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Study 329
Paroxetine, sold as Paxil and Seroxat
Study typeEight-week, placebo-controlled, double-blind, randomized clinical trial comparing paroxetine with imipramine in adolescents with major depressive disorder
Dates1994–1998
Locations10 centres in the United States, two in Canada
Lead researcherMartin Keller, then professor of psychiatry, Brown University
FundingSmithKline Beecham, now GlaxoSmithKline (GSK)
Protocol"Study drug: BRL29060/Paroxetine (Paxil)", SmithKline Beecham, 20 August 1993, amended 24 March 1994.
PublishedJuly 2001
Disputed articleMartin 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 retractionMay 2003,[1] April 2013[2]
RetractedNo[3][4]
Legal penaltyGSK fined in 2012 by US Department of Justice[5]
Study reanalysisJoanna 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]

Clinical trial

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Overview

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photograph
Over two million prescriptions for paroxetine were written for children or adolescents in the US in 2002.[29]

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.[6][30] 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.[6] 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.[15]

After a screening phase from April 1994, 275 male and female patients were randomly assigned paroxetine, imipramine or placebo (an inert pill).[31] 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.[32] The last study visit was in May 1997, and the blind was broken in October.[33]

Efficacy

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The trial's protocol had described two primary and six secondary outcomes by which it would measure efficacy.[34][33] 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."[f][33]

Safety

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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".[35][b]

1998 SmithKline Beecham position paper

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photograph
GlaxoSmithKline global headquarters, Brentford, west London

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.[11] The latter was a 12-week trial, comparing paroxetine and placebo in teenagers, conducted from 1995 to 1998.[g]

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".[15] 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."[37] 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."[11]

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".[11]

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."[15]

JAACAP article

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Authorship

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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.[38] 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.[6]

STI had worked with SmithKline Beecham on its promotion of paroxetine since the early 1990s.[h] 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.[38][40]

The estimate covered all writing, editing, library research, copy editing, art work and coordination with the physicians and others who would be named as authors. Martin Keller would be listed as the main author.[38] The first draft was ready by December 1998.[41] SmithKline Beecham documents show that Laden and STI coordinated the entire publication process, including writing the cover letter to the journal that published the article, JAACAP, which she sent to Keller with the instruction that he transfer it to his own letterhead.[42]

Publication

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STI first submitted the article to the Journal of the American Medical Association (JAMA), which rejected it in November 1999. Concerns cited by JAMA reviewers included that "the main finding of the study is the high placebo response rate". They also suggested that the named authors confirm they had been "granted full access to the data set to verify the accuracy of the report".[43][44]

Early drafts of the paper for JAMA did not mention the serious adverse events (SAEs). A SmithKline Beecham scientist, James McCafferty, added a paragraph about these in July 1999, adding that 11 patients on paroxetine had experienced SAEs, against two on placebo: "worsening depression, emotional lability, headache, and hostility were considered related or possibly related to treatment."[45][46] This was changed in the final draft to: "Of the 11 patients, only headache (1 patient) was considered by the treating investigator to be related to paroxetine treatment."[45][35]

In December 1999 Laden submitted the rewritten paper to JAACAP, led at the time by Mina K. Dulcan, editor-in-chief. According to Melanie Newman in the BMJ, JAACAP's reviewers wrote that the results did not "clearly demonstrate efficacy for paroxetine", and asked whether, because of the high placebo response rate, SSRIs should be regarded as first-line therapy.[47] JAACAP accepted the article in January 2001,[48] and published it in July.[6]

The article concluded: "Paroxetine is generally well tolerated and effective for major depression in adolescents."[14] McCafferty's paragraph about worsening depression and emotional lability possibly being related to the treatment had been removed. The only SAE attributed to paroxetine in the JAACAP article was in one patient who had reported headache.[35][45] The article continued: "Because these serious adverse events were judged by the investigator to be related to treatment in only 4 patients (paroxetine, 1; imipramine, 2; placebo, 1), causality cannot be determined conclusively." It concluded: "The findings of this study provide evidence of the efficacy and safety of the SSRI, paroxetine, in the treatment of adolescent depression."[14]

2001 GlaxoSmithKline sales memo, off-label use

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GSK used the JAACAP article to promote paroxetine to doctors for use in their teenage patients. The drug had not been approved for use in children and adolescents. Drug companies are prohibited from promoting drugs for unapproved uses, but doctors are permitted to prescribe drugs for what is known as off-label use. In the UK 32,000 prescriptions of paroxetine were written for children and adolescents in 1999,[49] and in the US that figure rose to 2.1 million in 2002, earning GSK $55 million.[29][3]

On 7 August 2001 Sally Laden of STI, apparently the main author of the JAACAP article, arranged for GSK to buy 500 reprints of the article—300 for Keller and 200 for Zachary Hawkins of GSK's Paxil Product Management team—to be distributed to the company's neuroscience sales force.[50] On 16 August 2001 Zachary Hawkins sent a memo about study 329 to "All Sales Representatives Selling Paxil", calling study 329 a "cutting-edge,' landmark study", the first to compare efficacy of a selective serotonin reuptake inhibitor and a tricyclic antidepressant with placebo in the treatment of depressed adolescents. "Paxil demonstrates REMARKABLE Efficacy and Safety in the treatment of adolescent depression," he wrote.[16]

The memo continued that paroxetine was "significantly more effective than placebo" on certain outcomes: "Paxil was generally well tolerated in this adolescent population and most adverse events were not serious. The most common adverse events occurred at rates that were similar to rates in the placebo group." It ended with:

In conclusion, the findings of this study provide evidence of the efficacy and safety of Paxil in the treatment of adolescent depression. Here's another example of GlaxoSmithKline's commitment to Psychiatry by bringing forth 'cutting edge' scientific data. Paxil is truly a REMARKABLE product that continues to demonstrate efficacy, even in this understudied population."[16]

Inquiries in the United Kingdom

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BBC Panorama, MHRA

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Scottish reporter Shelley Jofre presented four investigative programmes on paroxetine for BBC Panorama between 2002 and 2007, including one devoted to study 329, "Secrets of the Drug Trials", in January 2007.[51][52][53][54] The 2007 programme was based on thousands of internal company documents produced during lawsuits pursued against GSK by patients and families.[54]

Jofre's interest in paroxetine was triggered by the July 2001 case of Timothy J. Tobin v. SmithKline Beecham Pharmaceuticals in the United States. The family of 60-year-old Donald Schell sued the company after Schell shot and killed his wife, daughter and baby granddaughter, then committed suicide, 48 hours after starting a course of paroxetine in 1998. A Wyoming jury awarded the plaintiffs $6.4 million.[55][56]

The first of Jofre's programmes, "The Secrets of Seroxat", aired on 13 October 2002, and covered the Schell case, study 329, and GSK's efforts to market the drug for use in children. (At the time the Summary of Product Characteristics for paroxetine in Europe said that its use in children was "not recommended as safety and efficacy have not been established in this population".)[57] Discussing study 329 and the paediatric use of paroxetine, Alistair Benbow, head of European psychiatry for GlaxoSmithKline, told Jofre that, during study 329, paroxetine had been "generally well tolerated by this difficult to treat population".[i]

photograph
Paroxetine is sold in the UK as Seroxat.[58]

To examine the issues that Panorama had raised, Britain's Medicines and Healthcare products Regulatory Agency (MHRA) set up an ad hoc group of experts, which held a meeting with GSK on 14 November 2002. The MHRA asked GSK about its clinical trials in children. GSK was planning to apply for pediatric indications for paroxetine. According to the MHRA, "GSK did not raise any concern about lack of efficacy or adverse reactions in the clinical trials in the paediatric population at that meeting."[59]

Jofre's second Panorama programme on paroxetine, "Emails from the edge" (11 May 2003) focused on the 67,000 calls and 1,400 e-mails the BBC received, after the first programme, from people taking the drug.[60] They reported withdrawal symptoms, as well as acts of violence and self-harm that they believed were attributable to paroxetine. During this programme, Benbow told Jofre: "We have been asked by the regulatory authorities to provide all our information related to suicides and I can tell you the data that we provide to them clearly shows no link between Seroxat and an increased risk of suicide—no link."[52]

May 2003 GlaxoSmithKline briefing paper

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In February 2003 the MHRA's Committee on the Safety of Medicines (CSM) set up an Expert Working Group to investigate SSRIs and safety.[61] In preparation for its first meeting, the MHRA met GSK on 21 May 2003 to make sure that GSK had supplied all information relevant to paroxetine and safety, and to discuss Jofre's second Panorama programme.[58][62]

