Unpublished or misreported clinical trials whose data have entered the public domain should be made available to other “responsible” researchers for publication or formal correction through medical journals if the sponsors do not agree to set the record straight themselves, campaigners for data transparency propose.
Set out in an article published online by The BMJ, the concept of “restorative authorship” has been endorsed by editors of that journal and PLOS Medicine, who encourage other medical journals to follow suit.
“The public interest requires that we have a complete view of previously conducted trials and a mechanism to correct the record for inaccurately or unreported trials,” they state.
The concept includes a minimum set of criteria for responsible publication or republication of abandoned studies, while the authors envisage a collaborative, global, effort to develop more detailed policies on trial-publication practices as the initiative moves forward.
The notion of restoring invisible and abandoned trials (RIAT) is the brainchild of academic researchers and medical experts led by Peter Doshi, postdoctoral fellow at Johns Hopkins University School of Medicine in Baltimore, US.
Doshi is a Cochrane group researcher who in recent years has heavily criticised Roche over the difficulty of securing access to reliable clinical-trial data on the company’s antiviral Tamiflu (osteltamivir).
As the RIAT concept largely relies on access to clinical study reports (CSRs), it is unlikely to encompass non-industry funded trials that have been misreported or abandoned by their authors.
Indeed, the starting point for the initiative is some 178,000 pages of previously confidential company research documents obtained by Doshi and colleagues through trial reports from litigation over off-label marketing of medicines or through new freedom-of-information policies introduced by the European Medicines Agency.
These documents include reports on trials that remain unpublished years after completion (e.g., Roche’s study M76001, the largest treatment trial of oseltamivir, or Pfizer’s study A945-1008, the largest trial of gabapentin for painful diabetic neuropathy); and “thousands of pages of clinical study reports associated with trials that have been published in scientific journals but shown to contain inaccuracies, such as Roche’s oseltamivir study WV15671, GlaxoSmithKline’s paroxetine study 329, and Pfizer’s gabapentin study 945-291”.
Doshi et al consider these to be “examples of abandoned trials: either unpublished trials for which sponsors are no longer actively working to publish or published trials that are documented as misreported but for which authors do not correct the record using established means such as a correction or retraction”.
The campaigners say they will email a copy of the BMJ article to manufacturers of the listed trials, asking them to signal their intent within 30 days to publish, republish or formally correct the studies over the next year – which “should allow sufficient time for manuscript preparation, peer review, and publication”.
If any of the recipients who declare an intention to publish or correct do not do so within one year, “all available data for such trials should be considered ‘public access data’ that others are allowed to publish”, Doshi and his colleagues warn.
They also call for other researchers and volunteer authors to join them in the initiative, whether by contributing clinical-trial documents obtained from public sources that need publishing or republishing, or by helping to write up the collected documents for (re)publication.
“We need volunteers to act in place of those who should have but did not make trial reports visible and accessible,” Doshi et al comment.
While campaigners such as the AllTrials group have made considerable headway in pushing for wider availability of data from clinical trials in the future, the same does not go for past studies, particularly where the results of these trials may be used for comparisons with new treatments.
Recent studies have shown that even when disclosure of trial findings is mandated by law, “results often remain invisible”, Doshi et al comment. “In addition, trial registration does not address the problems of invisibility and distortion for trials that took place before registers were widely used.”
Like many pharmaceutical companies – and, indeed, some of the higher-profile transparency campaigners – the authors are not calling for a wholesale ‘data dump’ of clinical-trial results.
“We believe it is important to publish unpublished and other abandoned studies, even though they will at best represent a brief synopsis of all the publicly available data,” they state. “This is because we live in a research and practice environment based on publications, and unpublished trials remain largely invisible”.
As things stand, there is no indexing system along the lines of PubMed for unpublished clinical-trial reports, while most researchers “will not have the time to sift through hundreds or thousands of pages to understand what occurred in a single clinical trial”, Doshi et al argue.
“We therefore need a shorthand representation, and the best we know of is journal publication.”
To avoid “a continuation of journal papers with selective reporting”, though, trial publications of this kind should adhere to reporting standards that ensure accountability, the authors propose.
“With a compression factor in some cases well above 1000:1, summarising a clinical study report into a journal-length manuscript inevitably requires value judgments about which information to include,” they acknowledge, adding that the judgments should be transparent so that any bias can be identified and discussed.
Responsible restorative authorship should also include making the underlying trial data available simultaneously as an electronic appendix, Doshi et al believe.
Moreover, there should be public access to an auditable record that documents which parts of the study report were incorporated into the new publication, to help make restorative authors’ “value judgments about what to include in the summary explicit and transparent”.
Entrenched and widespread
Nothing "better underscores the urgency and importance ofr the RIAT proposal than the list of abandoned trials that accompanies it", comments an accompanying editorial in The BMJ on 'Restoring the integrity of the clinical trial evidence base'.
The number and variety of drugs on that list “show clearly that incomplete reporting of clinical trial results is not an isolated occurrence, confined to a few drugs”, add editors from The BMJ and PLOS Medicine. “Rather, it is an entrenched and widespread problem”.
Secrecy and selective reporting have been “an integral part” of that system, the editors maintain. “Reforms such as trial registration and mandatory results reporting will improve things in the future but can do nothing about the flawed evidence of the past.”