Global InformationStudy 329 information
| Study 329 | |
|---|---|
 Paroxetine, sold as Paxil and Seroxat | |
| Study type | Eight-week, placebo-controlled, double-blind, randomized clinical trial comparing paroxetine with imipramine in adolescents with major depressive disorder |
| Dates | 1994–1998 |
| Locations | 10 centres in the United States, two in Canada |
| Lead researcher | Martin Keller, then professor of psychiatry, Brown University |
| Funding | SmithKline Beecham, now GlaxoSmithKline (GSK) |
| Protocol | "Study drug: BRL29060/Paroxetine (Paxil)", SmithKline Beecham, 20 August 1993, amended 24 March 1994. |
| Published | July 2001 |
| Disputed article | Martin B. Keller, et al. (July 2001). "Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial", Journal of the American Academy of Child and Adolescent Psychiatry, 40(7), pp. 762–772. PMID 11437014 |
| Call for retraction | May 2003,[1] April 2013[2] |
| Retracted | No[3][4] |
| Legal penalty | GSK fined in 2012 by US Department of Justice[5] |
| Study reanalysis | Joanna Le Noury, et al. (16 September 2015). "Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence", BMJ, 351, 16 September 2015. PMID 26376805 |
Study 329 was a clinical trial which was conducted in North America from 1994 to 1998 to study the efficacy of paroxetine, an SSRI anti-depressant, in treating 12- to 18-year-olds diagnosed with major depressive disorder. Led by Martin Keller, then professor of psychiatry at Brown University, and funded by the British pharmaceutical company SmithKline Beecham—known since 2000 as GlaxoSmithKline (GSK)—the study compared paroxetine with imipramine, a tricyclic antidepressant, and placebo (an inert pill).[6] SmithKline Beecham had released paroxetine in 1991, marketing it as Paxil in North America and Seroxat in the UK. The drug attracted sales of $11.7 billion in the United States alone from 1997 to 2006, including $2.12 billion in 2002, the year before it lost its patent.[7]
Published in July 2001 in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP), which listed Keller and 21 other researchers as co-authors, study 329 became controversial when it was discovered that the article had been ghostwritten by a PR firm hired by SmithKline Beecham, had made inappropriate claims about the drug's efficacy, and had downplayed safety concerns.[8][9][3] The controversy led to several lawsuits and strengthened calls for drug companies to disclose all their clinical research data. New Scientist wrote in 2015: "You may never have heard of it, but Study 329 changed medicine."[10]
SmithKline Beecham acknowledged internally in 1998, that the study had failed to show efficacy for paroxetine in adolescent depression.[a] In addition, more patients in the group taking paroxetine had experienced suicidal thinking and behaviour.[b] Although the JAACAP article included these negative results, it did not account for them in its conclusion; on the contrary, it concluded that paroxetine was "generally well tolerated and effective for major depression in adolescents".[14][15] The company relied on the JAACAP article to promote paroxetine for off-label use in teenagers.[c]
In 2003 Britain's Medicines and Healthcare products Regulatory Agency (MHRA) analysed study 329 and other GSK studies of paroxetine, concluding that, while there was no evidence of paroxetine's efficacy in children and adolescents, there was "robust evidence" of a causal link between the drug and suicidal behaviour.[17][d] The following month the MHRA and US Food and Drug Administration (FDA) advised doctors not to prescribe paroxetine to the under-18s.[19] The MHRA launched a criminal inquiry into GSK's conduct, but announced in 2008, that there would be no charges.[20] In 2004, New York State Attorney Eliot Spitzer sued GSK for having withheld data,[21][22] and in 2012 the United States Department of Justice fined the company $3 billion, including a sum for withholding data on paroxetine, unlawfully promoting it for the under-18s, and preparing a misleading article on study 329.[e] The company denied that it had withheld data, and said it was only when data from its nine paediatric trials on paroxetine were analysed together that "an increased rate of suicidal thinking or attempted suicide [was] revealed".[24]
The JAACAP article on study 329 was never retracted.[3][4] The journal's editors say the negative findings are included in a table, and that therefore there are no grounds to withdraw the article.[25] In September 2015 the BMJ published a re-analysis of the study. This concluded that neither paroxetine nor imipramine had differed in efficacy from placebo in treating depression, that the paroxetine group had experienced more suicidal ideation and behaviour, and that the imipramine group had experienced more cardiovascular problems.[26][9][3][27][28]
- ^ Cite error: The named reference
JureidiniMay2003was invoked but never defined (see the help page). - ^ Cite error: The named reference
Jureidini26April2013was invoked but never defined (see the help page). - ^ a b c d Doshi, Peter (16 September 2015). "No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility", BMJ, 351. doi:10.1136/bmj.h4629
- ^ a b Heck, Isabel (2 April 2014). "Controversial Paxil paper still under fire 13 years later", The Brown Daily Herald.