Toward the end of the meeting, GSK handed over a 79-page briefing paper, "Paroxetine: Critical evaluation of paroxetine hydrochloride for the treatment of Paediatric Obsessive Compulsive Disorder and Social Anxiety Disorder in children and adolescents", dated 20 May 2003.[63][58] The paper included data from nine clinical trials GSK had conducted on paroxetine and children between April 1994 and September 2002:[64]

"Description of clinical programme for children"
Study no. Treatment
duration		 Design Age range Paroxetine
dosages
(mg/day)		 No. of
patients
704 OCD 10 weeks Randomized, db, parallel group, pc, flexible dose 7–17 10–50 203
676 SAD 16 weeks Randomized, db, parallel group, pc, flexible dose 8–17 10–50 318
329 MDD 8 weeks Randomized (1:1:1) db, parallel group, pc and actively controlled (imipramine), flexible dose 12–18 20–40 271
377 MDD 12 weeks Randomized (2:1), db, parallel group, pc, flexible dose 13–18 20–40 274
701 MDD 8 weeks Randomized, db, parallel group, pc, flexible dose 7–17 10–40 203
453 OCD/MDD 32 weeks Two-phase, relapse prevention design. Phase 1: 16 weeks, open-label paroxetine, flexible dose. "Responders" proceed to Phase II. 8–17 10–60 335
Phase II: 16 weeks, randomized, db, parallel group, pc, fixed dose (dose at end of Phase 1) 193
329 OCD/MDD 6 months Db, parallel group, continuation of responders from study 329 (acute) 12–18 20–40 125
716 OCD/MDD 6 months Open-label, extension for patients from studies 701 704 and 715 7–17 10–50 265
715 OCD/MDD 6 weeks Open-label, dose-rising, repeat dose, PK study 7–17 10–30 62

The briefing paper concluded that "analysis of the safety data demonstrates that paroxetine is generally well tolerated by paediatric patients ...," but suggested a label change to the effect that efficacy had not been established in children with major depressive disorder, and that adverse reactions could include hyperkinesia, hostility, emotional lability and agitation. The paper said these had occurred around twice as much in the paroxetine group than in those taking placebo.[65]

By "emotional lability", the paper alluded in particular to suicidal thoughts and behaviour. Of 20 reports of adverse events in the paroxetine groups, 12 had been suidical thoughts or suicide attempts (none successful), three self-mutilation and five general emotional lability. There had been eight adverse events in the patients taking placebo, of which four were suicidal thoughts or behaviour, one self-mutilation and three emotional lability.[66]

The paper suggested a label change regarding withdrawal symptoms, which it said had occurred with paroxetine at roughly twice the rate of placebo.[65]

MHRA response

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Alasdair Breckenridge, then-chair of the MHRA, told Panorama that the GSK briefing document caused "a very dramatic change in our thinking about Seroxat and children".[67] The MHRA asked GSK to submit the full clinical data, which they did on 27 May 2003. The data provided "robust evidence" of a causal link between paroxetine and suicidality, and no evidence that paroxetine was effective in treating depression in children.[18] The MHRA wrote:

On examination of the full clinical trial data in children submitted by GSK urgently on 27 May 2003 in response to requests from the Agency, it became clear that the evidence base for the safety concern of an increased risk of suicidal behaviour was derived from pooled analysis of all the trials (a meta-analysis). It was only when the trials were analysed together that the safety issue became apparent. These trials had been conducted over a number of years and some had been published in part, however the publications gave an incomplete and partial picture of the full data. Importantly, the trials conducted in a range of conditions in children and adolescents failed to demonstrate that Seroxat was effective in the treatment of depressive illness.

The analysis suggested an increased rate of suicidal thinking and behaviour of 3.4 percent on paroxetine versus 1.2 percent on placebo.[68] The committee concluded that the risks outweighed the benefits,[69] and on 10 June 2003 issued an advisory to physicians not to prescribe paroxetine to the under-18s.[70] The US Food and Drug Administration followed suit nine days later.[19]

Criminal inquiry

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The MHRA offices on Buckingham Palace Road, London. The MHRA announced in 2008 that GSK would not be prosecuted.

The MHRA launched a criminal inquiry in October 2003 into GSK's conduct. This was based on two concerns: (a) the length of time between the end of the trials and GSK's passing the safety concerns to the MHRA; and (b) the manner in which the material had been handed over. Rather than alerting the MHRA of a risk, GSK had supplied the data in relation to an application to extend the indications of paroxetine to children. The MHRA deemed this inappropriate for an urgent safety concern because of the length of time such applications can take.[71]

Medical ethicists Linsey McGoey and Emily Jackson argued that the 1998 SmithKline Beecham position paper, in which the company said it had decided not to show studies 329 and 377 to regulators,[11] represented a prima facie breach of the Medicines Act 1968 and Medicines for Human Use Regulations, which required pharmaceutical companies to pass to the regulator trial data that had safety and efficacy implications.[72][73]

The MHRA reviewed around one million pages of documentation in the course of the inquiry.[74] After a four-year investigation, independent counsel instructed by the MHRA advised, according to an MHRA report, that "no offence ha[d] been committed contrary to the 1994 Regulations [Medicines for Human Use (Marketing Authorisations Etc.) Regulations 1994]", because GSK's clinical trials and alleged failure to provide data from them "most likely did not fall within the regime implemented by those Regulations".[75] If the 1994 Regulations did apply, the report said, the "relevant provisions were not sufficiently clear so as to permit a criminal sanction for their breach".[76] The MHRA announced in March 2008 that there would be no prosecution.[77][73] In October 2008 the 1994 Regulations were amended to prevent a repetition of the case.[78]

Inquiries in the United States

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The Boston Globe

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In November 1995 Alison Bass of The Boston Globe began investigating Brown University's psychiatry department, chaired by Martin Keller, who led Study 329. There were allegations that the department had taken $218,000 of government funds for research that apparently had not been conducted.[79][80] In October 1999 she reported Keller's financial relationship with the pharmaceutical industry, which included receipt of $500,000 in consulting fees the previous year.[81] Bass's work developed into a book about GlaxoSmithKline, paroxetine, and Study 329, Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial (2008).[82]

FDA-mandated review

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In March 2004 the FDA mandated that drug companies review the use of their SSRIs in children. In 2006 GSK researchers published a review of five of their trials involving paroxetine and adolescents or children, including study 329 and the unpublished study 377. They wrote that suicidal ideation or behaviour had occurred in 22 of 642 patients on paroxetine (3.4 percent) against five of 549 on placebo (0.9 percent). The article concluded: "Adolescents treated with paroxetine showed an increased risk of suicide-related events. ... The presence of uncontrolled suicide risk factors, the relatively low incidence of these events, and their predominance in adolescents with MDD make it difficult to identify a single cause for suicidality in these pediatric patients.[83]

People v. GlaxoSmithKline

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photograph
Eliot Spitzer

In June 2004 New York State Attorney Eliot Spitzer filed a lawsuit against GSK in the New York State Supreme Court for having withheld clinical trial data about paroxetine, including from study 329.[84][85] GSK denied any wrongdoing and said it had disclosed the data to regulators, and to physicians at medical conventions and in other ways.[86]

GSK settled the case in August 2004, agreeing to pay $2.5 million, make its trial data about paroxetine and children available on its website, and establish a clinical trial register that would host summaries of all company-sponsored trials going back to 27 December 2000. By October 2004 other drug companies, including Pfizer, Eli Lilly and Merck, had agreed to create their own registers.[87] In 2013 GSK joined AllTrials, a British campaign to have all clinical trials registered and the results reported.[88][89]

Other lawsuits

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By 2009 GSK had paid almost $1 billion to settle paroxetine-related lawsuits related to 450 suicides, withholding data, as well as addiction, antitrust and other claims. An additional 600 unsettled claims related to birth defects.[7] The lawsuits produced thousands of internal company documents, some of which entered the public domain.[33] These formed the basis of some of Alison Bass's work and that of Shelley Jofre for the BBC.[51][52][53][54]

United States v. GlaxoSmithKline

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Further information: GlaxoSmithKline § 2012 criminal and civil settlement

In October 2011 the United States Department of Justice filed a lawsuit under the False Claims Act accusing GSK of promoting drugs for unapproved uses, failing to report safety data, reporting false prices to Medicaid, and paying kickbacks to physicians in the form of gifts, trips and sham consultancy fees. The complaint included preparing the JAACAP article about study 329, exaggerating paroxetine's efficacy while downplaying the risks, and using the article to promote the drug for adolescent use, which was not approved by the FDA.[23]

