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Study 329
Study 329 was a clinical trial conducted in North America from 1994 to 1998 to study the efficacy of paroxetine, an SSRI anti-depressant, in treating depressed teenagers.〔Martin B. Keller, Neal D. Ryan, Michael Strober, et al, ("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), July 2001, pp. 762–772. PMID 11437014〕 Marketed as Paxil and Seroxat (among other names), paroxetine had been released in 1991 by the British pharmaceutical company SmithKline Beecham, known since 2000 as GlaxoSmithKline (GSK). The drug made $11.6 billion between 1997 and 2006.〔
Led by Martin Keller, then professor of psychiatry at Brown University, study 329 became controversial when it was discovered that the article which reported the trial results – published in 2001 in the ''Journal of the American Academy of Child and Adolescent Psychiatry'' (''JAACAP'') – had downplayed the trial's negative findings and had been ghostwritten by a PR firm hired by SmithKline Beecham.〔Linsey McGoey, Emily Jackson, ("Seroxat and the suppression of clinical trial data: regulatory failure and the uses of legal ambiguity" ), ''Journal of Medical Ethics'', 35(2), February 2009, pp. 107–112. PMID 19181884〕 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."〔("New look at antidepressant suicide risks from infamous trial" ), ''New Scientist'', 16 September 2015.〕
The study, which compared paroxetine with imipramine, a tricyclic antidepressant marketed as Tofranil, failed to show efficacy for paroxetine in adolescent depression, something SmithKline Beecham acknowledged internally in 1998. In addition there were more examples of suicidal thinking and behaviour in the group taking paroxetine. Although the article included these negative results, it did not account for them in its conclusion. On the contrary, it concluded that paroxetine is "generally well tolerated and effective for major depression in adolescents."〔Wayne Kondro, Barbara Sibbald, "Drug company experts advised staff to withhold data about SSRI use in children," ''Canadian Medical Association Journal'', 170(5), 2 March 2004, p. 783. PMID 14993169〕 The company relied on the article to promote paroxetine for off-label use in teenagers.
In 2003 Britain's Medicines and Healthcare Products Regulatory Agency (MHRA) analysed study 329 and other GSK studies of paroxetine. It concluded that there was no evidence of paroxetine's efficacy and a clear increase in suicidal behaviour in teenagers using it. The following month the MHRA and US Food and Drug Administration (FDA) advised doctors not to prescribe paroxetine to the under-18s.〔("FDA statement regarding the anti-depressant Paxil for pediatric population" ), FDA, 19 June 2003.〕 The MRHA launched a criminal inquiry into GSK's conduct, but announced in 2008 that there would be no charges.〔("GSK investigation concludes" ), MHRA press release, 6 March 2008; (MHRA, 6 March 2008 ), p. 7ff.
(MHRA to GSK ), 6 March 2008; ("Transcription of a meeting at MHRA about Seroxat" ), MHRA meeting with patient group, 29 April 2008.〕 In 2004 New York State Attorney Eliot Spitzer sued GSK for having withheld the data.〔Emily Jackson, ''Law and the Regulation of Medicines'', Bloomsbury Publishing, 2012, p. 109; Gardiner Harris, ("Maker of Paxil to Release All Trial Results" ), ''The New York Times'', 27 August 2004.〕 In 2012 the US Justice Department 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.
The ''JAACAP'' article on study 329 was never retracted.〔Isabel Heck, ("Controversial Paxil paper still under fire 13 years later" ), ''The Brown Daily Herald'', 2 April 2014.〕 The journal's editors say the negative findings are included in a table, and that therefore there are no grounds to withdraw the article.〔Melanie Newman, ("The Rules of Retraction" ), ''BMJ'', 341(7785), 11 December 2010 (pp. 1246–1248), p. 1246. PMID 21138994〕 In September 2015 the ''BMJ'' published a re-analysis of study 329's data. This concluded that neither paroxetine nor imipramine had differed in efficacy in treating depression from placebo (an inert pill), that the paroxetine group had experienced more suicidal ideation and behaviour, and that the imipramine group had experienced more cardiovascular problems.〔Joanna Le Noury, et al., ("Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence" ), ''BMJ'', 351, 16 September 2015.
