The Ball is in their court–Is FDA preparing to drop it?

On Thursday, FDA’s Psychopharmacology Advisory Committee voted 12 to 1 to
reject approval of the drug modafinil as a treatment for ADHD in children.
FDA safety officers had similarly recommended rejection because of a link to
Stevens-Johnson Syndrome, a potentially fatal skin disease that usually
results from a drug reaction. However, FDA administrators had pushed for its
approval.

The following seemingly contradictory news reports reflect the pediatric committee’s mixed
message:
 
The New York Times: "Stimulants like Ritalin lead a small number of children
to suffer hallucinations that usually feature insects, snakes or worms,
according to federal drug officials, and a panel of experts said on
Wednesday that physicians and parents needed to be warned of the risk. The
panel members said they hoped the warning would prevent physicians from
prescribing a second drug to treat the hallucinations caused by the
stimulants, which one expert estimated affect 2 to 5 of every 100 children
taking them.” 
http://www.nytimes.com/2006/03/23/health/23fda.html?ei=5094&en=e18b3ebe56dce
6bf&hp=&ex=1143090000&partner=homepage&pagewanted=print

The Associated Press:  "A federal advisory panel on Wednesday rejected
recommending that popular drugs used to treat attention deficit
hyperactivity disorder should bear the strongest type of warning of the
potential cardiovascular and psychiatric risks they pose. The consensus move
by the Food and Drug Administration’s pediatric advisory committee leaves in
doubt whether the agency will require the so-called "black-box" labels on
the drugs, which include Ritalin. The panel, in simply recommending
easier-to-understand language on the labels, broke with another committee
that had recommended last month that the drugs include the more dire
warnings. The pediatric advisory committee, without voting, did recommend
adding more information to the labels for the benefit of doctors, patients
and parents."

FDA’s review of adverse effects of psychostimulant drugs and Strattera
(which is technically in the antidepressant class), shows that 2-5 children
out of every 100 treated with these drugs are at risk of becoming psychotic
with hallucinations. Hallucinations are  traumatic destabilizing symptoms of
severe pathology. No one knows what lasting  psychiatric risks such
experiences in young children may bode. These psychiatric risks are
compounded by cardiovascular risks.  In addition, the ADHD drugs are also
associated with violence towards self and others, including suicidal
behavior, violence, and serious cardiovascular risks.

The discussion focused on selected drugs and selected risks.  FDA safety
officers presented incontrovertible evidence of the drugs inducing psychosis
in children:

"A substantial proportion of psychosis-related cases were reported to occur
in children age ten years or less, a population in which hallucinations are
not common.
The occurrence of such symptoms in young children may be
particularly traumatic and undesirable, both to the child and the parents.
The predominance in young children of hallucinations, both visual and
tactile, involving insects, snakes and worms is striking, and deserves
further evaluation. Positive rechallenge (i.e., recurrence of symptoms when
drug is re-introduced) is considered a hallmark for causality assessment of
adverse events. Cases of psychosis related events which included a positive
rechallenge were identified in this review for each of the drugs included in
this analysis."
See: http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210B-Index.htm

The federal standards that guide the FDA actions are as follows:

FDA’s standard for warning labels: “The labeling shall be revised to include
a warning as soon as there is reasonable evidence of an association of a
serious hazard with a drug; a causal relationship need not have been
proved.” 21 C.F.R. § 201.57(e)

FDA’s standard for Black Box warning: “Special problems, particularly those
that may lead to death or serious injury, may be required by the Food and
Drug Administration to be placed in a prominently displayed box. The boxed
warning ordinarily shall be based on clinical data, but serious animal
toxicity may also be the basis of a boxed warning in the absence of clinical
data.” 21 C.F.R. § 201.57(e)
 
In 2004, when an FDa analysis revealed that antidepressants caused rather
than prevented suicidal behaviors, the APA proclaimed that putting Black Box
warnings on the drugs would induce a public health crisis:

“We restate our continued deep concern that a “black box” warning on may
have a chilling effect on appropriate prescribing for patients. This would
put seriously ill patients at grave risk.” (APA News Release, 2004)

AHRP challenges the APA to show evidence that any child suffered harm when
parents made an informed decision against exposing their child to
antidepressants—based on the information contained in these drugs’ Black Box
label warnings

On Wednesday, the APA and the other stakeholders repeated the familiar
chicken little refrain: “We urge the FDA to avoid the use of black box
warnings…[it] is we believe, premature and may lead to needless public alarm
that will discourage those who benefit from these medications from taking
them.”   

