October 26

Expert FDA Report: SSRI Suicide risk – SF Chronicle / NYT/ NJ Ledger/ AP

Expert FDA Report: SSRI Suicide risk_SF Chronicle / NYT/ NJ Ledger/ AP

Fri, 16 Apr 2004

FDA officials have provoked congressional hearings at which they will have to explain, not only why they concealed data linking antidepressants to increased violent and suicidal behavior, and why they covered up a report by the agency’s primary medical expert, Dr. Mosholder, confirming the risk. They will also have to explain why they should be allowed to continue in their office inasmuch as the information they deliberately concealed from physicians and parents is critical to the life safety and health of our nation’s children.

Congress is faced with an acute public health policy issue that pits children’s health and safety against Big Pharma and senior FDA officials who were caught covering up unpublished evidence demonstrating a two-fold suicidal risk for children taking an antidepressant.

FDA’s cover-up helped Big Pharma succeed in marketing these drugs widely–to pediatricians, family physicians, child psychiatrists, and directly to parents who were kept in the dark about the drugs’ potential life-threatening risks. As a result, nearly 11 million antidepressant prescriptions were written for children in 2002-of which 2.7 million were for children under 12. It is unfathomable why preschool children in the US are the fastest growing market for antidepressants! See: http://www.express-scripts.com/other/news_views/outcomes_research.htm.

On Feb 1, 2004, The San Francisco Chronicle reported that FDA officials were silencing Dr. Andrew Mosholder, the agency’s own expert medical officer, preventing him from reporting his analysis of the unpublished data and his recommendations to the FDA advisory committee at a public hearing (Feb 2, 2004).

Dr. Mosholder’s report was released only at the insistence of 2 Congressional committees. His recommendation puts the lives of children ahead of the drug industry’s marketing goals. He wrote: “Given the strength of the association shown by the present data, the clinical importance of the apparent effect, and the fact that the additional analyses are likely to take several more months to complete while considerable numbers of pediatric patients are being exposed to these drugs, I favor an interim risk management plan.”

The New York Times reports “Recent studies have shown that children given antidepressants are more likely to become suicidal than those given placebos. But the studies have lead to different interpretations by psychiatrists. The refusal by drug companies to publish the studies has worsened the confusion. Internal agency documents obtained by The New York Times show that federal health officials are divided, too.”

What is left out is the underlying reason for the “different interpretations by psychiatrists.” That is, the psychiatrists’ financial conflicts of interest which likely prompts them to defend the drugs’ value and safety. But given the absence of any scientific evidence to back up their assertions about the drugs, these assertions appear to reflect their bias toward the companies that pay them.

For this reason AHRP questions the credibility of a data analysis by investigators from the psychiatry department of Columbia University. Inasmuch as they are among the staunchest public defenders of these drugs, with very substantial financial ties to the drug manufacturers, they are neither objective nor unbiased. Dr. Mosholder, by contrast, is an impartial expert with no financial ties to the drug manufacturers; his independent analysis is, therefore, far more credible than theirs.

Dr. Mosholder’s analysis and conclusions confirm the British medicines authority and corroborate independent analyses of–not one, not two, but a growing number of analyses by expert international clinical trialists and statisticians.

The most recent critical analysis of the published antidepressant children trial reports by an independent team of Australian and British analysts refutes the claimed positive findings of the company-paid psychiatrists. See: Jon N Jureidini, Christopher J Doecke, Peter R Mansfield, Michelle M Haby, David B Menkes, Anne L Tonkin, Efficacy and safety of antidepressants for children and Adolescents by BMJ, online at: http://bmj.bmjjournals.com/cgi/content/full/328/7444/879

The New York Times reports, “Dr. Temple was unapologetic about the decision” to embargo the Mosholder report, and “The agency declined to make Dr. Mosholder available for an interview.” The Chronicle reports, “Despite repeated requests, senior FDA officials declined to comment for this story.”

Below excerpts from The San Francisco Chronicle and The New York Times.