GSK pleaded guilty in 2012 and paid a $3 billion settlement, including a criminal fine of $1 billion. The fine included an amount for "preparing, publishing and distributing a misleading medical journal article that misreported that a clinical trial of Paxil demonstrated efficacy in the treatment of depression in patients under age 18, when the study failed to demonstrate efficacy".[23][j]

Calls for retraction

[edit]
photograph
Jon Jureidini

Child psychiatrist Jon Jureidini of the Women's and Children's Hospital in Adelaide and Ann Tonkin of the University of Adelaide asked JAACAP in 2003 to retract the study 329 paper.[1][91][k]

In 2005 the philosopher Leemon McHenry complained to JAACAP's editor, Mina Dulcan, that Keller and some of the other researchers named as authors had worked for GSK but had not declared their conflict of interest and had violated the journal's policy regarding authorship.[43] Keller had acted as a consultant for several drug companies. The Boston Globe reported in 1999 that he had earned $500,000 the previous year from consultancy work, which, the newspaper said, he did not disclose to the journals that published his work or to the American Psychiatric Association.[93] Dulcan replied to McHenry that "unless there is a specific accusation of research fraud, it is not the role of scientific journals to police authorship."[94]

Jureidini and McHenry called again for the paper's retraction in 2009. Editor-in-chief Andrés Martin replied that there was no justification for retraction, and that the journal had "conformed to the best publication practices prevailing at the time".[43] In April 2013 Jureidini asked GSK's CEO Andrew Witty to request retraction.[2][95]

RIAT re-analysis of study 329

[edit]

In July 2013 Jureidini announced his intention to produce a new write-up of study 329 in accordance with the RIAT initiative (restoring invisible and abandoned trials).[96][95] The RIAT researchers—Joanna Le Noury, John M. Nardo, David Healy, Jon Jureidini, Melissa Raven, Catalin Tufanaru, and Elia Abi-Jaoude—published their re-analysis in the BMJ in September 2015. They concluded that "[t]he efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome," and that there were "clinically significant increases in ... suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group."[26]

Anti-depressants and suicidality in young people

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Further information: Antidepressants and suicide risk

In 2007 the FDA required that all anti-depressants include a boxed warning of an increased risk of suicidal thoughts and behaviour in young adults (18–24 years) during the first one to two months of treatment.[97][l] A 2012 Cochrane review on the use of SSRIs in children and adolescents concluded that there is evidence of an increased suicide risk in patients treated with antidepressants. It added: "However, given the risks of untreated depression in terms of completed suicide and impacts on functioning, if a decision to use medication is agreed, then fluoxetine might be the medication of first choice given guideline recommendations."[m]

See also

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Notes

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Study 329

View on Grokipedia
from Grokipedia
Study 329 was a multicenter, double-blind, randomized, -controlled sponsored by SmithKline Beecham (later GlaxoSmithKline) from 1994 to 1998, evaluating the efficacy and safety of versus and in 275 adolescents aged 12 to 18 with unipolar major depression. The trial featured an 8-week acute phase assessing response via the Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS), followed by a 6-month continuation phase. Published in 2001 by Keller et al. in the Journal of the American Academy of , the study reported as generally well tolerated and effective for reducing depressive symptoms compared to . However, internal analyses and full clinical study reports revealed paroxetine failed all protocol-specified efficacy outcomes, showing no statistically significant benefit over . Reanalysis in 2015 by LeNoury et al., accessing through legal channels, confirmed the absence of efficacy while identifying increased harms, including and behavior (8 events on paroxetine versus 1 on ) and other serious adverse events. These discrepancies, including selective reporting and ghostwriting allegations, contributed to U.S. Department of findings of fraudulent promotion by GlaxoSmithKline, resulting in a $3 billion settlement in for misleading safety claims on paroxetine in . The trial's fallout prompted the FDA to issue a warning in 2004 on all antidepressants for increased suicidality risk in children and adolescents, informed in part by Study 329's unreported events. It exemplifies challenges in pharmaceutical trial transparency, with advocates citing it to push for mandatory disclosure beyond summaries. Recent scrutiny, including a 2025 expression of concern on the original publication, underscores ongoing debates over and retraction standards.

Clinical Trial Design and Execution

Objectives and Protocol

Study 329, sponsored by SmithKline Beecham (later GlaxoSmithKline), aimed to evaluate the efficacy and safety of , an , relative to and , a , for treating unipolar in adolescents. The trial protocol specified two coprimary efficacy endpoints for the 8-week acute phase: the proportion of treatment responders, defined as participants achieving a total score of ≤8 on the 17-item (HAM-D) or a reduction of ≥50% from baseline HAM-D score at endpoint; and the mean change from baseline to endpoint in total HAM-D score. Secondary objectives encompassed additional measures of depressive symptoms, global improvement, and suicidality risk, with the protocol delineating five secondary efficacy endpoints alongside safety monitoring for adverse events, including emergent suicidality. The protocol outlined a multicenter, randomized, double-blind, -controlled, parallel-group conducted across 12 sites in the United States from 1994 to 1998. Eligible participants were outpatients aged 12-18 years meeting DSM-IV criteria for , with a baseline HAM-D score ≥20 or Clinical Global Impression-Severity score ≥4, and no significant comorbidities or recent psychotropic use. Following a 7- to 14-day screening and washout period, 189 adolescents were randomized in a 2:2:2 ratio to receive flexible dosing of (10-60 mg/day, targeting 20-40 mg), (titration to 100-200 mg/day), or matching over 8 weeks, with weekly clinic visits for assessments using scales such as the HAM-D, Montgomery-Åsberg Depression Rating Scale, and Children's Depression Rating Scale-Revised. Responders could enter an optional 6-month open-label continuation phase for long-term safety and relapse prevention data, though this was not powered for efficacy comparisons.

Methods and Participant Characteristics

Study 329 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group evaluating the efficacy and safety of compared to and in adolescents with . The acute phase lasted eight weeks and was conducted at 12 academic centers in (10 in the United States and 2 in ) from April 20, 1994, to February 15, 1998. Participants underwent a screening period of 7 to 14 days, followed by in a 1:1:1 ratio using a computer-generated list balanced in blocks of 6 or 8. Interventions included flexible dosing of (20-40 mg/day, titrated over four weeks with possible increases for non-responders), (starting at 50 mg/day up to 300 mg/day), or matching capsules, alongside weekly sessions. Assessments occurred weekly using standardized instruments, including the (HAM-D), (CGI) scale, and Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-L) for diagnostic confirmation. Eligibility required outpatients aged 12-18 years meeting DSM-IV criteria for non-psychotic of at least eight weeks' duration, a HAM-D total score of 12 or higher, a (CGAS) score below 60, and an estimated IQ of 80 or above via the . Exclusion criteria encompassed serious suicidality with intent or plan, , , , or dependence, certain comorbid conditions (e.g., eating disorders, obsessive-compulsive disorder, autism, within the past year), recent use, or medical contraindications to the study drugs. Of 425 screened adolescents, 275 were randomized: 93 to , 95 to , and 87 to . Baseline characteristics were similar across groups, with mean ages ranging from 14.8 to 15.1 years (standard deviation ±1.6 years), approximately 60% , and 80-87% participants. Mean HAM-D scores were 18.1-19.0, reflecting moderate depression severity, and mean episode duration was about 14 months, with 41-50% having at least one comorbid psychiatric (most commonly anxiety disorders in 19-28%). Many participants had chronic depression exceeding one year.

