E-DRUG: GSK 'held back' data on SSRI drug for children
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[this depressing case of unethical antidepressants use in children is going
to explode soon - see articles from The Guardian (UK) and The Chronicle.
Thanks to DRUGINFO for spotting these. Copied as fair use. WB]
http://society.guardian.co.uk/mentalhealth/story/0,8150,1137715,00.html
GSK 'held back' data on drug for children
Antidepressant had no effect, leak reveals
Sarah Boseley, health editor
Tuesday February 3, 2004
The Guardian
The British manufacturers of an antidepressant drug that was last year
banned from use in children knew as long ago as 1998 that it did not work
and deliberately avoided publishing the full data because of the risk to
their lucrative adult market, according to a leaked internal document.
A position paper dated October 1998 shows that managers at SmithKline
Beecham - now GlaxoSmithKline - were concerned at the commercial
implications of two clinical trials in which their drug Seroxat was given to
children and adolescents with major depression.
The results of both trials, known as protocols 329 and 377, showed that the
drug was no better than a placebo - an inert pill - in alleviating the
children's depression. An internal unit at the drug company called the
Central Medical Affairs team prepared a strategy.
The target, says the document - leaked to the BBC's Panorama team, which has
made two programmes on Seroxat - was "to effectively manage the
dissemination of these data in order to minimise any potential negative
commercial impact". About 500,000 adults were at the time taking the drug in
the UK. Seroxat was licensed for their use, but not for use in children.
Even so, some 8,000 to 10,000 children were also on it because doctors can
prescribe an unlicensed drug on their own responsibility.
The paper says that following consultations within the company, SmithKline
Beecham would not submit any data to the regulators to get a statement on
the efficacy or the safety of the drug. It says: "It would be commercially
unacceptable to include a statement that efficacy had not been demonstrated,
as this would undermine the profile of paroxetine [Seroxat]." It adds,
however, that "positive data" from the first and bigger study, protocol 329,
would be published in abstract form at a psychiatric meeting the following
month and that a full manuscript of the trial "will be progressed".
It was eventually published in July 2001 with the conclusion: "Paroxetine is
generally well tolerated and effective for major depression in adolescents."
It was only last spring, after Glaxo submitted the full data from protocols
329 and 377, together with a third study of depressed children on Seroxat
and data from trials of the drug in children with obsessive compulsive
disorder and social anxiety disorder, that the UK regulator, the Medicines
and Healthcare Products Regulatory Agency (MHRA), realised that not only was
Seroxat ineffective in children but that a bigger proportion of those taking
it in the trials thought about killing themselves than among those on
placebo. The drug was then banned.
Yesterday Alastair Benbow, GSK's head of European clinical psychiatry, said
the document "draws inappropriate conclusions and it is inconsistent with
the facts".
He insisted that there was no sign of a suicide problem until all the trials
were put together.
Richard Brook, the chief executive of Mind, the UK organisation for mental
health and a member of the Seroxat review panel convened by the MHRA, said
he was appalled by the revelations in the leaked document. To allow the drug
to be given to children when there were known side-effects and it could not
be proven to work was "morally and ethically bankrupt", he said.
---------
Drug report barred by FDA - Scientist links antidepressants to suicide in
kids
Rob Waters, Special to The Chronicle
Sunday, February 1, 2004
A scientist at the Food and Drug Administration has been barred from
publicly presenting his finding that several leading antidepressants may
increase the risk of suicidal behaviors among children, according to sources
inside the FDA.
FDA medical officer Andrew Mosholder was to present his report Monday at an
FDA advisory hearing in Washington that promises to be a contentious affair
involving competing medical experts and parents whose children took their
own lives while on the medications.
A senior FDA official said the study wouldn't be presented because it wasn't
"finalized." But critics fear that the agency's action indicates it is not
prepared to take stronger action against the drugs, despite warnings about
their possible effects on children.
Mosholder had been asked by the agency to perform a safety analysis of
antidepressants after reports emerged this summer of high rates of suicidal
behavior among children enrolled in clinical trials for Paxil, Effexor and
other antidepressants.
Mosholder, a child psychiatrist, reviewed data from 20 clinical trials
involving more than 4,100 children and eight different antidepressants. His
preliminary analysis, according to two FDA sources familiar with the
report's contents, concluded that there was an increased risk of suicidal
behavior among children being treated for depression with Paxil and several
other antidepressants.
An initial agenda for Monday's hearing listed Mosholder and his findings,
but his presentation was removed from a revised agenda, and Mosholder was
told that he could not present his findings at the hearing, one FDA
official, who wished to remain anonymous, told The Chronicle.
According to the official, in early January, Russell Katz, director of the
division of neuropharmacological drug products, called Mosholder in for a
meeting. "He told him that he was sorry, but he wasn't going to be able to
present (his report) because he had reached a conclusion and therefore was
biased," the official said.
Mosholder declined several requests to be interviewed and was not made
available despite repeated requests to FDA's press office. Katz was
unavailable to comment on the charges.
