October 26

FDA Tones Down Warning–Shyra Kallas an SSRI Suicide Victim

FDA Tones Down Warning–Shyra Kallas an SSRI Suicide Victim

Fri, 4 Mar 2005

In his recent testimony before the Senate Health, Education, Labor, and Pensions committee, Dr. David Fassler, representing the American Psychiatric Association (APA) and the American Academy of Child and Adolescent Psychiatry (AACAP), misrepresented the scientific facts about the safety and effectiveness of antidepressants for children. But he acknowledged something that neither he nor the APA, nor the AACAP ever acknowledged prior to the public hearings in 2004: “It does appear that these medications may increase the likelihood that a patient will actually tell someone about their suicidal thoughts or even about a suicide attempt.”

For more than a decade, prescribing doctors – psychiatrists and pediatricians alike – and the public had little, if any, knowledge about these drugs’ potentially lethal side-effects – including a twofold increased risk of violent and suicidal behavior. Dr. Fassler says that from his perspective

“this is actually a good thing…” One is hard pressed to find a child having suicidal thoughts and suicide attempts, as “a good thing” under any circumstances.

Dr. Fassler told the Senate committee: “We are concerned that the available research findings do not support a warning that may be misinterpreted by some practitioners or parents to mean that antidepressant medications actually cause children and adolescents to commit suicide. Such a conclusion is simply not supported by the data.” http://help.senate.gov/bills/hlh_66_bill.html

On the contrary, the evidence from controlled clinical trials shows a twofold increased risk of suicidal behavior in children prescribed an SSRI antidepressant compared to those given a sugar pill. The evidence has been scientifically validated by multiple independent scientists, including FDA’s own medical officers. The uncensored evidence from clinical trials mirrors testimonies by families whose children committed suicide after ingesting one of the SSRI’s. The evidence is compelling: FDA’s advisory panel was persuaded by the evidence from clinical trials and the living testimonies. The expert panel urged the FDA to issue Black Box warnings on the labels of antidepressants. The FDA finally issued Black Box warnings on October 15. [http://www.fda.gov/cder/drug/antidepressants/SSRIlabelChange.htm ]

On February 3, 2005, the FDA made an unprecedented label change without supporting new evidence to back it up. It would seem that the FDA changed the agreed upon wording of the antidepressant warning labels under pressure from organizations that Dr. Fassler’s represents, and from these organizations’ benefactors – i.e., drug industry. The FDA deleted a key sentence that had been recommended by the advisory committee: “A causal role for antidepressants in inducing suicidality has been established in pediatric patients.” [www.fda.gov/cder/drug/antidepressants/default.htm ]

Millions of children are being exposed to antidepressants–mostly for conditions not approved by the FDA for children. Contrary to the assertion of industry and their chorus of Amen sayers, children who had been prescribed an antidepressant – SSRI or SNRI–have committed suicide. FDA’s unexplained deletion of a key sentence does not negate the evidence backing it up.

Shyra Kallas is one among all too many tragedies that should never have happened. According to a complaint filed in US district court of Utah against Pfizer [2], on October 8, 2002, Shyra, aged 15, went to see her family physician for warts. In the course of relating her history, Shyra indicated that she had been having trouble sleeping and felt “overwhelmed” with school work. The suit notes: “Her doctor then did precisely what Pfizer’s salesmen regularly encourage doctors to do, i.e., he (a) diagnosed “depression” and (b) prescribed Zoloft.” It was an “off-label” prescription. There was no warning on the label.

According to the suit, on her follow-up visit with her doctor on October 29, Shyra reported that she was “irritable” and that she continued to have significant problems sleeping. The doctor failed to realize that the irritability could be drug-induced, and indeed could be an early warning sign for incipient suicidality. The doctor told Shyra her to continue taking her Zoloft pills. On November 4, 2002, Shyra shot herself to death.

Dr. Joseph Glenmullen, author of Prozac Backlash and The Antidepressant Solution, who is a practicing psychiatrist who teaches at Harvard Medical School (and is a board member of AHRP) said: “To give a child a drug that can make them suicidal for conditions where there is nonexistent or inadequate proof that the drugs work is irresponsible.” [1]

Pfizer’s expert reports submitted to the FDA (1996 and 1997) about suicidal events in pediatric trials testing Zoloft (sertraline), reveal that in a 12 week double-blind, placebo controlled Zoloft trial in 6-17 year old children and adolescents – 92 were prescribed Zoloft and 95 a placebo. Of these, 61 were subjects of a 51-day, open label extension study. Of these 61 children and adolescents – 44 were diagnosed with depression, and 17 with OCD. Pfizer’s report to the FDA about these trials indicates that 6 children on Zoloft attempted suicide and a number of other children became suicidal. Four of the 6 who attempted suicide were in the depressed group – that’s a 9% attempted suicide rate.

But the published reports by leading child psychiatrists about these trials, in the Journal of the American Academy of Child & Adolescent Psychiatry and the Journal of the American Medical Association (JAMA) reported only one suicide attempt. [5, 6, 7]

Why, one wonders did the Senate HELP committee fail to ask FDA officials who testified this week, what the agency’s justification was for inexplicably changing the wording of a warning label that the agency had just issued? The public deserves to know the rationale that drives FDA decisions.


