Despite the legal and ethical requirements, recent research has suggested that most clinical trial results remain unpublished, both in the scientific literature and on ClinicalTrials.gov.
April 14, 2016 | by Sarah Massey, M.Sc.
The discovery of new and innovative treatments and therapies for human diseases is entirely dependent upon pharmaceutical industry-sponsored research and clinical trials. In turn, researchers rely on the successes and failures of previous studies, in order to determine where their efforts will be most impactful.
Peer-reviewed publications – most often medical journals – are the major source of current research in disease pathology and potential drug targets. In recent years, clinical trials registries – like ClinicalTrials.gov – have become an invaluable resource for researchers, clinicians and patients alike.
ClinicalTrials.gov was founded in 2000 as a web-based resource for information on both publicly and privately funded clinical trials. The site was created following the launch of the Food and Drug Administration Modernization Act of 1997 (FDAMA), which required the National Institutes of Health (NIH) to establish a clinical trials registry. This database would contain vital information on all interventional studies involving human participants under US Food and Drug Administration (FDA) investigational new drug applications.
As of September 2007, all clinical trials testing the safety and efficacy of an investigational drug, biologic or medical device, are required to register on ClinicalTrials.gov. In addition, the principal investigator or sponsor company of a given interventional trial is required to report the results of the trial within 12 months of the completion date.
Aside from the legal obligations of clinical trial reporting, some groups have attempted to increase clinical trials registration by providing incentives. The International Committee of Medical Journal Editors (ICMJE) – a small group of journal editors that create standards for publication in medical journals – requires clinical trials to be registered with ClinicalTrials.gov before any research can be published in their affiliated journals.
Interestingly, the ICMJE does not require study investigators to report clinical trials results in the registry prior to publication. The NIH also lists a variety of benefits to clinical trial registration and results reporting, aimed at educating sponsor companies on the value of mandatory results reporting. According to the NIH, clinical trial registration on ClinicalTrials.gov:
- Satisfies ethical commitments made to clinical trial participants.
- Increases understanding of trial design for prospective participants and their physicians.
- Reduces publication bias by providing a platform for indeterminate – or so-called ‘negative’ – results.
- Helps funding bodies determine where to best invest research funds.
- Aids institutional review boards (IRB) in assessing the ethics of a study.
Many Trials Unrepresented On Federal Registry
Despite the legal and ethical requirements, recent research has suggested that most clinical trial results remain unpublished, both in the scientific literature and on ClinicalTrials.gov. Researchers at the Yale University of Medicine, found that of 4347 interventional clinical trials conducted at 51 academic medical centers in the US, and registered on ClinicalTrials.gov, only 29 percent were published within 24 months of the study completion date. The primary completion date for the studies was listed between October 2007 and September 2010.
Furthermore, only 13 percent of these clinical trials conducted at major academic institutions reported results on ClinicalTrials.gov. Some academic centers performed better than others when it came to trial reporting, however no academic institution reported results for more than 41 percent of all interventional studies conducted there.
The researchers included interventional clinical trials spanning a wide range of qualifying factors, including conditions being studied, study phase, and total number of enrolled participants. Nearly 34 percent of the trials involved cancer and other neoplasms, while behavior and other mental disorders was the second most common study condition at 12.7 percent.
Twenty-seven percent of the clinical trials under review were Phase II, and just over 71 percent of the studies enrolled over 100 participants. The Yale researchers also found that 56.4 percent of the trials were randomized.
Interestingly, the data collected on each study from ClinicalTrials.gov, had significant gaps in trial attributions. For example, just over 23 percent of investigational studies failed to disclose whether the trial was randomized or non-randomized. This statistic points to the need for an internal validation system to ensure all clinical trials information is complete and accurate.
The research presents a dismal picture of the current state of clinical trials results reporting. Though academic centers are not required to publish their data in peer-reviewed medical journals, omitting clinical trials results from the literature – especially so-called “negative” results – has an overall negative affect on the research industry as a whole.
This selective publication only serves to reinforce the publication bias toward trials with positive findings – an issue inherent in medical journals. As information on failed clinical trial designs is wholly underrepresented in the literature, researchers are doomed to repeat other’s mistakes. Unfortunately, for the majority of history, very few academic journals have existed that support the publication of indeterminate clinical trial outcomes.
Earlier this year, a new open-access journal – called Contemporary Clinical Trials Communications – was established by the publishing company, Elsevier. The journal has a clear platform of providing an outlet in which clinical trials sponsors can publish negative, or less-impactful, trial results.
While this new publication has the potential to reduce some of the stigma associated with inconclusive results, it may not be able to even the playing field when it comes to securing research funding. Poorly-performing academic centers could lose their public or private funding if their publication record displays primarily negative results.
As for results reporting on ClinicalTrials.gov, all interventional studies being performed in the US – or seeking approval by the FDA – must be registered on the government website. The agency requires clinical investigators to report their results no later than 12 months after the primary completion date.
The sponsor company may apply for an extension request to delay results reporting until after an investigational new drug product or device is approved by the FDA. This only pushes the results reporting deadline until 30 days after FDA clearance, and does not completely excuse the responsible parties from submitting their results on ClinicalTrials.gov.
The FDA does reserve the right to inflict monetary penalties to the tune of $10,000 per day for noncompliance, however this consequence has little impact on reporting practices as it has never been applied. This lack of accountability likely puts results reporting low on the list of priorities for clinical trials professionals.
If ethical and legal requirements are insufficient to promote complete compliance with clinical trials registration and results reporting on ClinicalTrials.gov, it may be necessary for regulators to establish new ways to ensure clinical trials data is submitted in a timely manner. Perhaps positive incentives – such as accelerated drug approval or reduced application fees – could be offered to sites that consistently enter all trial-related information on the government-maintained database. As the industry faces increased pressure to share clinical trial data and make their study operations more transparent, the issue of trial registration is likely to continue to be debated.
What do you think of major academic centers failing to report clinical trials results on ClinicalTrials.gov? Should harsher penalties be established for noncompliance, or would offering incentives be a better way to encourage sponsors to report results? Share your opinion in the comments section below!
Keywords: Clinical Trials, Results Reporting, Drug Development
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