January 21, 2004 — American College of Neuropsychopharmacology (ANCP) report declares that SSRIs do not increase suicide risk in people under 19. The report notes that:
"The evidence linking SSRIs to suicide is weak," said J. John Mann, M.D., Co-Chair of the ACNP Task Force. "There are strong lines of evidence in youth - from clinical trials, epidemiology and autopsy studies - that led the ACNP Task Force to conclude that SSRIs do not cause suicide in youth with depression."
ACNP established the Task Force after regulatory agencies in the US and the UK voiced concerns in 2003 about the possibility that treatment of depression in children and adolescents with SSRIs may increase the risk for suicide. The FDA is convening an advisory committee hearing to review the issue on Feb. 2, 2004. "The most likely explanation for the episodes of attempted suicide while taking SSRIs is the underlying depression, not the SSRIs," said Graham Emslie, M.D., Co-Chair of the ACNP Task Force "The potential benefits of SSRIs outweigh the risks."
Of the 10 members of the Task Force (J John Mann, Graham Emslie, Ross J Baldessarini, William Beardslee, Jan A Fawcett, Frederick K Goodwin, Andrew C Leon, Herbert Y Meltzer, Neal D Ryan, David Shaffer and Karen D Wagner), 9 are paid consultants to drug companies that sell SSRIs. Seven (names underlined) are fated to become targets of Iowa Senator Chuck Grassley for failing to disclose to their universities all the payments they receive from pharma, in violation of conflict of interest policies. (See April, 2008)
February 1, 2004 — Andrew Mosholder, an epidemiologist with the FDA, is told he cannot testify at the planned FDA hearings (see Feb 2, 2004). Dr. Mosholder has reviewed all the published and unpublished data on SSRIs, and concluded that the risk of suicidal events and serious self-harm is about twice as high for young people taking these medications. His review of paroxetine 4-11-02 finds "The three randomized, controlled trials in MDD, listed above, all failed to show a separation of paroxetine treatment from placebo on their primary efficacy measures."
He also notes that: "The most prominent adverse reactions not seen in corresponding adult trials appear to involve behavioral effects; these events were coded with terms such as hostility and emotional lability. As previously noted, the sponsor's method of coding these events was potentially confusing, and thus additional information will be helpful for the purpose of definitively assessing the potential behavioral toxicity of paroxetine treatment in pediatric patients."
February 2, 2004 — The FDA Psychopharmacologic Drugs Advisory Committee convenes special hearings with the Pediatric Subcommittee to determine if there is any basis for recent concerns about reports of suicidal ideas and behavior developing in some children and adolescents during treatment of depression with an SSRI or similar newer antidepressants.
The committees hears from 51 witnesses who are granted leave to present. Committee members express uncertainty regarding the implications of different classifications for adverse events, including events relating to suicidality.
Among the criticisms of methodology presented at the hearing is the following by Dr. Irving Kirsch and Dr. David Antonuccio:
"The effect of SSRIs is statistically significant, but it is not clinically significant (and) These results were drawn from studies with design flaws that typically favor the study drug. For example, they frequently exclude placebo responders before random assignment, rely on ratings by clinicians who have a vested interest in the outcome, and are likely to be unblinded by medication side effects. Furthermore, adding unpublished studies, most of which have negative results, will surely shrink the difference between antidepressants and placebo even further Clinically meaningful benefits (of SSRI use) have not been adequately demonstrated in depressed children. Therefore, no extra risk is warranted."
February 7, 2004 — Traci Johnson, a 19-year-old college student and a subject taking part in trials for Cymbalta (Lilly's "next generation" version of Prozac), is found hanging by a scarf from a shower rod in a drug company laboratory. After this event, the fact that 4 other young people had committed suicide on Prozac in earlier trials is revealed. None of these deaths were attributed to the medication. As the Independent (U.K.) notes on June 5, 2005:
"Now, medical researchers attempting to establish the truth about Cymbalta are asking why her (Traci's) disturbing and very public suicide is completely absent from the official record, at least as it is released to academics and the public. According to an investigation by The Independent on Sunday, this and at least four other suicides by volunteers have been hidden by the US regulators, the Food and Drug Administration (FDA).
As the FDA admits, even a young woman's death counts as a commercial secret in the world of pharmaceuticals."
February 13, 2004 — Report: GSK: Paxil Sales Depressed By Generics explains the impact on GSK of losing its patent protection on Paxil in the 3rd fiscal quarter of 2003. " "GlaxoSmithKline has announced that sales of its antidepressant Paxil (paroxetine) fell 40% in Q4 2003. The company must now look to minimizing the impact of generic competition by focusing attention on its newer controlled release version, Paxil CR.
