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Wednesday, September 16, 2009

Clinical trials: inadequate reporting, publication biases continue

Joseph S. Ross, et al., Trial Publication after Registration in ClinicalTrials.Gov: A Cross-Sectional Analysis, PLoS Medicine, September 8, 2009. Editors' summary:

Background: People assume that whenever they are ill, health care professionals will make sure they get the best available treatment. But how do clinicians know which treatment is most appropriate? In the past, clinicians used their own experience to make treatment decisions. Nowadays, they rely on evidence-based medicine—the systematic review and appraisal of the results of clinical trials, studies that investigate the efficacy and safety of medical interventions in people. However, evidence-based medicine can only be effective if all the results from clinical trials are published promptly in medical journals. Unfortunately, the results of trials in which a new drug did not perform better than existing drugs or in which it had unwanted side effects often remain unpublished or only appear in the public domain many years after the drug has been approved for clinical use by the US Food and Drug Administration (FDA) and other governmental bodies.

Why Was This Study Done?: The extent of this “selective” publication, which can impair evidence-based clinical practice, remains unclear but is thought to be substantial. In this study, the researchers investigate the problem of selective publication by systematically examining the extent of publication of the results of trials registered in, a Web-based registry of US and international clinical trials. was established in 2000 by the US National Library of Medicine in response to the 1997 FDA Modernization Act. This act required preregistration of all trials of new drugs to provide the public with information about trials in which they might be able to participate. Mandatory data elements for registration in initially included the trial's title, the condition studied in the trial, the trial design, and the intervention studied. In September 2007, the FDA Amendments Act expanded the mandatory requirements for registration in by making it necessary, for example, to report the trial start date and to report primary and secondary outcomes (the effect of the intervention on predefined clinical measurements) in the registry within 2 years of trial completion.

What Did the Researchers Do and Find?: The researchers identified 7,515 trials that were registered within after December 31, 1999 (excluding phase I, safety trials), and whose record indicated trial completion by June 8, 2007. Most of these trials reported all the mandatory data elements that were required by before the FDA Amendments Act but reporting of optional data elements was less complete. For example, only two-thirds of the trials reported their primary outcome. Next, the researchers randomly selected 10% of the trials and, after excluding trials whose completion date was after December 31, 2005 (to allow at least two years for publication), determined the publication status of this subsample by systematically searching MEDLINE (an online database of articles published in selected medical and scientific journals). Fewer than half of the trials in the subsample had been published, and the citation for only a third of these publications had been entered into Only 40% of industry-sponsored trials had been published compared to 56% of nonindustry/nongovernment-sponsored trials, a difference that is unlikely to have occurred by chance. Finally, 61% of trials with a completion date before 2004 had been published, but only 42% of trials completed during 2005 had been published.

What Do These Findings Mean?: These findings indicate that, over the period studied, critical trial information was not included in the registry. The FDA Amendments Act should remedy some of these shortcomings but only if the accuracy and completeness of the information in is carefully monitored. These findings also reveal that registration in does not guarantee that trial results will appear in a timely manner in the scientific literature. However, they do not address the reasons for selective publication (which may be, in part, because it is harder to publish negative results than positive results), and they are potentially limited by the methods used to discover whether trial results had been published. Nevertheless, these findings suggest that the FDA, trial sponsors, and the scientific community all need to make a firm commitment to minimize the selective publication of trial results to ensure that patients and clinicians have access to the information they need to make fully informed treatment decisions.

Sylvain Mathieu, et al., Comparison of Registered and Published Primary Outcomes in Randomized Controlled Trials, Journal of the American Medical Association, September 2, 2009. Only this abstract is OA, at least so far:

Context: As of 2005, the International Committee of Medical Journal Editors required investigators to register their trials prior to participant enrollment as a precondition for publishing the trial's findings in member journals.

Objective: To assess the proportion of registered trials with results recently published in journals with high impact factors; to compare the primary outcomes specified in trial registries with those reported in the published articles; and to determine whether primary outcome reporting bias favored significant outcomes.

Data Sources and Study Selection: MEDLINE via PubMed was searched for reports of randomized controlled trials (RCTs) in 3 medical areas (cardiology, rheumatology, and gastroenterology) indexed in 2008 in the 10 general medical journals and specialty journals with the highest impact factors.

Data Extraction: For each included article, we obtained the trial registration information using a standardized data extraction form.

Results: Of the 323 included trials, 147 (45.5%) were adequately registered (ie, registered before the end of the trial, with the primary outcome clearly specified). Trial registration was lacking for 89 published reports (27.6%), 45 trials (13.9%) were registered after the completion of the study, 39 (12%) were registered with no or an unclear description of the primary outcome, and 3 (0.9%) were registered after the completion of the study and had an unclear description of the primary outcome. Among articles with trials adequately registered, 31% (46 of 147) showed some evidence of discrepancies between the outcomes registered and the outcomes published. The influence of these discrepancies could be assessed in only half of them and in these statistically significant results were favored in 82.6% (19 of 23).

Conclusion: Comparison of the primary outcomes of RCTs registered with their subsequent publication indicated that selective outcome reporting is prevalent.

Also see coverage by Nature News (subscription required) and Science Progress.