BMJ Publishes Study Revealing How Flawed Drug Research Fails a Trusting Public

Restoring Study 329 is a reanalysis and rebuttal of the original Study 329, a randomized, controlled trial published in 2001 of the efficacy and harms of paroxetine (known as Paxil in the US) and imipramine in the treatment of adolescent major depression, which concluded that “paroxetine is generally well tolerated and effective for major depression in adolescents.”

Using the same data 14 years later, Restoring Study 329 comes to exactly the opposite conclusion, namely that “Neither paroxetine nor high-dose imipramine demonstrated efficacy for major depression in adolescents, and there was an increase in harms with both drugs.”

Although the FDA has issued several black box warnings about SSRI suicidality in the years following the original study, many thousands of children and adolescents have been harmed, some of them killed, by Paxil and other SSRIs. Global sales of these drugs have increased dramatically, including for pediatric and adolescent patients.²

The BMJ Press Release

The widely used antidepressant paroxetine is neither safe nor effective for adolescents with depression, concludes are analysis of an influential study originally published in 2001.The new results, published by The BMJ today, contradict the original research findings that portrayed paroxetine as an effective and safe treatment for children and adolescents with major depression. It is the first trial to be re-analysed and published by The BMJ under an initiative called RIAT (Restoring Invisible and Abandoned Trials), which encourages abandoned or misreported studies to be published or formally corrected to ensure doctors and patients have complete and accurate information to make treatment decisions.

In 2001 SmithKline Beecham, now GlaxoSmithKline (GSK),funded a study (known as Study 329) to compare the effectiveness and safety of the antidepressant drugs paroxetine and imipramine with placebo for adolescents diagnosed with major depression.

It reported that paroxetine was safe and effective for adolescents and was published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) in2001.

The study was criticized by the Food and Drug Administration (FDA) in 2002. Yet, that year, over two million prescriptions were written for children and adolescents in the United States.

In 2012 GSK was fined a record $3billion in part for fraudulently promoting paroxetine.

The RIAT team, led by Professor Jon Jureidini at the University of Adelaide, identified this study as an example of a misreported trial in need of restoration.

Using previously confidential trial documents, they reanalyzed the original data and found that neither paroxetine nor high dose imipramine was more effective than placebo in the treatment of major depression in adolescents. The authors considered the increase in harms with both drugs to be clinically significant.

They conclude that “paroxetine was ineffective and unsafe in this study.”

The reanalysis of Study 329 “illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base,” say the authors.

In an accompanying article, Peter Doshi, Associate Editor for The BMJ says the new paper “has reignited calls for retraction of the original study and put additional pressure on academic and professional institutions to publicly address the many allegations of wrongdoing.”

He points out that the original manuscript was not written by any of the 22 named authors but by an outside medical writer hired by GSK. And that the paper’s lead author – Brown University’s chief of psychiatry, Martin Keller - had been the focus of a front page investigation in the Boston Globe in 1999 that documented his under-reporting of financial ties to drug companies.

Doshi also details the refusal of the American Academy of Child and Adolescent Psychiatry to intervene and retract the paper, and Brown University’s silence over its faculty’s involvement in Study 329.

“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.

Dr Fiona Godlee, The BMJ Editor-in-Chief says publication of the reanalysed data from Study 329 "sets the record straight" and “shows the extent to which drug regulation is failing us.” It also shows that the public and clinicians do not have the unbiased information they need to make informed decisions.

She calls for independent clinical trials rather than trials funded and managed by industry, as well as legislation “to ensure that the results of all clinical trials are made fully available and the individual patient data are available for legitimate independent third party scrutiny.”

Liberating the data from clinical trials has the potential to benefit patients, prevent harm, and correct misleading research, writes Professor David Henry at the University of Toronto, in an accompanying editorial.

Data sharing is not without its risks, he says, but the pay-off from a systematic effort to reactivate important clinical trials will be high and will further justify the original huge investments of time and money, he concludes.²

Dr. David Healy, one of the authors of Restoring Study 329 believes that the issues uncovered are bigger that what happened with Study 329. “This was not an anomaly, but rather what has become standard industry practice for branded medicines. It raises many questions about drug safety, the limitations of randomized controlled trials, the need for access to individual patient level data, and the question of how to reduce harms from misleading health information.”¹

Fellow author Dr. Jon Jureidini says, “Our reanalysis of Study 329 reveals that drug regulators, pharmaceutical companies, senior ‘independent’ researchers, and journal editors are all failing patients. The core problem is that the process for safety and effectiveness testing is left to drug manufacturers, who have a vested interest in seeing positive results without the medical and scientific community being able to scrutinize what they are doing.”¹



Jon Jueridini and colleagues have reanalysed SmithKline Beecham’ infamous Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression.

The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine.

Their analysis finds that neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs.

References:
1 http://bmjcom.c.presscdn.com/company/wp-content/uploads/2015/09/Riat-package.pdf
2 http://www.boughtmovie.com/study329/