Study 329

Last updated

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]

Calls for retraction

Jon Jureidini Jon Jureidini, 22 May 2010 (2).jpg
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] [lower-alpha 11]

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

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

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] [lower-alpha 12] 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." [lower-alpha 13]

See also

Notes

  1. ↑ SmithKline Beecham (October 1998): "Study 329 (conducted in the US) showed trends in efficacy in favour of Seroxat/Paxil across all indices of depression. However, the study failed to demonstrate a statistically significant difference from placebo on the primary efficacy measures." [11]
    U.S. Food and Drug Administration to GlaxoSmithKline (21 October 2002): "We agree that ... the results from Studies 329, 377, and 701 failed to demonstrate the efficacy of Paxil in pediatric patients with MDD. Given the fact that negative trials are frequently seen, even for antidepressant drugs that we know are effective, we agree that it would not be useful to describe these negative trials in labeling." [12]
    UK Medicines and Healthcare products Regulatory Agency report (6 March 2008): "The first trial conducted by SKB, trial number 329, failed to show that Seroxat was effective in treating major depressive disorder in children. A second trial, number 377, was conducted and this also failed to show that Seroxat was effective. Both studies were completed towards the end of 1998. SKB made no amendment to the SPC on the basis of these data. An internal GSK management document (which subsequently came into the public domain) dated October 1998 says that 'it would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine'. During 1999, 32,000 Seroxat prescriptions were issued to children in the UK." [13]
  2. 1 2 Wayne Kondro and Barbara Sibbald ( Canadian Medical Association Journal , 2004): "Study 329 was eventually published (J Am Acad Child Adolesc Psychiatry 2001;40[7]:762-72) in 2001. The authors concluded that paroxetine is 'generally well tolerated and effective for major depression in adolescents.' Among the 93 adolescents taking Seroxat, there were 5 serious cases of 'emotional lability' (e.g., suicidal ideation/gestures). Among the 95 patients taking the comparison treatment, imipramine (Tofranil), there was 1 such case, and among the 89 subjects receiving placebo there was also 1. According to the article, only 1 serious adverse event—headache in 1 patient—was considered by the treating investigator to be related to paroxetine treatment." [15]
  3. ↑ In August 2001, a month after publication, a member of GSK's Paxil Product Management team sent a memo to "all sales representatives selling Paxil" calling study 329 a "'cutting-edge,' landmark study", and stating that "Paxil demonstrates REMARKABLE Efficacy and Safety in the treatment of adolescent depression." [16]
  4. ↑ Medicines and Healthcare products Regulatory Agency (6 March 2008): "The significance of the data provided in the GSK briefing document was that they represented robust evidence from controlled studies of a causal association between an SSRI and suicidal behaviour. It had previously been argued by some manufacturers that a causal link could not be drawn between suicidality and SSRIs because no link was evident from (adult) clinical trial data. 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." [18]
  5. ↑ United States Department of Justice (2 July 2012): "The United States alleges that, among other things, GSK participated in 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]
  6. ↑ Melanie Newman, BMJ, 2010: "Study 329's results showed that paroxetine was no more effective than the placebo according to measurements of eight outcomes specified by Martin Keller, professor of psychiatry at Brown University, when he first drew up the trial.
    "Two of these were primary outcomes: the change in total Hamilton Rating Scale (HAM-D) score, and the proportion of 'responders' at the end of the eight-week acute treatment phase (those with a ≥50% reduction in HAM-D or a HAM-D score ≤8). The drug also showed no significant effect for the initial six secondary outcome measures.