Conduct and Data Collection

Study 329 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group sponsored by SmithKline Beecham (later GlaxoSmithKline), conducted across 12 North American sites—10 in the United States and 2 in —from April 20, 1994, to February 15, 1998. Participants were 275 adolescents aged 12-18 years diagnosed with unipolar per DSM-III-R criteria, requiring a Hamilton Depression Rating Scale (HAM-D) total score of at least 12 and symptoms persisting for no less than 8 weeks. Following a 7- to 14-day screening period to confirm eligibility and exclude conditions such as suicidality, , or significant comorbidities, eligible participants were randomized in a 2:2:1 ratio to receive (initially 10-20 mg/day, titrated to 20-40 mg/day), (initially 25-50 mg/day, titrated to 200-300 mg/day), or matching over an 8-week acute phase, with an optional 6-month continuation phase for responders. The trial adhered to the protocol, which underwent amendments in 1993, 1994, and 1996, and was executed by investigators from university-affiliated and hospital psychiatry departments. Data collection occurred through standardized forms (CRFs) completed at each site, encompassing approximately 77,000 pages across all participants, with assessments scheduled at baseline and weekly for the first four weeks, then at weeks 6 and 8. were gathered using validated instruments, including the 17-item HAM-D for total score change and responder status (defined as ≥50% reduction from baseline or endpoint score ≤8), supplemented by depression-specific items from the Kiddie Schedule for Affective Disorders and (K-SADS-L), (CGI) scales, and secondary measures such as the Scholastic Performance Profile (SPP) and Adolescent Family Conflict (AFC). Safety monitoring involved systematic recording of adverse events elicited through open-ended investigator queries, alongside , tests, electrocardiograms (EKGs), and plasma/serum drug levels at weeks 4 and 8; treatment compliance was verified via capsule counts. All were compiled for intent-to-treat analysis using last observation carried forward (LOCF) imputation, with categorical outcomes analyzed via and continuous measures via analysis of variance (ANOVA). The protocol specified a taper phase for all completers and a 30-day post-treatment follow-up for safety monitoring, though execution focused primarily on the acute phase data for initial reporting. No significant deviations in trial conduct were reported in contemporaneous documents, though later independent access to raw data highlighted inconsistencies in adverse event transcription from CRFs to summary reports.

Original Results and Internal Analyses

Efficacy Outcomes

The protocol for Study 329 specified two co-primary efficacy endpoints: the change from baseline to week 8 in the total Hamilton Depression Rating Scale (HAM-D) score, and the percentage of responders defined as a Clinical Global Impression-Improvement (CGI-I) score of 1 ("very much improved") or 2 ("much improved"). Secondary efficacy outcomes included changes in depression symptoms measured by the Kiddie-Schedule for Affective Disorders and (K-SADS), CGI-Severity (CGI-S), and responder rates based on a ≥20% reduction in HAM-D total score or K-SADS depressed mood item. In the original analysis reported by GlaxoSmithKline (GSK), (20-40 mg/day) did not demonstrate superiority over on the HAM-D total score change (-9.0 for vs. -10.4 for ; not statistically significant). However, the publication claimed efficacy based on the CGI-I responder rate, reporting 66% for versus 47% for (p=0.002, unadjusted). showed no superiority on either co-primary endpoint compared to . GSK internal documents from 1998, revealed through litigation, concluded that the study "failed to demonstrate a statistically significant difference from on the primary efficacy measures," labeling it a negative for efficacy on all eight protocol-specified outcomes. Reanalysis of the full under the Restoring Invisible and Abandoned Trials (RIAT) initiative confirmed no for or over across all nine pre-specified outcomes, including both co-primaries and key secondaries like K-SADS and CGI-S changes. The apparent CGI-I finding in the original report relied on selective reporting of a single secondary measure without adjustment for multiplicity or protocol deviations, such as post-hoc handling of dropouts; when analyzed per protocol with all data, no significant benefits emerged (e.g., CGI-I 1.4, 95% CI 0.8-2.5, p=0.23). These discrepancies highlight how outcome selection influenced the published claim of , despite internal recognition of failure.

Safety and Adverse Events

In Study 329's acute phase, treatment was linked to elevated rates of serious adverse events (SAEs) relative to , with 11 of 93 participants (11.8%) on experiencing SAEs—9 leading to discontinuation—compared to 2 of 87 (2.3%) on and 5 of 95 (5.3%) on . The original 2001 publication reported as generally well tolerated, noting adverse event-related discontinuation in 9.7% of participants versus 6.9% on , without emphasizing the disparity in SAEs or classifying certain events (e.g., severe psychiatric issues, 32 under ) as clinically significant harms. Suicidality emerged as a key concern in the reanalysis of the , revealing suicidal or self-injurious behaviors in 11 participants (11.8%) versus 2 on (2.3%)—a rate over fivefold higher—while showed 4 cases (4.2%); this contrasted with the original report's lower counts of 5, 1, and 3 events across groups, respectively, which aggregated or omitted some ideations and gestures from raw data. Overall psychiatric adverse events totaled 103 under but only 24 with , including heightened incidences of agitation, , and . The reanalysis concluded clinically meaningful harm elevations with , including these suicidality risks and other SAEs not deemed superior to in internal GSK assessments reflected in the full , though the original downplayed such patterns by selective outcome selection and coding. Total adverse events were also higher (481 MedDRA-coded under versus 330 on ), with underreporting in the appendices by up to 14%.

GSK Internal Interpretations

GSK's internal clinical study synopsis for Study 329, prepared following database lock in 1998, concluded that did not achieve on either of the two pre-specified primary endpoints: the mean change from baseline to week 8 in the total (HAM-D) score (-10.7 for versus -8.9 for , p=0.113) and the proportion of treatment responders based on the (CGI) Improvement score (67% for versus 55% for , p=0.112). , the active comparator, also failed to separate from on these measures. Despite these results, GSK highlighted statistically significant improvements on select secondary endpoints, including the depressed mood item of the HAM-D (p=0.003) and the K-SADS-L depression item (p=0.049), interpreting the overall findings as demonstrating a "modest benefit" of over for adolescent major depression. On safety, the internal synopsis reported 11 serious adverse events (SAEs) in the group compared to 2 in the group and 5 in the group, with SAEs in the arm predominantly involving psychiatric issues such as , , worsening depression, and intentional overdose. GSK noted that 's safety profile was "generally similar" to that observed in adults, though additional adolescent-specific adverse events like tooth disorder and hostility were identified; common treatment-emergent adverse events for included (24%), (17%), and (15%). Internally, these findings contributed to GSK's acknowledgment that Study 329 and related trials provided insufficient evidence to support FDA approval of for pediatric depression. An internal SmithKline Beecham (predecessor to GSK) memorandum from 1998 emphasized the commercial risks of the negative primary results, directing efforts to "effectively manage the dissemination of these data in order to minimise any potential negative commercial impact." This approach involved prioritizing secondary analyses for publication while de-emphasizing the failed primaries and elevated SAE rates, reflecting GSK's strategic framing of the study as supportive of paroxetine's utility despite the absence of robust efficacy signals.

Publication Process

Authorship and Ghostwriting

The manuscript reporting Study 329 was drafted primarily by Sally K. Laden, a medical writer from Scientific Therapeutics Information (STI), a firm contracted by SmithKline Beecham (SKB, now GlaxoSmithKline or GSK) to prepare the publication. STI received $17,250 for producing up to six drafts based on SKB's internal synopsis, with Laden acknowledged in the final article only for "editorial assistance"—a phrase often used to obscure substantive ghostwriting contributions in pharmaceutical-sponsored research. Listed as lead author was Martin B. Keller of , accompanied by 21 co-authors, including principal investigators like Neal D. Ryan and Michael Strober, many of whom contributed primarily through site-level or coordination rather than development. Internal SKB documents, disclosed during subsequent litigation, reveal that Keller originated the study as a key opinion leader but did not produce the initial draft, despite his public assertions to the contrary; Laden confirmed drafting it independently under SKB guidance. SKB's central medical affairs team exerted significant control, with employees such as Donna McCafferty and Murray Oakes directing 11 iterations of the manuscript from 1998 to 2000 to emphasize efficacy signals and downplay adverse events, aiming to offset potential commercial harm from the negative results. The company, as data owner, required all content to undergo medico-legal before release to academic authors for journal submission, which proceeded first to (rejected) and then to the Journal of the American Academy of (JAACAP), where Laden handled responses leading to acceptance and publication on July 1, 2001.

