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). 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.
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 false claims about the drug's efficacy, and had downplayed safety concerns. 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."Wilson, Clare (16 September 2015). "New look at antidepressant suicide risks from infamous trial", New Scientist.
SmithKline Beecham acknowledged internally in 1998, that the study had failed to show efficacy for paroxetine in adolescent depression. In addition, more patients in the group taking paroxetine had experienced suicidal thinking and behaviour. 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". The company relied on the JAACAP 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, 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. 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", Food and Drug Administration, 19 June 2003, courtesy of the Drug Industry Documents Archive, University of California, San Francisco. The MHRA launched a criminal inquiry into GSK's conduct, but announced in 2008, that there would be no charges. In 2004, New York State Attorney Eliot Spitzer sued GSK for having withheld data,Harris, Gardiner (27 August 2004). "Maker of Paxil to Release All Trial Results", The New York Times. 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. 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"."Seroxat: Statement from GlaxoSmithKline", 29 January 2007, courtesy of BBC News.
The JAACAP article on study 329 has not been retracted.Heck, Isabel (2 April 2014) "Controversial Paxil paper still under fire 13 years later", The Brown Daily Herald. The journal's editors say the negative findings are included in a table, and that therefore there are no grounds to withdraw the article., p. 1246. 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.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. Godlee, Fiona (17 September 2015). "Study 329", BMJ, 351, 17 September 2015. Doshi, Peter (16 September 2015). "No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility", BMJ, 351. Henry, David; Fitzpatrick, Tiffany (16 September 2015)). "Liberating the data from clinical trials", BMJ, 351. Boseley, Sarah (16 September 2015). "Seroxat study under-reported harmful effects on young people, say scientists", The Guardian.
Clinical trial Overview
Funded by SmithKline Beecham, the acute phase of 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.
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. The last study visit was in May 1997, and the blind was broken in October.
Efficacy The trial's protocol had described two primary and six secondary outcomes by which it would measure efficacy."Study drug: BRL29060/Paroxetine (Paxil)" , SmithKline Beecham, 20 August 1993, amended 24 March 1994. The data showed that, according to those eight outcomes, paroxetine was no more effective than placebo. According to Melanie Newman, writing for the BMJ, "[t]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."
Safety 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 10 experiencing psychiatric problems. Seven of the 10 were hospitalized. Two of the 10 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. Yet Keller's article in the Journal of the American Academy of Child and Adolescent Psychiatry concluded that, of the 11 patients who had experienced SAEs while taking paroxetine, "only headache (1 patient) was considered by the treating investigator to be related to paroxetine treatment".Keller 2001, p. 769.
1998 SmithKline Beecham position paper
In October 1998 the neurosciences division of SmithKline Beecham's Central Medical Affairs (CMAT) department distributed a position paper, "Seroxat/Paxil Adolescent Depression: Position piece on the phase III clinical studies", that discussed studies 329 and 377."Seroxat/Paxil Adolescent Depression: Position piece on the phase III clinical studies", SmithKline Beecham, October 1998, courtesy of the Drug Industry Documents Archive, University of California, San Francisco; also available here, courtesy of the United States Department of Justice. The latter was a 12-week trial, comparing paroxetine and placebo in teenagers, conducted from 1995 to 1998.
The SmithKline Beecham position paper explained that the company had decided not to submit trial data from studies 329 and 377 to regulators, and discussed how to "effectively manage the dissemination of these data in order to minimise any potential negative commercial impact". An attached memo noted that the results were disappointing and would not support a label claim that paroxetine could be used to treat adolescents: "The best that could have been achieved was a statement that, although safety data was reassuring, efficacy had not been demonstrated."Jackie Westaway, SmithKline Beecham (14 October 1998) Memo, courtesy of the United States Department of Justice. The paper said: "it would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine."
Study 329 had shown "trends in efficacy in favour of Seroxat/Paxil across all indices of depression ...", according to the paper, "[but had] failed to demonstrate a statistically significant difference from placebo on the primary efficacy measures". Study 377 had shown a high placebo response rate and had "failed [to] demonstrate any separation of Seroxat/Paxil from placebo". SmithKline Beecham decided to publish study 329 but not 377, and not to submit either trial to the regulators, because they were "insufficiently robust to support a regulatory submission and label change for this patient population".
The document was leaked during a lawsuit and first published by the Canadian Medical Association Journal in March 2004. In response a GSK spokesperson said that "the memo draws an inappropriate conclusion and is not consistent with the facts ... GSK abided by all regulatory requirements for submitting safety data. We also communicated safety and efficacy data to physicians through posters, abstracts, and other publications."
JAACAP article Authorship Although the JAACAP article listed its authors as Martin Keller and 21 other physicians or researchers, the article had in fact been ghostwritten by Scientific Therapeutics Information (STI), a PR company in Springfield, New Jersey, specializing in communications for the pharmaceutical industry. The JAACAP article did not mention STI; the only mention of Laden was: "Editorial assistance was provided by Sally K. Laden, M.S." The list of authors included James P. McCafferty of GSK, but the article did not disclose his company affiliation.
STI had worked with SmithKline Beecham on its promotion of paroxetine since the early 1990s. In April 1998 Sally K. Laden and John A. Romankiewicz of STI sent SmithKline Beecham an estimate of $17,250 to work on six drafts of the study 329 paper, including the final draft, to cover the period up to March 1999. The sum was payable in installments: $8,500 upon initiation, $5,125 after draft three, and $3,625 upon submission to the journal.Deposition of Sally K. Laden, United States District Court, Northern District of California, 15 March 2007.