1. Manson, P. Lawsuit blames Zoloft for teenager’s suicide, The Salt Lake Tribune Oct 27, 2004 http://www.sltrib.com/utah/ci_2434365

2. Cato J. Depression drugs to be distributed with warning label, The Herald (North Carolina), October, 16th, 2004 http://www.heraldonline.com/local/story/4115379p-3882366c.html

3. Ambrosini, P. J., Wagner K. D., Biederman, J., Glick, I., Tan , C., Elia, J., et al. (1999). Multicenter open-label sertraline study in adolescent outpatients with major depression. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 566-572.

4. March, J. S., Biederman, J., Wolkow, R., Safferman, A., Mardekian, J., Cook, E. H., et al. (1998). Sertraline in children and adolescents with obsessive-compulsive disorder. JAMA, 280, 1752-1756.

5. Wagner KD, MD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, Childress A, Donnelly C, Deas D, for the Sertraline Pediatric Depression Study Group . Efficacy of Sertraline in the Treatment of Children and Adolescents With Major Depressive Disorder. JAMA. 2003. 290:1033-1041

Contact: Vera Hassner Sharav


FDA Tones Down Warning on Use Of Antidepressants In Children
Jim Rosack

The U.S. Food and Drug Administration (FDA) posted the final language for its new, required labeling of antidepressants last month, including the black-box warning and patient medication guide that must be dispensed with each prescription.

With no explanation, the FDA has significantly modified the wording describing the association between antidepressants and suicidal thoughts and behaviors.

In the final version of the warning, the first sentence in the black box has changed. The October draft’s sentence initially read: “Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.” The revised sentence limits the association between the two, more narrowly defining its scope. The sentence now reads: “Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.”

The change may be subtle, but it is significant. Even more significant is the deletion of a sentence from the first paragraph of text in the “WARNINGS-Clinical Worsening and Suicide Risk” section of the label. The draft warnings posted by the agency last October read: “A causal role for antidepressants in inducing suicidality has been established in pediatric patients.” That sentence has been deleted from the final version of the new label and replaced with “Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.”

“This is clearly an important change,” said David Fassler, M.D., a child and adolescent psychiatrist and clinical associate professor of psychiatry at the University of Vermont School of Medicine. Fassler, an APA trustee, chaired the combined APA/American Academy of Child and Adolescent Psychiatry task force that developed the new resource , which reviews the clinical trials data on the use of antidepressants in kids, and explains the FDA warnings (see story at left).

“The change in wording,” Fassler continued, “brings the FDA warning closer to the actual science. I’m glad they responded to the extensive and detailed input from both practicing psychiatrists and the research community. Hopefully, the FDA will consider further revisions in the future, as more long-term and follow-up data become available.”

However, Darrel Regier, M.D., M.P.H., director of research at APA and executive director of the American Psychiatric Institute for Research and Education, emphasized, “We continue to be concerned about the use of the term `suicidality,’ which the public widely equates with risk for completed suicides.”

It would have been more instructive, Regier said, had the FDA noted that there was no systematic monitoring for suidicality in some of the clinical trials it reviewed; thus, the only suicidal thoughts or behaviors that were noted were those that were spontaneously reported. In 17 of the 24 clinical trials reviewed, however, participants were directly questioned about suicidal thoughts or behaviors.

“We believe that additional research is necessary to determine how to evaluate both the systematic assessment and spontaneous adverse-event reports in these studies,” Regier said. “Such research should continue to inform recommendations coming from the FDA.”

The process that leads to the final approved language included in drug-product labeling is often convoluted, complicated, and intricate. Essentially the FDA and the drug company (which the FDA refers to as the “sponsor” of the application for approval to market a drug) negotiate the final wording. In many instances the sponsor submits its own version of the wording for FDA approval. In the case of the antidepressant warnings, however, it was the FDA that had informed sponsors of the language it was proposing in October of last year.

While the FDA would not comment on what input shaped the final wording of the labeling, it is likely that the agency’s staff in the Office of Drug Safety took primary responsibility for drafting the language. They may have taken into account input from the advisory committees; public comments; and written comments submitted by clinicians, researchers, and professional associations, including APA and AACAP, as well as others.

Revisions of draft language usually occur through a back-and-forth negotiation that ends with the ball in the FDA’s court.

“Although every attempt is made to negotiate labeling with the sponsor,” noted FDA spokesperson Christine Parker, “the agency has the final say on the wording.”

Indeed, Parker told Psychiatric News, “In our January 12, 2005, and January 26, 2005, letters, we informed the sponsors that `Failure to make these changes within the specified period of time could make your product misbranded.’ ” Drugs that are labeled misbranded no longer meet agency standards and thus lose marketing approval.

The new labeling was effective immediately upon issuance of the January 26 letter, Parker said. Sponsors were required to submit their individual revised product labeling to the FDA within 10 days, and all sponsors complied. However, weeks or even months may pass before patients see the new labeling.

“Stock on pharmacy shelves with the old labeling can be dispensed, and stock in distributors’ warehouses with the old labeling can still be shipped to pharmacies,” noted Parker. The new labeling “will gradually make its way into the pharmacies over the next couple of months.”

Parker emphasized that “all Internet listings of the labeling would be expected to include the new labeling immediately.”

Medications with black-box warnings may continue to be advertised to both health care professionals and consumers, Parker noted.

“The body of the ads do not have to contain the box warning verbatim, but the body of the ad must include the information contained in the boxed warning, along with other important risk information about the product,” she explained. “Risk information, including the black-box warning, must be presented with comparable prominence to benefit information.”

The FDA’s final versions of the warnings on antidepressants are posted online at < www.fda.gov/cder/drug/antidepressants/default.htm>.

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