Strong federal legislation is needed to ensure comprehensive disclosure of clinical trials and their outcomes that puts “patient health above the pharmaceutical industry’s bottom line”, says US activist group Public Citizen.
In a study of existing and proposed trial registries and results databases, Public Citizen identified and assessed a total of 22 registries and/or databases, four of which were publicly accessible while the remaining 18 were private websites. All four of the public sites included trial registries but none of them extended to results databases.
Although these public registries met the requirements set from July 2005 by the International Committee of Medical Journal Editors (ICMJE) – and subsequently amended to incorporate Phase I studies – they were not without limitations. For example, the US National Institutes of Health’s registry, clinicaltrials.gov – by far the largest in the world – includes only federally and privately funded trials of experimental treatments for “serious or life-threatening diseases and conditions.” Registration of any other studies is voluntary.
The only accommodation for clinical trial results on a public website is clinicaltrial.gov’s provision for listing of a PubMed citation, which applies only to published studies, Public Citizen noted. By contrast, 13 of the 18 private websites include a clinical trial registry and 12 of them have both a registry and a results database.
Nonetheless, these privately maintained results databases are “voluntary, of variable quality and [of] inconsistent design”, the study found. Moreover, they are not consolidated into a single website, forcing potential users to search multiple sites for information. Cross-listing of trials in several databases adds to the confusion.
As with any non-public venture, the private sites also raise “significant questions as to transparency, enforceability and quality assurance”, Public Citizen commented. All the websites incorporating both clinical trial registries and results databases are operated by for-profit entities. Public Citizen sees this as an “apparent attempt” by the pharmaceutical industry to forestall legislation requiring more extensive disclosure of trial data.
It cites a study published earlier this year in the Journal of the American Medical Association, which noted that any conclusions listed in these databases “tended to be more favourable for the company’s product than those found in published articles or [Food and Drug Administration] reviews of the same trials.”
Form and function
One feature of the clinical trial sites highlighted in Public Citizen’s report is that “form and function are intertwined”. Sites that include registries only typically succeed in reducing the potential for publication bias, helping to ensure that published results accord with study protocols and facilitating trial recruitment, the authors said. But they “accomplish nothing in terms of allowing objective reviews of study results or permitting meta-analysis”. Results-only databases serve these analytical purposes but “do little to ensure the publication of results for studies not known to exist.” Nor do they facilitate recruitment or prevent trials from straying outside their protocols.
The only way to ensure that a combined registry/results database is set up is “for the federal government to enact legislation and to assess significant penalties for non-compliance,” Public Citizen insists. Both the US House of Representatives and the Senate have recently passed bills seeking to formalise the information that must be posted in clinical trial registries and, potentially, results databases. Of these, Public Citizen much prefers the House bill, H.R. 2900, as it requires a summary for patients covering the most important elements of the study design and results in non-scientific terms.
The Senate bill, S. 1082, calls for an 18-month feasibility study for the results database, followed by a “negotiated rulemaking” that would guarantee pharmaceutical industry involvement. As it is “quite unclear” how strong the resulting final guidelines would be, or what kind of timeframe would be provided for their enactment, the Senate’s approach “has the potential to completely gut the results database initiative,” Public Citizen warned.
The current deficiencies in clinical trial disclosure should be considered from the perspective of study participants, who have “laid their bodies on the line,” it suggested. “It is the altruism of human study subjects that allows clinical trials to proceed, an altruism grounded in the belief that they are contributing to scientific research to make the world better for others,” the report stated. “Yet studies that fail to be published cannot advance medical science (although their non-publication, if the study results are adverse, can advance the financial interests of pharmaceutical companies).”