See also: The NJ Star Ledger. FDA denies silencing reviewer BY ED SILVERMAN, http://www.nj.com/search/index.ssf?/base/business-0/1082098358140500.xml?sta rledger?bpha See also: AP Breaking News, House committee to investigate FDA’s review of antidepressants and their possible link to suicide in children by Lauran Neergaard, Thursday, April 15, 2004

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

http://www.sfgate.com/cgi-bin/article.cgi?file=/chronicle/archive/2004/04/1 6/MNGQN668FL1.DTL

FDA was urged to limit kids’ antidepressants Advice citing risk of suicide rejected Rob Waters, Special to The Chronicle Friday, April 16, 2004 Page A – 1

—–cut — Dr. Andrew Mosholder, an epidemiologist in the FDA’s Office of Drug Safety, analyzed 22 clinical trials of nine antidepressants and concluded that the drugs appeared to double the risk of suicidal behavior among children. A copy of his report, obtained by The Chronicle, shows that Mosholder recommended that the FDA adopt a “risk management strategy directed at discouraging off-label pediatric use of antidepressants” other than Prozac in the treatment of children with depression. As reported by The Chronicle at the time, Mosholder’s presentation to an FDA advisory committee in February was removed from the agenda by his superiors at the agency.

The FDA opted not to issue a recommendation to doctors that they stop prescribing the drugs to children, as British regulators did last year and as Mosholder had urged. Instead, the agency took a much milder step last month and called on drug companies to include warnings in the prescribing information provided to doctors about the risks of negative side effects among patients who start taking a drug or increase its dosage.

The agency also contracted with a group of doctors at Columbia University to reanalyze the clinical trial data provided by drug companies, the same data Mosholder reviewed, to see whether suicidal events were correctly classified. Agency officials have argued that the data from those trials are sometimes vague and that some behaviors — such as a child slapping herself in the head — may have been labeled wrongly as suicidal events by researchers conducting the drug company-funded studies.

Committees in both the House and Senate have opened investigations into the withholding of Mosholder’s report and into efforts by the FDA’s Office of Internal Affairs to identify the staff members who leaked information to The Chronicle. One congressional source predicted that the investigation was likely to trigger congressional hearings. “I think eventually there will be some hearings,” the source said. “There’s no way to put a good face on this decision not to allow Dr. Mosholder to present his conclusions to the advisory committee.”

—cut — …in a letter sent Wednesday to House Energy and Commerce Committee Chairman Joe Barton, R-Texas, an agency representative defended the agency’s decision to keep Mosholder from presenting his report. Agency officials “decided that having Dr. Mosholder present his conclusion to the Advisory Committee, with the appearance that it was an agency determination, would be potentially harmful to public health as it might lead patients who were actually benefiting from the use of these drugs to inappropriately discontinue therapy,” wrote Amit Sachdev, acting associate commissioner for legislation.

Critics of the FDA’s handling of the antidepressant ruling reacted to details of the Mosholder report with outrage. “It’s astounding that FDA officials actively blocked vital, possibly life-saving information about the suicide risks to children” of these drugs, said Vera Sharav, president of the Alliance for Human Research Protection, an advocacy group. “Every day that doctors and parents are not informed about the risks, children are at risk of dying.”

In arguing that the agency should take strong action rather than wait for the reanalysis by the Columbia University group, Mosholder made much the same point in his report. “Given the strength of the association shown by the present data, the clinical importance of the apparent effect, and the fact that the additional analyses are likely to take several more months to complete while considerable numbers of pediatric patients are being exposed to these drugs, I favor an interim risk management plan,” he wrote.

Mosholder’s report found that 74 children out of 2,298 who took antidepressants engaged in a “suicide-related event,” compared to 34 of the 1, 952 patients who took placebos, or fake pills. The drugs presenting the highest risk were Effexor and Paxil, which nearly tripled the risk of a suicidal event, and Zoloft, which more than doubled the risk, his research showed. .cut..

Joseph Glenmullen, a clinical instructor in psychiatry at Harvard University, said the agency’s withholding of the Mosholder report and its failure to take stronger action was an example of the FDA’s failure to protect the public from the dangerous side effects of antidepressants. “They have mishandled this issue for 15 years,” he said. “They have not adequately protected American children.”

