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February, 2003 —Article: Physicians Raise Concerns About Undisclosed Financial Ties Between Researcher, Pharmaceutical Companies.

Bernard J Carroll, Scientific Director, Pacific Behavioral Research Foundation, and Robert T Rubin, Professor of Neurosciences and Psychiatry at Drexel note Charles Nemeroff's conflict of interest. "Rubin and Carroll said that they sent a letter to the editors of the Nature journals in February to ask them to publish a letter that outlined Nemeroff's conflicts of interest. They said that they have not received a response. Jennings said that the editors have considered the request and also may revise their disclosure policy."

The details of their concerns are published in an editorial letter in Nature Neuroscience in Oct, 2003.

See: Nov, 2002, Sept 26, 2003, Aug 25, 2006

February 28, 2003 —GSK pre-emptively sends the MHRA additional data on paroxetine as it related to suicidal behaviour to support a planned June request for approval of expanded use of the drug for young people. The letter accompanying the submission of the data, dated Oct 25, 2002, indicates that "there was no signal identified as regards suicidality revealed by these analyses." Only later does the MHRA discover that this submission contains adverse event data but fails to identify or differentiate between adult and paediatric trials. Paediatric studies have been merged together with the adult data, thus "hiding" the higher rate of paediatric adverse events. (Source: Bad Pharma, by Ben Goldacre, Page 60)

March, 2003 —Article: "Lines of Evidence on SSRIs and Risk of Suicide" by David Healy. This meta-analysis reveals clear indications of "a possible doubling of the relative risks of both suicides and suicide attempts on SSRIs compared to older antidepressants or non-treatments" and recommends further studies.

May 11, 2003 — BBC Panorama broadcast "Emails from the Edge" - Shelley Jofre follows up the many e-mails and calls the BBC has received after its first broadcast. In this segment, Alastair Benbow of GSK admits that the company knows that their study shows that more people are suicidal on Seroxat/Paxil than on placebo, and that he does not consider this important. David Healy's research, showing that it is the drug, and not depression that causes suicidality, is quoted.

May, 2003 —Letter: The Jon Jureidini and Anne Tonkin letter to the Editor of JAACAP, (see Dec 26, 2002), pointing out flaws in Study 329, is finally published:

PAROXETINE IN MAJOR DEPRESSION

To the Editor:

The article by Keller et al. (2001) is one of only two to date to show a positive response to selective serotonin reuptake inhibitors (SSRIs) in child or adolescent depression. We believe that the Keller et al. study shows evidence of distorted and unbalanced reporting that seems to have evaded the scrutiny of your editorial process. The study authors designated two primary outcome measures: change from baseline in the Hamilton Rating Scale for Depression (HAM-D) and response (set as fall in HAM-D below 8 or by 50%). On neither of these measures did paroxetine differ significantly from placebo. Table 2 of the Keller article demonstrates that all three groups had similar changes in HAM-D total score and that the clinical significance of any differences between them would be questionable. Nowhere is this acknowledged. Instead:

The definition of response is changed…

In reporting efficacy results, only "response" is indicated as a primary outcome measure, and it could be misunderstood that response was the primary outcome measure…Given that the research was paid for by GlaxoSmithKlein, the makers of paroxetine, it is tempting to explain the mode of reporting as an attempt to show the drug in the most favorable light.

Given the frequency with which it is cited,… this article may have contributed to the increased prescribing of SSRI medication to children and adolescents. We believe it is a matter of importance to public health that you acknowledge the failings of this article, so that its findings can be more realistically appraised in decision-making about the use of SSRIs in children.

May 23, 2003 —A first meeting of the CMA Expert Working Group is called to discuss proposed communication by GSK with the prescribing community following the May 11 Panorama programme. At this meeting, GSK hands out a briefing document relating to an application to extend indications for Seroxat to include use in children. GSK draws the Agency's attention to an increased rate of events relating to suicidal behaviour among paediatric patients with major depressive disorder (MDD) treated with Seroxat.

June 10, 2003 — Based on the information provided by GSK May 23, a "Dear Doctor" letter is issued by the MHRA warning against prescribing Seroxat to paediatric populations. At this time, 7,000 - 8,000 people under 18 are being treated with the drug in the U.K.

Late June, 2003 — U.K.CSM Expert Working Group on SSRIs produces its first finding, on Prescribing SSRIs to people under the age of 18. They conclude:

"The balance of risks and benefits for the treatment of depressive illness in under-18s is judged to be unfavourable for paroxetine (Seroxat), venlafaxine (Efexor), sertraline (Lustral), citalopram (Cipramil), escitalopram (Cipralex) and mirtazapine (Zispin). It is not possible to assess the balance of risks and benefits for fluvoxamine (Faverin) due to the absence of paediatric clinical trial data.Only fluoxetine (Prozac) has been shown in clinical trials to be effective in treating depressive illness in children and adolescents, although it is possible that, in common with the other SSRIs, it is associated with a small increased risk of self-harm and suicidal thoughts. Overall, the balance of risks and benefits for fluoxetine in the treatment of depressive illness in under-18s is judged to be favourable."

Sept 26, 2003 —The Editors of the Nature group of publications, which includes Nature Neuroscience, announce a change in editorial policy requiring that conflicts of interest be disclosed in all published material. They note that Dr Nemeroff did not violate the policy in place in 2002, thereby acknowledging that until the revised policy, reviews which look like scientific analysis can be biased product promotions without readers being aware of this fact.

Oct 1, 2003 —The Pharmacovigilance Group of the MHRA refers the matter of GSK failing to advise the regulator on a timely basis about issues relating to safety and lack of efficacy of Paroxetine. However, GSK's failure to advise the MHRA about the known lack of efficacy and dangers of paroxetine did not result in a prosecution. The MHRA report gives a number of reasons for its decision not to prosecute:

Relevant EU legislation requires the reporting of adverse reactions occurring in the normal conditions of use. A clinical trial in relation to an unlicensed indication did not fall within "normal conditions of use".
Although EU legislation also required adverse events to be reported in "post authorisation studies", such studies did not include studies on a product outside of its licensed indications.
UK legislation did require the reporting of adverse events during clinical trials, but it applied only to clinical trials in the UK and a failure to do so was not a criminal offence.
Although 2002 UK legislation required a marketing authorisation holder's Qualified Person to report any information relevant to the risk/benefit evaluation of a product, the MRHA received legal advice that the legislation was not sufficiently clear that this obligation applied to clinical trials outside a product's licensed indications.

December, 2003 —In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA) issues an advisory warning against prescribing SSRI antidepressants, with the exception of Prozac (fluoxetine), to under 18s.