October 26

Black Box Warnings for Antidepressants – What’s Next?

Black Box Warnings for Antidepressants – What’s Next?

Thu, 16 Sep 2004

NY TIMES Quotations of the Day:

A. “I think that we now all believe that there is an increase in suicidal thinking and action that is consistent across all the drugs.” Dr. ROBERT TEMPLE, of the Food and Drug Administration

B. “The blood of these children is on your hands.” Mathy Milling Downing of Laytonsville, Md., whose 12-year-old daughter hanged herself in January, said: “Candace’s death was entirely avoidable had we been given the appropriate warnings.”

We have turned a corner in this segment of the prescription drug war! The Washington Post reports: “In a sharp departure from a decade-old position, agency officials said the increase in suicidal tendencies was not a result of the children’s underlying depression but was caused by the medications themselves.”

For the first time in the 20-year controversy about SSRI drug-induced suicidal acts in some people–a battle has been won! First, the FDA acknowledged a causal link between SSRIs and suicidal behavior: “If 100 children and teenagers are given the drugs, two or three will become suicidal who would not have been suicidal if given placebos.”

Second, AHRP’s unequivocal demand for a black box warning requirement *[see below]-a demand of families who testified as well–has been recommended by FDA’s advisory panel. All antidepressant drugs will have to carry a black box warning about the suicidal risk on the label and on consumer package inserts.

However, the issues that were brought to a head in the SSRI children debacle continue to plague the process of drug testing, data disclosure, safety and efficacy assessment, and drug approval. The FDA’s complicity in years of deception cannot be underestimated.

1. WHY DO PUBLIC OFFICIALS WITH INSIDER INFORMATION—who are closest to the smoke alarms–wait for outsider critics to report the fires?

FDA officials have deliberately engaged in paralysis through analysis–i.e., the Columbia University reclassification was simply a delay tactic that added nothing toward improving children’s safety. It is FDA’s responsibility to establish a unified consistent adverse event classification system and to require drug manufacturers to use it. However, FDA officials turned a blind eye whereas every independent knowledgeable analyst recognized the cluster of red flags without the Columbia classification scheme.

The Associated Press reported [below]: “Dr. Robert Temple, director of the FDA’s office of drug evaluation, told reporters he had no regrets delaying the testimony at a previous hearing because he still thinks Mosholder’s data may be flawed.”

Does no one bear responsibility for putting additional children in harm’s way because of an unjustifiable unconscionable delay in warnings?


Inasmuch as senior FDA officials have made numerous safety and efficacy claims that proved to be unsupported by the evidence-some would call these pronouncements deliberate lies–it is odd that members of the press have failed to question FDA officials about the charge that suicides had occurred in adult clinical trials. Evidence about those suicides was presented at AHRP’s press briefing by a foremost authority on the subject. Indeed, Dr. David Healy’s analyses of both the pediatric and adult data have forced the FDA to re-evaluate the data that has been concealed in FDA’s files.

But then, the press had similarly failed to follow up on the suppression of Dr. Andrew Mosholder’s report–even though its suppression was announced at the Feb. 2 advisory meeting. Indeed, the press did not wake up to the Mosholder muzzling, nor the significance of the SSRI children debacle until two congressional committees began investigations-and only after New York State Attorney General Eliot Spitzer charged GlaxoSmithKline with fraud.


The FDA waived financial disclosure requirements for advisory panel members and excluded any independent authorities in psychopharmacology who have analyzed the data and raised the issue of unreported suicides. Furthermore, FDA withheld all published scientific analyses of the SSRI data by knowledgeable independent experts who would have brought greater clarity to the discussion. The FDA’s failure to conduct a fair and open debate–with all sides of the debated represented–is endemic to the culture of secrecy and concealment. FDA’s suppression of evidence and exclusion of independent experts who have additional evidence, were calculated to create confusion and uncertainty.

Observers noted that two of the most outspoken opponents to warnings on antidepressant labels were Dr. Matthew Rudofer and Dr. Daniel Pine-they are public officials at the National Institute of Mental Health (NIMH).

Their position reflected NIMH’s bias toward expanding psychotropic drug use in children and adults, and the agency’s defense of industry’s products. NIMH and its psychiatrists have unacknowledged financial relationships with pharmaceutical companies.

WHO HAS WHAT TIES TO WHOM? These three strands can be found in each and every one of the revelations that the Alliance for Human Research has brought to public attention.

Ed Silverman of The Newark Star Ledger put the SSRI debacle in proper perspective: “The recommendations cap more than a year of escalating controversy over antidepressants, which generated more than $11 billion in retail sales last year and include well-known names such as Zoloft, Paxil and Effexor. Scientists, parents and politicians have weighed in on a debate that starts with a basic question: Do these drugs help or hurt?”

“The controversy may not be over, though. Congressional inquiries are under way, and momentum is building to require drug makers to register their clinical trials with a national registry. A hearing by a House panel is scheduled for next week on the FDA’s handling of the issue.”

