Pfizer Dodges Fraud Prosecution AGAIN By Paying Over $1 Billion Fine

Pfizer Dodges Fraud Prosecution AGAIN By Paying HUGE Government

Fine

If it were you or I or your neighbor down the street you can
bet that NO presecutor on the planet would “look the other way” to avoid
prosecution. But, when it involves the lergest drug company on the planet they
seem to be able to do just that and do it VERY WELL!!!
So, before going into the amazing facts in this most recent
case let me give you a reminder of the last big case involving a large fine for
off label marketing with Pfizer‘s Neurontin. After learning that Pfizer sales
reps had been drastically increasing profits by pushing Neurontin for off label
uses for several years felony charges were filed against the company for
doing so. (Keep in mind that this drug now carries warnings of increases in
suicide.) In 2004 they plead guilty to two felonies and agreed to pay $430
Million in fines as well. See the first article below as a quick
overview.
Now they have a whole new twist when it comes to approaching
similar charges with the off label prescribing of Bextra (Pfizer‘s version of
Vioxx) which was pulled from the market just the following year after pleading
guilty to the two felonies in the Neurontin case and paying the largest fine
ever for such a practice. Pfizer acquired a smaller drug company
called Pharmacia and they wanted to market Bextra for surgical pain.
When the FDA put their foot down and clearly said, “NO because of safety
issues,” Pfizer and Pharmacia went right ahead with their marketing campaign. So
when caught red handed in doing this, the prosecutor decides that Pharmacia can
plead guilty so that Pfizer is off the hook because it would have put them out
of business!!!!!

I quote from the article below: “So Pfizer and the feds cut a deal. Instead
of charging Pfizer with a crime, prosecutors would charge a Pfizer subsidiary,
Pharmacia & Upjohn Co. Inc.

“The CNN Special Investigation found that the subsidiary is nothing more than
a shell company whose only function is to plead guilty.”

As it turned out ONE HALF of their $1.7 Billion in profits on Bextra came
from off label prescribing and the government fine for that will be
the biggest ever once again. This time the figure is $1.2 Billion plus an
additional $1 Billion to settle a batch of civil suits (how many deaths those
involved is not mentioned) and denied wrongdoing in another dozen
similar charges involving illegal promotions!

“It paid nearly $1.2 billion in a criminal fine for Bextra, the largest fine
the federal government has ever collected.

“It paid a billion dollars more to settle a batch of civil suits — although
it denied wrongdoing — on allegations that it illegally promoted 12 other
drugs.”

This begins to make one wonder just how far we will get with changes in
government policy when they have learned how to extract such large sums of money
from these drug companies in the way of fines. Why are those fines not
distributed to those who were damaged by the off label prescribing?

Ann Blake-Tracy, Executive Director
International Coalition for Drug Awareness
Author: Prozac: Panacea or Pandora? – Our Serotonin
Nightmare & Help! I Can’t Get Off My
Antidepresant!

http://articles.sfgate.com/2004-05-14/business/17426572_1_neurontin-pfizer-fda

Huge penalty in drug fraud / Pfizer settles felony case in Neurontin
off-label promotion

May
14, 2004
|By Bernadette Tansey,
Chronicle Staff Writer

A division of Pfizer Inc., the world’s largest drugmaker, has agreed to plead
guilty to two felonies and pay $430 million in penalties to settle charges that
it fraudulently promoted the drug Neurontin for a string of unapproved uses.

In an agreement announced by government prosecutors Thursday, Pfizer unit
Warner-Lambert admitted that it aggressively marketed the epilepsy drug by

illicit means for unrelated conditions including bipolar disorder, pain,
migraine headaches, and drug and alcohol withdrawal.

A company whistle-blower, whose 1996 civil suit spurred
government investigations of Neurontin’s marketing campaign, will receive about
$26.6 million through the settlement under legal provisions that reward citizens
for helping to recover government money obtained by fraud.

The settlement includes $152 million to pay back amounts spent on Neurontin
by the federal Medicare program and 50 state Medicaid programs for the poor. In
addition, Pfizer will pay a $240 million criminal fine, the second-largest such

fine ever imposed in a health care fraud prosecution, the Department of Justice
said.

Prosecutors said Warner-Lambert turned Neurontin into a blockbuster drug with
tactics like paying doctors to listen to pitches for unapproved uses and
treating them to luxury trips to Hawaii, Florida or the 1996 Olympics in
Atlanta. One doctor received almost $308,000 to tout Neurontin at conferences.

“This illegal and fraudulent promotion scheme corrupted the information
process relied on by doctors in their medical decision making, thereby putting
patients at risk,” said U.S. Attorney Michael Sullivan, chief prosecutor for the
federal district based in Boston.

Doctors are free to prescribe drugs for uses not specified on their FDA-
approved labels, but the FDA forbids drug companies from promoting them for
those off-label uses. Prosecutors said Neurontin’s manufacturers decided not to
seek an expanded FDA label for the drug, an expensive process requiring solid
proof from clinical trials. Instead, the company boosted sales through
aggressive promotional strategies, even when scientific studies had demonstrated
that it was not effective, the Justice Department said.

The tactics included planting company operatives in the audience at medical
education events to contradict unfavorable comments about Neurontin, and paying
doctors to allow sales representatives to sit in on patient visits, prosecutors
said.

Feds found Pfizer too big to nail

Submitted by Drew Kaplan on April 22, 2010 – 11:39 amOne Comment

Imagine being charged with a crime, but an imaginary friend takes the rap for
you. That is essentially what happened when Pfizer, the world’s largest
pharmaceutical company, was caught illegally marketing Bextra, a painkiller that
was taken off the market in 2005 because of safety concerns. When the criminal case was announced last fall, federal
officials touted their prosecution as a model for tough, effective enforcement.
“It sends a clear message” to the pharmaceutical industry, said Kevin Perkins,
assistant director of the FBI’s Criminal Investigative Division.

But beyond the fanfare, a CNN Special Investigation found another story, one
that officials downplayed when they declared victory. It’s a story about the
power major pharmaceutical companies have even when they break the laws intended
to protect patients.

Big plans for Bextra

The story begins in 2001, when Bextra was about to hit the market. The drug
was part of a revolutionary class of painkillers known as Cox-2 inhibitors that
were supposed to be safer than generic drugs, but at 20 times the price of
ibuprofen.

Pfizer and its marketing partner, Pharmacia, planned to sell Bextra as a
treatment for acute pain, the kind you have after surgery.

But in November 2001, the U.S. Food and Drug Administration said Bextra was
not safe for patients at high risk of heart attacks and strokes.

The FDA approved Bextra only for arthritis and menstrual cramps. It rejected
the drug in higher doses for acute, surgical pain.

Promoting drugs for unapproved uses can put patients at risk by circumventing
the FDA’s judgment over which products are safe and effective. For that reason,
“off-label” promotion is against the law.

If we prosecute Pfizer … a lot of the people who work for the company who
haven’t engaged in criminal activity would get hurt.

–Mike Loucks, federal prosecutor But with billions of dollars of profits at
stake, marketing and sales managers across the country nonetheless targeted
anesthesiologists, foot surgeons, orthopedic surgeons and oral surgeons. “Anyone
that use[d] a scalpel for a living,” one district manager advised in a document
prosecutors would later cite.

A manager in Florida e-mailed his sales reps a scripted sales pitch that
claimed — falsely — that the FDA had given Bextra “a clean bill of health” all
the way up to a 40 mg dose, which is twice what the FDA actually said was
safe.

Doctors as pitchmen

Internal company documents show that Pfizer and Pharmacia (which Pfizer later
bought) used a multimillion-dollar medical education budget to pay hundreds of
doctors as speakers and consultants to tout Bextra.

Pfizer said in court that “the company’s intent was pure”: to foster a legal
exchange of scientific information among doctors.

But an internal marketing plan called for training physicians “to serve as
public relations spokespeople.”

According to Lewis Morris, chief counsel to the inspector general at the U.S.
Department of Health and Human Services, “They pushed the envelope so far past
any reasonable interpretation of the law that it’s simply outrageous.”

Pfizer’s chief compliance officer, Doug Lanker, said that “in a large sales
force, successful sales techniques spread quickly,” but that top Pfizer
executives were not aware of the “significant mis-promotion issue with Bextra”
until federal prosecutors began to show them the evidence.

By April 2005, when Bextra was taken off the market, more than half of its

$1.7 billion in profits had come from prescriptions written for uses the FDA had
rejected.

Too big to nail

But when it came to prosecuting Pfizer for its fraudulent marketing, the
pharmaceutical giant had a trump card: Just as the giant banks on Wall Street
were deemed too big to fail, Pfizer was considered too big to nail.

Why? Because any company convicted of a major health care fraud is
automatically excluded from Medicare and Medicaid. Convicting Pfizer on Bextra
would prevent the company from billing federal health programs for any of its
products. It would be a corporate death sentence.

Prosecutors said that excluding Pfizer would most likely lead to Pfizer’s
collapse, with collateral consequences: disrupting the flow of Pfizer products
to Medicare and Medicaid recipients, causing the loss of jobs including those of
Pfizer employees who were not involved in the fraud, and causing significant
losses for Pfizer shareholders.

“We have to ask whether by excluding the company [from Medicare and
Medicaid], are we harming our patients,” said Lewis Morris of the Department of
Health and Human Services.

So Pfizer and the feds cut a deal. Instead of charging Pfizer with a crime,
prosecutors would charge a Pfizer subsidiary, Pharmacia & Upjohn Co.
Inc.

The CNN Special Investigation found that the subsidiary is nothing more than
a shell company whose only function is to plead guilty.

According to court documents, Pfizer Inc. owns (a) Pharmacia Corp., which
owns (b) Pharmacia & Upjohn LLC, which owns (c) Pharmacia & Upjohn Co.
LLC, which in turn owns (d) Pharmacia & Upjohn Co. Inc. It is the
great-great-grandson of the parent company.