    "The 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." [25]
  7. ↑ Study 377 was conducted in 33 centres in Europe (Belgium, Netherlands, Italy, Spain, UK), Canada, South America (Argentina and Mexico), South Africa and the United Arab Emirates. [36]
  8. ↑ In 1993, for example, STI sent a proposal to GSK for a meeting between its psychiatrist advisory board and Paxil advisory board in the Ritz Carlton Hotel in Palm Beach, Florida. [39]
  9. ↑ NICK ALCOCK, pharmaceutical company analyst ("The Secrets of Seroxat", BBC Panorama, 13 October 2002): "In the United States, if a company such as GlaxoSmithKline can gain an additional licence for the treatment of children, it means that they get a six month extension to their overall patent."
    JOFRE: "And is that worth a lot of money?"
    ALCOCK: "For Paxil it's worth ... six month's worth of sales is around a billion dollars, so yes."
    JOFRE: "That billion dollar windfall now looks tantalisingly close, thanks to a recent study co-written by American child psychiatrist Neal Ryan. It was the biggest ever trial of Seroxat in children funded by Glaxo SmithKline. The depressed children who took Seroxat did better than those who took an older drug, or were just given sugar pills. That's the good news. The bad news is that ten of the ninety-three children on Seroxat suffered serious psychiatric problems within weeks of going on the drug. Most of them had to be hospitalised. There were five children out of ninety-three children on Seroxat who had suicidal thoughts and gestures. Another five out of that ninety-three had serious psychiatric side effects. Don't you think parents would be worried about that if their child was to be given this drug?"
    Dr ALASTAIR BENBOW, Head of European Clinical Psychiatry, GlaxoSmithKline: "I think what parents would be more worried about is the risk that their children have of committing suicide and other symptoms of severe depression if no treatment was available. I think parents would want treatments to be properly evaluated during clinical trials before their children are given any medicine."
    JOFRE: "But the evidence here suggest that their children might be at more risk of suicide if they go on Seroxat."
    BENBOW: "No, the evidence is not there, there is no statistical difference between the groups. The reality of the situation is that in this trial, Seroxat was generally well tolerated by this difficult to treat population." [51]
  10. ↑ Simon Neville (The Guardian, 3 July 2012): "GSK also published an article in a medical journal that mis-stated the drug's safety for children, despite the journal asking several times to change the wording.
    "Copies of the misleading article were given to sales representatives to pass on to doctors in the hope that it would secure more business. Tickets to sports matches were exchanged for discussions about Paxil, with one doctor writing: 'Dinner and a Yankee game with family. Talked about Paxil studies in children.'
    "Despite knowing that three trials had failed to prove its effectiveness on children, Glaxo published a report entitled 'Positioning Paxil in the adolescent depression market – getting a headstart'". [90]
  11. ↑ The Committee on Publication Ethics states that journal editors should consider retracting an article if, inter alia, "they have clear evidence that the findings are unreliable, either as a result of misconduct ... or honest error." [92]
  12. ↑ Food and Drug Administration (June 2014): "Paxil and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed." [98]
  13. ↑ Sarah E. Hetrick, et al. (Cochrane Database of Systematic Reviews, 14 November 2012): "Caution is required in interpreting the results given the methodological limitations of the included trials in terms of internal and external validity. Further, the size and clinical meaningfulness of statistically significant results are uncertain. 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. Clinicians need to keep in mind that there is evidence of an increased risk of suicide-related outcomes in those treated with antidepressant medications." [99]

