Thursday, September 17, 2015

qotd: Paxil: Same data, opposite conclusion

September 16, 2015
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

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called on funders and investigators of abandoned (unpublished) or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 "restoring invisible and
abandoned trials" (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their intention to publish the unpublished trials or publish corrected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undertake to correct a trial that had been identified as unpublished or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

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 "accurately reflects the honestly-held views of
the clinical investigator authors" and that GSK did "not agree that the
article is false, fraudulent or misleading."

Study 329 was a multicentre eight week double blind randomised
controlled trial (acute phase), followed by a six month continuation
phase. SKB's 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 "an extended
period of time"; 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 "the data have spoken." 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 Beecham's 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


Comment by Don McCanne

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

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 can't hear the outrage that should be expressed over this.

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