Retract Antidepressant Drug Trial, Experts Say

Megan Brooks

September 17, 2015

A reanalysis of the now infamous Study 329 of the antidepressant paroxetine (multiple brands) shows that the drug is ineffective and unsafe for adolescents, prompting experts to call for a retraction of the original study.

Study 329 was funded by SmithKline Beecham (now GlaxoSmithKline [GSK]) and was published in 2001 in the Journal of the American Academy of Child and Adolescent Psychiatry. The reanalysis of the study, reported September 16 in the BMJ, contradicts the original publication that found that paroxetine was generally safe and effective in treating adolescents with major depression.

"Hundreds of Thousands" Potentially Harmed

The reanalysis used previously confidential trial documents and found that the efficacy of paroxetine and imipramine (multiple brands) was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome, the researchers report.

Further, they observed "clinically significant increases in harms, including suicidal ideation and behavior and other serious adverse events in the paroxetine arm and cardiovascular problems in the imipramine arm."

"Hundreds of thousands" of adolescents took this drug, and "we can't know how many were harmed," Jon Jureidini, PhD, Critical and Ethical Medical Research Group, University of Adelaide, South Australia, told Medscape Medical News.

"This is the first reanalysis" of a randomized controlled trial under the Restoring Invisible and Abandoned Trials (RIAT) initiative, he noted.

In 2013, in the face of "selective reporting of outcomes of randomized controlled trials," an international group of researchers formed RIAT and called on funders and investigators of abandoned (unpublished) or misreported trials to publish undisclosed outcomes or correct misleading publications, Dr Jureidini and colleagues explain in the article.

Study 329 was criticized by the US Food and Drug Administration in 2002. In 2004, the agency added a black box warning advising against use of paroxetine in adolescents. In 2012, GSK was fined $3 billion, in part for fraudulently promoting paroxetine.

The reanalysis of Study 329 "illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base," the investigators write.

Failed Drug Regulation

In an accompanying editorial, Peter Doshi, PhD, an associate editor at the BMJ, says this article "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."

"Rationally, I can't see how they cannot retract it, but my guess is they won't," Dr Jureidini told Medscape Medical News.

In a statement, BMJ Editor-in-Chief Fiona Godlee, MD, said publication of the reanalyzed 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.

Approached by Medscape Medical News for comment on the BMJ article, GSK said in an emailed statement, "We were able to help this team to carry out their reanalysis by providing access to the detailed data from the original trial. This reflects our commitment to data transparency ― we publish the results of all our studies regardless of whether they are positive or negative."

"Importantly," the company noted, "the findings from this team's analysis appear to be in line with the long-standing view that there is an increased risk of suicidality in pediatric and adolescent patients given antidepressants like paroxetine. This is widely known, and clear warnings have been in place on the product label for more than a decade. As such, we don't believe this reanalysis affects patient safety."

"This particular trial," GSK said, "which was conducted in the 1990s, was included in detailed reviews carried out many years ago by regulators and by GSK which identified the increased risk. It's something the medical community and regulators are aware of."

Medscape Medical News also approached the American Academy of Child and Adolescent Psychiatry (AACAP) for comment on the BMJ article and the calls for retraction of the study.

"AACAP has the utmost respect for the BMJ, and we thank them for their continued efforts to bring science to the forefront. AACAP supports transparency in clinical trial reporting and welcomes the RIAT initiative. The statements and opinions expressed in JAACAP articles are those of the authors and not necessarily those of AACAP, the editors, or the publisher. Inquiries about the articles and study in question should be addressed to their respective authors."

The study had no specific funding. Dr Jureidini has been paid to provide expert analysis and opinion about documents obtained from GSK in a class action suit concerning Study 329. A complete list of author disclosures may be found in the original article.

BMJ. Published September 16, 2015. Full text, Editorial

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