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  64. ↑ GSK briefing paper, 20 May 2003, p. 9, table 1.
  65. 1 2 MHRA, 22 May 2003. For twice that of placebo, section 5.2.5, p. 27. For the rest, section 5.4, p. 32.
  66. ↑ MHRA, 22 May 2003, section 5.2.5.3, p. 29.
  67. ↑ Joffre, Shelley (3 October 2004). "Taken on Trust", BBC Panorama.
  68. ↑ Carrey, Normand; Pharm, Adil Virani (November 2003). "Suicidal Ideation Reports From Pediatric Trials for Paroxetine and Venlafaxine", The Canadian Child and Adolescent Psychiatry Review, 12(4), pp. 101–102. PMID   19030150 PMC   2533826
  69. ↑ MHRA, 4 June 2003, p. 16.
  70. ↑ Duff, Gordon (10 June 2010). "Safety of Seroxat (paroxetine) in children and adolescents under 18 years—contradindication in the treatment of depressive illness", Committee on Safety of Medicines, Scottish Executive.
  71. ↑ MHRA, 6 March 2008(a), pp. 5–6, para. 16–17.
  72. ↑ McGoey and Jackson 2009, p. 108.
  73. 1 2 Jackson 2012, p. 109.
  74. ↑ MHRA, 6 March 2008(a), p. 7, para. 21.
  75. ↑ MHRA, 6 March 2008(a), p. 8, para. 28; p. 9, para 35.
  76. ↑ MHRA, 6 March 2008(a), p. 9, para. 36.
  77. ↑ MHRA, 6 March 2008(a), p. 9, para. 38.
  78. ↑ McGoey and Jackson 2009, p. 107.
  79. ↑ Bass, Alison; Howe, Peter J. (29 March 1996). "Probe of Brown mental health contract handed over to AG"], The Boston Globe.
  80. ↑ Bass 2008, p. vii.
  81. ↑ Bass, Alison (4 October 1999). "Drug companies enrich Brown professor", The Boston Globe.
  82. ↑ Leddy, Chuck (5 July 2008). "The unhealthy ties that bind FDA to drug firms", The Boston Globe.
  83. ↑ Apter, Alan, et al. (22 March 2006). "Evaluation of Suicidal Thoughts and Behaviors in Children and Adolescents Taking Paroxetine," Journal of Child and Adolescent Psychopharmacology, 16(1–2), pp. 77–90. doi:10.1089/cap.2006.16.77 PMID   16553530 ;
  84. ↑ The People of the State of New York against GlaxoSmithKline, 2 June 2004, courtesy of FindLaw.
  85. ↑ Kagle, Abigail (undated). "Driven to Settle: Eliot Spitzer v. GlaxoSmithKline and Undisclosed Clinical Trials Data Regarding Paxil", University of Columbia Law School, p. 4.
  86. ↑ Kagle, p. 6.
  87. ↑ Kagle, pp. 7–8; Jackson 2012, p. 109; Gardiner Harris, "Maker of Paxil to Release All Trial Results", The New York Times, 27 August 2004.
  88. ↑ Goldacre, Ben (2013). Bad Pharma , London: Fourth Estate, first published 2012, p. 387.
  89. ↑ Kmietowicz, Zosia (7 February 2013). "GSK backs campaign for disclosure of trial data", BMJ, 346. doi:10.1136/bmj.f819 PMID   23393115
  90. ↑ Simon Neville, "GlaxoSmithKline fined $3bn after bribing doctors to increase drugs sales", The Guardian, 3 July 2012.
  91. ↑ Also see Letter from Jon Jureidini to Mina K. Dulcan, 26 December 2002, courtesy of Healthy Skepticism.
  92. ↑ Elizabeth Wager, et al., "Retraction guidelines", Committee on Publication Ethics, September 2009.
  93. ↑ Alison Bass, "Drug companies enrich Brown professor", The Boston Globe, 4 October 1999.
  94. ↑ McHenry, Leemon, Jureidini, Jon. (2008). "Industry-Sponsored Ghostwriting in Clinical Trial Reporting: A Case Study" Accountability in Research , 15, p. 160.
  95. 1 2 Peter Doshi, "Putting GlaxoSmithKline to the test over paroxetine," BMJ, 12 November 2013. doi : 10.1136/bmj.f6754 PMID   24222673
  96. ↑ Jureidini, Jon N. (13 June 2013). "Restoring invisible and abandoned trials: a call for people to publish the findings" (letter), BMJ, 13(346). doi : 10.1136/bmj.f2865
    Jon Jureidini–GSK correspondence, BMJ, 347, 12 November 2013.
    For RIAT, see Loder, Elizabeth, et al. (13 June 2013). "Restoring the integrity of the clinical trial evidence base", BMJ, 346. doi : 10.1136/bmj.f3601
  97. ↑ "Antidepressant Use in Children, Adolescents, and Adults", Food and Drug Administration, 2 May 2007, courtesy of the Drug Industry Documents Archive, University of California, San Francisco.
  98. ↑ "Medication guide Paxil", FDA, June 2014, courtesy of the Drug Industry Documents Archive, University of California, San Francisco.
  99. ↑ Hetrick, Sarah E.; McKenzie, Joanne E.; Cox, Georgina R., et al. (14 November 2012). "Newer generation antidepressants for depressive disorders in children and adolescents", Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD004851.pub3 PMID   23152227

Further reading

Letters

Study 329
Paxil, June 2003.jpg
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 researcher Martin 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
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