Study 329

Overview

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

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."^{[lower-alpha 6][33]}

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".^{[35][lower-alpha 2]}

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.^[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.^{[lower-alpha 8]} 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

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]

BBC Panorama, MHRA

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".^{[lower-alpha 9]}

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

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]

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

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

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]

The Boston Globe

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

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

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

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

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][lower-alpha 10]}