Experts call to restore abandoned trial data
RIAT may lead to better understanding of data
Not every clinical trial report sees the light of day. Some are abandoned when trial sponsors no longer actively seek publication, or when a study is misreported and no efforts are made to correct it.
A group of researchers put out a call to pharmaceutical companies and medical journals to get those studies published. Peter Doshi, PhD, postdoctoral fellow at Johns Hopkins University in Baltimore, is the lead author of an article published in the June issue of the British Medical Journal(BMJ) in which Doshi and colleagues described the process of Restoring Invisible and Abandoned Trials (RIAT).
The RIAT idea was born when Doshi's co-author S. Swaroop Vedula was preparing for his PhD defense. Vedula looked into 20 trials of epilepsy drug gabapentin (Neurontin), eight of which had gone unpublished. The data were released by Pfizer in the course of litigation over off-label marketing of the drug. The documents on the unpublished trials, Doshi says, were "rich in details." "Why is it that all these years later, we're still referring to these trials as unpublished? We're looking at the results, but no one else really can," he says. "If Pfizer isn't going to publish this, then why don't we?"
Doshi and colleagues created a process for submission of such studies to peer-reviewed journals that are on board with the concept, including BMJ, PLOS Medicine, PLOS One, and Headache.
The steps for RIAT submission and publication include:
- obtain clinical study reports and any other study data;
- collect documentation of trial abandonment;
- issue a "call to action" by publicly registering possession of data sufficient for publication;
- collect documentation of the need for restoration;
- presubmission inquiry to RIAT-friendly journal;
- prepare and submit manuscript according to RIAT procedures.
RIAT publishing will become possible, in part, by documents entering the public domain through litigation or through new freedom of information rules in Europe. And pharmaceutical company GlaxoSmithKline (GSK) announced earlier this year that it is planning to make its clinical study reports available to researchers. (For more details on the RIAT publishing guidelines, see box below.)
Doshi's BMJ article puts out a call to action for trial sponsors: Publish, or be published. A copy of the article has been sent to trial sponsors and investigators, calling on them for formal correction of studies. If those who signal intent to publish do not do so within a year, the studies should be considered "public access data" and should be published by others, RIAT authors say. So far, pharmaceutical company GSK has expressed "they'd have no problems with RIAT authors writing up their unpublished studies," Doshi says.
The intention of RIAT isn't just to bring unpublished studies to light, Doshi stresses it's also about restoring those that have been abandoned and correcting the record on misreported trials. "Because abandonment can lead to false conclusions about effectiveness and safety, we believe that it should be tackled through independent publication and republication of trials," Doshi and colleagues write in the BMJ article.1
Trials can become abandoned when they are misreported and not corrected due to lack of time, budget, interest, or an investigator not agreeing that it's misreported. Some may languish unpublished also because of little time or budget, or lack of statistical significance. Studies can also go unpublished if the results are not favorable to a sponsor which can result in publication bias.
"Some reasons [for not publishing studies] are understandable, while some are not so excusable," Doshi says. "Whatever the reasons, there really is a need to have the scientific record be accurate and complete. That's what RIAT is all about making happen."
Many of the abandoned studies include well-known and widely used drugs. "Read it and weep: On the list are clinical trials for drugs used by millions of people, including zanamivir, atorvastatin, gabapentin, and paroxetine. The number and variety of drugs on the list show clearly that incomplete reporting of clinical trial results is not an isolated occurrence, confined to a few drugs. Rather, it is an entrenched and widespread problem. Secrecy and selective reporting were an integral part of the system," according to BMJ research papers editor Elizabeth Loder, MD, and colleagues in an editorial response to the RIAT article.2
IRBs should have interest in these studies, Doshi says, to ensure that the studies they approve and monitor can benefit the public beyond just the study participants. "Unpublished and misreported studies put other patients in harm's way by exposing other patients to risks that are recorded but not reported," he says. "How are IRBs ensuring that publications are accurately reporting studies they're signing off on? That's part of the ethical responsibilities of the researchers to the subjects."
IRBs can also become involved in the RIAT process. "In trials where there may have been ethical questions, it would make sense to consult an IRB in the publication of that trial," Doshi says. "That should not mean that IRBs should be preventing us from learning from studies because the context of the studies was problematic. Learning from studies that have already been done is crucial to preventing unnecessary harm by unnecessarily repeating those studies."
Doshi says that linking the data with the republished trials will move clinical trials publishing to a new level of credibility. "One of the key elements of RIAT is that it will set a new standard by linking publications of trials with data and audit records so that the full data set will be available to anyone who wants to see it and explore it," he says.
A guide to the RIAT process
Here are the steps Doshi and colleagues outlined for the Restoring Invisible and Abandoned Trials publishing process:
Proposal for restoring invisible and abandoned trials (RIAT)
1. Obtain clinical study reports and any other study data
2. Collect documentation of trial abandonment
For unpublished trials: No primary publication detected by systematic search of the literature and/or confirmation from original trial sponsor or current responsible party that no publication exists.
For misreported trials: Evidence of misreporting (ideally, published letters or other articles in the scientific literature or documentation of communication with the original trial publication author[s] detailing the misreporting) and a failure to correct the scientific record.
3. Issue a "call to action" by publicly registering your possession of data sufficient for publication
At least initially, this should be by an electronic response to this article and should include, as a minimum, trial identifiers, number of participants, date completed, publication status, pages in your holding, and level of access to trial data. This declaration offers original sponsors and trialists an opportunity to publish or formally correct their studies within the next 365 days. Send a copy of the rapid response by email to trial sponsors (and authors, for published trials), requesting confirmation of receipt.
4. Collect documentation of the need for restoration
Save time-stamped copies of all rapid responses to this article (or other relevant websites) to document the time elapsed and consequent need for third party restoration.
5. Presubmission inquiry to RIAT friendly journal
Present editors with documentation from steps 1-4 and seek confirmation of editors' interest.
6. Prepare and submit manuscript according to RIAT procedures
- Include explanation (with references) in the Introduction of why this trial is being restored.
- Provide auditable record of decisions (use RIATAR template), documenting which parts of the clinical study report (page number and paragraph) were used.
- Report analyses specified in protocol.
- Denote any analyses that were not prespecified.
- Make all underlying data available electronically.1
Reference
1. Doshi P, Dickersin K, et al. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013;346:f2865.
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References
1. Doshi P, Dickersin K, et al. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013;346:f2865.
2. Loder E, Godlee F, et al. Restoring the integrity of the clinical trial evidence base. BMJ 2013;346:f3601.
