In mid-September 2015, the British Medical Journal (BMJ) published the findings of a reassessment of the 1999 Study 329 trial which led to the recommendation of the use of paroxetine (known in the UK as Seroxat) as a treatment for adolescents with depression.
Under the title ‘Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence (BMJ 2015;351:h4320)’, the reassessment found that the limited part of the original data which these new researchers were able to examine showed no efficacy for treatment for major depression in adolescents and that there was increase in harms reported with both drugs. They found that the way that the risks, including suicidal ideation and behaviour, were analysed and categorised in the original paper, minimised their importance.
Major depression is a “lethal disorder and requires treatment”. That was a quote from one of the researchers who promoted the drug paroxetine for unlicensed use in adolescents in 1999. He also said that “we can say that paroxetine has both efficiency and safety data for treating depression in adolescents”.
The paper reporting the trial (known as Study 329) that led to that data was published in the Journal of the American Academy of Child and Adolescent Psychiatry in 2001. That paper named 22 authors but was, in fact, written by a ghost writer on behalf of GlaxoSmithKline (GSK), the drug company behind this drug. It proclaimed paroxetine as generally well tolerated and effective in the treatment of adolescents. This drug was then widely marketed for off label use for adolescents emphasising its “remarkable efficiency and safety”.
Although widely prescribed to adolescents in the US, it was less so in the UK. However, there were soon concerns that the drug increased the risk of suicidal ideation and behaviour particularly in children and adolescents. Following an enquiry in the UK, it was directed in 2003 that paroxetine should not be used for young people under the age of 18. Reaction was slower in the US but extensive litigation took place against GSK and, as a result, it became clear in the discovery process that there was evidence of deliberate systematic suppression of unfavourable research results in Study 329.
In 2004 GSK paid out damages for consumer fraud in the US and in 2012 the company paid a fine of $3 billion as a result of criminal charges brought in New York State, partly concerning this misrepresentation.
There has, of course, been general concern at the way that drug companies report the results of failed research and suppress unfavourable results. That has led to reanalysis of some trials under the restoring invisible and abandoned trials (RIAT) initiative. Study 329 was an obvious candidate for this independent analysis.
Tim Wright of the Penningtons Manches clinical negligence team, comments: “The risks from this medication were clear from the Study 329 trial but the evidence of those risks was very carefully distorted and disguised. Although the findings of this reassessment are not surprising, of even greater concern is the unwillingness of GSK or any of the named authors or the publisher of the original paper to acknowledge these errors in what seems to amount to an appalling deception.
“Talking therapy may be replacing medication but we can but hope that this episode will lead to a new sense of disclosure and responsibility in clinical trials of new drugs.”
There has been litigation - some of which is ongoing - from individuals and families of those that have suffered. But the cost to GSK in the UK will have been very small because of the limited damages that are available to a UK claimant on the death of an adolescent minor.