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, and in the us that figure rose to 2.1 million in 2002, earning gsk $55 million. 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. 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. 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." inquiries in the united kingdom 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. the 2007 programme was based on thousands of internal company documents produced during lawsuits pursued against gsk by patients and families. 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. 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".) 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". paroxetine is sold in the uk as seroxat. 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." 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. 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." 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. 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. 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. the paper included data from nine clinical trials gsk had conducted on paroxetine and children between april 1994 and september 2002: "description of clinical programme for children" study no.treatmentdurationdesignage rangeparoxetinedosages(mg/day)no. ofpatients 704ocd10 weeksrandomized, db, parallel group, pc, flexible dose7–1710–50203 676sad16 weeksrandomized, db, parallel group, pc, flexible dose8–1710–50318 329mdd8 weeksrandomized (1:1:1) db, parallel group, pc and actively controlled (imipramine), flexible dose12–1820–40271 377mdd12 weeksrandomized (2:1), db, parallel group, pc, flexible dose13–1820–40274 701mdd8 weeksrandomized, db, parallel group, pc, flexible dose7–1710–40203 453ocd/mdd32 weekstwo-phase, relapse prevention design. phase 1: 16 weeks, open-label paroxetine, flexible dose. "responders" proceed to phase ii.8–1710–60335 phase ii: 16 weeks, randomized, db, parallel group, pc, fixed dose (dose at end of phase 1)193 329ocd/mdd6 monthsdb, parallel group, continuation of responders from study 329 (acute)12–1820–40125 716ocd/mdd6 monthsopen-label, extension for patients from studies 701 704 and 7157–1710–50265 715ocd/mdd6 weeksopen-label, dose-rising, repeat dose, pk study7–1710–3062 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. 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. the paper suggested a label change regarding withdrawal symptoms, which it said had occurred with paroxetine at roughly twice the rate of placebo. 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". 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. 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. the committee concluded that the risks outweighed the benefits, and on 10 june 2003 issued an advisory to physicians not to prescribe paroxetine to the under-18s. the us food and drug administration followed suit nine days later. 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. 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, 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. the mhra reviewed around one million pages of documentation in the course of the inquiry. after a four-year investigation, independent counsel instructed by the mhra advised, according to an mhra report, that "no offence ha been committed contrary to the 1994 regulations ", 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". 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". the mhra announced in march 2008 that there would be no prosecution. in october 2008 the 1994 regulations were amended to prevent a repetition of the case. inquiries in the united states 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. 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. 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). 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. 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. gsk denied any wrongdoing and said it had disclosed the data to regulators, and to physicians at medical conventions and in other ways. 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. in 2013 gsk joined alltrials, a british campaign to have all clinical trials registered and the results reported. other lawsuits by 2009 gsk had paid almost $1 billion to settle paroxetine-related lawsuits related to 450 suicides, withholding