JAACAP Article Content

The Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) article, published in July 2001 and titled "Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial," presented Study 329 as a multicenter, double-blind, randomized, placebo- and active-controlled parallel-group trial evaluating paroxetine hydrochloride (Paxil) against placebo and imipramine in adolescents with unipolar major depressive disorder. The trial enrolled 275 outpatients aged 12 to 18 years meeting DSM-IV criteria, with randomization to paroxetine (n=189, mean endpoint dose 30.3 mg/day), imipramine (n=92, mean endpoint dose 236.6 mg/day), or placebo (n=94).60309-9/abstract) Treatment lasted 8 weeks, with assessments using the Hamilton Rating Scale for Depression (HAM-D, 17-item), Kiddie Schedule for Affective Disorders and Schizophrenia-Lifetime Version (K-SADS-L) depression section, and Clinical Global Impression (CGI) scales. The article reported efficacy primarily through secondary endpoints, stating that paroxetine yielded statistically significant improvements over placebo in achieving a HAM-D total score of ≤8 at endpoint (17% vs. 6%, p=0.02), the HAM-D depressed mood item score (p<0.001), the K-SADS-L depressed mood item score (p=0.006), and CGI-improvement responder status (75% vs. 61%, p=0.002). Imipramine showed no significant differences from placebo on these or primary measures like HAM-D total change or responder rates (≥50% reduction), though a post-hoc combined active treatment analysis suggested overall superiority to placebo (p=0.02 for HAM-D responders).60309-9/abstract) The authors described paroxetine's effects as consistent with adult SSRI trials and positioned the results as extending evidence for selective serotonin reuptake inhibitors (SSRIs) to adolescents. Safety data in the article emphasized general tolerability comparable to adult populations, with the most frequent adverse events for paroxetine including asthenia (14%), insomnia (13%), and headache (12%), versus placebo rates of 8%, 9%, and 16%, respectively.60309-9/abstract) Serious adverse events occurred in 5 paroxetine patients (2.6%), 5 imipramine patients (5.4%), and 2 placebo patients (2.1%), including one hospitalization for dehydration on paroxetine; investigators attributed none to the study drug. Suicidal ideation or gestures were noted in 6 paroxetine, 2 imipramine, and 1 placebo patient, with no completed suicides across groups.60309-9/abstract) Cardiovascular parameters showed no clinically meaningful changes, though paroxetine patients experienced mean decreases in supine heart rate (-4.8 bpm) and diastolic blood pressure (-2.1 mm Hg); a small mean weight loss of 1.2 kg was observed across all arms. The conclusions asserted that "paroxetine is generally well tolerated and effective for major depression in adolescents," recommending it as a first-line treatment option while calling for further long-term studies on maintenance and relapse prevention. The article highlighted the trial's flexibility in dosing (paroxetine 10-60 mg/day after initial titration) and exclusion of patients with suicidality at baseline, framing these as strengths for real-world applicability.60309-9/abstract)

Discrepancies with Raw Data

The original 2001 publication in the Journal of the American Academy of Child & Adolescent Psychiatry (JAACAP) reported paroxetine as generally well tolerated and effective for adolescent major depression, citing improvements on several secondary measures such as the Clinical Global Impression-Improvement (CGI-I) responder status and certain Hamilton Depression Rating Scale (HAM-D) subscales. However, reanalysis of the full clinical study report (CSR) and raw data revealed that the protocol-specified primary efficacy endpoint—change in total HAM-D score from baseline to endpoint—showed no statistically significant difference between paroxetine and placebo (mean decrease of 10.7 points for paroxetine versus 9.1 points for placebo; P=0.20), falling short of the prespecified clinical significance threshold of a 4-point difference. The publication emphasized four non-protocol-specified depression scales as evidence of efficacy, representing selective outcome reporting that deviated from the original protocol's nine prespecified efficacy measures, none of which demonstrated superiority of paroxetine or imipramine over placebo. On safety, the JAACAP article described paroxetine as having a profile comparable to placebo, listing 265 adverse events without highlighting increased risks, and minimized psychiatric adverse events by categorizing suicidal ideation or gestures under less severe terms. In contrast, the raw data documented 481 adverse events for paroxetine, including 11 serious adverse events (versus 2 for placebo), with five suicidal acts or ideation events on paroxetine compared to one on placebo; these included behaviors such as overdoses and preparatory acts not emphasized in the publication. Reanalysis confirmed higher withdrawal rates due to adverse effects (15% for paroxetine versus 6.9% for placebo) and an overall increase in harms, including aggression and akathisia, which the original article omitted or downplayed through post-hoc classifications that excluded protocol-defined severe events. Statistical discrepancies further underscored misrepresentation: the publication relied on pairwise comparisons without establishing overall omnibus significance (e.g., ANOVA F-test P>0.05 across groups), selectively reporting favorable p-values from secondary analyses while ignoring nonsignificant primary results and multiplicity adjustments. For instance, the claimed CGI-I benefit was a post-hoc endpoint not prioritized in the protocol, and hazard ratios for remission favored in unadjusted models. The reanalysis, adhering to the CSR and protocol without such switches, found no of and confirmed elevated signals, attributing the original deviations to outcome switching and selective emphasis inconsistent with the raw dataset.

Marketing and Promotional Use

Off-Label Promotion Strategies

GlaxoSmithKline (GSK) promoted (Paxil) for in treating in children and adolescents by distributing reprints of the 2001 Journal of the American Academy of Child & Adolescent Psychiatry (JAACAP) article on Study 329 to physicians through its sales representatives. These materials selectively highlighted claims of and tolerability from secondary outcomes, despite the study's failure to meet its primary endpoints for and internal analyses showing no benefit over . Sales detailing emphasized paroxetine's supposed advantages for adolescent patients, positioning it as a viable option in a market where the drug lacked FDA approval for individuals under 18. To further incentivize off-label prescribing, GSK provided free Paxil samples to physicians who primarily treated pediatric patients, a practice documented in internal records as part of broader efforts to penetrate practices. This distribution occurred alongside verbal promotions during sales visits, where representatives cited Study 329's published results to counter concerns about unapproved uses, even as GSK's own data indicated increased risks of suicidality and behavioral adverse events in youth. Such tactics contributed to a reported surge in off-label prescriptions, with U.S. scripts for adolescents rising significantly following the article's release in July 2001. GSK's promotional activities extended to internal sales strategies that framed Study 329 as supportive evidence for expanding paroxetine's indications, despite regulatory prohibitions on off-label under the Food, Drug, and Cosmetic Act. A 2001 internal sales memo acknowledged the off-label potential, noting plans to leverage the JAACAP for pediatric promotion amid awareness that primary trial data did not justify approval submissions to the FDA. These efforts persisted until 2003, when New York Eliot Spitzer's investigation revealed suppressed suicidality data, prompting GSK to issue a "" letter on June 10, 2003, acknowledging heightened risks in youth without conceding inefficacy. The strategies culminated in GSK's 2012 guilty plea to misdemeanor misbranding charges, including off-label promotion of Paxil, resulting in a $3 billion settlement—the largest in U.S. healthcare fraud history at the time.

Internal Sales Documents

GSK's internal sales training materials for Paxil misrepresented Study 329 as evidence of the drug's efficacy and safety for adolescent depression, despite internal analyses concluding the trial failed its primary and secondary endpoints. In September 1999, sales representatives received training from Dr. Karen Wagner, a paid consultant, who presented selective data from Study 329 to emphasize positive outcomes while omitting the lack of statistical significance on key measures like Hamilton Depression Rating Scale improvements and response rates. These sessions targeted a 150-person neuroscience specialty sales force, instructing reps to promote off-label use to physicians treating patients under 18. Promotional aids distributed to approximately 2,000 sales representatives included an August 16, 2001, cover memo accompanying the Journal of the American Academy of Child and Adolescent Psychiatry article on Study 329, which highlighted "remarkable efficacy" claims but concealed negative results and the FDA's non-approval for pediatric use. Sales call notes, accessible to supervisors, documented representatives citing the article and Wagner's lectures to advocate Paxil for adolescent depression, often without disclosing increased risks such as suicidality. GSK's Paxil Forum events from 2000 to 2002, held at resorts and attended by child psychiatrists, featured slides and presentations by Wagner that selectively portrayed Study 329 data to support expansion into pediatric markets, aligning with a 2000 internal consultant report recommending such positioning despite known trial shortcomings. Training manuals and seminars, such as the December 5, 2000, TSR Representatives Training, further encouraged off-label promotion by framing Study 329 alongside Studies 377 and 701 as supportive of Paxil's benefits, burying findings of no and up to threefold increased risk. FaxBack materials and comparative documents, like those in Wellbutrin Semester II training (2001), lacked fair balance and promoted Paxil as "generally well-tolerated and effective" for children, contributing to fraudulent claims under federal health programs. An August 2002 strategic brand plan internally identified pediatric depression as a sales opportunity, guiding these materials toward maximizing prescriptions despite regulatory constraints.