At the annual results meeting, GlaxoSmithKline announced that its leading antidepressant Paxil had suffered a 40% decline in sales from $597 million in Q3 2003 to $325 million in Q4 2003. The company says that performance in the US had been severely impacted by generic competition, which began in September 2003, resulting in a decline in global sales from $3,084 million in 2002 to $3,078 million in 2003." (bolding added)
February 16, 2004 — "Because of concerns about whether the varied events identified by sponsors under the broad category of "possibly suicide-related" could all reasonably be considered to represent suicidality, the FDA asked Columbia University (See Page 5) to assemble an international panel of pediatric suicidality experts to undertake a blinded review of the reported behaviors using a rigorous classification system*. The Columbia group submitted its completed review to FDA in June 2004."
Columbia was invited because they had already developed a suitable classification system.
March 2, 2004 — Article: Drug Company Experts Advised Staff To Withhold Data About SSRI Use In Children appears in the Canadian Medical Association Journal (CMAJ). It begins:
"An internal document advised staff at the international drug giant GlaxoSmithKline (GSK) to withhold clinical trial findings in 1998 that indicated the antidepressant paroxetine (Paxil in North America and Seroxat in the UK) had no beneficial effect in treating adolescents."
The internal document referenced is the Oct 14, 1998 Jackie Westaway memo. The publication of this information is noted by the Office of the Attorney General in the State of New York and provides important ammunition for a fraud lawsuit against GSK. See Oct 14, 1998, June 3, 2004)
April 27, 2004 —In a Letter to Congressmen Joe Barton and James Greenwood, the AHRP notes that: "A new and accurate method for calculating the number of patients that have died as a result of taking SSRIs was developed by our colleague in the UK, Graham Aldred, a systems engineer whose wife, Rhona died just 11 days after being prescribed Paxil /Seroxat." This methodology is used by the IMR (Institute of Medical Research).
Noting that the most dangerous time is within a couple of months of starting the drug, and taking the number of people who started on Paxil in the USA every year from 1993 to 2002, Mr. Aldred calculated that at a bare minimum there were 6,004 suicides in America that were solely attributable to Paxil during this time, with a still-conservative and more likely estimate of 19,271 suicides. About these rates, Mr Aldred asked: "Assuming the lowest rate (32/100K) would the FAA support an airworthiness certificate for a certain aircraft type, that for 10 years consistently crashed and killed 300 to 1,000 passengers per year and injured many others? How would the FAA react if the aircraft manufacturer consistently blamed the crashes on the passengers but not the aircraft?"
May 1, 2004 — EU Directive, Directive 2001/20EC, regarding legal requirements for the disclosure of adverse events in clinical trials, comes into force, fixing gaps and inconsistencies in the previously existing legal framework. Failure to report such events from trials within the EU became a criminal offence.
June 3, 2004 — New York State Attorney General Elliot Spitzer files a lawsuit in New York State Supreme Court accusing British drug giant GlaxoSmithKline PLC of "repeated and persistent fraud" for concealing known problems with efficacy and safety of Paxil (paroxetine) for children and adolescents.
The suit contends that Glaxo hid the fact that in some of its trials Paxil failed to show better efficacy in adolescents and children than a placebo and in some cases could be more likely to cause suicidal thinking.
This lawsuit is different that the civil suits of individual plaintiffs harmed by Paxil. A charge of consumer fraud for medication is unprecedented, although arguably warranted given that Study 329 probably represents the greatest divide in all of medicine between what the academic literature says about the drugs and what the data actually show.
June 21, 2004 — Launch of class action lawsuit , Beverly Smith vs Smithkline Beecham, for false and deceptive business practices and false and misleading advertising of Paxil, in California.
June 22, 2004 — Letter: The Alliance for Human Research Protection (AHRP) writes to Thomas Insel of the National Institute of Mental Health complaining that:
"clinical trial data about the potential hazards of Prozac (fluoxetine) for children and adolescents may have been concealed from physicians, other health care professionals, and the public." "According to FDA documents posted on the FDA website on September 25, 2003, at least 2 of 48 children treated with Prozac in the NIMH-sponsored trial attempted suicide. In the published report, there is no mention of any children attempting suicide. Instead, the published report states: Side effects, as a reason for discontinuation, were minimal, affecting only 4 patients who were receiving fluoxetine. (Emslie et al., 1997, p. 1033)"
Referring to the FDA medical review of the application, AHRP notes that: "According to the FDA medical review, the ISS summaries indicate that 22 children dropped out because of ADRs in the Prozac-treated group compared to 5 in the placebo groups. The FDA review also states that there were 3 suicide attempts among the Prozac-treated group versus one such attempt among the placebo group. The FDA's review refers to additional children being hospitalized for suicidal events: "In addition, one fluoxetine patient was hospitalized because of suicidality" (p. 26)".
August 26, 2004 — GSK announces that it will pay US $2.5 million as part of a settlement of the lawsuit filed by New York Attorney General Eliot Spitzer. GSK also agreed to publicly disclose all of its clinical drug trials about the safety of paroxetine for children in a "Clinical Trials Registry"
"We are pleased that the Attorney General believes the Clinical Trial Register we have been developing will provide useful information to the medical and scientific community," said Mark Werner, Senior Vice President for US Legal Operations at GlaxoSmithKline. "We believe that GlaxoSmithKline's initiative to launch this register is a responsible step in ensuring transparency of our clinical trial data."
