File this under ‘hidden clinical trial disorder.’ For a decade, the US military regularly prescribed its service members atypical antipsychotics, which are approved to treat schizophrenia and bipolar disorder, for various off-label uses, notably insomnia and post-traumatic stress disorder. And the antipsychotic that was most widely prescribed has been the Seroquel pill, which is sold by AstraZeneca.
For instance, a 2009 review of off-label use in the Veterans Affairs health care system found that 60 percent of patients who received an antipsychotic had no record of a diagnosis for which these drugs are approved. The largest proportion of prescriptions for off-label use were written for PTSD and Seroquel had the greatest off-label use (see this).
Last year, the armed services issued more than 54,500 prescriptions for Seroquel alone, which was, by far, the most for any antipsychotic (see here). And by 2009, Seroquel became the VA’s second-biggest pharmaceutical expenditure, reaching $125.4 million, up from $14.4 million in 2001 (back story).
This off-label use occurred even though VA clinical guidelines issued in 2004 stated that “there is insufficient evidence to recommend atypical antipsychotics for the treatment of PTSD” (see page I-5 here). By 2010, though, the VA guidelines were recommending atypical antipsychotics for augmented therapy, reflecting various small studies that indicated the pills were useful in treating symptoms (see page 151).
By 2008, however, AstraZeneca (AZN) was aware of at least one study that indicated Seroquel – when added to an existing therapy – was no better than a placebo in reducing PTSD symptoms, and 65 percent of the participants experienced side effects related to the drug. But the study, which was sponsored by the drugmaker, was never published and a VA spokeswoman says the agency was not aware of its existence. At some point, however, the results were posted on the AstraZeneca web site (here it is).
The disclosure comes amid a growing controversy over hidden clinical trial data that has plagued the pharmaceutical industry. In recent years, scandals over undisclosed data linked to serious side effects involved Merck and its Vioxx painkiller, as well as the Avandia diabetes pill sold by GlaxoSmithKline. In fact, Glaxo recently pledged to make data available after paying a $3 billion fine, in part, for failing to release some Avandia data (read here).
The failure to disclose the Seroquel study prompts concern, experts say, not only because AstraZeneca failed to make the findings known, but because antipsychotics have been linked to irregular heartbeats. For instance, a 2009 study in The New England Journal of Medicine found the rate of sudden cardiac death doubled for those taking atypical antipsychotics, and there were three such deaths each year for every 1,000 patients taking such a drug (here is the abstract). The Seroquel study says that electrocardiagrams were taken, but there is no mention of any findings.
For these reasons, industry critics say the Seroquel study is only the latest example of a clinical trial result that should have been publicized, especially given what was growing use in the military for an unapproved purpose. “This seems to be important and useful information that should be publicly known,” says Yale University cardiologist Harlan Krumholz, who has pushed for greater disclosure (read this). “It speaks to the importance of the totality of data being available for public scrutiny.”
There was no explanation given by the drugmaker for not publicizing the study, but the failure to do so raises questions about the extent to which AstraZeneca has willingly shared all the available data about its drug and just how difficult it can be to identify and access some of this data. The only other place that any information about this study is available is on ClinicalTrials.gov, but the results are not noted (see here).
However, the Seroquel brand – there is Seroquel and Seroquel XR – has been a huge seller for AstraZeneca, which has been struggling to bolster its pipeline at the same time that various big-selling medicines have lost patent protection. Last year, the Seroquel brand accounted for 17 percent of total sales of $33.6 billion; the only drug to ring the register even more was the Crestor cholesterol pill.
As for the VA, the agency spokeswoman notes that last year, a study sponsored by the VA found that Johnson & Johnson’s Risperdal antipsychotic was not effective in reducing PTSD symptoms (read here). The agency acknowledged this “called earlier studies on this topic into question. Previous small, single-site studies were considered impressive because they involved veterans with chronic PTSD who were not responding” to antidepressants and suggested “augmentation with atypical antipsychotics,” according to a VA statement.
At least one of those small studies was co-authored by Mark Hamner, an associate professor of psychiatry at the Ralph Johnson VA Medical Center in Charleston, South Carolina (see here). A study published in 2003 in the Journal of Clinical Psychopharmacology (read this) concluded that Seroquel is “well tolerated and may have efficacy in reducing PTSD symptoms in patients who have not had an adequate response other medications.”
Hamner, who also co-authored a 2005 paper that found Seroquel improves sleep disturbances in combat veterans with PTSD, has been a paid speaker for – and a consultant to – AstraZeneca and has also received grant money from the drugmaker (look here). We asked him if he was aware of the study that had not been published, but he did not respond to the question and referred us to VA public affairs.
This was not the only instance, by the way, in which the handling of Seroquel data has been inconsistent. Two versions of another study, which explored the use of the pill for maintenance treatment of major depressive disorder, reveal an inconsistency concerning QT prolongation, the medical term for irregular heartbeat. One version was published in a journal two years ago and the other, which concluded in January 2008, is located on the AstraZeneca web site.
The published paper states “there were no clinically relevant mean changes from baseline in vital signs, ECG, hematology, or clinical chemistry parameters” (see page 970). But the same study from the web site reports clinically relevant changes in the QT interval in more than one place (see page 15). We reached out to Michael Leibowitz of the psychiatry department at Columbia University about the discrepancy, but he has not responded.
An AstraZeneca spokeswoman, meanwhile, wrote us that “the traditional presentation of clinical trial results is in the form of a group mean (average) change and this is reported in the clinical study report and the publication. The interpretation of ‘no clinically relevant mean changes’ is supported by the data. When secondary analyses, like the ECG shift analysis, do not contradict the mean changes (which are the primary analyses) they are generally not included in study publications.” Of course, ‘not generally’ does not mean never.