The World Health Organization (WHO) announced what many feel is a strong, long-overdue statement condemning parties who do not report results of clinical trials in a timely way.
According to different studies, between 30 and 50-plus percent of industry and academic groups, required to report results of trials to the U.S. government, failed in recent years to do so. The situation worldwide is equally grim.
In response, the WHO outlined specific, and strict, solutions. Reiterating an earlier contention that “the registration of all interventional trials is a scientific, ethical, and moral responsibility,” the WHO’s new statement established timelines. In PLOS Medicine, WHO official Vasee Moorthy’s team noted that WHO demands all researchers report main findings of trial results to their nations’ primary clinical trial registries within 12 months of their studies’ end. WHO also demanded such groups publish results in peer-reviewed journals within 24 months of studies’ end.
WHO also called for “ethics committees, regulatory authorities, professional bodies, sponsors, investigators, and funding agencies to act in their jurisdictions to ensure results from all interventional clinical trials are reported and publicly disclosed.”
“WHO’s statement has very important implications for health and science around the world,” University of California psychologist Robert Rosenthal, Ph.D., told Drug Discovery & Development. A Rosenthal study found negative anti-depressant trial results often go unreported.
The U.S. situation is bad, yet “to my knowledge, the U.S. is leading the pack—except for perhaps U.K. and Australia,” FDA deputy commissioner of medical products Robert Califf, M.D., told Drug Discovery & Development.
Still, Califf said, the WHO’s statement, along with an expected NIH move to make reporting “mandatory for grantees…will have a big effect.”
The majority of 13,327 clinical trials ending between 2008 and 2012, all required to report results to clinicaltrials.gov, failed to do so by the end of an analysis published in a March 2015 New England Journal of Medicine. Senior author Califf told Drug Discovery & Development, “I am aware some feel the whole effort is an imposition….I have never understood why reporting results from studies should be an imposition, when the consent and requirements to be an investigator clearly articulate the creation of generalizable knowledge as the purpose of research done on people.”
Timothy Platts-Mills, M.D., an emergency medicine assistant professor with the University of North Carolina, is senior author on a 2013 British Medical Journal paper, which found that, of 585 registered U.S. trials, the number unpublished after a median of 60 months was 171, or 29 percent, representing 299,763 patients. And of the 171 unpublished trials, 133 (78 percent) had no results available in ClinicalTrials.gov at time of the paper’s publication.
Platts-Mills told Drug Discovery & Development this represented an enormous problem for many reasons. Patients’ time was wasted. Science was impacted, as work from the unreported trials could not be built on by other researchers.
“Of course, many trials are not paid for with tax dollars because they are done by pharmaceutical companies,” said Platts-Mills. “But, for all trials that are unpublished regardless of payer, non-publication of results is a violation of an explicitly stated agreement between the investigator and the patient that the results of the trial will be used to improve the care of patients with similar conditions.”
A way to describe it, according to Platts-Mills: “Clinical trials are the best tool we have to understand the effect of specific treatments on health outcomes. However, most trials are not conducted by people whose sole interest is to optimize health outcomes. Often, career and/or financial motives are also present, and sometimes these motives lead investigators to decide not to publish results, or to alter the primary outcome in published results. We probably can’t change these motivations, and we don’t want to discourage anyone from conducting clinical trials. But we do need regulations to ensure that knowledge obtained from trials is made broadly available in a timely manner.”
The WHO’s aggressive position
Platts-Mills thinks the WHO statement is much needed and “will be helpful. By asking for a peer review publication, and posting of results to the trial registry within 12 months, they have taken a fairly aggressive position. The questions going forward are, one, will other organization and entities including the U.S. government adopt similar positions, and two, what enforcement mechanisms will be used by the WHO and these other entities.
“Funding agencies and Institutional Review Boards may play a role in enforcement. But any polices enacted to “promote the availability of trial results in a timely manner need to also be sure not to stifle clinical investigation. In the long run, one could imagine that results of trials would be publicly available in real time, i.e., complete transparency of data collection during the course of the trial. Whether this can be done in a manner that protects the privacy of research subjects and the intellectual investments made by investigators is unclear.”
The unenforced FDA Act of 2007
Chris Jones, a Cooper University Emergency Medicine attending physician, is lead author on the 2013 paper. He told Drug Discovery & Development that, in the U.S., the U.S. Food and Drug Administration Act of 2007 (FDAAA) requires that results are posted within 12 months of trial completion within most cases. “There are some circumstances under which some sponsors can apply for extensions to this deadline, but 12 months is the requirement, barring an exception. I have seen publications suggesting that the provision has never been enforced, though in fairness I can’t independently verify that this is the case. I think it is fair to say that enforcement has not been sufficient to ensure that the regulations are consistently followed.”
While Jones thinks that enforcing the FDAAA “would be a good start, there are a number of loopholes in the current law, including exclusions for Phase 1 trials, and exclusions for trials which involve particular protocols rather than FDA-regulated drugs/biologics/devices. For example, several important, large trials have recently tested various treatment protocols for septic patients, and these landmark trials would probably not be considered subject to the existing regulations. Additionally, many of the interventions used in everyday clinical care were adopted based on the results of trials which were performed before the FDAAA went into effect, and the legislation doesn’t do anything to promote the release of previously conducted but unpublished trials dealing with these interventions. “
In Jones’ opinion, what makes the WHO statement “so critical is the explicit statement that there is an ethical imperative to report the results from all trials, including trials which were completed in the past.”
In a perspective piece, London School of Hygiene and Tropical Medicine epidemiologist Ben Goldacre noted that the 2007 FDA Act gives the FDA the power to fine transgressors $10,000 a day—which it has never done.
Awaiting the EU
Regarding the European Union (EU), Jones said, “It is encouraging that trial transparency has been a key issue in the updated clinical trial directive, and that the EU recognizes the need to make outcome data publicly available. But I have not yet seen details as to how data will be provided to the public, what loopholes will be present, or how the final regulations will be enforced. The answers to these questions will determine whether the new regulations truly make a difference.”
Academics worse than industry
Yale University assistant professor of medicine Joseph Ross found, in 2012, that a median of 51 months after the completion of NIH-funded clinical trials, a full one third still had not published results.
Ross believes fines won’t necessarily be an answer. “Most large manufacturers, with substantial compliance departments and legal assistance, are doing what they are supposed to,” Ross told Drug Discovery & Development. “It’s the less organized actors in academia and at the National Institutes of Health (NIH)—and small manufacturers—that need to do better. For those, a fine won’t necessarily incentivize better compliance, as part of the reason they are non-compliant is because of lack of resources. Perhaps it’s the NIH’s recent policy change,” along with statements of the WHO and the Institutes of Medicine, “that will get these parties to realize that this is not voluntary, but needs to happen.”
If not, he noted, “In a couple of years, fines might then be necessary.”
But overall, Ross was encouraged. “Compliance with FDAAA continues to improve. We are now at the point where the vast majority of trials are registered.” Advances need to be made in reporting, especially by academics and National Institutes of Health (NIH) sponsors. “But I expect that with greater attention to this issue, and greater support from organizations like the WHO, these compliance rates will continue to improve… The WHO position statement affirming the ethical imperative of publicly reporting clinical trials and their results represents an important step forward for the field of clinical trial research. As clinical trial funders, medical product manufacturers, clinician investigators, and academic organizations increasingly become aware of the importance of public transparency in clinical trial research, and accept new requirements to make information about their studies available, the support of organizations like the WHO and the Institute of Medicine (IOM) becomes critical to creating the sea change that is needed.”
Filed Under: Drug Discovery