Regulatory Context of Promotion

In the United States, the (FDA) regulates pharmaceutical promotion under the Federal Food, , and Cosmetic Act (FD&C Act), specifically 21 U.S.C. § 352, which deems a drug misbranded if its labeling or promotion includes unapproved uses, false or misleading claims about safety or efficacy, or failure to reveal material facts. Promotion is confined to FDA-approved indications listed in the drug's labeling, with off-label promotion—disseminating information to encourage use beyond approved populations, dosages, or conditions—prohibited as it risks without established benefit-risk data. Violations can trigger FDA warning letters, product seizures, injunctions, or referral to the Department of Justice (DOJ) for civil penalties or criminal prosecution, including fines and for willful misbranding. For (Paxil), approved by the FDA in 1992 for adult and certain anxiety disorders but not pediatric use until later rejections, GlaxoSmithKline (GSK) began promoting it for adolescent depression in the early despite internal recognition that clinical trials, including Study 329 (completed in ), failed to meet endpoints and indicated heightened risks like suicidality. GSK sales representatives distributed materials citing the 2001 Journal of the American Academy of Child & Adolescent Psychiatry publication of Study 329, which portrayed as effective and well-tolerated in adolescents, to physicians for off-label prescribing, even as FDA supplemental applications for pediatric approval were pending and ultimately denied in 2003 due to inadequate evidence. This practice contravened FDA guidance requiring promotional claims to be consistent with substantial evidence from adequate, well-controlled studies and balanced with risks, as outlined in regulations predating the 2007 FDA Amendments Act expansions on off-label communications. The regulatory breaches culminated in DOJ charges against GSK for misbranding of Paxil from 1998 to 2003, alleging fraudulent promotion via sales aids, speaker programs, and detailing that omitted Study 329's negative raw data—such as non-significance on primary efficacy measures (e.g., Hamilton Depression Rating Scale change scores) and emergent suicidality in 5.1% of paroxetine-treated adolescents versus 1.5% on placebo—while emphasizing selective positive secondary outcomes. In 2012, GSK entered a deferred prosecution agreement, pleading guilty to the charges and paying a $757 million criminal fine and forfeiture for Paxil misbranding as part of a $3 billion global settlement, the largest healthcare resolution at the time, underscoring against systemic off-label schemes rather than isolated claims. No FDA pre-approval of Study 329-based promotions occurred, as manufacturers self-certify compliance, with post-market surveillance revealing the discrepancies.

Regulatory and Investigative Responses

United Kingdom Inquiries

In 2003, the UK's Medicines and Healthcare products Regulatory Agency (MHRA), through its Committee on Safety of Medicines (CSM), initiated an urgent review of paroxetine (marketed as Seroxat) following a BBC Panorama broadcast on 13 May 2003 that disclosed internal GlaxoSmithKline (GSK) emails indicating suppressed data on suicidality risks in paediatric patients from trials including Study 329. GSK submitted full clinical trial datasets, prompting the CSM Expert Working Group to analyze efficacy and safety in children and adolescents. The review of three paroxetine trials (767 patients total, 378 on paroxetine at 10-50 mg/day for 8-12 weeks) found no demonstrated efficacy against major depressive disorder, with common adverse events including emotional lability, hostility, and insomnia leading to discontinuation in 10% of paroxetine-treated patients versus 5% on placebo. Suicide-related adverse events were reported in 3.7% (14/378) of recipients compared to 2.5% (7/285) on , yielding an of 1.5 (p=0.5), indicating an elevated though not statistically significant risk that, combined with the absence of efficacy, tipped the risk-benefit balance unfavorably. Research Database (GPRD) analyses further supported heightened non-fatal suicidal behavior risk with versus tricyclic antidepressants in under-19s (adjusted 1.6, 95% CI 1.0-2.5). On 10 June 2003, the MHRA issued guidance contraindicating for treating depressive illness in under-18s, noting its unlicensed status for this group despite prior in approximately 8,000 patients. The CSM's broader Expert Working Group report, finalized in 2004 after reviewing all SSRIs, affirmed paroxetine's contraindication and extended cautions to , sertraline, , , and for under-18s due to similar inefficacy and suicidality risks, exempting based on modest from two trials despite its own elevated events (10.2% versus 5.4% ). In December 2003, the MHRA advised against routine SSRI use in paediatric depression except , emphasizing close monitoring for agitation, , and early in treatment. These actions stemmed from integrated of selective reporting in GSK submissions, as Study 329's published claims of and tolerability contrasted with showing neither.

United States Actions

![Eliot Spitzer, New York Attorney General who initiated legal action against GlaxoSmithKline over Paxil promotion][float-right] In June 2004, New York Attorney General Eliot Spitzer filed a civil lawsuit against GlaxoSmithKline (GSK) in New York State Supreme Court, alleging consumer fraud for concealing negative results from clinical trials, including Study 329, which demonstrated that paroxetine (Paxil) was ineffective for treating depression in children and adolescents and associated with increased risks of suicidality and other adverse events. The complaint highlighted GSK's promotion of Paxil for off-label pediatric use despite internal knowledge that the drug failed to show efficacy over placebo in Study 329, conducted from 1994 to 1998. The lawsuit was settled in August 2004, with GSK agreeing to post summaries of all results for its drugs on a public website within 30 days and to refrain from suppressing negative data in future promotions, without admitting liability; GSK also covered the state's legal costs estimated at around $250,000. The U.S. (FDA) reviewed data, including from Study 329, and in 2003 determined the drug was not proven safe or effective for treating in children and adolescents, leading to a rejection of GSK's supplemental application for pediatric labeling. In response to emerging safety signals, the FDA issued a advisory on June 19, 2003, warning of increased risk of suicidality in pediatric patients treated with Paxil, and by October 2004, mandated a warning on all antidepressants regarding heightened suicide risk in youth under 18. In July 2012, the U.S. Department of Justice (DOJ) announced a $3 billion settlement with GSK—the largest healthcare fraud settlement in U.S. history—resolving civil and criminal allegations, including GSK's unlawful promotion of Paxil for pediatric use from 1998 to 2003 despite negative findings. GSK pleaded guilty to misdemeanor misbranding under the Food, Drug, and Cosmetic Act for falsely representing Paxil as safe and effective for adolescents, specifically citing its role in authoring and approving the 2001 Journal of the American Academy of Child & Adolescent Psychiatry article that misrepresented 's results as demonstrating efficacy. The settlement included $2 billion in criminal fines and forfeiture, plus $1 billion in civil settlements for off-label promotion and failure to report safety data.

Outcomes of Investigations

In the United States, investigations into GlaxoSmithKline's (GSK) promotion of (Paxil) for adolescent depression, relying on selective interpretations of Study 329, led to multiple settlements. In August 2004, GSK settled a consumer fraud lawsuit filed by New York , agreeing to pay $2.5 million and to post summaries of all data, including negative results from Study 329, on its corporate website to enhance transparency. This action addressed allegations that GSK had suppressed data showing paroxetine's lack of efficacy and potential harms in youth, which had fueled off-label prescribing. The Spitzer case contributed to expanded probes, culminating in a 2012 civil and criminal settlement with the U.S. Department of Justice (DOJ). GSK paid $3 billion—the largest healthcare fraud settlement in U.S. history at the time—including a $1 billion criminal fine and forfeiture, after pleading guilty to three counts, two of which involved misbranding Paxil and another drug with intent to defraud or mislead. The DOJ highlighted Study 329, alleging GSK falsely promoted it in publications and materials as demonstrating paroxetine's efficacy and safety for patients under 18, despite internal analyses showing otherwise on primary and secondary outcomes. An additional $14 million multi-state settlement in 2006 resolved related claims over Paxil's pediatric promotion. In the , the Medicines and Healthcare products Regulatory Agency (MHRA) investigated disclosures of unpublished adverse data from Study 329 and other trials in children, prompted by media reports and parliamentary inquiries in 2003. On December 10, 2003, the MHRA issued guidance advising against prescribing (Seroxat) to those under 18 due to evidence of doubled and behavior risks compared to , leading to the suspension of its pediatric license. This regulatory response extended to restricting other selective serotonin reuptake inhibitors except , influencing actions, though no financial penalties were levied on GSK. The outcomes emphasized data transparency reforms over punitive measures.