The AP reported on Sept. 14: “The FDA isn’t bound by advisers’ recommendations but usually follows them. FDA drug chief Dr. Robert Temple said a decision could come within months but noted advisers were divided, making it “less of a sure thing.”

In light of FDA’s record of inaction and its willingness to sacrifice children’s lives to maintain sales goals, AHRP believes that mandatory legislative requirements are essential to ensure enforcement of safety warnings.

* AHRP recommendations for immediate FDA action submitted to the FDA advisory committee:

(1) information concerning the increase in suicide-related events associated with exposure to antidepressants in pediatric clinical trials be placed at the front of product labels of antidepressants of the SSRI and SNRI class;

(2) this information should be contained in a bold black box warning in the product label;

(3) manufacturers of SSRIs (selective serotonin reuptake inhibitors) and SNRIs (selective norepinephrine reuptake inhibitors) should be required to send “Dear Doctor” letters to the nation’s physicians detailing the risk of suicide-related events associated with their products, reminding physicians that these products have not demonstrated a benefit for children and have not been approved by the FDA for pediatric use.

[AHRP’s written comments–FDA’s Waiting Game Exposes Children to Preventable Risks-will be posted on our website shortly–as will the presentations of the panel of experts from AHRP’s press briefing.]

An excellent article in The Denver Post, See: http://www.denverpost.com/Stories/0,1413,36%257E11676%257E2394179,00.html

Press reports about the advisory committee meeting:

New York Times:

Associated Press:

Washington Post:

Bloomberg News:

Denver Post:

Contact: Vera Hassner Sharav
Tel: 212-595-8974


Top News
Warnings urged for depression fighters Youth risk spurs call for strongest caution
Wednesday, September 15, 2004

BETHESDA, Md. — A panel of medical experts yesterday recommended the Food and Drug Administration issue the most severe type of warning for antidepressants, a popular group of medicines that has been linked to suicide.

The panel voted 15-to-8 for a so-called Black Box warning for children and adolescents after reviewing clinical-trial data that showed the drugs are twice as likely as a placebo to cause suicidal thoughts or behavior. The warning does not apply to adults.

“The purpose is to put physicians on notice that this group of drugs is a problem,” said James McGough, a psychiatry professor at the UCLA School of Medicine during a two-day meeting here.

This type of warning, which is currently found on hundreds of medications, was chosen by the panel because it is prominently placed on package inserts in hopes of quickly capturing the attention of doctors and patients. The warning could affect current and future antidepressants.

“A Black Box is something that catches everybody’s eye, because it’s the first thing you see,” Robert Temple, the director of the FDA’s Office of Drug Evaluation, explained to the panel. “It’s used for things that matter.”

Although the FDA does not have to adopt a panel recommendation, the agency often follows its advice, and a decision is expected in a few months. The panel also suggested that the FDA issue Medication Guides, which are information sheets that are distributed to patients by their pharmacies.

The recommendations cap more than a year of escalating controversy over antidepressants, which generated more than $11 billion in retail sales last year and include well-known names such as Zoloft, Paxil and Effexor. Scientists, parents and politicians have weighed in on a debate that starts with a basic question: Do these drugs help or hurt?

The issue is complicated and emotional because many doctors and families say antidepressants are life-saving medicines for people suffering from depression. Any move, they argued, to restrict availability may rob patients of needed help.

Only one antidepressant, Prozac, is approved for use by people under age 18. But doctors are free to prescribe whatever drugs they want, a controversial practice known as off-label use. As a result, prescriptions to youngsters accounted for nearly 8 percent of the total written during the first six months of 2004, according to IMS Health, a market-research firm.

The issue was triggered last year by U.K. regulators who warned doctors not to prescribe the medicines to children. The furor intensified after it became known that pharmaceutical companies never fully disclosed clinical trials showing links to suicidal behavior.

Reaction yesterday was largely favorable.

One consumer advocate, Vera Sharav of the Alliance for Human Research Protection, described the panel recommendation as a “good first step,” but continued to demand tighter standards for clinical-trial testing and disclosure of data.

Similarly, David Healy, a psychiatrist from the U.K. who has criticized drug makers for failing to disclose unfavorable data and has served as an expert witness in lawsuits against drug makers, said a Black Box “is the right thing and makes sense.”

And Joseph Camardo, senior vice president for medical affairs at Wyeth, which sells Effexor, said the Madison-based drug maker was pleased. While Effexor showed the greatest link to suicide in the review, Wyeth hopes any warning would apply equally to all antidepressants, he said.

The vote followed a highly emotional session on Monday afternoon, when dozens of people described how a family member attempted or committed suicide while taking an antidepressant.

One parent, Lisa Van Syckel of Raritan Township, was angry the panel did not support a ban, and chastised the FDA for not releasing trial data sooner. Her teenage daughter attempted suicide while taking Paxil, a GlaxoSmithKline drug.