September 23, 2004 — Statement of Robert Temple, M.D., Director, Office of Medical Policy, FDA. In his statement to the Committee, Dr Temple explains why Andrew Mosholder was not allowed to testify at the Feb 2 hearings:
"While CDER was moving ahead with plans for the February 2, 2004, Advisory Committee meeting, Dr. Mosholder was nearing completion of his review of the data from the clinical trials provided in response to our July 22, 2003, request. Based on his review, he believed that the available data were sufficient to reach a conclusion about an association between the use of anti-depressants and suicidality in children and to recommend additional regulatory action, without the need for the more in-depth case classification or analyses that had already been initiated by DNDP. Dr. Mosholder had shared his conclusions with his supervisors and with the DNDP/ODE I review team involved in reviewing this issue. The review team and Dr. Mosholder's direct supervisors did not agree that the available data were sufficient to reach a conclusion and believed that definitive action should await the re-analysis by Center staff using the Columbia data. There was a discussion within the DNDP/ODE I review team, as well as higher CDER management including Drs. Katz, Laughren, and Temple, as to whether Dr. Mosholder's scientific and regulatory conclusions on the data should be presented in some form at the February meeting, given that they did not represent the Agency's (but rather an individual staff member's) determination; it was concluded that they should not be."He concluded 20 pages of testimony, which appears to have been accepted by the committee, despite the clear "red flags" in Dr Mosholder's review being known inside the FDA. He made this comment:
"The results of pediatric depression studies to date raise very important problems. First, the poor effectiveness results, except for Prozac, make it very difficult for practitioners to know what to do to treat a very serious, life-threatening illness. While we believe that these drugs may be effective in children, studies have not shown this to be true." (italics added)
Sept 13-14, 2004 — Committees from Feb FDA special hearings reconvene (Sept 13, Sept 14) and conclude that there is a causal link between the newer antidepressants and pediatric suicidality. They vote 15 to 8 that a Black Box warning label be placed on all antidepressant medications for which data had been presented (Prozac, Zoloft, Remeron, Paxil, Effexor, Celexa, Wellbutrin, Luvox and Serzone), indicating the special risks for young people.
October 3, 2004 — BBC Panorama broadcast "Taken on Trust". In the third of four episodes about Seroxat (paroxetine, Paxil) Shelley Jofre interviews a number of people who confirm that the drug made them suicidal, paranoid, and violent. One man described his father committing suicide after being on the drug 4 days.
Dr. David Healy notes that: "I think in due course we may look at all of this and think this was one of the biggest medical scandals ever."
Oct 14, 2004 — Dr David Healy statement to the U.K. House of Commons Health Committee includes the following: "In the case of fluoxetine an early series of clinical trials failed to establish efficacy for this drug in treating childhood nervous problems. This work led to a study that started in 1990, which involved extensive pre-screening of patients so that less than one-fifth of those screened entered the study, and those who did were put through a placebo washout phase in an effort to reduce the high rate of placebo responsiveness found in SSRI trials in children. Using these procedures, [the Nov. 1997 Emslie article] claimed that Prozac could produce beneficial effects for children and adolescents. However, in fact on the primary end-point measure, Prozac was no better than placebo and on secondary measures benefits were apparent on physician-based ratings but not on patient or carer ratings. In addition, there was a 29% drop-out rate on Prozac and the rate of behavioral side effects was greater on Prozac than on placebo."
October 15, 2004— The Food and Drug Administration (FDA) issues a Public Health Advisory directing manufacturers of all antidepressant drugs to revise the labeling for their products to include a boxed warning and expanded warning statements that alert health care providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these medications, and to include additional information about the results of pediatric studies.
Dec 6, 2004 — Report Of The CSM Expert Working Group On The Safety Of Selective Serotonin Reuptake Inhibitor Antidepressants is published. The findings for children and adolescents have already been issued in June, 2003. Findings for the safety of SSRIs for other age groups are as follows:
Young Adults (18-24)
"The clinical trial data for each product was reviewed in relation to a possible effect in young adults, and the GPRD study looked specifically at this age group. From these analyses, the Group concluded that there is no clear evidence of an increased risk of self-harm and suicidal thoughts in young adults of 18 years or over. However, given that individuals mature at different rates and that young adults are at a higher background risk of suicidal behaviour than older adults, as a precautionary measure young adults treated with SSRIs should be closely monitored."
"There is no clear evidence that there is an increased risk of self-harm or suicidal thoughts when SSRIs are discontinued. Evidence of a relationship between suicidal behaviour and increasing/decreasing dose is not robust; however, patients should be monitored around the time of dose changes for any new symptoms or worsening of disease."
Dec, 2004 —The MHRA issues a warning about Seroxat for adults.