BMJ calls for retraction of Seroxat trial in adolescents

A re-analysis of a clinical trial of GlaxoSmithKline's antidepressant Seroxat suggests the drug is ineffective and unsafe in younger patients, contradicting its earlier conclusions.

The new study - published in the British Medical Journal (BMJ) - is the first to be published under an initiative called RIAT (Restoring Invisible and Abandoned Trials), which the journal said "encourages abandoned or misreported studies to be published or formally corrected."

The aim is to ensure doctors and patients have "complete and accurate information to make treatment decisions," it added, calling for a retraction of the original study.

The trial - known as Study 329 - was published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) in 2001, before the merger of SmithKline Beecham and Glaxo to form GSK, and was influential in portraying Seroxat (paroxetine) as a safe and effective treatment for children and adolescents with depression.

The year after the original study was published, the FDA took issue with its findings, saying it had not shown efficacy, but the BMJ notes that despite this "over two million prescriptions were written for children and adolescents in the US that year.

The MHRA in the UK followed that with a recommendation not to use paroxetine in younger patients, which led to a similar recommendation by the European Medicines Agency in 2005. GSK eventually warned doctors of an elevated risk of suicidal behaviour in young adults and updated the drug's labeling.

The long-running controversy culminated in a $3 billion payment by GSK to the US government in 2012 to settle allegations it had covered up scientific evidence and manipulated articles in medical journals.

One of the criticisms levelled at Study 329 is that it was written by a ghost writer rather than one of the 22 named authors on the paper, notes the BMJ. The company pleaded guilty to criminal charges related to the marketing of Paxil for use by children between 1999 and 2003.

The reanalysis of Study 329 was made possible after GSK made 77,000 pages of de-identified case reports available to the investigators. It "illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base," according to lead author Professor Jon Jureidini at the University of Adelaide.

In an editorial accompanying the new study, BMJ associate editor Peter Dish criticises the refusal of the American Academy of Child and Adolescent Psychiatry to intervene and retract the paper.

He also takes issue with Brown University, whose chief of psychiatry Martin Keller was lead author of Study 329 but has remained silent on the issue.

"It is often said that science self corrects. But for those who have been calling for a retraction of the Keller paper for many years, the system has failed," argues Doshi.

The re-analysis was welcomed by the AllTrials organisation which campaigns for clinical trial transparency, which counts GSK among its members and acknowledged the company's decision to make the raw data available.

"Among pharmaceutical companies, GSK under its current management has led the way in promoting clinical trial transparency and provides a practical mechanism to make trial re-analyses possible," said AllTrials' co-founder Sir Iain Chalmers.

"Today's GSK has shown moral and scientific leadership that puts to shame many in the academic community."