The panel yesterday briefly considered recommending a ban for anyone younger than 18, but the idea was shelved after several panel members indicated they would not support it.

A Black Box “will make prescribing more difficult,” said Wayne Goodman, a University of Florida psychiatry professor who chaired the meeting. “And it will raise the threshold to prescribing.”

The warning may also have the practical effect of limiting direct-to-consumer advertising, because such ads must contain information that is difficult to convey on television. These ads are blamed by critics for creating unwarranted consumer demand.

Last March, the FDA issued a public-health advisory instructing doctors to monitor their patients for signs of suicidal behavior or thoughts. That warning applied to adults and children; the new panel recommendation is targeted only at teens and children.

The agency also commissioned a team of Columbia University researchers to sift through clinical trial data from the drug makers. The goal was to identify, if possible, any reasonable links to suicide.

This week’s meeting was held to review those findings, as well as an internal FDA review, which found that two to three of every 100 patients who are given an antidepressant can be expected to develop suicidal thoughts or behavior.

The reviews revealed weaknesses in the data that confounded panel members during much of yesterday’s discussions. At times, the debate was little more than a series of statistical skirmishes as panel members sought to decipher the information.

Yesterday, FDA officials appeared relieved the panel took a strong step.

“I’m sure there will continue to be people who think we didn’t act fast enough or were (not) critical enough,” Temple said.

The controversy may not be over, though.

Congressional inquiries are under way, and momentum is building to require drug makers to register their clinical trials with a national registry. A hearing by a House panel is scheduled for next week on the FDA’s handling of the issue.

Ed Silverman can be reached at (973) 392-1542

Sept. 13, 2004, 2:34PM
Researcher warns against antidepressants for kids
Associated Press

WASHINGTON – A Food and Drug Administration epidemiologist who triggered a closer look at suicidal behavior among children taking antidepressants cited independent experts at hearings today who he said support his findings.

In addition to seeing increases in suicidal thoughts among children receiving all the antidepressants he studied, Dr. Andrew Mosholder noted a clustering of serious events involving suicide within the first four days after youths discontinued Paxil treatment.

Mosholder testified before two FDA panels considering whether agency action — including stronger warning labels — is needed on antidepressants because they have been linked to suicidal tendencies among children who take them. The joint panel will weigh the benefits of nine drugs given to depressed children against the risk that the remedies may increase suicidal thoughts and suicidal actions among those youths.

Mosholder said analyses of data confirmed “an association of suicidality with antidepressant drug treatment.”

He was praised by grieving family members, who wore pins and carried posters and oversized photographs of deceased children whose deaths they blame on antidepressants. Last year, he had requested clarification from GlaxoSmithKline and received data in May 2003 that suggested a link between the company’s drug Paxil and increased suicidal acts among children taking the antidepressant.

“He was finally allowed to speak. Last time, he was muzzled,” said Vera Hassner Sharav, president of the Alliance for Human Research Protection.

Dr. Robert Temple, director of FDA’s office of drug evaluation, told reporters he had no regrets delaying the testimony at a previous hearing because he still fears Mosholder’s data are flawed. “Scaring people needlessly, overdoing it, is worrisome also,” Temple said.

Last June, the FDA issued a public warning about Paxil. In July, FDA asked all antidepressant manufacturers to resubmit clinical trial data.

Independent experts, working with Columbia University, were asked to review the research. This summer, the Columbia reanalysis came to conclusions that backed Mosholder.

An additional 2 percent to 3 percent of children are likely to incur increased suicidal thoughts from taking any antidepressant, Tarek Hammad, an FDA senior medical reviewer, testified.

Hammad told reporters that looking at all the drug company studies painted a more nearly complete picture. “Then, you can see significant findings,” Hammad told reporters.

Relative risks of suicidal behavior or thoughts were highest among youths taking Luvox, Effexor and Paxil and lower among youths taking Celexa, Zoloft and Prozac.

Temple said it was “interesting and persuasive” that studies link all antidepressants to heightened suicidal thoughts and actions among youth. “They all lean the same way, including Prozac now,” he said.

Researchers discussed charts that explained individual tragedies: an 18-year-old heeding a voice that called the teen to the roof, but then refusing to jump; self-inflicted cuts that looked like cat scratches; suicidal role-playing with knifes and hanging ropes.

The descriptions brought tears to Lisa Van Syckel, 43, who recognized the self-destructive actions of her daughter while the 15-year-old was taking Paxil. Van Syckel was among 73 family members who reopened painful wounds to prod the FDA to order more strident warning labels on antidepressants they blame for their children’s deaths.

Most medicines children take are prescribed off-label, meaning they are not specifically designed or approved for use in children, said Dianne Murphy, director of FDA’s office of pediatric therapeutics. Some 100 pharmaceutical products subjected to 200 studies found that about one-quarter of the time, the FDA had changed the dosages for children, found new adverse reactions that occurred only among children or found the drugs didn’t work in kids at all.

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