Public records show that the subsidiary was incorporated in Delaware on March
27, 2007, the same day Pfizer lawyers and federal prosecutors agreed that the
company would plead guilty in a kickback case against a company Pfizer had
acquired a few years earlier.

As a result, Pharmacia & Upjohn Co. Inc., the subsidiary, was excluded
from Medicare without ever having sold so much as a single pill. And Pfizer was
free to sell its products to federally funded health programs.

An imaginary friend

I can tell you, unequivocally, that Pfizer perceived the Bextra matter as an
incredibly serious one.

Two years later, with Bextra, the shell company once again pleaded guilty. It
was, in effect, Pfizer’s imaginary friend stepping up to take the rap.

“It is true that if a company is created to take a criminal plea, but it’s
just a shell, the impact of an exclusion is minimal or nonexistent,” Morris
said.

Prosecutors say there was no viable alternative.

“If we prosecute Pfizer, they get excluded,” said Mike Loucks, the federal
prosecutor who oversaw the investigation. “A lot of the people who work for the
company who haven’t engaged in criminal activity would get hurt.”

Did the punishment fit the crime? Pfizer says yes.

It paid nearly $1.2 billion in a criminal fine for Bextra, the largest fine

the federal government has ever collected.

It paid a billion dollars more to settle a batch of civil suits — although it
denied wrongdoing — on allegations that it illegally promoted 12 other
drugs.

In all, Pfizer lost the equivalent of three months’ profit.

It maintained its ability to do business with the federal government.

Pfizer says it takes responsibility for the illegal promotion of Bextra. “I
can tell you, unequivocally, that Pfizer perceived the Bextra matter as an
incredibly serious one,” said Doug Lankler, Pfizer’s chief compliance
officer.

To prevent it from happening again, Pfizer has set up what it calls
“leading-edge” systems to spot signs of illegal promotion by closely monitoring
sales reps and tracking prescription sales.

It’s not entirely voluntary. Pfizer had to sign a corporate integrity
agreement with the Department of Health and Human Services. For the next five
years, it requires Pfizer to disclose future payments to doctors and top
executives to sign off personally that the company is obeying the law.

Pfizer says the company has learned its lesson.

But after years of overseeing similar cases against other major drug
companies, even Loucks, isn’t sure $2 billion in penalties is a deterrent when
the profits from illegal promotion can be so large.

“I worry that the money is so great,” he said, that dealing with the
Department of Justice may be “just of a cost of doing business.”

http://www.cnn.com/2010/HEALTH/04/02/pfizer.bextra/index.html?hpt=T2

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Sen. Grassley: Drug Companies “Bamboozled the FDA” on SSRI Antidepressants

Mon Nov 10, 2008

The following information should go out to every reporter and every other
human on the planet. Please. Please. Please help us get this information out to
as many as possible as a warning. [BUT in doing so always remember to warn
of the extreme potential danger of abrupt withdrawal with the FDA warning that
such can cause suicide, hostility or psychosis.

Please give them our 800 order line or website to download or order my CD, “Help! I Can’t Get Off My
Antidepressant!” so that they will have the formula for safe and almost
painless withdrawal and methods of recovery from the damage they have suffered.]
Now if you have read my book most of this will sound all too familiar and
old. But now the cold hard facts are coming out to the public with Iowa’s own
Senator Grassley leading the way because these drugs grabbed his attention
after overseeing many of the hearings on children and antidepressants. THANK
YOU

SENATOR GRASSLEY FOR YOUR EFFORTS!!!
Some of the most important points in the article to file in your memory
banks and repeat as often as possible to as many as possible are as follows:

#1 US HIGHEST USER OF ANTIDEPRESSANTS & ANTIDEPRESSANTS ARE AMERICA’S
MOST WIDELY PRESCRIBED DRUGS:

“Antidepressant prescribing is more rampant in this country than any other.
The US accounted for 66% of the global market in 2005, compared to 23% in
Europe and 11% for the rest of world, according to a December 2006 report by
Research and Markets.
“A June 2007 survey by the Centers for Disease Control of doctor and
hospital visits in 2005 showed that the most commonly prescribed drugs were
antidepressants, with 48% of the prescriptions issued by primary care
physicians. They have remained in the number one position ever since. Last year, 232
million prescriptions were filled for antidepressants worth nearly $12 billion,
according to a March 2008 report by IMS Health. . . .


#2 YET THE MANUFACTURERS KNEW AND HID THE FACT THAT THESE DRUGS INCREASE
THE RISK OF SUICIDE:

“For fifteen years, the SSRI makers fought against adding a warning about an
increased risk of suicidality, knowing all the long that the risk existed.
[We had the data in court cases for years but could not get the press to cover
it.] Now, the companies are making the irresponsible argument (in defense of
lawsuits claiming they failed to warn doctors and the public of the risk)
that the FDA did not require them to add a warning, so they are immune from
liability. . . .

#3 SINCE 1989 THE MANUFACTURER OF PAXIL KNEW THAT THIS DRUG INCREASES SUICIDE ATTEMPTS BY EIGHT TIMES MORE THAN PLACEBO!

“The report shows that Glaxo [makers of Paxil] knew in 1989, long before
Paxil was FDA approved, that people taking the drug were 8 times more likely to
engage in suicidal behavior than people given a placebo, or sugar pill. Now,
it stands to reason that even the most depressed person would decline to take
Paxil if given these facts. Also, parents certainly would decline if they
were told about the risks. . . .

“The FDA approved Paxil on December 29, 1992, with no warning to doctors or
patients of the significant increased risk of suicidal behavior,” he writes.
. . .

#4 SENATOR GRASSLEY FINDS THAT PAXIL MAKER “BAMBOOZLED” THE FDA PUTTING
PATIENT SAFETY AT RISK

“Senator Grassley has also asked the FDA to go back and review the clinical
trial data submitted on Paxil. In a statement on the Senate floor on June 11,
2008, he said: “Essentially, it looks like GlaxoSmithKline bamboozled the
FDA.”
“We cannot live in a nation where drug companies are less than candid, hide
information and attempt to mislead the FDA and the public,” he stated. “These
companies are selling drugs that we put in our bodies, not sneakers.”
“When they manipulate or withhold data to hide or minimize findings about
safety and/or efficacy they put patient safety at risk,” Senator Grassley said.
“And with drugs like Paxil, the risks are too great.”
Now I need to note here that the only reason Paxil is taking so much heat
and the only reason we have all of this inside information on Paxil is because
of the information obtained during the Wyoming murder/suicide case of Donald
Schell. Before that these companies were settling cases so that they did not
have to go to court and disclose all of this information to the attorneys
working in our behalf.
After waiting three long years for one attorney to decide if he would take
the case, it went to Andy Vickery’s office. Andy took the case and Glaxo
allowed it to go all the way into court instead of settling the case. The jury
heard and saw enough to rule that the two pills of Paxil that Donald Schell
took before getting up one morning and shooting his wife, his daughter and his
baby grand daughter before shooting himself was the main cause.
Glaxo did all they could to seal that information back up again, but it was
too late. The cat was out of the bag. And it is long past time to let the cat
out of the bag on all these other antidepressants as well!
#5 THE RESULTS OF SENATOR GRASSLEY’S INVESTIGATION OF THE LARGE PAYMENTS
AND KICKBACKS TO DOCTORS BY DRUG MAKERS

“According to Senator Grassley’s June 4, 2008 statement in the Congressional
record, although conflict-of-interest disclosure forms make it appear that
the Harvard psychiatrists only received a couple hundred thousand from drug
companies over the past 7 years, the true figures show Dr Biederman received
over “$1.6 million,” Dr Spencer “over $1 million” and Dr Wilens “over $1.6
million” in payments from the drug companies.

“Based on reports from just a handful of drug companies,” he states, “we
know that even these millions do not account for all of the money.”
“Senator Grassley also notes that Dr Schatzberg owns stock worth more than
$6 million in one drug company. Ed Silverman reports on Pharmalot that there
are “30 or so physicians at two dozen universities which the Senate Finance
Committee is probing concerning disclosure of grants from drugmakers.” The
names of those 30 doctors, along with the research mills they operate out of,
need to be made public. . . . .


#6 RESEARCH INSTITUTIONS AND ACADEMIA ON THE TAKE FROM DRUG MAKERS AS WELL
ACTING AS “APOLOGISTS FOR COMMERCIAL SCIENTIFIC FRAUD” – SENIOR ACADEMICS
PROSTITUING MEDICINE.

“It is no longer a case where Americans need only be concerned about the
amount of money the academics are pulling in. The pharmaceutical industry also
has a stronghold on most major research institutions in this country. Many
could not exist if the drug companies withdrew all their research funding, a
state of affairs that did not occur by accident.

“In fact, according to Dr Aubrey Blumsohn, who publishes the Scientific
Misconduct Blog, when all is said and done:

“The chief villains remain our academic institutions and medical leadership.
They have colluded with and have acted as apologists for commercial
scientific fraud. They have tolerated the telling of lies by senior academics.
They have encouraged the prostitution of medicine. They have allowed abuse of the
most fundamental safeguards of science. Most importantly, they have set
terrible examples for our students.”

#7 WHO TOOK THE MONEY TO PUSH ANTIDEPRESSANTS TO CHILDREN?

“. . . . While Dr Keller took the lead on pushing Paxil for children and
adolescents, Dr Emslie was the main man on the Prozac trials, and Dr Wagner was
the queen bee on Zoloft studies. The co-authors of papers that appear in the
medical literature encouraging the use of SSRI’s for kids include Drs
Biederman, Schatzberg, Wilens and, of course, Charles Nemeroff.
“Dr Nemeroff was recently forced to resign as chairman of Emory’s psychiatry
department after Senator Grassley’s investigation revealed that he failed to
disclose to his university more than a million dollars in drug industry
income. All total, Nemeroff had earnings of $2.8 million from drug companies
between 2000 and 2007, but failed to report at least $1.2 million. . . . .


#8 YET AMAZINGLY ENOUGH . . . .

