Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
By Joanna Le Noury, John M Nardo, David Healy, Jon Jureidini, Melissa Raven, Catalin Tufanaru, Elia Abi-Jaoude
BMJ, September 16, 2015
From the Introduction
In 2013, in the face of the selective reporting of outcomes of randomised controlled trials, an international group of researchers called on funders and investigators of abandoned (unpublished) or misreported trials to publish undisclosed outcomes or correct misleading publications. This initiative was called ārestoring invisible and abandoned trialsā (RIAT). The researchers identified many trials requiring restoration and emailed the funders, asking them to signal their intention to publish the unpublished trials or publish corrected versions of misreported trials. If funders and investigators failed to undertake to correct a trial that had been identified as unpublished or misreported, independent groups were encouraged to publish an accurate representation of the clinical trial based on the relevant regulatory information.
The current article represents a RIAT publication of Study 329. The original study was funded by SmithKline Beecham (SKB; subsequently GlaxoSmithKline, GSK). We acknowledge the work of the original investigators. This double blinded randomised controlled trial to evaluate the efficacy and safety of paroxetine (Paxil) and imipramine (Toafranil) compared with placebo for adolescents diagnosed with major depression was reported in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) in 2001, with Martin Keller as the primary author. The RIAT researchers identified Study 329 as an example of a misreported trial in need of restoration. The article by Keller and colleagues, which was largely ghostwritten, claimed efficacy and safety for paroxetine that was at odds with the data. This is problematic because the article has been influential in the literature supporting the use of antidepressants in adolescents.
On 14 June 2013, the RIAT researchers asked GSK whether it had any intention to restore any of the trials it sponsored, including Study 329. GSK did not signal any intent to publish a corrected version of any of its trials. In later correspondence, GSK stated that the study by Keller and colleagues āaccurately reflects the honestly-held views of the clinical investigator authorsā and that GSK did ānot agree that the article is false, fraudulent or misleading.ā
Study 329 was a multicentre eight week double blind randomised controlled trial (acute phase), followed by a six month continuation phase. SKBās stated primary objective was to examine the efficacy and safety of imipramine and paroxetine compared with placebo in the treatment of adolescents with unipolar major depression. Secondary objectives were to identify predictors of treatment outcomes across clinical subtypes; to provide information on the safety profile of paroxetine and imipramine when these drugs were given for āan extended period of timeā; and to estimate the rate of relapse among patients who responded to imipramine, paroxetine, and placebo and were maintained on treatment. Study enrolment took place between April 1994 and March 1997.
Conclusion and implications for research and policy
Contrary to the original report by Keller and colleagues, our reanalysis of Study 329 showed no advantage of paroxetine or imipramine over placebo in adolescents with symptoms of depression on any of the prespecified variables. The extent of the clinically significant increases in adverse events in the paroxetine and imipramine arms, including serious, severe, and suicide related adverse events, became apparent only when the data were made available for reanalysis. Researchers and clinicians should recognise the potential biases in published research, including the potential barriers to accurate reporting of harms that we have identified. Regulatory authorities should mandate accessibility of data and protocols.
As with most scientific papers, Keller and colleagues convey an impression that āthe data have spoken.ā This authoritative stance is possible only in the absence of access to the data. When the data become accessible to others, it becomes clear that scientific authorship is provisional rather than authoritative.
What is already known on this topic
- There is a lack of access to data from most clinical randomised controlled trials, making it difficult to detect biased reporting
- In the absence of access to primary data, misleading conclusions in publications of those trials can seem definitive
- SmithKline Beechamās Study 329, an influential trial that reported that paroxetine was safe and effective for adolescents, is one such study
What this study adds
- On the basis of access to the original data from Study 329, we report a reanalysis that concludes that paroxetine was ineffective and unsafe in this study
- Access to primary data makes clear the many ways in which data can be analysed and represented, showing the importance of access to data and the value of reanalysis of trials
- There are important implications for clinical practice, research, regulation of trials, licensing of drugs, and the sociology and philosophy of science
- Our reanalysis required development of methods that could be adapted for future reanalyses of randomised controlled trials
http://www.bmj.com/content/351/bmj.h4320
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Comment:
By Don McCanne, MD
Although questions and concerns have already been raised about the SmithKline Beecham study of the use of Paxil in adolescents, this study provides definitive answers in that it is a reanalysis of the full original data set that had not previously been released. Contrary to the original, ghostwritten published report that concluded that Paxil was safe and effective for depression in adolescents, this meticulous reanalysis of the same data led to the conclusion that Paxil is actually ineffective and harmful.
The research and marketing abuses of the pharmaceutical industry abound, now compounded by price gouging behavior. Donald Light and his colleagues have previously discussed the institutional corruption of pharmaceuticals here.
There is a crying need for much greater government oversight, but it likely will not come from an administration that allowed this industry to assist in writing the Affordable Care Act. Citizen involvement in electoral politics does matter, or at least it should. But nothing will happen if we canāt hear the outrage that should be expressed over this.