provide the clearest evidence of whether health care interventions, including interventions for patients with rheumatic diseases, have the desired effect on patient outcomes (1,2). RCTs are prioritized in the evaluation of evidence for clinical guidelines and thus play a major role in determining clinical practice standards (2). However, the extent to which publications that describe the results of RCTs accurately portray what would occur in practice depends on the completeness and transparency of trial reports (1,3,4). In order to provide valid, replicable answers to clinical questions, trials should ideally be designed with one major question in mind and, prior to initiating a trial, investigators should identify a single primary outcome variable that will be used to test the primary study hypothesis (1,5). In some cases, more than one primary outcome may be specified with appropriate statistical adjustment, although this introduces complexity related to the interpretation of potentially contradictory results. Key secondary outcomes that may address other important outcome variables or subgroups should also be specified a priori (1,5). If outcomes are not completely and precisely declared prior to initiating a trial, or if they are not fully reported posttrial in a manner consistent with the prespecified plan for testing the trial hypothesis, reporting biases can exaggerate the benefits of therapies and potentially mislead policy makers, clinicians, and patients about the likely benefits of interventions (4,6,7). Biases related to trial reporting may include 1) study publication bias, in which studies with statistically significant or positive results are more likely to be published than studies with negative findings; 2) selective outcome reporting bias, in which statistically significant or positive outcomes from a study are published, whereas nonsignificant outcomes from the same study are not; 3) selective analysis reporting bias, in which data analyses are conducted using multiple methods, but only those that generate positive results are reported; and 4) other biases, such as relegating a non– statistically significant primary outcome to secondary status when results are published and describing a positive outcome that was intended to be secondary as the primary outcome (4,6–8). A Cochrane review of publication bias that examined 5 reviews investigating trials registered in national trial registries or with research ethics boards found that trials with non–statistically significant results were only half as likely to be published as trials with positive results (3). With respect to selective outcome reporting, it has been estimated that 40–62% of all published studies include at least one primary outcome that has been changed, omitted, or introduced post hoc (6). Clinical trial registration has been proposed as a way to reduce the influence of reporting biases on the evidence base and to ensure that all research results are made available to research participants, clinicians and researchers, and the public. In 2004, the International Committee of Medical Journal Editors (ICMJE) announced a policy that stated that clinical trials intended to influence clinical practice initiated on or after July 1, 2005 would only be considered for publication if they were registered in a publically accessible trial registry prior to the enrolment of patients. Trials that were ongoing as of July 1, 2005 were required to have registered by September 13, 2005 (9). The ICMJE trial registration policy includes a priori specification of the primary trial outcome and key secondary trial outcomes (9). In 2005, the editors of Arthritis Care & Research announced a similar policy that took effect in January 2007 and required trial registration in either www. ClinicalTrials.gov or www.controlled-trials.com (10). Clinical trial registration goes a long way toward solving the problem of entire studies remaining unpublished because of disappointing results. While negative studies still may not get published, at least there is a record of their existence. The ability of trial registration policies to rein in other reporting biases, however, depends on the degree to which trial registration records adequately define primary and secondary outcomes prior to the initiation of trials. As described in the 2013 Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Statement Dr. Thombs’ work was supported by an Investigator Salary Award from the Arthritis Society. Dr. Kwakkenbos’ work was supported by a Fonds de la Recherche en Santé Québec Bourse de Formation Postdoctorale. Ms. CoronadoMontoya’s work was supported by a Frederick Banting and Charles Best Canadian Graduate Scholarship–Master’s Award from the Canadian Institutes of Health Research. Brett D. Thombs, PhD, Linda Kwakkenbos, PhD, Stephanie Coronado-Montoya, BSc: McGill University and Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada. Address correspondence to Brett D. Thombs, PhD, Jewish General Hospital, 4333 Cote Sainte Catherine Road, Montreal, Quebec H3T 1E4, Canada. E-mail: brett.thombs@ mcgill.ca. Submitted for publication February 28, 2014; accepted in revised form March 25, 2014. Arthritis Care & Research Vol. 66, No. 10, October 2014, pp 1435–1437 DOI 10.1002/acr.22335 © 2014, American College of Rheumatology