“Shrinks on the take are so addicted to industry money that it’s impossible
to embarrass them. Last year, the press ran major stories when this report
came out, highly critical of how much money they were making. This year, the
average amount rose by 25%.

Now for some hard questions. . . .

*** When Glaxo knew in 1989 that Paxil was inducing suicide at a rate EIGHT
TIMES HIGHER than with a placebo and did not warn, is that not at least
negligent homicide?

Or is it not in some way contributing to a premeditated loss of life?

How often do we read in criminal cases where someone has died and someone
else did not assist that person in need but instead allowed the death to happen
and that person has then been prosecuted and given a prison term?

What is the difference here? The only difference I see is that these people
at Glaxo made a lot of money by keeping quiet and allowing these deaths to
continue!!

*** I have been asking this question for a very long time. Why is it okay
for our academic institutions to peddle drugs and use our students as guinea
pigs in studies?

Why is it okay for them to make so much money from drug companies? Much of
their operating expenses come from this drug company blood money.

Why would anyone be surprised, when seeing this close financial situation
with the drug companies and the academic institutions, that so many students
are placed on these same drugs by campus health centers often addicting them to
the drugs for many years to come?

*** How can shrinks be so stupid, or just plain “in your face” with it, as
to take even more money from these companies while they are already in the
process of being investigated for doing so???

Oh, that’s right we already know the answer to that one – they take more of
these mind altering drugs than just about anyone else! The psychiatric nurse
attending my lecture last year estimated that at least 75% of her colleagues
are on these drugs.

And why are they on these drugs? Because the drug reps are telling them all
that they are in a stressful profession and that sooner or later they are
going to be hit by the anxiety or depression that comes with the stress . . .
so they need to start on the drugs now so as to ward off “the pending
inevitable” anxiety or depression.

Of course then we need to ask the question, “How could they have fallen for
that old sales pitch?” That alone makes you wonder about their sanity!

But then you must ask if it is okay for a drug user to then be a drug pusher
even when we are discussing “legal” drugs? Because that is exactly what we
are seeing happen with this situation with antidepressants – doctors on the
drugs pushing them to others – no different than what you see in street drug
use where those hooked on the drugs are the ones pushing them to others. When
you see how similar in action these antidepressants are to LSD or PCP that
whole scenario becomes totally transparent.

Ann Blake-Tracy, Executive Director,
International Coalition for Drug Awareness
_www.drugawareness.org_ (http://www.drugawareness.org/) &
_www.ssristories.org_ (http://www.ssristories.org/)
Author of Prozac: Panacea or Pandora? – Our
Serotonin Nightmare & the audio, Help! I Can’t
Get Off My Antidepressant!!! ()

_atracyphd1@…_ (mailto:atracyphd1@…)

_http://www.scoop.co.nz/stories/HL0811/S00080.htm_
(http://www.scoop.co.nz/stories/HL0811/S00080.htm)

Pharmaceutical Industry Hustlers – Part I
Thursday, 6 November 2008, 1:25 pm
Column: Evelyn Pringle
Pharmaceutical Industry Hustlers – Part I
SSRI Antidepressants Pushers

By _Evelyn Pringle_
(http://www.scoop.co.nz/stories/print.html?path=HL0811/S00080.htm#a)
After twenty long years, it appears that the epidemic in mental disorders in
America might be coming to an end. It won’t happen because of any great
medical breakthrough but rather because the perpetrators of the greatest
healthcare fraud in history are finally being exposed. The demolition of the
giant “psycho-pharmaceutical complex” appears to be on the horizon.
For far too long, the focus has been on the drugmakers only. In recent
months, the spotlight has shown where it belongs – on the highly-paid
opportunists responsible for fueling the epidemic in prescribing of psychiatric drugs by
doctors in every field of medicine and the research institutions that enabled
the process.
The antidepressants known as selective serotonin reuptake inhibitors, or
SSRI’s, such as Prozac, Paxil, Zoloft, Celexa and Lexapro are at the center of
the storm. These drugs have been prescribed to more Americans than any other
class of medications over the past two decades. Cymbalta, Effexor and
Wellbutrin are often referred to as SSRI’s, but they are slightly different
chemically. However, the drugs all carry similar side effects and warnings.
The top sales pitch for SSRI’s has been the “chemical-imbalance-in-the-brain”
myth.

“There is no evidence whatsoever that depression is caused by a
biochemical imbalance,” says Dr Peter Breggin, one of the world’s leading
experts on psychiatric drugs and author of the new book, “Medication Madness.”
People take for granted pronouncements such as, “You have a biochemical
imbalance,” and “mental disorders are like diabetes,” he explains in the book.

“In reality,” Dr Breggin writes, “these are not scientific observations –
they are promotional slogans, so adamantly repeated in the media and by
individual psychiatrists that people assume them to be true.”
“The psycho-pharmaceutical complex fosters these falsehoods in order to
promote the widespread use of their products,” he says. “Reluctant patients by
the millions are pushed into taking drugs by doctors who tell them with no
uncertainty that they need medication.”

“If you have got a biochemical imbalance in your brain,” Dr Breggin advises
in the book, “the odds are overwhelming that your doctor put it there with a
psychiatric drug.”

All Eyes on Glaxo
At the moment, all eyes are on Paxil maker, GlaxoSmithKline (formerly
SmithKline Beecham), due to reports that the company is under investigation by
the US Department of Justice, as well as the Senate Finance Committee, with
Iowa’s Senator Charles Grassley, the ranking Republican on the Committee,
leading the charge.

The report that led to the investigation by Senator Grassley was generated in
litigation and was only recently made public after it was unsealed by the
court. It was submitted by Dr Joseph Glenmullen, a Clinical Instructor in
Psychiatry at Harvard Medical School and author of “The Antidepressant
Solution”

and Prozac Backlash: Overcoming the Dangers of Prozac, Zoloft, Paxil, and
Other Antidepressants with Safe, Effective Alternatives.” He was retained as
an expert by the Los Angeles-based law firm of Baum, Hedlund, Aristei & Goldman.
The litigation involves several Paxil-induced suicide cases, including a 13-year-old child.

The report shows that Glaxo knew in 1989, long before Paxil was FDA approved,
that people taking the drug were 8 times more likely to engage in suicidal
behavior than people given a placebo, or sugar pill. Now, it stands to reason
that even the most depressed person would decline to take Paxil if given
these facts.

Also, parents certainly would decline if they were told about the
risks. Dr Glenmullen explains that, by submitting what he refers to as “bad” Paxil
numbers to the FDA, Glaxo was able to avoid adding a warning about suicide to
the label when the drug was approved. “GlaxoSmithKline’s ‘bad’ Paxil numbers
carried the day: The FDA approved Paxil on December 29, 1992, with no warning
to doctors or patients of the significant increased risk of suicidal behavior,” he writes.

Instead, Glaxo listed suicide and suicide attempts that took place during the
“run-in” period of the studies as if they happened in the placebo group. The
run-in period, also called the “wash-out” phase, occurs when all patients
are taken off their existing drugs to let the old drugs wash out of their
systems, and all patients are given placebos. The rationale for washing out old
drugs is to prevent them from confusing the results of the study, so that
patients start out in a similar condition, according to the report.
The official trial only begins after the wash-out phase, once the patients
are assigned to receive either the antidepressant or a placebo. The patients
who continue to receive the placebo are referred to as the placebo group.

“Confusing the pre-study placebo wash-out phase with the placebo group in the
actual study is improper,” Dr Glenmullen writes, “especially when the
concern is a potentially lethal side effect.”

The “correct data shows that suicide attempts in patients on Paxil occurred
at a rate eight times higher than the rate in patients on placebo,” he notes.
Senator Grassley has also asked the FDA to go back and review the clinical
trial data submitted on Paxil. In a statement on the Senate floor on June 11,
2008, he said: “Essentially, it looks like GlaxoSmithKline bamboozled the
FDA.”

“We cannot live in a nation where drug companies are less than candid, hide
information and attempt to mislead the FDA and the public,” he stated. “These
companies are selling drugs that we put in our bodies, not sneakers.”
“When they manipulate or withhold data to hide or minimize findings about
safety and/or efficacy they put patient safety at risk,” Senator Grassley said.
“And with drugs like Paxil, the risks are too great.”

A good start as the Glaxo scandal unravels, the public will learn that other
antidepressant makers such as Eli Lilly, Pfizer, Wyeth and Forest Laboratories
are equally guilty. Likewise, there are many more supposedly independent academic
doctors who have been receiving substantial financial benefits from drug
companies than are currently identified in the media as being under investigation.

Exposing Harvard University’s Joseph Biederman, Thomas Spencer, Timothy
Wilens, Stanford’s Alan Schatzberg, Brown University’s Martin Keller, Melissa
DelBello at the University of Cincinnati, and Drs Karen Wagner and John Rush,
who operated out of the University of Texas, might be a good place to start, but
the trail of Big Pharma’s funding academic research for marketing
purposes certainly does not end with a handful of psychiatrists.

According to Senator Grassley’s June 4, 2008 statement in the Congressional
record, although conflict-of-interest disclosure forms make it appear that the
Harvard psychiatrists only received a couple hundred thousand from drug
companies over the past 7 years, the true figures show Dr Biederman received
over “$1.6 million,” Dr Spencer “over $1 million” and Dr Wilens “over $1.6
million” in payments from the drug companies.

“Based on reports from just a handful of drug companies,” he states, “we know
that even these millions do not account for all of the money.”
Senator Grassley also notes that Dr Schatzberg owns stock worth more than $6
million in one drug company. Ed Silverman reports on Pharmalot that there are
“30 or so physicians at two dozen universities which the Senate Finance
Committee is probing concerning disclosure of grants from drugmakers.” The names
of those 30 doctors, along with the research mills they operate out of, need
to be made public.

The new book, “Side Effects: A Prosecutor, a Whistleblower, and a
Best-selling Antidepressant on Trial,” by investigative journalist Alison Bass,
provides the inside scoop on the fraudulent SSRI research conducted at Brown
University by Dr Keller.