In 2004, two combined FDA advisory committees rejected the self-serving
arguments of the APA and the other drug promoters whose claims rested on an
appeal to their own presumed “authority.”  By contrast, Wednesday’s
committee hearing gave one the sense of a "show trial"—as if the outcome had
been pre-determined in support of an agenda. That agenda was to facilitate
industry’s marketing goals no matter what the validated evidence shows.

“We know that appropriate intervention for ADHD actually saves lives.
Specifically, treatment reduces the risk of serious accidents, including
accidents which lead to head injury and permanent disability.” (David
Fassler, MD, APA Trustee-at large)

Dr. Fassler cannot provide evidence to support that claim. 
To do so would require scientific studies showing that
(1) ADHD increases the risk of death, and
(2) ADHD drugs prevent the risk of death.
There is no such evidence.

Instead, the evidence contradicts his claims.  The Pediatric Advisory
Committee shut its eyes and ears to documented scientific evidence
contradicting such unsupported claims. A 2005 Meta-Analysis of ALL (2,287)
ADHD studies worldwide found:  no evidence demonstrating clinical efficacy;
no evidence that drugs improve academic performance, risky behaviors, social
achievements or other measures; and no evidence on long-term safety of the
drugs.  See:
http://www.ohsu.edu/drugeffectiveness/reports/documents/ADHD%20Final%20Repor
t.pdf 

See also, Are ADHD drugs safe? Report finds little proof, News Tribune: http://www.ahrp.org/infomail/05/09/13a.php

Underscoring the Committee’s blind acceptance of arguments that appeal to
“authority” (i.e., “we know…” ), the committee chairman, Dr. Robert Nelson, ignored
the Oregon Meta analysis, ignored the FDA review, and echoed instead, APA’s
unsubstantiated claims: "You have overwhelming evidence of efficacy with two
rare adverse events … A black box would scare many patients away from
treatment." (Reuters News/ ABCNews:http://abcnews.go.com/Health/wireStory?id=1757521 )

No one can argue—indeed, even FDA officials agree that documented evidence
shows that some children prescribed ADHD drugs have been harmed. If parents
are warned about the nature of the potential drug-induced harms, some may
decide to forgo drugs and try alternative interventions. What possible good
can come from keeping parents uninformed about evidence of a 2% to 5% risk
of psychosis for children taking psychostimulant drugs?

The committee’s reluctance to recommend strong warnings about
life-threatening risks presumes, without evidence, that reduced prescribing
of psychotropic drugs will “put seriously ill patients at grave risk.”   But
the evidence shows that clinical benefits are uncertain, while serious risks
to children are inevitable.

The Pediatric Advisory Committee served industry’s interests while ignoring
the nature and magnitude of the alarming risks for children. The same agenda
is also reflected in FDA’s acceptance of "evidence" of a drug’s safety from
clinical trials not designed to detect a psychoactive drug’s adverse
effects, from trials not lasting long enough to detect hazards that do not
emerge immediately.  

One probing question (by panel member, Dr. Thomas Newman, at the end of a sponsor’s
presentation  in which the magnitude of risk was trivialized) addressed the
time frame in which adverse effects were reported:  Company representatives
acknowledged that the safety data reported to the FDA had been obtained from a clinical trial
in which 300 children were exposed to the drug for only TWO WEEKS.

The drug is being prescribed daily for long-term
use…This invalid standard of drug safety makes a mockery of the drug
approval process, raising doubt about the credibility of an FDA seal of
approval.
 
See: AHRP recommendations for action needed to protect children from
widespread prescribing of psychoactive drugs for ill-defined behavioral
symptoms.  Action is also needed to protect the safety of their school mates
who are also at risk of drug-induced violence.
http://www.ahrp.org/cms/content/view/113/28/ 
 
* The FDA has not even analyzed the high incidence of severe drug-induced
adverse effects associated with antipsychotics.  Though these drugs have not
been approved for use in children, the prescribing rate for children aged
2-18 increased fivefold between 1995-2002. More than 2.5 million children
were prescribed antipsychotics in 2002–50% of the time for ADHD.

Contact: Vera Hassner Sharav
veracare@ahrp.org
 
 
http://www.nytimes.com/2006/03/23/health/23fda.html?ei=5094&en=e18b3ebe56dce
6bf&hp=&ex=1143090000&partner=homepage&pagewanted=print
THE NEW YORK TIMES
March 23, 2006
Panel Advises Disclosure of Drugs’ Psychotic Effects
By GARDINER HARRIS

GAITHERSBURG, Md., March 22 —
Stimulants like Ritalin lead a small number of children to suffer
hallucinations that usually feature insects, snakes or worms, according to
federal drug officials, and a panel of experts said on Wednesday that
physicians and parents needed to be warned of the risk.