- ^ "GSK's off-label marketing of Paxil", United States v. GlaxoSmithKline, United States District Court for the District of Massachusetts, 26 October 2011, pp. 3–19.
"GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data", United States Department of Justice, 2 July 2012.
- ^ Keller, Martin B.; Ryan, Neal D.; Strober, Michael, et al. (July 2001). "Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial", Journal of the American Academy of Child and Adolescent Psychiatry, 40(7), pp. 762–772. doi:10.1097/00004583-200107000-00010 PMID 11437014
- ^ Cite error: The named reference
Bloomberg14Dec2009was invoked but never defined (see the help page). - ^ McGoey, Linsey; Jackson, Emily (February 2009). "Seroxat and the suppression of clinical trial data: regulatory failure and the uses of legal ambiguity", Journal of Medical Ethics, 35(2), pp. 107–112. doi:10.1136/jme.2008.025361 PMID 19181884 JSTOR 27720271
- ^ a b Godlee, Fiona (17 September 2015). "Study 329", BMJ, 351, 17 September 2015. doi:10.1136/bmj.h4973
- ^ Wilson, Clare (16 September 2015). "New look at antidepressant suicide risks from infamous trial", New Scientist.
- ^ Cite error: The named reference
SKBpositionpaperwas invoked but never defined (see the help page). - ^ Letter from FDA to GlaxoSmithKline, 21 October 2002, courtesy of the Drug Industry Documents Archive, University of California, San Francisco.
- ^ "MHRA Investigation into GlaxoSmithKline/Seroxat", Medicines and Healthcare products Regulatory Agency, 6 March 2008(a), (pp. 1–13), p. 2, para. 2.
- ^ Cite error: The named reference
Keller2001p770was invoked but never defined (see the help page). - ^ Kondro, Wayne; Sibbald, Barbara (2 March 2004). "Drug company experts advised staff to withhold data about SSRI use in children", Canadian Medical Association Journal, 170(5), p. 783. doi:10.1503/cmaj.1040213 PMID 14993169
- ^ Hawkins, Zachary (18 August 2001). "To all sales representatives selling Paxil", Paxil Product Management, GlaxoSmithKline, courtesy of the Drug Industry Documents Archive, University of California, San Francisco.
- ^ "MHRA Investigation into GlaxoSmithKline/Seroxat", Medicines and Healthcare products Regulatory Agency, 6 March 2008(a).
- ^ Cite error: The named reference
MHRA6March2008p5pa12was invoked but never defined (see the help page). - ^ "FDA statement regarding the anti-depressant Paxil for pediatric population", Food and Drug Administration, 19 June 2003, courtesy of the Drug Industry Documents Archive, University of California, San Francisco.
- ^ "GSK investigation concludes", Medicines and Healthcare products Regulatory Agency, press release, 6 March 2008(b).
Letter from Kent Woods, MHRA, to Jean-Pierre Garnier, GSK, Medicines and Healthcare products Regulatory Agency, 6 March 2008(c).
"Transcription of a meeting at MHRA about Seroxat", Medicines and Healthcare products Regulatory Agency, meeting with patient group, 29 April 2008.
- ^ Jackson, Emily (2012). Law and the Regulation of Medicines, London: Bloomsbury Publishing, p. 109.
- ^ Harris, Gardiner (27 August 2004). "Maker of Paxil to Release All Trial Results", The New York Times.
- ^ Cite error: The named reference
DOJ2012was invoked but never defined (see the help page). - ^ "Seroxat: Statement from GlaxoSmithKline", 29 January 2007, courtesy of BBC News.
- ^ Newman, Melanie (11 December 2010). "The Rules of Retraction", BMJ, 341(7785), pp. 1246–1248. doi:10.1136/bmj.c6985 PMID 21138994 JSTOR 20800711, p. 1246.
- ^ Le Noury, Joanna, et al. (16 September 2015). "Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence", BMJ, 351. doi:10.1136/bmj.h4320 PMID 26376805 PMC 4572084
- ^ Henry, David; Fitzpatrick, Tiffany (16 September 2015)). "Liberating the data from clinical trials", BMJ, 351. doi:10.1136/bmj.h4601
- ^ Boseley, Sarah (16 September 2015). "Seroxat study under-reported harmful effects on young people, say scientists", The Guardian.
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