The book also supplies background information on the financial ties between
the so-called “opinion leaders” in psychiatry and the other antidepressant
makers. For instance, Ms Bass explains that Drs Schatzberg and Keller worked as
a team a decade ago to promote Bristol-Myers Squibb’s antidepressant Serzone.

In 1998, Dr Schatzberg was paid to moderate an industry-sponsored symposium
that touted the benefits of Serzone, and Dr Keller was one of the paid
speakers at the event. The same year, Dr Keller received $77,400 in consulting
fees from Bristol-Myers, Ms Bass points out.

Dr Keller later published a study in the New England Journal of Medicine also
touting the benefits of Serzone. The drug was removed from the market in
2004 after it was found to cause liver damage but not before a number of
patients died.

Ms Bass reports that Keller did not report any income from Glaxo on his 1998
tax return. But during her research for “Side Effects,” she discovered he had
earned personal income from Glaxo in 1998, as well as subsequent years.
Keller admitted as much during a September 2006 deposition for a lawsuit filed
against Glaxo, she says.

It is no longer a case where Americans need only be concerned about the
amount of money the academics are pulling in. The pharmaceutical industry also
has a stronghold on most major research institutions in this country. Many could
not exist if the drug companies withdrew all their research funding, a state
of affairs that did not occur by accident.

In fact, according to Dr Aubrey Blumsohn, who publishes the Scientific
Misconduct Blog, when all is said and done:

“The chief villains remain our academic institutions and medical leadership.
They have colluded with and have acted as apologists for commercial
scientific fraud. They have tolerated the telling of lies by senior academics.
They have encouraged the prostitution of medicine. They have allowed abuse of the
most fundamental safeguards of science. Most importantly, they have set
terrible examples for our students.”


U
niversities keep corrupt academics on board for good reason. “Side Effects”
reports that, between 1990 and 1998, “Martin Keller brought in nearly $8.7
million in research funding from pharmaceutical companies.”
The clinical trial industry itself provides a perfect slush fund. Spending in
the U.S. was an estimated $25 billion in 2006 and is expected to reach about
$32 billion by 2011.

Most of the money for trials comes from private
industry, and federal funding assumes a second place position, with the
National Institute of Health budgeting $3 billion for clinical trials in 2006, according
to the paper, “State Medical Board Responses To An Inquiry On Physician
Researcher Misconduct,” by Dr Stefan Kruszewski, Dr Richard Paczynski and
Marzana Bialy, in the Journal of Medical Licensure and Discipline 2008: Vol 94 No 1.
Paxil Study 329 “Side Effects” also covers the whole sordid affair on Paxil Study 329, the
most infamous fraudulent pediatric trial of all time. The study “offers a
landmark for the point at which science turned into marketing,” according to Dr
David Healy.

Dr Healy is a Professor of psychiatry and Director of the North Wales School
of Psychological Medicine at the University of Wales, and an outspoken critic
of the psycho-pharmaceutical complex, with 21 books to his name, including
“The Creation of Psychopharmacology.”

He explains that, in 1998, Glaxo’s original assessment of Study 329 had
concluded that it and another study had shown Paxil did not work for children,
but that it would not be “commercially acceptable” to publicize this finding.
“Instead the positive findings from the study would be published; they were in
an article whose authorship line contains some of the best known names in
psychopharmacology (Keller et al., 2001),” Dr Healy writes in the 2007 paper,
“The Engineers of Human Souls & Academia.”

Dr Keller gets most of the credit for the study, which was completed in
the mid-90’s. Keller et al had some difficulty getting it published at first,
but finally found a journal willing to take the bate in 2001, the Journal of
the American Academy of Child and Adolescent Psychiatry. In all, 20 academics
allowed their names to be attached to this ghostwritten infomercial, and not
one has stepped forward to acknowledge wrongdoing or to admit that a mistake
was made.

Long before the paper was published, the authors of study 329 were fanned out
all the way to Canada giving lectures and presentations to prescribing
doctors at medical conferences and seminars to promote the off-label use of
Paxil for kids. More than any other paper, Study 329 led to an epidemic in
pediatric prescribing. “After its publication, the use of antidepressants for
children skyrocketed,” Dr Glenmullen notes.

These handsomely paid key opinion leaders all deserve to have their names
in lights, especially Drs Graham Emslie and Karen Wagner from the University
of Texas.

Between 2000 through 2005, Glaxo paid Dr Wagner $160,404, but the only
payment she reported to the university was $600 in 2005, according to Senator
Grassley. Dr Wagner also failed to disclose earnings of more than $11,000 from
Prozac-maker Eli Lilly in 2002.

On August 18, 2008, the Dallas Morning News reported that a state mental
health plan naming the preferred psychiatric drugs for children has been quietly
put on hold over fears drug companies may have given researchers consulting
contracts, speakers fees or other perks to help get their products on the
list.

The Children’s Medication Algorithm Project, or CMAP, was supposed to
determine which psychiatric drugs were most effective for children and in what
order they should be tried at state-funded mental health centers, the Morning
News explains.

The academics who developed the CMAP include Drs Wagner and Emslie. Records
show Dr Emslie may have made up to $125,000 from drug companies since
2004, according to the report in the Morning News. While Dr Keller took the lead on
pushing Paxil for children and adolescents,Dr Emslie was the main man on the Prozac
trials, and Dr Wagner was the queen bee on Zoloft studies.

The co-authors of papers that appear in the medical
literature encouraging the use of SSRI’s for kids include Drs Biederman,
Schatzberg, Wilens and, of course, Charles Nemeroff.
Dr Nemeroff was recently forced to resign as chairman of Emory’s psychiatry
department after Senator Grassley’s investigation revealed that he failed to
disclose to his university more than a million dollars in drug industry
income. All total, Nemeroff had earnings of $2.8 million from drug companies
between 2000 and 2007, but failed to report at least $1.2 million.

A complete list of academics who should to be investigated can be found among
the authors of the SSRI papers and studies highlighted in the 2006 Third
Edition of, “Essentials of Clinical Psychopharmacology,” described as “a
synopsis and update of the most clinically relevant material from ‘The American
Psychiatric Publishing Textbook of Psychopharmacology,'” by none other than Drs
Schatzberg and Nemeroff.

Keep Following the Money
On July 10, 2008, Senator Grassley extended his investigation to include
psychiatry’s top industry-funded front group with a letter to Dr James Scully,
Medical Director and Chief Executive Officer of the American Psychiatric
Association, asking for “an accounting of industry funding that pharmaceutical
companies and/or the foundations established by these companies have provided to
the American Psychiatric Association.”

The Senator wants records from January 2003 to the present. According to the
July 12, 2008, New York Times, in 2006, the “industry accounted for about 30
percent of the association’s $62.5 million in financing.”
A factor rarely discussed in this debate is the amount of money doctors who
prescribe SSRI’s make during brief office calls charged at regular rates. This
practice has taken a tremendous toll on public healthcare programs and has
resulted in higher insurance premiums and overall healthcare costs for all
Americans.

In fact, the bilking of public healthcare programs is what led to the current
investigations by the Finance Committee, which has the responsibility of
overseeing spending in Federal programs. When doctors prescribe drugs for
unnecessary uses, public programs not only have to pay for the drugs, they must
also pay the fees of the prescribing doctors and for the medical care for
injuries caused by the drugs. Government spending tied to the prescribing of
psychiatric drugs has gone through the roof in the past decade.

While testifying before the House Committee on Oversight and Government
Reform on February 9, 2007, Lewis Morris, Chief Counsel at the Department of
Health and Human Services’ Office of Inspector General, discussed kickbacks to
doctors and told the panel:

“Kickbacks potentially increase the costs to Federal programs because they
encourage overutilization and may encourage the prescribing of more expensive
drugs when clinically appropriate and cheaper options (such as generic drugs)
may be equally effective.”

Mr Morris explained that, “kickbacks offered to prescribing physicians by
pharmaceutical manufacturers take a variety of forms, ranging from free samples
for which the physician bills the programs to all-expense-paid trips and sham
consulting agreements.”

Vermont is a rare state in requiring the pharmaceutical industry to disclose
the money paid to doctors. On July 8, 2008, Vermont’s Attorney General
William Sorrell released the state’s annual report on “Pharmaceutical Marketing
Disclosures,” which lists the payments made by drug companies in 2007. Of the
top 100 recipients, once again, psychiatrists received the highest payments.
Eleven psychiatrists received a total of $626,379, or about 20% of the total
value of payments made, according to the report.

Shrinks on the take are so addicted to industry money that it’s impossible to
embarrass them. Last year, the press ran major stories when this report came
out, highly critical of how much money they were making. This year, the
average amount rose by 25%.

The report also analyzes the payments based upon the drugs being marketed. Of
the top 10 drugs for which disclosures were reported, five are used to treat
mental illness and include Lilly’s Cymbalta and Forest Lab’s Lexapro.
Ironically, Cymbalta sales are also up 25%, according to Lilly’s latest SEC
filing.

Overall, estimates indicate that the drug industry spends $19 billion
annually on marketing to physicians in the form of gifts, travel, meals and
other consulting fees, according to a May 22, 2008, press release by Senator
Grassley’s office. In the November 1, 2007, New England Journal of Medicine
paper, “Doctors and Drug Companies Scrutinizing Influential Relationships,” Dr
Eric Campell, associate professor at the Institute of Health Policy at
Massachusetts General Hospital and Harvard Medical School, writes:

“Individual physicians can take some steps to maximize the benefits for
patients and minimize the risks associated with their own industry
relationships. They can start by recognizing that such relationships are designed to
influence prescribing behavior and by carefully considering the potential
effects that their own associations may have on their patients.”

“And they can bear in mind,” he says, “that the costs of industry dinners,
trips, and other incentives are passed along to their patients in the form of
higher drug prices.” Antidepressant prescribing is more rampant in this country than any other.
The US accounted for 66% of the global market in 2005, compared to 23% in
Europe and 11% for the rest of world, according to a December 2006 report by
Research and Markets.

