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.”
According Jon Jureidini, PhD, Critical and Ethical Medical Research Group, University of Adelaide, South Australia, hundreds of thousands of adolescents took this drug, and “we can’t know how many were harmed,”. “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trials,” an international group of researchers formed RIAT and called on funders and investigators of abandoned (unpublished) or misreported trials to publish undisclosed outcomes or correct misleading publications, Dr Jureidini and colleagues explain in the article. “Rationally, I can’t see how they cannot retract it, but my guess is they won’t,”
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.”