In a telephone interview Friday with The Chronicle, Anne Trontell, deputy
director of the agency's Office of Drug Safety, who is Mosholder's direct
supervisor, said the analysis would not be presented because it had not yet
been approved within her office.
"The consult on that is not finalized. It's not a final document within the
Office of Drug Safety," Trontell said.
However, Trontell said that at Monday's hearing, Mosholder would provide a
rundown of reports of suicidal behavior received by the agency from doctors
and other professionals.
While Mosholder's safety analysis report may eventually be completed and
made public, some FDA insiders fear that withholding it from Monday's
hearing indicates that the agency may be siding with the pharmaceutical
industry in its long-running battle with critics of antidepressants.
"Why is the agency sitting on its hands and acting as if there isn't a risk
when their own scientists have looked at the data and concluded that there
is?" one FDA official remarked.
The use of antidepressants and other psychiatric medication among children
has more than tripled in recent years and now approaches adult usage rates,
according to a January 2003 study in the Archives of Pediatric and
Adolescent Medicine. Study author Julie Zito, an associate professor of
pharmacy and medicine at the University of Maryland, estimates that more
than 1 million American children used antidepressants in 2000.
Advocates of the drugs argue that they are imperfect but necessary weapons
against a rising tide of mental illness among children.
Last month, a task force of the American College of Neuropsychopharmacology
released its own preliminary review of published studies on antidepressants
and suicide and stated it found no statistically significant increase in
suicide attempts among children taking the drugs.
"The most likely explanation for the episodes of attempted suicide while
taking SSRIs (selective serotonin reuptake inhibitors) is the underlying
depression, not the SSRIs," said Graham Emslie, a child psychiatrist and
researcher at the University of Texas Southwestern Medical Center in Dallas.
But critics, including consumer advocates and mental health professionals
contend, based on other studies, that the drugs are often ineffective and
sometimes dangerous and that the FDA has failed to vigorously investigate
the risks and protect children's safety.
"The FDA is shielding the industry," said Vera Sharav, president of the
Alliance for Human Research Protection, a consumer advocacy group.
Mosholder's analysis appears to be similar to the conclusions reached by
British regulators, who told doctors in December to stop prescribing Paxil,
Zoloft, Effexor and three other antidepressants to children because of an
apparent "increased rate of self-harm and suicidal thoughts."
British regulators took action against Paxil in early June after new data
presented to U.S. and British authorities showed that children taking the
drug were nearly three times as likely to consider or attempt suicide as
children taking placebos.
Later that month, the FDA issued a similar warning, urging doctors not to
prescribe Paxil to children and announced that it would conduct a detailed
review of pediatric trials of Paxil. The review was subsequently broadened
to include seven other antidepressants, including top sellers Prozac, Zoloft
and Effexor.
In October, the agency wrote to physicians to "call to (their) attention"
reports of suicide among children in antidepressant trials. The agency did
not, however, urge doctors to stop prescribing the drugs.
Several current and former FDA staff members interviewed by The Chronicle
said the dispute over Mosholder's report highlights a lack of assertiveness
within the agency over safety issues. They spoke of a split between the
Office of Drug Safety -- Mosholder's office -- and the FDA's drug-reviewing
divisions.
As an example, they cite a hearing last March on a rheumatoid arthritis
drug, Arava, which had generated numerous reports of adverse effects,
including nine deaths, after being approved by the FDA.
Members of the Office of Drug Safety, who had prepared a 37-page safety
report, were present at the hearing but were not allowed to speak. A
representative of the FDA division that originally approved the drug, along
with the pharmaceutical company that makes the drug, did most of the
talking.
A documentary crew from the PBS series Frontline filmed the meeting and
afterward, in the hallway, caught up with David Graham, a senior
epidemiologist with the Office of Drug Safety. The producers had been denied
previous requests to interview Graham, but the government scientist gave a
brief interview without permission.
"We had a different perspective, and we really weren't given an opportunity
to present our side of the story," Graham, on camera, told the producers.
"And the people who did present, the reviewing division and the company, you
know, they didn't see a problem. This was a very hostile process. And let's
just leave it at that."
Paul Stolley, a professor and former chairman of the department of
epidemiology at the University of Maryland, spent a sabbatical year as a
senior consultant in the Office of Drug Safety in 2000 and 2001. While
there, he recalls, he tussled with agency managers over the safety of
Lotronex, a drug used to treat irritable bowel syndrome, a chronic but
usually not serious disease.
Stolley said his investigation uncovered high rates of negative side
effects, including a number of deaths, among patients using the drug and led
the company to withdraw the drug from the market.
A few months later, over Stolley's objections, the agency allowed the drug
back on the market with a "risk management" program aimed at educating
patients and doctors about the drug's risks. Stolley said he was excluded
from internal FDA meetings on the issue.
"I'm worried about the agency," he says. "I didn't expect people to think I
was right just because I was very senior. What I did expect was a vigorous
debate and instead of having a vigorous debate, they made a policy decision
and then excluded me."
Rob Waters' article, "A Suicide Side Effect? What parents aren't being told
about their kids' antidepressants," appeared in the Jan. 4 edition of The
Chronicle Magazine. E-mail him at robw001@pacbell.net.
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