Fiona Godlee, ("Study 329" ), ''BMJ'', 351, 17 September 2015.
Peter Doshi, ("No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility" ), ''BMJ'', 351, 16 September 2015.
David Henry, Tiffany Fitzpatrick, ("Liberating the data from clinical trials" ), ''BMJ'', 351, 16 September 2015.
Sarah Boseley, ("Seroxat study under-reported harmful effects on young people, say scientists" ), ''The Guardian'', 16 September 2015.〕
==Clinical trial==
Funded by SmithKline Beecham, study 329 was an eight-week, double-blind, randomized clinical trial conducted in 12 university or hospital psychiatric departments in the United States and Canada between 1994 and 1997.〔〔For university or hospital psychiatric departments, ("Paroxetine (Seroxat) – Variation assessment report" ), MHRA, 4 June 2003, p. 6.〕 The study compared paroxetine, a selective serotonin reuptake inhibitor marketed as Paxil and Seroxat, with imipramine, a tricyclic antidepressant marketed as Tofranil, in teenagers aged 12–18 with a diagnosis of major depressive disorder of at least eight weeks duration.〔 Martin Keller, then professor of psychiatry at Brown University, had proposed the trial to the company in 1992 as the largest study until then to examine the efficacy of SSRIs in children.〔 The trial's protocol described two primary and six secondary outcomes by which it would measure efficacy.〔Jon N. Jureidini, Leemon B. McHenry, Peter R. Mansfield, ("Clinical trials and drug promotion: Selective reporting of study 329" ), ''International Journal of Risk & Safety in Medicine'', 20, 2008 (pp. 73–81), p. 74. 〕〔("Study drug: BRL29060/Paroxetine (Paxil)" ), SmithKline Beecham, 20 August 1993, amended 24 March 1994.〕
After a screening phase from April 1994, 275 male and female patients were randomly assigned paroxetine, imipramine or placebo (an inert pill).〔(Keller 2001 ), p. 763.〕 Of the 275, 93 were given paroxetine, 95 imipramine and 89 placebo. The paroxetine group were given 20 mg daily for four weeks, rising to 30 mg at week five and 40 mg at week six if the clinician thought it appropriate.〔(Keller 2001 ), p. 764.〕 One hundred and ninety completed the trial.〔(Keller 2001 ), p. 765.〕 The last study visit was in May 1997 and the blind was broken in October.〔
The results showed that, according to the eight outcomes Keller had first specified, paroxetine was no more effective than placebo. According to Melanie Newman, writing for the ''BMJ'', "()he drug only produced a positive result when four new secondary outcome measures, which were introduced following the initial data analysis, were used instead. Fifteen other new secondary outcome measures failed to throw up positive results."〔
In addition, eleven subjects on paroxetine, compared to five on imipramine and two on placebo, experienced serious adverse events (SAE), including behavioral problems and emotional lability. The researchers defined an event as an SAE if it resulted in hospitalization, involved suicidal gestures, or was regarded as serious by the subject's doctor. In the 93 taking paroxetine, the SAEs consisted of one subject experiencing headache while tapering off, and ten experiencing psychiatric problems. Seven of the ten were hospitalized. Two of the ten experienced worsening depression, two conduct problems such as aggression, one euphoria, and five emotional lability, including suicidal ideation and behaviour. Of the 95 patients on imipramine and the 89 on placebo, one in each group experienced emotional lability.〔(Keller 2001 ), p. 769.〕 The article in ''JAACAP'' later concluded that, of the 11 patients who experienced SAEs, "only headache (1 patient) was considered by the treating investigator to be related to paroxetine treatment."〔
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