The panel members said they hoped the warning would prevent physicians from
prescribing a second drug to treat the hallucinations caused by the
stimulants, which one expert estimated affect 2 to 5 of every 100 children
taking them. Instead, they said, the right thing to do in such cases was to
stop prescribing the stimulants.

On Feb. 9, a different advisory committee voted 8 to 7 to recommend that the
Food and Drug Administration place its most serious warning label, a
so-called black box, on the labels of stimulants to warn that they could
have dangerous effects on the heart, particularly in adults. That
recommendation grew out of reports that 25 people, mostly children, had died
suddenly while taking the drugs.

The twin conclusions come more than 50 years after Ritalin was first
approved to treat attention deficit disorder and hyperactivity. Since then,
stimulants have become among the most widely prescribed medicines in the
world. In the United States alone, about 2.5 million children and 1.5
million adults take them; as many as 10 percent of boys ages 10 to 12 do. In
addition to Ritalin, two other stimulants, Adderall and Concerta, are
popular.

The drugs have been studied in hundreds of trials over five decades and have
proven to be extremely effective. But they have always been controversial,
with some experts saying they are overprescribed. It is a measure of the
difficulty of uncovering the physiological effects of medicines that experts
are only now grappling with some of the drugs’ serious, though rare,
physical and mental effects.

Dr. Thomas B. Newman, an epidemiologist at the University of California, San
Francisco, who is a member of the pediatric advisory committee, estimated
that out of 100 patients treated for a year with stimulants, 2 to 5 will
suffer serious psychotic episodes like hallucinations.
"It’s a small number, but it’s real," said Dr. Robert M. Nelson, an
intensive-care physician at Children’s Hospital of Philadelphia and chairman
of the committee.

Dr. Kate Gelperin, an F.D.A. drug-safety specialist, told the committee that
the agency had discovered a surprising number of cases in which young
children given stimulants suffered hallucinations. Most said that they saw
or felt insects, snakes or worms, Dr. Gelperin said.

Dr. Gelperin described the case of a 12-year-old girl who said that insects
were crawling under her skin. Another child was found by his parents
crawling on the ground and complaining that he was surrounded by
cockroaches. In both cases, the hallucinations disappeared after drug
therapy was stopped. The boy’s doctor persuaded his parents to give him
stimulants again, and his hallucinations reappeared.

F.D.A. officials made clear to the advisory panel that they considered the
reports of hallucinations a problem that deserved a label warning.
"We were struck by the hallucinations," said Dr. Rosemary Johann-Liang,
deputy director of the division of drug-risk evaluation at the F.D.A. "We
felt it was a drug effect."

The agency does not have to follow the conclusions of its advisory panels,
but it usually does. Dr. Robert Temple, director of the Office of Medical
Policy at the agency, said after the meeting that the agency would "turn
quite quickly to implementing the recommendations we’ve gotten."
Dr. Temple added, "The area of uncertainty is what to do about the black-box
warning on cardiovascular risks in adults."

After the advisory committee meeting in February, agency officials said they
had no intention in the near future of placing such warnings on stimulant
labels about their potential heart risks.

Wednesday’s panel, made up mostly of experts in pediatric medicine and
psychiatry, discussed only the potential risks of the drugs among children,
while February’s group focused mostly on the risks to adults. The pediatric
panel agreed with the earlier group that children who have heart problems
should probably not be given stimulants. But most children who die suddenly
from heart ailments never knew they were at risk, and most children put on
stimulant therapy are not given thorough heart evaluations.