A June 2007 survey by the Centers for Disease Control of doctor and hospital
visits in 2005 showed that the most commonly prescribed drugs were
antidepressants, with 48% of the prescriptions issued by primary care
physicians. They have remained in the number one position ever since. Last year, 232 million
prescriptions were filled for antidepressants worth nearly $12 billion,
according to a March 2008 report by IMS Health.

The top dogs in the pharmaceutical industry are literally laughing all the
way to the bank. For example, in 2007, Pfizer CEO Jeff Kindler’s pay package
was worth $9.5 million, according to the March 14, 2008, Wall Street Journal. A
previous CEO, David Shedlarz, left last year with an “exit package” worth
over $34 million. In 2007, the total value of Wyeth’s then-CEO Robert Essner’s
pay package was $24.1 million, the Journal reports.

In the meantime, state Medicaid programs are going bankrupt as a result of
the mental illness epidemic occurring only in the US. Attorneys General all
over the country are using consumer fraud statutes to sue the drug giants to
recoup the money lost due to the illegal off-label promotion of psychiatric
drugs and the concealment of their side effects.

For instance, Baum Hedlund has been litigating Private Attorney General
consumer fraud class-action lawsuits against Glaxo since 2004, on behalf of
individuals and entities such as insurance companies in California, Florida,
Illinois, Massachusetts, Minnesota, Missouri, New Jersey, North Dakota, Ohio and
Washington.

The cases are based on documents showing Glaxo promoted Paxil for kids, fully
aware that Paxil failed to out-perform a placebo in the clinical trials and
had higher suicidality rates. A national class settlement of individual
claims was reached in April 2007 in which Glaxo agreed to reimburse parents for
all of the money paid for Paxil prescriptions for their children. A national
class settlement on behalf of third party payors (insurance companies) was just
approved in September 2008.

If not for the few law firms willing to stay the course, the truth would
never have been revealed. Baum Hedlund has been pursuing the SSRI makers for
nearly two decades. Most recently, it has taken up the fight for babies born
with birth defects caused by SSRI’s.

Because the industry was so successful at keeping the original SSRI trial
data hidden, the drugs most serious side effects largely became public only
as a result of the bravery and integrity of such medical experts as Dr Healy, Dr
Glenmullen and Dr Breggin, who could not be bought and could not be bullied.

For fifteen years, the SSRI makers fought against adding a warning about an
increased risk of suicidality, knowing all the long that the risk existed.
Now, the companies are making the irresponsible argument (in defense of
lawsuits claiming they failed to warn doctors and the public of the risk) that the
FDA did not require them to add a warning, so they are immune from liability.
Worse yet, the industry-controlled FDA under the Bush Administration is
supporting this audacious preemption defense and siding with the SSRI makers
against private citizens in courts all over the country, telling judges to rule
in favor of the drug companies and throw out the SSRI cases before they even
make it to a jury.

Although not an SSRI case, the Supreme Court heard oral argument in a case
involving federal preemption, in Wyeth v Levine, on November 3, 2008.
*************
Evelyn Pringle
epringle05@…
(Written as part of the Paxil Litigation Round-Up, Sponsored by Baum,
Hedlund, Aristei & Goldman’s Pharmaceutical Litigation Department
_www.baumhedlundlaw.com_ (http://www.baumhedlundlaw.com/) )


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NEJM: On Zoloft Homicidal Ideation Frequent In Those 17 & Under

Since I believe that people should always get credit for the hard work and contribution they make in life I want to give our thanks to Rosie Meysenburg for getting this out to us today and for her comments on it. Rosie has done so much, along with her husband Gene, in posting our years and years worth of work gathering these SSRI & SNRI cases together for the _www.ssristories.drugawareness.org_
(http://www.ssristories.drugawareness.org) site.

“This Adverse Event Report, from a study appearing in the New England Journal of Medicine, shows that of 133 children 17 & under on Zoloft there were 2 who reported “Homicidal Ideation”. There were no reports of “Homicidal Ideation” in the placebo group.

[According to the Physicians Desk Reference, a Frequent adverse reaction is one that occurs in 100 people or less.  Homicidal Ideation occurred in 1 in 66 children on Zoloft aged 17  and under.]

“According to the Physicians Desk Reference, a Frequent adverse reaction is one that occurs in 100 people or less. Homicidal Ideation occurred in 1 in 66 children on Zoloft aged 17 and under.

“This Adverse Event Report was the appendix for this study in the New England Journal of Medicine.”

adverse event report1.pdf

This Adverse Event Report was the appendix for this study in the New England Journal of Medicine:

http://content.nejm.org/cgi/content/full/NEJMoa0804633

And with this new information from the New England Journal of Medicine I want to include information out of Australia which is that Pfizer, the maker of Zoloft, along with the Therapeutic Goods Administration (TGA similar to our FDA), recommends that any SSRI antidepressant should not be prescribed to Australians under the age of 24. Funny, but I missed that warning from Pfizer for Americans under 24, didn’t you?

Next I will send that article that just came out over the weekend because it ties in so closely with this new information on Zoloft. And because there is so much to read in this article alone I am going to cut my comments at this point and let the article speak for itself.

Ann Blake-Tracy, Executive Director,
International Coalition for Drug Awareness
_www.drugawareness.org_ (http://www.drugawareness.org/) &
_www.ssristories.org_ (http://www.ssristories.org/)
Author of Prozac: Panacea or Pandora? – Our
Serotonin Nightmare & the audio, Help! I Can’t
Get Off My Antidepressant!!! ()

_atracyphd1@…_ (mailto:atracyphd1@…)

_http://content.nejm.org/cgi/content/full/NEJMoa0804633_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633)

Published at www.nejm.org October 30, 2008 (10.1056/NEJMoa0804633)
Cognitive Behavioral Therapy, Sertraline, or a Combination in Childhood
Anxiety

John T. Walkup, M.D., Anne Marie Albano, Ph.D., John Piacentini, Ph.D.,
Boris Birmaher, M.D., Scott N. Compton, Ph.D., Joel T. Sherrill, Ph.D., Golda
S. Ginsburg, Ph.D., Moira A. Rynn, M.D., James McCracken, M.D., Bruce Waslick,
M.D., Satish Iyengar, Ph.D., John S. March, M.D., M.P.H., and Philip C. Kendall, Ph.D.

ABSTRACT
Background Anxiety disorders are common psychiatric conditions affecting children and adolescents. Although cognitive behavioral therapy and selective serotonin-reuptake inhibitors have shown efficacy in treating these disorders, little is known about their relative or combined efficacy.

Methods In this randomized, controlled trial, we assigned 488 children between the ages of 7 and 17 years who had a primary diagnosis of separation anxiety disorder, generalized anxiety disorder, or social phobia to receive 14 sessions of cognitive behavioral therapy, sertraline (at a dose of up to 200 mg per day), a combination of sertraline and cognitive behavioral therapy, or a placebo drug for 12 weeks in a 2:2:2:1 ratio. We administered categorical and dimensional ratings of anxiety severity and impairment at baseline and at
weeks 4, 8, and 12.

Results The percentages of children who were rated as very much or much improved on the Clinician Global Impression “Improvement scale were 80.7% for combination therapy (P<0.001), 59.7% for cognitive behavioral therapy (P<0.001), and 54.9% for sertraline (P<0.001); all therapies were superior to placebo
(23.7%). Combination therapy was superior to both monotherapies (P<0.001).

Results on the Pediatric Anxiety Rating Scale documented a similar magnitude and pattern of response; combination therapy had a greater response than cognitive behavioral therapy, which was equivalent to sertraline, and all therapies were superior to placebo. Adverse events, including suicidal and homicidal
ideation, were no more frequent in the sertraline group than in the placebo group. No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness associated with cognitive behavioral therapy than with sertraline.

Conclusions
Both cognitive behavioral therapy and sertraline reduced the severity of anxiety in children with anxiety disorders; a combination of the two therapies had a superior response rate.

(ClinicalTrials.gov number,
NCT00052078 _[ClinicalTrials.gov]_
(http://content.nejm.org/cgi/external_ref?access_num=NCT00052078&link_type=CLINT\
RIALGOV
) .)

____________________________________
Anxiety disorders are common in children and cause substantial impairment in
school, in family relationships, and in social functioning._1_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R1) ,_2_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R2) Such disorders
also predict adult anxiety disorders and major depression._3_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R3) ,_4_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R4) ,_5_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R5) ,_6_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R6) Despite a high
prevalence (10 to 20%_3_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R3)
,_7_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R7) ,_8_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R8) ) and substantial
morbidity, anxiety disorders in childhood remain underrecognized and
undertreated._1_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R1)
,_9_

(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R9)

An improvement in outcomes for children with anxiety disorders would have important public health
implications.In clinical trials, separation and generalized anxiety disorders and social
phobia are often grouped together because of the high degree of overlap in
symptoms and the distinction from other anxiety disorders (e.g., obsessive compulsive disorder). Efficacious treatments for these disorders include cognitive behavioral therapy_10_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R10) ,_11_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R11) and
the use of selective serotonin-reuptake inhibitors (SSRIs)._12_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R12) ,_13_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R13)

However, randomized, controlled trials comparing cognitive behavioral therapy, the use of an SSRI, or the combination of both therapies with a control are lacking. The evaluation of combination therapy is particularly important because approximately 40 to 50% of children with these disorders do not have a response to short-term treatment with either monotherapy.
_14_(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R14) ,_15_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R15)

Our study, called the Child “Adolescent Anxiety Multimodal Study, was designed to address the current gaps in the treatment literature by evaluating the relative efficacy of cognitive behavioral therapy, sertraline, a combination of the two therapies, and a placebo drug. This article reports the results of short-term treatment.

Methods

Study Design and Implementation

This study was designed as a two-phase, multicenter, randomized, controlled trial for children and adolescents between the ages of 7 and 17 years who had separation or generalized anxiety disorder or social phobia. Phase 1 was a 12-week trial of short-term treatment comparing cognitive behavioral therapy, sertraline, and their combination with a placebo drug. Phase 2 is a 6-month open extension for patients who had a response in phase 1.