C2004 San Francisco Chronicle ~~~~~~


THE NEW YORK TIMES April 16, 2004 A-16 Expert Kept From Speaking at Antidepressant Hearing By GARDINER HARRIS

Top Food and Drug Administration officials admitted yesterday that they barred the agency’s top expert from testifying at a public hearing about his conclusion that antidepressants cause children to become suicidal because they viewed his findings as alarmist and premature.

“It would have been entirely inappropriate to present as an F.D.A. conclusion an analysis of data that were not ripe,” Dr. Robert Temple, the Food and Drug Administration’s associate director of medical policy, said in an interview. “This is a very serious matter. If you get it wrong and over-discourage the use of these medicines, people could die.” Dr. Temple was seeking to quell a growing controversy into whether the agency’s warnings on March 22 that antidepressant therapy could lead patients to become suicidal were sufficient.

“There is concern that we hid data,” said Dr. Temple. “We did not hide data. It was there for all to see.” Recent studies have shown that children given antidepressants are more likely to become suicidal than those given placebos. But the studies have lead to different interpretations by psychiatrists. The refusal by drug companies to publish the studies has worsened the confusion. Internal agency documents obtained by The New York Times show that federal health officials are divided, too.

Dr. Andrew D. Mosholder, an agency epidemiologist, was the man charged with analyzing 22 studies involving 4,250 children and seven drugs. In a carefully argued, 33-page memorandum, he concluded that children given antidepressants were almost twice as likely as those given placebos to become suicidal.

He urged the agency to discourage doctors from prescribing to children all antidepressants except Prozac. Prozac is the only antidepressant proven effective in treating depressed children, and its studies showed no link with suicide, Dr. Mosholder wrote. Dr. Mosholder’s conclusions mirrored those made by British health authorities. But Dr. Mosholder’s supervisors, Drs. Mark Avigan and Anne Trontell, wrote memorandums disagreeing, according to the documents. “In particular, we disagree that the data are sufficiently robust to advocate preferential use of” Prozac in children, Dr. Trontell wrote.

Health officials convened a special advisory committee on Feb. 2 to offer guidance on how the agency should respond to the studies. As the agency’s principal reviewer, Dr. Mosholder was scheduled to speak. He was removed from the agenda, Dr. Temple said.

Senator Charles E. Grassley, a Republican from Iowa and chairman of the Senate Finance Committee, said he was investigating whether the agency inappropriately suppressed crucial findings. Representative Joe L. Barton, a Republican from Texas who is chairman of the House Energy and Commerce Committee, said he was also investigating. “It would have been very wrong for the F.D.A. to withhold any information it had about unintended consequences that might result from the use of antidepressants, especially for children and adolescents,” Mr. Grassley said.

Dr. Temple was unapologetic about the decision. He said that Dr. Mosholder’s underlying data were presented to the committee but that agency officials explained that Dr. Mosholder had failed to treat with the appropriate skepticism some reports of suicidal behavior. The Food and Drug Administration has hired investigators at Columbia University to examine reports from about 400 of the 4,250 children and determine independently which should be classified as suicidal.

The controversy had its start when GlaxoSmithKline sought a six-month extension to its patents on Paxil. To help guide pediatricians’ prescribing habits, federal law grants such extensions when companies test their medicines in children.

The company’s studies in depressed children failed to show any positive effect. It was a disappointing finding, but patent extensions are granted even when studies fail. Reviewing the data, Dr. Mosholder noticed in October 2002 that they showed a disturbing number of problems listed under the category, “emotional liability.” Suicidal thoughts and self-injurious behavior were among the things lumped into this category. Dr. Mosholder asked GlaxoSmithKline to provide more detail about these cases, according to one of the documents.

In May 2003, the company submitted a new report. It showed that children given Paxil were more likely to become suicidal than those given placebos. In June, the agency announced that doctors should avoid using Paxil in depressed children. Three days later, according to documents and interviews, the agency asked for similar data from the makers of Prozac, Zoloft, Luvox, Celexa, Wellbutrin, Effexor, Serzone and Remeron. Dr. Mosholder found that 108 of the 4,250 children had done something that merited being called suicidal. He divided the cases into those who were given drugs and those given placebos and found that children given drugs were almost twice as likely to become suicidal as those given placebo.

The agency declined to make Dr. Mosholder available for an interview.

Copyright 2004 The New York Times Company


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