Non-publication of large randomized clinical trials: cross sectional analysis
By Christopher W Jones, Lara Handler, Karen E Crowell, Lukas G Keil, Mark A Weaver, Timothy F Platts-Mills
BMJ, October 29, 2013 Randomized clinical trials are a critical means of advancing medical knowledge. Clinical trials depend on the willingness of participants to expose themselves to the risks of randomization, blinding, and unproven interventions. The ethical justification for these risks is that society will eventually benefit from the knowledge gained from the trial. Because the risks involved in trial participation may be significant, and because individual trial participants often do not benefit directly from trial participation, substantial safeguards have been implemented to protect the interests of study participants both prior to and during the trial. These safeguards take multiple forms, including oversight by institutional review boards, the informed consent process, and data and safety monitoring boards. Until recently, the protection of the interests of study participants after trial completion has received significantly less emphasis. This began to change in 1997 with the signing of the Food and Drug Administration Modernization Act in the United States, which mandated that the US Department of Health and Human Services establish a registry of clinical trials, thereby providing permanent, public access to information on the conduct of both publicly and privately funded clinical trials. In 2005 the International Committee of Medical Journal Editors (ICMJE) required that prospective trials involving human participants be registered prior to the beginning of study enrollment in order to be considered for publication in member journals. This requirement was later incorporated into the ICMJE’s “uniform requirements for manuscripts submitted to biomedical journals,” along with the updated CONSORT 2010 statement for the reporting of randomized controlled trials. The prospective registration of phase II-IV clinical trials subsequently became federal law in the United States in 2007 with the passage of the Food and Drug Administration Amendments Act. This legislation also expanded the scope of ClinicalTrials.gov to include a database of trial results. Results from all registered studies may be posted to ClinicalTrials.gov, including studies completed prior to enactment of the Food and Drug Administration Amendments Act. In addition, reporting results is now mandatory for many trials. Failure to comply with this mandate can result in substantial penalties, including civil fines of up to $10 000 (£6200; €7400) per day and withholding of funds from investigators sponsored by the National Institutes of Health. The registration of clinical trials serves an important role in protecting the interests of study participants after trial completion. In addition to discouraging investigators from preferentially choosing to report statistically significant positive outcomes, trial registration can increase awareness of possible publication bias within the medical literature by allowing the public to compare the subset of trials with published results to the total number of trials that were registered and conducted. Publication bias can distort the apparent efficacy of interventions, which complicates the interpretation of the medical literature. The non-publication of trial data also violates an ethical obligation that investigators have towards study participants. When trial data remain unpublished, the societal benefit that may have motivated someone to enroll in a study remains unrealized. Systematic trial registration provides a tool that can help to assess both the magnitude and the causes of these problems. Data sources PubMed, Google Scholar, and Embase were searched to identify published manuscripts containing trial results. The final literature search occurred in November 2012. Registry entries for unpublished trials were reviewed to determine whether results for these studies were available in the ClinicalTrials.gov results database. Results Of 585 registered trials, 171 (29%) remained unpublished. These 171 unpublished trials had an estimated total enrollment of 299 763 study participants. The median time between study completion and the final literature search was 60 months for unpublished trials. Non-publication was more common among trials that received industry funding (150/468, 32%) than those that did not (21/117, 18%), P=0.003. Of the 171 unpublished trials, 133 (78%) had no results available in ClinicalTrials.gov. From the Discussion Trial investigators and sponsors have an ethical obligation to study participants to publish trial results. This principle is implicit in the US Federal Policy for the Protection of Human Subjects, also known as the “Common Rule,” which outlines the scope and responsibilities of institutional review boards for overseeing research using human participants. The Common Rule states that institutional review board approval requires demonstration that “risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result.” Similarly, the Declaration of Helsinki, which was instrumental in developing the modern system of oversight by institutional review boards, also acknowledges the importance of disseminating research results, stating “Authors have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports.” By directing institutional review boards to assess the societal importance of resulting knowledge in addition to the possible risks and harms to individual research participants, the Common Rule provides justification for institutional review board oversight of results reporting, including trial registration and publication. Because the involvement of institutional review boards with clinical trial oversight begins prior to participant enrollment, these institutions are uniquely positioned to protect the rights of study participants throughout all stages of trial conduct, from study planning to reporting results. Given the persistent problem of unpublished trial results despite continued emphasis on trial registration from governmental agencies, funding organizations, and the editorial community, increased institutional review board attention toward this issue may be needed.
Conclusions We observed that non-publication is common among large randomized clinical trials. Furthermore, the sponsors and investigators of these unpublished trials infrequently utilize the ClinicalTrials.gov results database. The lack of availability of results from these trials contributes to publication bias and also constitutes a failure to honor the ethical contract that is the basis for exposing study participants to the risks inherent in trial participation. Additional safeguards are needed to ensure timely public dissemination of trial data. http://www.bmj.com/content/347/bmj.f6104
By Don McCanne, M.D. Publication bias of drug and device studies has bordered on the criminal. Industry funded studies in particular were often withheld from publication if the results were not favorable for the future marketing of the product; that is, if the studies showed no benefit or, worse, if they showed that the products were harmful. Recognizing the problem, in 2005 medical journal editors began to require that studies be registered before clinical trials began or the studies would not be published in peer reviewed journals. In 2007 the federal government began to mandate the reporting of studies with the threat of civil fines for failing to comply. Many of us recognized that this failure of the private sector required government intervention, and we were relieved to finally see it. Alas, this study shows that non-compliance is still common, especially with industry funded studies. Not only does this corrupt the data bases on which our knowledge of new drugs and devices relies, it is also a failure of ethics by withholding results of human experimentation consented to by individuals who placed their health at stake to advance our understanding of the benefits and potential harms of these products. That ethical failure extends to future individuals who might be exposed to ineffective or harmful interventions merely because this adverse information was withheld from the medical community. There is an analogy with single payer. Private sector enthusiasts insist on exposing us to the waste, inefficiencies, and sometimes harm inflicted on us by the private insurance industry and its marketplace applications. The administrators of a government single payer program do not experiment with patients in order to expand the market for health care. However, they do collect generic data, rather than hiding it, to help advance our understanding of beneficial health care interventions. Whether it’s drug and device research or health care financing, we need more government involvement, not less.]]>