The authors designed the study, wrote the manuscript, and vouch for the data gathering and analysis. Pfizer provided sertraline and matching placebo free of charge but was not involved in the design or implementation of the study, the analysis or interpretation of data, the preparation or review of the manuscript, or the decision to publish the results of the study.

Study Subjects

Children between the ages of 7 and 17 years with a primary diagnosis of separation or generalized anxiety disorder or social phobia (according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision
[DSM-IV-TR]_16_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R16) ),
substantial impairment, and an IQ of 80 or more were eligible to participate. Children with coexisting psychiatric diagnoses of lesser severity than the three target disorders were also allowed to participate;
such diagnoses included attention deficit–hyperactivity disorder (ADHD) whilereceiving stable doses of stimulant and obsessive compulsive, post-traumatic stress, oppositional defiant, and conduct disorders. Children were excluded if they had an unstable medical condition, were refusing to attend school
because of anxiety, or had not had a response to two adequate trials of SSRIs or an adequate trial of cognitive behavioral therapy.

Girls who were pregnant or were sexually active and were not using an effective method of birth control
were also excluded. Children who were receiving psychoactive medications other than stable doses of stimulants and who had psychiatric diagnoses that made participation in the study clinically inappropriate (i.e., current majordepressive or substance-use disorder; type ADHD; or a lifetime history of bipolar, psychotic, or pervasive developmental disorders) or who presented an acute risk to themselves or others were also excluded.

Recruitment occurred from December 2002 through May 2007 at Duke University Medical Center, New York State Psychiatric Institute Columbia University Medical Center New York University, Johns Hopkins Medical Institutions, Temple University University of Pennsylvania, University of California, Los Angeles,and
Western Psychiatric Institute and Clinic University of Pittsburgh Medical Center. The protocol was approved and monitored by institutional review boards at each center and by the data and safety monitoring board of the National Institute of Mental Health. Subjects and at least one parent provided written informed consent.

Interventions

Cognitive behavioral therapy involved fourteen 60-minute sessions, which included review and ratings of the severity of subjects’ anxiety, response to treatment, and adverse events. Therapy was based on the Coping Cat program,_17_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R17) ,_18_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R18) which was adapted for the
subjects’ age and the duration of the study._19_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R19)

Each subject who was assigned to receive cognitive behavioral therapy received training in anxiety-management skills, followed by behavioral exposure to anxiety-provoking situations. Parents
attended weekly check-ins and two parent-only sessions. Experienced psychotherapists, certified in the Coping Cat protocol, received regular site-level and cross-site supervision.

Pharmacotherapy involved eight sessions of 30 to 60 minutes each that included review and ratings of the severity of subjects’ anxiety, their response to treatment, and adverse events. Sertraline (Zoloft) and matching placebo were administered on a fixed flexible schedule beginning with 25 mg per day and adjusted up to 200 mg per day by week 8. Through week 8, subjects who were considered to be mildly ill or worse and who had minimal side effects were eligible for dose increases.

Psychiatrists and nurse clinicians with experience in medicating children with anxiety disorders were certified in the study pharmacotherapy protocol and received regular site-level and cross-site supervision.
Pill counts and medication diaries were used to facilitate and document adherence. Combination therapy consisted of the administration of sertraline and cognitive behavioral therapy. Whenever possible, therapy and medication sessions occurred on the same day for the convenience of subjects.

Objectives
Study objectives were, first, to compare the relative efficacy of the three active treatments with placebo; second, to compare combination therapy with either sertraline or cognitive behavioral therapy alone; and third, to assess the safety and tolerability of sertraline, as compared with placebo. We hypothesized that all three active treatments would be superior to placebo and that combination therapy would be superior to either sertraline or cognitive behavioral therapy alone.

Outcome Assessments
We obtained demographic information, information on symptoms of anxiety, and data on coexisting disorders and psychosocial functioning using reports from both the subjects and their parents and from interviews of subjects and parents at the time of screening, at baseline, and at weeks 4, 8, and 12.

The interviews were administered by independent evaluators who were unaware of study-group assignments.
We used the Anxiety Disorders Interview Schedule for DSM-IV-TR, Child Version,_20_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R20) to establish diagnostic eligibility. The categorical primary outcome was the treatment response at week 12, which was defined as a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression Improvement scale,_21_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R21) which ranges from 1 to 7, with lower scores indicating more improvement, as compared with baseline. A score of 1 or 2 reflects a substantial, clinically meaningful improvement in anxiety severity and normal functioning. The dimensional primary
outcome was anxiety severity as measured on the Pediatric Anxiety Rating Scale, computed by the summation of six items assessing anxiety severity, frequency, distress, avoidance, and interference during the previous week._22_(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R22)

Total scores on this scale range from 0 to 30, with scores above 13 indicating clinically meaningful anxiety. The Children’s Global Assessment Scale_23_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R23) was used to rate
overall impairment.

Scores on this scale range from 1 to 100; scores of 60 or lower are considered to indicate a need for treatment, and a score of 50 corresponds to moderate impairment that affects most life situations and is readily observable. Agreement among the raters was high for anxiety severity (r=0.85) and diagnostic
status (intraclass correlation coefficient= 0.82 to 0.88) on the basis of a videotaped review of 10% of assessments by independent evaluators that were performed at baseline and at week 12.

Adverse Events
Adverse events were defined as any unfavorable change in the subjects’ pretreatment condition, regardless of its relationship to a particular therapy. Serious adverse events were life-threatening events, hospitalization, or events leading to major incapacity. Harm-related adverse events were defined as thoughts of harm to self or others or related behaviors. All subjects were interviewed at the start of each visit by the study coordinator with the use of a standardized script. Identified adverse events and harm-related events were then evaluated and rated by each subject’s study clinician.

This report presents data on all serious adverse events, all harm-related adverse events, andmoderate and severe (i.e., functionally impairing) adverse events that occurred in 3% or more of subjects in any study group. The data and safety monitoring board of the National Institute of Mental Health performed a quarterly review
of reported adverse events. Given the greater number of study visits (and hence more reporting
opportunities) and the unblinded administration of sertraline in the combination-therapy group, the test of the adverse-event profile of sertraline focused on statistical comparisons between sertraline and placebo and sertraline and cognitive behavioral therapy.

Randomization and Masking
The randomization sequence in a 2:2:2:1 ratio was determined by a computer-generated algorithm and maintained by the central pharmacy, with stratification according to age, sex, and study center. Subjects were assigned to study groups after being deemed eligible and undergoing verbal reconsent with a study investigator. Subjects in the sertraline and placebo groups did not know whether they were receiving active therapy, nor did their clinicians. However, subjects who received combination therapy knew they were receiving active sertraline. The study protocol called for independent evaluators who completed assessments to be unaware of all treatment assignments.

Statistical Analysis
On the basis of previous studies,_10_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R10) ,_11_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R11) ,_12_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R12)
,_13_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R13) ,_14_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R14) ,_15_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R15)
we hypothesized that 80% of children in the combination-therapy group, 60% in either the sertraline group
or the cognitive-behavioral-therapy group, and 30% in the placebo group would be considered to have had a response to treatment at week 12. We determined that we needed to enroll 136 subjects in each active-treatment group and 70 subjects in the placebo group for the study to have a power of 80% to detect a minimum difference of 17% between any two study groups in the rate of response, assuming an alpha of 0.05 and a two-tailed test with no adjustment for multiple comparisons.

Analyses were performed with the use of SAS software, version 9.1.3 (SAS Institute). For categorical outcomes (including data regarding adverse events), treatments were compared with the use of Pearson’s chi-square test, Fisher’s exact test, or logistic regression, as appropriate. Logistic-regression models included the study center as a covariate. For dimensional outcomes, linear mixed-effects models (implemented with the use of PROC MIXED) were used to determine predicted mean values at each assessment point (weeks 4, 8, and 12)
and to test the study hypotheses with respect to between-group differences at week 12.

In each linear mixed-effects model, time and study group were included as fixed effects, with linear and quadratic time and time-by-treatment group interaction terms. Each model also began with a limited number of covariates (e.g., age, sex, and race), followed by backward stepping to identify thebest-fitting and most parsimonious model. In all models, random effects included intercept and linear slope terms, and an unstructured covariance was used to account for within-subject correlation over time. All comparisons were planned and tests were two-sided. A P value of less than 0.05 was considered to indicate statistical significance. The sequential Dunnett test was used to control the overall (familywise) error rate._24_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R24)

We analyzed data from all subjects according to study group. Sensitivity analyses were performed with the last observation carried forward (LOCF) and multiple imputation assuming missingness at random. Results were similar for the two missing-data methods. We report the results of the LOCF analysis because the
response rates were lower and hence provide a more conservative estimate of outcomes.

Results
Subjects
A total of 3066 potentially eligible subjects were screened by telephone
(_Figure 1_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#F1) ). Of these subjects, 761 signed consent forms and completed the inclusion and exclusion evaluation, 524 were deemed to be eligible and completed the baseline assessment, and 488 underwent randomization. Eleven subjects (2.3%) stopped
treatment but were included in the assessment (treatment withdrawals); 46 subjects (9.4%) stopped both treatment and assessment (study withdrawals).

On the basis of logistic-regression analyses, pairwise comparisons indicated that subjects in the cognitive-behavioral-therapy group were significantly less likely to withdraw from treatment than were those in the sertraline group (odds ratio, 0.33; 95% confidence interval [CI], 0.13 to 0.87; P=0.03) or the placebo
group (odds ratio, 0.24; 95% CI; 0.09 to 0.67; P=0.006). Of the 488 subjects who underwent randomization, 459 (94.1%) completed at least one postbaseline assessment, 396 (81.1%) completed all four assessments, and 440 (90.2%) completed the assessment at week 12. Subjects were recruited primarily through advertisements (52.2%) or clinical referrals (44.1%).
(http://content.nejm.org/cgi/content/full/NEJMoa0804633v2/F1)
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Figure 1. Enrollment and Outcomes.