Civil Lawsuits

In June 2004, New York Attorney General filed a civil lawsuit against GlaxoSmithKline (GSK), accusing the company of consumer fraud for promoting Paxil () as safe and effective for treating in children and adolescents, despite internal knowledge from clinical trials, including Study 329, indicating a lack of efficacy and elevated risks of suicidality. The suit specifically charged GSK with suppressing negative results from four pediatric trials, misrepresenting data to physicians and the public through sales representatives, and distributing materials that falsely portrayed Paxil as beneficial for underage patients. The litigation prompted GSK to agree in August 2004 to publicly post raw data and clinical study reports from its pediatric Paxil trials on a , marking an early push for greater transparency in pharmaceutical data. This initial resolution did not include monetary penalties but set the stage for broader scrutiny. In March 2006, Spitzer reached a multi-state settlement with GSK valued at approximately $14 million, resolving allegations of fraudulent promotion of Paxil for off-label pediatric use across multiple jurisdictions; the funds supported and on pediatric safety rather than direct restitution. Civil claims extended beyond state actions to federal proceedings under the False Claims Act, where whistleblowers and the U.S. Department of Justice pursued GSK for inducing false claims reimbursements through off-label promotion of Paxil supported by misrepresented Study 329 findings. These efforts contributed to GSK's $3 billion settlement in July 2012, of which over $2 billion addressed civil liabilities for fraudulent promotion practices, including the portrayal of Paxil as effective in adolescents contrary to trial evidence. GSK did not admit liability in these resolutions but ceased certain promotional activities and enhanced compliance measures. Private civil lawsuits from patients or families alleging harm from Paxil-induced suicidality in adolescents often referenced Study 329's concealed risks, though most were consolidated into multidistrict litigation focused on failure-to-warn claims rather than direct challenges to the study's publication. Outcomes varied, with GSK prevailing in several trials by arguing insufficient causation evidence, but the cumulative legal pressure underscored systemic issues in data disclosure tied to the study.

Criminal and Settlement Aspects

In July 2012, GlaxoSmithKline (GSK) agreed to plead guilty to three felony counts under the Food, Drug, and Cosmetic Act, including two counts of introducing misbranded drugs into interstate commerce—specifically Paxil () and Wellbutrin (bupropion)—through off-label promotion for pediatric without FDA approval. The plea resolved allegations that GSK promoted Paxil as safe and effective for children and adolescents despite internal knowledge of inadequate efficacy and elevated risks of suicidality from clinical trials, including Study 329 conducted from 1994 to 1998. This criminal resolution formed part of a broader $3 billion settlement with the U.S. Department of Justice (DOJ), the largest healthcare fraud settlement in U.S. history at the time, encompassing $757 million in criminal fines directly tied to Paxil and Wellbutrin misbranding. The DOJ charged that GSK's promotional tactics for Paxil in youth included distributing articles and sales aids that misrepresented trial data, such as portraying Study 329's null efficacy results as supportive of benefit while downplaying adverse events like , agitation, and observed in 6.7% of paroxetine-treated adolescents versus 1.5% on . Tactics encompassed funding "ghostwritten" articles citing favorable interpretations of pediatric data, sponsoring programs to influence prescribers, and incentivizing sales representatives with bonuses for off-label pediatric prescriptions, contributing to over $1 billion in improper reimbursements. The settlement also addressed GSK's failure to report accurate safety data from Paxil trials to the FDA, including underreporting suicidal behaviors in pediatric populations. Beyond the federal criminal plea, the $3 billion total included civil settlements resolving False Claims Act violations, with approximately $2.24 billion for civil liabilities related to off-label promotion across multiple drugs, including Paxil's pediatric use. States received portions of the funds, such as California's share supporting Medicaid recovery, stemming from GSK's alleged pattern of suppressing negative Study 329 outcomes while aggressively marketing to offset adult sales declines post-1998 patent concerns. GSK entered a corporate integrity agreement with the Office of Inspector General, mandating enhanced compliance monitoring for five years, though the company maintained it did not admit liability for all civil claims. No individual executives faced criminal charges in connection with these events.

Reanalyses and Scientific Reexaminations

RIAT Reanalysis

The Restoring Invisible and Abandoned Trials (RIAT) initiative reanalyzed Study 329 using the complete dataset, including the , appendices, and over 77,000 pages of case report forms provided by GlaxoSmithKline via its SAS Solutions OnDemand platform. Published in on 16 September 2015 by Le Noury and colleagues, this independent examination followed the trial's original 1994–1996 protocol, applying last observation carried forward and multiple imputation to address . Efficacy assessments revealed no significant benefits for or high-dose over in treating adolescent major depression. Mean reductions in Hamilton depression rating scale (HAM-D) total scores were comparable across groups, with no statistical difference (p=0.20).
TreatmentMean HAM-D Change (95% CI)
10.7 (9.1 to 12.3)
9.0 (7.4 to 10.6)
9.1 (7.5 to 10.7)
Responder rates, defined as at least a 50% HAM-D reduction, similarly showed no advantage for active treatments. Harms analysis indicated elevated risks with both drugs. Paroxetine linked to 11 serious adverse events versus 2 for placebo, including 5 suicidal or self-injurious behaviors compared to 1 in placebo. Total adverse events totaled 481 for paroxetine (70 severe or very severe), exceeding placebo counts, with heightened psychiatric events (103 versus 24). Imipramine showed additional cardiovascular effects. The reanalysis concluded that neither nor proved efficacious, while both increased harms beyond , highlighting discrepancies with the original 2001 report's claims of paroxetine's superiority and safety. Authors emphasized that full data access exposed underreporting of suicidal risks and selective outcome reporting in the initial publication.

Methodological Criticisms and Defenses

The original methodological approach in Study 329 involved a randomized, double-blind, -controlled comparing (20-40 mg/day), (titrated to 200-300 mg/day), and in 275 adolescents aged 12-18 with , using an 8-week acute phase followed by an optional continuation phase. Primary efficacy endpoints were change in Hamilton Depression Rating Scale (HAM-D) total score and (CGI) severity score, analyzed via last observation carried forward (LOCF) intent-to-treat with , a standard but bias-prone method given the 36% discontinuation rate in the group versus 23% on . Critics, particularly in the 2015 RIAT reanalysis by Le Noury et al., highlighted selective outcome reporting as a core flaw: the pre-specified primary endpoints failed to demonstrate superiority over (HAM-D change: -9.7 vs. -10.2, p=0.60; CGI: no significant difference), yet the 2001 publication emphasized post-hoc secondary measures like K-SADS-L depression item responders (65% vs. 41%, p=0.02) and CGIC responders, without acknowledging the primaries' failure or multiplicity adjustments for multiple comparisons. This approach inflated apparent efficacy by shifting focus to exploratory analyses, potentially capitalizing on chance in a trial with modest power (n=189 completers). Adverse event reporting drew further scrutiny for inconsistent and underemphasis of risks; the original dichotomized events as severe/non-serious based on intensity rather than clinical narrative, omitting full /behavior details from clinical study reports (CSRs). Reanalysis, coding all events using full CSR data and standardized criteria, identified 11 harm-related discontinuations on versus one on , including five suicidal acts (versus one on ) and one completion, contradicting claims of comparable tolerability and highlighting suppression of events labeled as "behavioral syndrome" or "." High dosing also confounded harms, as it similarly increased adverse events without efficacy. Defenses from original authors and GSK representatives asserted that the multi-faceted endpoint —incorporating dimensional (HAM-D) and categorical (responder) measures—provided a clinically nuanced assessment suitable for pediatric trials lacking established standards, where binary outcomes might overlook partial benefits in a heterogeneous population. They argued LOCF was appropriate per contemporaneous guidelines (e.g., FDA 1998 draft) for handling in short-term studies, and that responder analyses aligned with regulatory precedents for antidepressants. Responses to the RIAT critiqued its post-hoc harm recoding as non-protocol-driven and reliant on incomplete subsets (e.g., excluding some non-random completers), potentially introducing bias, while maintaining the original's overall design met CONSORT-equivalent rigor for 1990s multicenter trials. However, these arguments have been undermined by FDA's 2002 rejection of pediatric approval, citing insufficient efficacy and emergent suicidality signals across trials, including Study 329.

Retraction Calls and Journal Responses

Calls for retraction of the Study 329 article, published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) in 2001, emerged shortly after its release, with initial complaints directed to the journal in 2003 citing discrepancies between the reported findings and the underlying data. In 2005, philosopher and medical ethicist Leemon McHenry formally complained to then-editor Mina Dulcan, highlighting evidence of ghostwriting and selective reporting by GlaxoSmithKline (GSK) that misrepresented paroxetine's efficacy and safety in adolescents. These efforts intensified in December 2009 when Jon Jureidini and McHenry explicitly requested retraction, arguing that the paper conflated primary and secondary outcomes to fabricate positive results, violating standards of scientific integrity. JAACAP's leadership consistently rebuffed these demands, maintaining that the article's tables disclosed negative primary endpoint results sufficiently to preclude retraction. Editor-in-chief stated in responses to critics that no justification existed for retraction, emphasizing the paper's overall transparency despite acknowledged limitations in interpretation. Following the 2015 RIAT reanalysis in , which re-examined raw data and concluded lacked efficacy while increasing harms like suicidality, additional calls for retraction were lodged, supported by a dedicated site (study329.org) tracking the campaign. The journal and the American Academy of Child and Adolescent Psychiatry (AACAP) upheld their position, with authors including Martin B. Keller issuing a collective denial of ghostwriting allegations in a 2015 letter. Persistent refusal prompted legal action on September 8, 2025, when attorney George W. Murgatroyd III filed suit in D.C. Superior Court against AACAP and publisher , alleging the unretracted paper enabled fraudulent promotion of , contributing to adolescent harms including suicides in represented cases. In response, JAACAP issued an expression of concern on September 30, 2025—the first formal editorial notice after over two decades—stating it aimed "to alert readers to concerns that have been raised about the article" while an ongoing review proceeds, without conceding grounds for full retraction. Critics, including Jureidini, viewed this as a belated acknowledgment insufficient to rectify the paper's influence, which has garnered over 450 citations.