"You can’t screen 2.5 million children" with intensive heart evaluation
tests, Dr. Nelson said.  Copyright 2006The New York Times Company

~~~~~~~~~~~~~~~~~
ASSOCIATED PRESS
 By ANDREW BRIDGES,
Wed Mar 22, 6:59 PM ET

A federal advisory panel on Wednesday rejected recommending that popular
drugs used to treat attention deficit hyperactivity disorder should bear the
strongest type of warning of the potential cardiovascular and psychiatric
risks they pose.

The consensus move by the Food and Drug Administration’s pediatric advisory
committee leaves in doubt whether the agency will require the so-called
"black-box" labels on the drugs, which include Ritalin. The panel, in simply
recommending easier-to-understand language on the labels, broke with another
committee that had recommended last month that the drugs include the more
dire warnings.

The pediatric advisory committee, without voting, did recommend adding more
information to the labels for the benefit of doctors, patients and parents.
"I wouldn’t use the word ‘tougher,’ said panel chair Dr. Robert Nelson.
"’Clearer.’"
The agency isn’t required to follow the advice of its advisory committees,
but usually does.

Nearly 3.3 million Americans age 19 and younger used an ADHD drug last year,
according to Medco Health Solutions Inc., a prescription drug benefit
program manager.
Psychiatrists and others had urged the committee to move cautiously before
recommending strengthened warnings of heart attacks, hallucinations and
other potential risks associated with the drugs.

In February, the FDA’s Drug Safety and Risk Management advisory committee
voted to recommend the agency add the strongest possible warning to some of
the drugs, in that case to alert doctors, patients and parents of the
uncertainty regarding the risk they may pose to the cardiovascular system.
The FDA then asked the pediatric panel to examine that same issue, as well
as reports that psychosis or mania can occur in some juvenile patients at
normal doses of any ADHD drug.

Adding black-box warnings to some or all the drugs, which also include
Adderall and Strattera, could cause more harm than good, some experts told
the panel prior to the vote.  "I suggest confusion, polarizing viewpoints,
initial press hysteria. But then what?" asked Julie Zito, a University of
Maryland associate professor in pharmacy and psychiatry.

The FDA has struggled since last year with the question of how to
communicate the potential risks associated with ADHD drugs. Psychiatrists
and mental health advocates said leaving the disease untreated could rival
the risks the drugs may pose.
"It is important to not let the discussion of ADHD medications overshadow
the public health crisis of untreated mental health disorders in children,"
said Cynthia Wainscott of the National Mental Health Association. Her
16-year-old granddaughter has ADHD.

Ritalin is manufactured by Novartis Pharmaceuticals Corp. and in generic
form by other companies; Adderall is made by Shire Pharmaceuticals Inc.; and
Strattera, which is produced by Eli Lilly and Co.

FDA officials say patients and doctors should be aware that the small number
of reported psychiatric events could represent side effects of the drugs,
although they cannot point to a definitive link. However, they noted a
"complete absence" of similar reports in children treated with dummy pills
during dozens of clinical trials of the drugs. In many children, the events
ceased once they stopped taking the drugs — and resumed in some once they
restarted. "That’s unlikely to be due to random chance, suggesting some
effect of the drugs," said Dr. Andrew Mosholder, of the FDA’s division of
drug risk evaluation.

McNeil Consumer & Specialty Pharmaceuticals said in briefing documents that
it is customary to weigh the "therapeutic benefits and potential risks" of
treatment. The unit of Johnson & Johnson makes Concerta, a long-acting form
of methylphenidate, the drug in Ritalin. Novartis believes current Ritalin
labels are adequate, company medical safety director Dr. Todd Gruber said.

Jacqueline Bessner of Ishpeming, Mich., said her daughter, Leanne, 15,
hanged herself last year two months after starting treatment with Concerta.
Bessner said more black-box warnings would be useless without increased
counseling and monitoring of patients.
"It’s being handed out like it’s candy," Bessner said of ADHD drugs. "It’s
too easily accessible."

A different FDA panel planned to consider on Thursday an application by
Cephalon Inc. to sell its sleep-disorder drug Provigil, or modafinil, as an
ADHD treatment for children.
The FDA wants members of its psychopharmalogic drugs advisory committee to
examine that request, including whether serious skin rashes seen in children
treated with modafinil should merit special warnings, follow-up studies and
steps to limit the risk.

Copyright © 2006 Yahoo! Inc. All rights reserved.

http://abcnews.go.com/Health/wireStory?id=1757521
ABC News
Mar 22, 2006 — GAITHERSBURG, Maryland (Reuters) – U.S. advisers on Wednesday
called for new information about health risks on the labels of attention
deficit drugs, but stopped short of recommending the strongest possible
warning saying they did not want to frighten patients.
The panel of pediatric experts reviewed reports of heart problems and
psychotic behavior such as hallucinations in children who took the
medicines, which include Novartis AG’s Ritalin and Shire Plc’s Adderall.

Patients and parents should know about the reports even though it is unclear
if the drugs contributed to the problems, panel members said. They stopped
short of recommending the strong "black box" warning that a different
advisory panel supported last month.

"You have overwhelming evidence of efficacy with two rare adverse events … A
black box would scare many patients away from treatment," panel chairman Dr.
Robert Nelson, the panel’s chairman.

Xxxxx cut xxxxx Copyright 2006 Reuters News Service.

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