Subjects who are shown as having withdrawn from treatment discontinued their assigned therapy but continued to undergo study assessment. Subjects who are shown as having withdrawn from the study discontinued both therapy and assessment. CBT denotes cognitive behavioral therapy.

Of 14 possible sessions of cognitive behavioral therapy, the mean (±SD) number of sessions completed was 12.7±2.8 in the combination-therapy group and 13.2±2.0 in the cognitive-behavioral-therapy group. The mean dose of sertraline at the final visit was 133.7±59.8 mg per day (range, 25 to 200) in the combination-therapy group, 146.0±60.8 mg per day (range, 25 to 200) in the sertraline group, and 175.8±43.7 mg per day (range, 50 to 200) in the placebo group.

Demographic and Clinical Characteristics
There were no significant differences among study groups with respect to baseline demographic and clinical characteristics (_Table 1_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#T1) ). The mean age of participants was 10.7±2.8 years, with 74.2% under the age of 13 years.

There were nearly equal numbers of male and female subjects. Most subjects were white (78.9%), with
other racial and ethnic groups represented. Subjects came from predominantly middle-class and upper-middle-class families (74.6%) and lived with both biologic parents (70.3%). Most subjects had received the diagnosis of two or more primary anxiety disorders (78.7%) and one or more secondary disorders
(55.3%). At baseline, subjects had moderate-to-severe anxiety and impairment (_Table
2_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#T2) ).

Given the geographic diversity among study centers, there were significant differences among sites on several baseline demographic variables (e.g., race and socioeconomic status). Overall, these variables were equally distributed among study groups within each center; however, three centers had one instance each of
unequal distribution for sex, race, or socioeconomic status.

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Table 1. Baseline Characteristics of the Subjects and Recruitment According
to Study Center.

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Table 2. Key Outcomes at 12 Weeks.

Clinical Response
In the intention-to-treat analysis, the percentages of children who were rated as 1 (very much improved) or 2 (much improved) on the Clinical Global Impression–Improvement scale at 12 weeks were 80.7% (95% CI, 73.3 to 86.4) in the combination-therapy group, 59.7% (95% CI, 51.4 to 67.5) in the cognitive-behavioral-therapy group, 54.9% (95% CI, 46.4 to 63.1) in the sertraline group, and
23.7% (95% CI, 15.5 to 34.5) in the placebo group (_Table 2_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#T2) ).

With the study center as a covariate, planned pairwise comparisons from a logistic-regression model showed
that each active treatment was superior to placebo as follows: combination therapy versus placebo, P<0.001 (odds ratio, 13.6; 95% CI, 6.9 to 26.8); cognitive behavioral therapy versus placebo, P<0.001 (odds ratio, 4.8; 95% CI, 2.6 to 9.0); and sertraline versus placebo, P<0.001 (odds ratio, 3.9; 95% CI, 2.1 to 7.4). Similar pairwise comparisons revealed that combination therapy was superior to either sertraline alone (odds ratio, 3.4; 95% CI, 2.0 to 5.9; P<0.001) or cognitive behavioral therapy alone (odds ratio, 2.8; 95% CI, 1.6 to 4.8; P=0.001). However, there was no significant difference between sertraline and cognitive behavioral therapy (P=0.41).

There was no main effect for center (P=0.69); however, a comparison among centers according to study group revealed a significant difference in response to combination therapy but no differences with respect to the response to sertraline alone (P=0.15) or cognitive behavioral therapy alone (P=0.25).

Further evaluation of response rates revealed that the average response rate for combination therapy at one center was significantly lower than at the other centers (P=0.002). A sensitivity analysis of site response rates showed that when data from the one site were removed, the average response rate of the other sites was consistent with that of the full sample.

The mixed-effects model for the Pediatric Anxiety Rating Scale revealed a significant quadratic effect for time (P<0.001) and a significant quadratic time-by-treatment interaction for cognitive behavioral therapy versus placebo (P=0.01) but not for either combination therapy or sertraline versus placebo. In other words, as compared with placebo, cognitive behavioral therapy had a linear mean trajectory (_Figure 2_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#F2) ). Planned pairwise comparisons of the expected mean scores on the Pediatric Anxiety Rating Scale at week 12 revealed a similar ordering of
outcomes, with all active treatments superior to placebo, according to the following comparisons: combination therapy versus placebo, t=–5.94 (P<0.001); cognitive behavioral therapy versus placebo, t=–2.11 (P=0.04); and sertraline versus placebo, t=–3.15 (P=0.002). In addition, combination therapy was
superior to both sertraline alone (t=–3.26, P=0.001) and cognitive behavioral therapy alone (t=–4.73, P<0.001). No significant difference was found between sertraline and cognitive behavioral therapy (t=1.32, P=0.19). The same magnitude and pattern of outcome was found for the Clinical Global Impressio Severity
scale and the Children’s Global Assessment Scale.
(http://content.nejm.org/cgi/content/full/NEJMoa0804633v2/F2)
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Figure 2. Scores on the Pediatric Anxiety Rating Scale during the 12-Week
Study.

Scores on the Pediatric Anxiety Rating Scale range from 0 to 30, with scores higher than 13 consistent with moderate levels of anxiety and a diagnosis of an anxiety disorder. The expected mean score is the mean of the sampling distribution of the mean.

Estimates of the effect size (Hedges’ g) and the number needed to treatbetween the active-treatment groups and the placebo group were calculated. Effect sizes are based on the expected mean scores on the Pediatric Anxiety
Rating Scale, derived from the mixed-effects model. The number needed to treat is based on the dichotomized, end-of-treatment scores on the Clinical Global Impression–Improvement scale with the use of LOCF. The effect size was 0.86 (95% CI, 0.56 to 1.15) for combination therapy, 0.45 (95% CI, 0.17 to 0.74) for
sertraline, and 0.31 (95% CI, 0.02 to 0.59) for cognitive behavioral treatment.

The number needed to treat was 1.7 (95% CI, 1.7 to 1.9) for combination therapy, 3.2 (95% CI, 3.2 to 3.5) for sertraline, and 2.8 (95% CI, 2.7 to 3.0) for cognitive behavioral therapy. Treatment and Study Withdrawals
Most treatment and study withdrawals were attributed to reasons other than adverse events (43 of 57, 75.4%) (_Table 3_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#T3) ).

Of the 14 withdrawals that were attributed to an adverse event, 11 (78.6%) were in the groups receiving either sertraline alone or placebo and consisted of 3 physical events (headache, stomach pains, and tremor) and 8 psychiatric adverse events (worsening of symptoms, 3 subjects; agitation or disinhibition, 3; hyperactivity, 1; and nonsuicidal self-harm and homicidal ideation, 1).
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Table 3. Subjects Who Withdrew from Treatment or the Study.

Serious Adverse Events
Three subjects had serious adverse events during the study period. One child in the sertraline group had a worsening of behavior that was attributed to the parents’ increased limit setting on avoidance behavior; the event was considered to be possibly related to sertraline. A child in the combination-therapy
group had a worsening of preexisting oppositional defiant behavior that resulted in psychiatric hospitalization; this event was considered to be unrelated to a study treatment. The third subject was hospitalized for a tonsillectomy, which was also considered to be unrelated to a study treatment
(_Table
4_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#T4) ).
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Table 4. Moderate-to-Severe Adverse Events at 12 Weeks.

Adverse Events
Subjects in the combination-therapy group had a greater number of study visits and therefore significantly more opportunities for elicitation of adverse events than did those in the other study groups, with a mean of 12.8±4.0 opportunities (range, 1 to 22) in the combination-therapy group, as compared with 9.9±3.6 (range, 1 to 14) in the sertraline group, 10.6±2.0 (range, 1 to 14) in the cognitive-behavioral-therapy group, and 9.7±4.2 (range, 1 to 14) in the placebo group (P<0.001 for all comparisons). Rates of adverse events,
including suicidal and homicidal ideation, were not significantly greater in the sertraline group than in the placebo group. No child in the study attempted suicide. Among children in the cognitive-behavioral-therapy group, there were fewer reports of insomnia, fatigue, sedation, and restlessness or fidgeting than in the sertraline group (P<0.05 for all comparisons). For a list of mild adverse events that were not associated with functional impairment, as well as moderate and severe events, see the _Supplementary Appendix_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633/DC1) ,

available with the full text of this article at www.nejm.org.

Discussion
Our study examined therapies that many clinicians consider to be the most promising treatments for childhood anxiety disorders. Our findings indicate that as compared with placebo, the three active therapies combination therapy with both cognitive behavioral therapy and sertraline, cognitive behavioral therapy alone, and sertraline alone — are effective short-term treatments for children with separation and generalized anxiety disorders and social phobia, with combination treatment having superior response rates. No physical,psychiatric, or harm-related adverse events were reported more frequently in the sertraline group than in the placebo group, a finding similar to that for SSRIs, as identified in previous studies of anxious children._12_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R12) ,_13_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R13) ,_25_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R25)

Few withdrawals from either treatment or the study were attributed to adverse events. Suicidal ideation and homicidal ideation were uncommon. No child attempted suicide during the study period. Since they were recruited at multiple centers and locations, the study subjects were racially and ethnically diverse. However, despite intense outreach, the sample did not include the most socioeconomically disadvantaged children.
Subjects were predominantly younger children and included those with ADHD and other anxiety disorders, factors that allow for generalization of the results to these populations.

Conversely, the exclusion of children and teens with major depression and pervasive developmental disorders may have limited the generalizability of the results to these populations.The observed advantage of combination therapy over either cognitive behavioral therapy or sertraline alone during short-term treatment (an improvement of 21 to 25%) suggests that among these effective therapies, combination therapy
provides the best chance for a positive outcome. The superiority of combination therapy might be due to additive or synergistic effects of the two therapies. However, additional contact time in the combination-therapy group, which was unblinded, and expectancy effects on the part of both subjects and
clinicians cannot be ruled out as alternative explanations.

