The results of five large-scale clinical trials of antidepressants have never been made accessible to the public, a data set compiled by an international team of researchers shows. Their discovery highlights the incompleteness of available data on the safety and efficacy of antidepressant drugs.
In total, 3,127 people with major depression participated in the five clinical trials, whose results have neither been uploaded onto the public Clinicaltrials.gov registry nor have been published in an academic journal.
All five trials, which aimed to study the safety and efficacy of a variety of drugs, were sponsored by industry. Three of the trials were run by the French pharmaceutical company Sanofi. Novartis and Sunovion each sponsored one trial.
|Trial number||Company||Patients||Antidepressant drug(s)||Completed|
|saredutant (SR48968) and escitalopram||Jan 2009|
|dasotraline (SEP-225289) and venlafaxine||May 2009|
|saredutant (SR48968) and paroxetine||Feb 2009|
|crinecerfont (SSR125543) and escitalopram||Mar 2011|
|agomelatine (AGO178C)||June 2011|
The data set also contains a large-scale clinical trial of the drug imagabalin (PD-332334). Pfizer enrolled 551 patients with generalized anxiety disorder in trial NCT00542685. The trial was completed in December 2008, but never made its results public.
In the past, the outcomes of antidepressant trials have often been reported selectively, incompletely, misleadingly, or not at all. Click on the slide show below to discover how this has distorted the evidence base on antidepressant drugs:
In the wake of a series of high profile scandals and court cases, large pharmaceutical companies tried to rebuild trust with doctors and patients by posting the results of clinical trials onto public trial registries as and when legally required to do so.
Research consistently shows that industry now outperforms academia in this regard. In recent years, many of the largest companies have moved towards full compliance with American and European transparency rules. For example, Sanofi has posted the results of 25 out of 26 recently completed clinical trials that are subject to US disclosure rules.
However, the trials listed above suggest that some companies’ transparency efforts do not extend to older trials, and/or those not covered by legal disclosure requirements. Irrespective of legal requirements, since the 2013 Declaration of Helsinki, failing to make the results of any clinical trial public has been unambiguously unethical. World Health Organisation standards, which are not legally binding, require every clinical trial to make its results public on a trial registry within 12 months of trial completion.
TranspariMED, a campaign working to end evidence distortion in medicine, identified the antidepressants trials flagged above using a data set of the 67 largest preregistered clinical trials that had never made their results public. That data set formed the basis of a paper recently published in the Annals of Internal Medicine. The paper’s authors shared their data with TranspariMED upon request.
TranspariMED then contacted the press teams of the companies involved to ensure that no relevant publications had been overlooked, and to check whether they were planning to make them public in future.
Sanofi and Sunovion did not respond at all.
Pfizer provided the following statement:
“Pfizer complies with all legal and ethical obligations regarding the disclosure of our sponsored clinical trial data. At the time of the discontinuation of this trial in 2009, the legal and regulatory requirements that exist today had not yet been enacted. Federal regulations and Pfizer’s policies have evolved in the intervening years, and Pfizer has enhanced our data disclosure and publications practices to achieve even greater transparency. While we do not publish past studies retroactively our current practice is to post all sponsored clinical trial basic results on ClinicalTrials.gov or the EU clinical trials register within 1 year of the primary completion date and to submit primary results to a peer-reviewed journal within 18 months of the primary completion date.”
Novartis responded as follows:
“The depression program (aglomelatine) was co-developped by Servier and Novartis from 2006-2011. Phase 3 studies where Novartis conducted but Novartis gave rights back to Servier in 2011. Therefore, thank you very much for reaching out to Servier directly.”
Contacted by TranspariMED, Servier explained that:
“Indeed, Novartis gave this depression program (aglomelatine) rights back to Servier in 2011. But as Novartis was the sponsor of this study, it was up to Novartis to publish these results. I recommend you to check whether these results are not on the Novartis site, where Novartis publishes its protocols and results.”
(Note: This is correct. The registry entry for the trial clearly identifies Novartis as the party responsible for uploading results. Servier is not in any way responsible for making the results on this trial public.)
In a follow-up email sent a few days later, Servier helpfully added that:
“In fact, Novartis, as the sponsor of the NCT01110902 study, has made public a technical results summary on his website”
Servier noted that the study’s results can be found under the number
CAGO178C2302 on the Novartis database:
Making trial results available exclusively on a company website does not meaningfully constitute making them publicly available, for two reasons:
- Company-run registries lack third party quality assurance mechanisms and integrity safeguards. Uploaded results have been reviewed neither by public trial registry staff (as happens with tabular results posted onto Clinicaltrials.gov) nor by peer reviewers (as happens with results published in academic journals).
- Standard search strategies for trial results used by researchers usually do not cover company websites, so these data are for all practical intents and purposes invisible to the systematic reviewers, other researchers in the field, doctors and patients.
Judging by their (non-)responses to enquiries by TranspariMED, Novartis, Pfizer, Sanofi and Sunovion have no intention of making publicly accessible the results of these older — but scientifically and clinically relevant — clinical trials.
This is not illegal. However, the companies’ failure to upload the trials’ results onto Clinicaltrials.gov and publish them in academic journals betrays the trust of the over three thousand patients who volunteered their time and energy to participate in these trials in the hope of contributing to the discovery of better and more effective ways to treat depression and anxiety.
Erick Turner, a former FDA drug reviewer and co-author of a recently published network meta-analysis of antidepressant drugs told TranspariMED that:
“These trials contain data on three widely used antidepressants, so their results should have been made available to meta-analysts, clinicians, and patients. It’s unfortunate that they have been kept secret.”
TranspariMED is currently working with other groups to develop a tool that tracks the reporting performance of companies and universities across all interventional clinical trials that they sponsor. This tool will complement EBM Data Lab’s existing EU Trials Tracker and FDAAA Trials Tracker, which focus exclusively on the minority of clinical trials that are currently subject to legal reporting requirements.
Once that tool is up and running, we will have data on companies’ and universities’ performance on making public the results of all clinical trials, including trials not covered by disclosure laws.
TranspariMED would like to thank researchers Athina Tatsioni, Fotini B. Karassa, Steven N. Goodman, Deborah A. Zarin, Daniele Fanelli, and John P.A. Ioannidis for sharing their data set, and the Servier press team for flagging the link to the Novartis website.
Mad in America hosts blogs by a diverse group of writers. These posts are designed to serve as a public forum for a discussion—broadly speaking—of psychiatry and its treatments. The opinions expressed are the writers’ own.