Broader Scientific Implications

Antidepressants Efficacy in Adolescents

The original publication of Study 329 in 2001 claimed that demonstrated efficacy in treating (MDD) in adolescents aged 12-18, reporting a response rate of 66% compared to 49% for based on secondary outcomes like the Clinical Global Impression-Improvement (CGI-I) scale. However, the trial's predefined primary outcomes—change in (HAM-D) total score and HAM-D-defined depressive response—showed no statistically significant differences between paroxetine and (p=0.11 for HAM-D change; response rates 60.3% vs. 56.9%). The 2015 RIAT reanalysis of the full dataset confirmed the absence of efficacy, finding inferior to on one primary outcome (HAM-D response: 56.9% vs. 60.3% , but not significant after multiplicity adjustment) and no benefit on the other, with also ineffective versus . This reexamination highlighted selective reporting in the original paper, where efficacy claims relied on post-hoc analyses of non-primary measures, contributing to overstated benefits amid high response rates typical in adolescent trials (often 40-50%). Broader meta-analyses of randomized controlled trials (RCTs) for selective serotonin reuptake inhibitors (SSRIs) in youth MDD reinforce limited efficacy signals. A 2016 network meta-analysis of 34 RCTs involving over 5,000 children and adolescents found only fluoxetine superior to placebo (standardized mean difference [SMD] -0.51, 95% credible interval -0.93 to -0.11), while paroxetine showed no efficacy advantage (SMD -0.07, -0.62 to 0.46) and higher adverse event-related dropouts.30385-3/fulltext) Other SSRIs like sertraline and citalopram similarly lacked robust evidence, with overall effect sizes small (SMD ~0.2-0.3 where positive) and confounded by publication bias favoring positive results.30385-3/fulltext) High placebo response rates—median 45% in pediatric RCTs, exceeding adult rates—further diminish apparent drug-placebo differences, often rendering active treatments statistically non-significant in low-response subgroups.30385-3/fulltext) Industry-sponsored trials, which dominate the evidence base, exhibit SMDs of 0.13-0.20 for antidepressants versus placebo in adolescents, but these shrink or reverse when excluding high-placebo-response studies or adjusting for selective outcome reporting. Regulatory approvals remain restricted: the U.S. FDA has greenlit only fluoxetine (2002) and escitalopram (2009) for pediatric MDD based on pivotal trials like TADS (fluoxetine SMD -0.68 vs. placebo), while paroxetine's application was rejected in 2003 due to inefficacy and harm signals from Study 329 and others. These findings underscore methodological challenges, including unblinding from side effects and overreliance on subjective scales, questioning causal antidepressant effects beyond nonspecific factors in this population.

Suicidality Risks: Evidence and Debates

In the original (CSR) for Study 329, conducted from 1994 to 1998, the group (n=93 in the acute phase) experienced 10 possibly suicidal events, compared to 1 event in the group (n=87). These included suicide attempts, gestures, and ideation, with 5 explicit suicide attempts reported in the arm during acute treatment versus none in . The 2001 publication in the Journal of the American Academy of Child & Adolescent Psychiatry minimized these risks, stating no clinically significant differences in adverse events related to suicidality between groups, attributing events to the underlying depression rather than the drug. The 2015 RIAT reanalysis of the full dataset, published in , confirmed elevated harms, including and behavior, in the group across acute, continuation, and taper phases: 23 suicidality-related events occurred in 15 patients versus 7 events in 5 patients. This reexamination classified events using standardized criteria, revealing that was associated with a higher incidence of serious adverse events (SAEs) involving or suicidality (11% of patients vs. 2% ), contributing to the conclusion of net harm without efficacy benefits. Continuation phase data further indicated 1 suicidal gesture or trauma event potentially linked to , alongside ongoing risks during taper. These findings informed the U.S. Food and Drug Administration's (FDA) 2004 black-box warning for all antidepressants, including , highlighting a doubled risk of suicidality (ideation, attempts, or behavior) in pediatric patients during initial treatment months, based on pooled analyses of 24 trials showing rates of 4% versus 2% for (risk ratio ≈2.0). specifically faced non-approval for adolescent depression in 2003 due to inefficacy and adverse signals, including from Study 329. Debates persist on causality and interpretation. Proponents of antidepressant use, including some industry-linked analyses, argue that elevated events reflect behavioral activation in severely depressed youth rather than direct causation, noting high baseline suicide risk in major depressive disorder and no completed suicides in the trial. Critics, drawing from raw CSR data and meta-analyses, contend this understates a class effect of selective serotonin reuptake inhibitors (SSRIs) like paroxetine, which may disinhibit impulses or induce akathisia-like states exacerbating suicidality, as evidenced by dose-dependent increases in events. Post-warning studies have debated net population effects, with some observational data suggesting reduced youth prescriptions correlated with stable or slightly rising suicide rates, potentially indicating undertreatment harms outweighing drug risks; however, randomized trial evidence, including Study 329, prioritizes the acute elevation in events as a causal signal requiring vigilant monitoring.

Transparency and Trial Data Access Lessons

The original publication of Study 329 in the Journal of the American Academy of Child & Adolescent Psychiatry in 2001 selectively reported outcomes, emphasizing efficacy and tolerability of while downplaying harms, including and behavior, as internal GlaxoSmithKline (GSK) documents later revealed through litigation. This selective reporting was facilitated by ghostwriting, where GSK employees drafted the manuscript and academic authors provided limited input, obscuring discrepancies between raw data and published claims. Access to full clinical study reports (CSRs), protocols, and individual patient-level data was restricted to GSK, preventing independent verification for over a decade and allowing the misleading conclusions to influence prescribing practices. The Restoring Invisible and Abandoned Trials (RIAT) initiative reanalysis, published in on September 16, 2015, overcame these barriers by compiling data from publicly available FDA review documents, CSRs obtained via legal discovery in U.S. lawsuits against GSK, and other regulatory filings, rather than relying on sponsor-provided summaries. This effort demonstrated that lacked efficacy for adolescent major depression on primary outcomes and was associated with significantly higher rates of harms, including suicidality ( 4.63 for or behavior versus ), contradicting the original report's narrative. The process highlighted practical challenges, such as reconciling inconsistent datasets across sources and the absence of a complete protocol, underscoring how sponsor control impedes rigorous scrutiny. Key lessons from Study 329 emphasize the necessity of mandatory, prospective access to raw trial data, protocols, and CSRs to enable independent reanalyses and mitigate selective reporting. Transparent reporting standards, such as those advocated by RIAT, reveal that inadequate design flaws often underlie poor outcomes, as evidenced by the trial's underpowered sample and flexible efficacy endpoints not predefined in the protocol. Open databases for individual participant data would facilitate network meta-analyses and harm assessments, reducing reliance on sponsor interpretations prone to commercial bias, while pre-registration of trials and outcomes could prevent post-hoc adjustments. These reforms address systemic issues where pharmaceutical companies historically withheld negative results, as GSK did here, contributing to distorted evidence bases in . Broader implications include advocacy for enforceable data-sharing mandates, as seen in post-Study 329 pushes for initiatives like the European Medicines Agency's clinical data and the AllTrials campaign, though implementation gaps persist, particularly for harms data in older trials. Without such access, public health risks from ineffective or harmful drugs endure, as paroxetine's adolescent approval pathway was influenced by this and similar misrepresented studies until regulatory reevaluations in the mid-2000s. The case exemplifies how litigation, rather than routine scientific processes, often forces transparency, reinforcing calls for independent data custodians to prioritize evidentiary integrity over proprietary interests.

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