Pattern of behavior - FDA - Promoting openness and full disclosure

2004-04-17 10:15:36 AM
ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)
Promoting openness and full disclosure
www.ahrp.org <www.ahrp.org>
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were caught covering up unpublished evidence demonstrating a two-fold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:
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preventing him from reporting his analysis of the unpublished data and his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:
bmj.bmjjournals.com/cgi/content/full/328/7444/879
<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,
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
e-mail: veracare@ahrp.org
<www.sfgate.com/cgi-bin/article.cgi
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
~~~~~~
www.nytimes.com/2004/04/16/politics/16DEPR.html?hp
<www.nytimes.com/2004/04/16/politics/16DEPR.html?hp>
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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