Nonetheless, the magnitude of the treatment effect in the combination-therapy group (with two
subjects as the number needed to treat to prevent one additional event) suggests that children with anxiety disorders who receive quality combination therapy can consistently expect a substantial reduction in the severity of anxiety. An increased number of visits in the combination-therapy group resulted in increased opportunities for elicitation of adverse events. Consequently, the potential for expectancies among subjects, parents, and clinicians regarding the side effects of medications in the context of more visits may have increased the rate of some adverse events in the combination-therapy group and may limit conclusions that can be drawn regarding the rates of adverse events in combination therapy.

The positive benefit of cognitive behavioral therapy, as compared with placebo, adds new information to the existing literature._26_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R26)
The number needed to treat for cognitive behavioral therapy in this study (three subjects) is the same as that
identified in a meta-analysis of studies comparing subjects who were assigned to cognitive behavioral therapy with those assigned to a waiting list for therapy or to sessions without active therapy._14_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R14)

Our study’s test of cognitive behavioral therapy included children with moderate-to-severe anxiety and addresses criticism of previous trials that included children with only mild-to-moderate
anxiety._14_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R14)
Before our study, cognitive behavioral therapy for childhood anxiety was considered to be
“probably efficacious.”_26_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R26)

This evaluation of cognitive behavioral therapy and other recent studies_27_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R27)
,_28_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R28) suggests that
such therapy for childhood anxiety is a well-established, evidenced-based treatment._29_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R29)

Given that the risk of some adverse events was lower in the behavioral-therapy group than in the sertraline group, some parents and their children may consider choosing cognitive behavioral therapy as their initial treatment.

The results of our study confirm the short-term efficacy of sertraline for children with generalized anxiety disorder_25_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R25) and show that
sertraline is effective for children with separation anxiety disorder and social phobia. The number needed
to treat for sertraline in our study (three subjects) was the same as that previously identified in a meta-analysis_15_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R15) of six
randomized, placebo-controlled trials of SSRIs for childhood anxiety disorders._12_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R12) ,_13_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R13) ,_25_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R25)
,_30_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R30) ,_31_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R31)

These studies and others_27_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R27)
suggest that SSRIs, as a class, are the medication of choice for these conditions. The titration schedule that we used, which emphasized upward dose adjustment in the absence of response and adverse events, suggests that the average end-point dose of sertraline in this study is the highest dose consistent with good outcome and tolerability. No adverse events were observed more frequently in the sertraline group than in the placebo group. In contrast to the apparent risk of suicidal ideation and behavior in studies of depression in children and
adolescents,_15_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R15) our study did not demonstrate any increased risk for suicidal behavior in the sertraline group. Given the benefit of sertraline alone or in combination with cognitive behavioral therapy and the limited risk of adverse events associated with the drug in our study, the well-monitored use of sertraline and other SSRIs in the treatment of childhood anxiety disorders is indicated.

Cognitive behavioral therapy and sertraline either in combination or as monotherapies appear to be effective treatments for these commonly occurring childhood anxiety disorders. Results confirm those of previous studies of SSRIs and cognitive behavioral therapy and, most important, show that combination
therapy offers children the best chance for a positive outcome. Our findings indicate that all three of the treatment options may be recommended, taking into consideration the family’s treatment preferences, treatment availability, cost, and time burden. To inform more prescriptive selection of patients for
treatment, further analysis of predictors and moderators of treatment response may identify who is most likely to respond to which_32_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R32) of these
effective alternatives.
Supported by grants (U01 MH064089, to Dr. Walkup; U01 MH64092, to Dr.
Albano; U01 MH64003, to Dr. Birmaher; U01 MH63747, to Dr. Kendall; U01 MH64107,
to Dr. March; U01 MH64088, to Dr. Piacentini; and U01 MH064003, to Dr. Compton)
from the National Institute of Mental Health (NIMH).

Sertraline and matching placebo were supplied free of charge by Pfizer. Dr. Walkup reports receiving consulting fees from Eli Lilly and Jazz Pharmaceuticals and fees for legal consultation to defense counsel and
submission of written reports in litigation involving GlaxoSmithKline, receiving lecture fees from CMP Media, Medical Education Reviews, McMahon Group, and DiMedix, and receiving support in the form of free medication and matching placebo from Eli Lilly and free medication from Abbott for clinical trials funded by the NIMH; Dr. Albano, receiving royalties from Oxford University Press for the Anxiety Disorders Interview Schedule for DSM-IV, Child and Parent Versions, but not for interviews used in this study, and royalties from the Guilford Press; Dr. Piacentini, receiving royalties from Oxford University Press for treatmentmanuals on childhood obsessive compulsive disorder and tic disorders and from the Guilford Press and APA Books for other books on child mental health and receiving lecture fees from Janssen-Cilag; Dr. Birmaher, receiving consulting fees from Jazz Pharmaceuticals, Solvay Pharmaceuticals, and Abcomm, lecture fees from Solvay, and royalties from Random House for a book on children with bipolar disorder; Dr. Rynn, receiving grant support from Neuropharm, BoehringerIngelheim Pharmaceuticals, and Wyeth Pharmaceuticals, consulting fees from Wyeth, and royalties from APPI for a book chapter on pediatric anxiety disorders; Dr. McCracken, receiving consulting fees from Sanofi-Aventis and Wyeth, lecture fees from Shire and UCB, and grant support from Aspect, Johnson & Johnson, Bristol-Myers Squibb, and Eli Lilly; Dr. Waslick, receiving grant support from Baystate Health, Somerset Pharmaceuticals, and GlaxoSmithKline; Dr. Iyengar, receiving consulting fees from Westinghouse for statistical consultation; Dr. March, receiving study medications from Eli Lilly for an NIMH-funded clinical trial and receiving royalties from Pearson for being the author of the Multidimensional Anxiety Scale for Children, receiving consulting fees from Eli Lilly, Pfizer, Wyeth, and GlaxoSmithKline, having an equity interest in MedAvante, and serving on an advisory board for AstraZeneca and Johnson & Johnson; and Dr. Kendall, receiving royalties from Workbook Publishing for anxiety-treatment materials.

No other potential conflict of interest relevant to this article was reported.

The views expressed in this article are those of the authors and do not necessarily represent the official views of the NIMH, the National Institutes of Health, or the Department of Health and Human Services.
We thank the children and their families who made this study possible; and J. Chisar, J. Fried, R. Klein, E. Menvielle, S. Olin, J. Severe, D. Almirall, and members of NIMH’s data and safety monitoring board.
* The study investigators are listed in the Appendix.
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#RFN1)

Source Information
From the Johns Hopkins Medical Institutions, Baltimore (J.T.W., G.S.G.); New York State Psychiatric Institute–Columbia University Medical Center, New York (A.M.A., M.A.R.); the University of California at Los Angeles, Los Angeles (J.P., J.M.); Western Psychiatric Institute and Clinic University of Pittsburgh Medical Center, Pittsburgh (B.B., S.I.); Duke University Medical Center, Durham, NC (S.N.C., J.S.M.); the Division of Services and Intervention Research, National Institute of Mental Health, Bethesda, MD (J.T.S.); Baystate
Medical Center, Springfield, MA (B.W.); and Temple University, Philadelphia
(P.C.K.).

This article (10.1056/NEJMoa0804633) was published at www.nejm.org on
October 30, 2008. It will appear in the December 25 issue of the Journal.
Address reprint requests to Dr. Walkup at the Division of Child and
Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Johns
Hopkins Medical Institutions, 600 N. Wolfe St., Baltimore, MD 21287.
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Appendix
The following investigators participated in this study: Steering Committee:
J. Walkup (chair), A. Albano (cochair); Statistics–Experimental Design: S.
Compton, S. Iyengar, J. March; Cognitive Behavioral Therapy: P. Kendall, G.
Ginsburg; Pharmacotherapy: M. Rynn, J. McCracken; Assessment: J. Piacentini,
A. Albano; Study Coordinators: C. Keeton, H. Koo, S. Aschenbrand, L. Bardsley,
R. Beidas, J. Catena, K. Dever, K. Drake, R. Dublin, E. Fontaine, J. Furr, A.
Gonzalez, K. Hedtke, L. Hunt, M. Keller, J. Kingery, A. Krain, K. Miller, J.
Podell, P. Rentas, M. Rozenmann, C. Suveg, C. Weiner, M. Wilson, T. Zoulas;
Data Center: M. Fletcher, K. Sullivan; Cognitive Behavior Therapists: E.
Gosch, C. Alfano, A. Angelosante, S. Aschenbrand, A. Barmish, L. Bergman, S.
Best, J. Comer, S. Compton, W. Copeland, M. Cwik, M. Desari, K. Drake, E.
Fontaine, J. Furr, P. Gammon, C. Gaze, R. Grover, H. Harmon, A. Hughes, K.
Hutchinson, J. Jones, C. Keeton, H. Kepley, J. Kingery, A. Krain, A. Langley,
J. Lee, J. Levitt, J. Manetti-Cusa, E. Martin, C. Mauro, K. McKnight, T. Peris, K.
Poling, L. Preuss, A. Puliafico, J. Robin, T. Roblek, J. Samson, M.
Schlossberg, M. Sweeney, C. Suveg, O. Velting, T. Verduin; Pharmacotherapists:
M. Rynn, J. McCracken, A. Adegbola, P. Ambrosini, D. Axelson, S. Barnett, A. Baskina,
B. Birmaher, C. Cagande, A. Chrisman, B. Chung, H. Courvoisie, B. Dave, A.
Desai, K. Dever, M. Gazzola, E. Harris, G. Hirsh, V. Howells, L. Hsu, I.
Hypolite, F. Kampmeier, S. Khalid-Khan, B. Kim, D. Kondo, L. Kotler, M.
Krushelnycky, J. Larson, J. Lee, P. Lee, C. Lopez, L. Maayan, J. McCracken, R.
Means,L. Miller, A. Parr, C. Pataki, C. Peterson, P. Pilania, R. Pizarro, H. Ravi,
S. Reinblatt, M. Riddle, M. Rodowski, D. Sakolsky, A. Scharko, R. Suddath, C.
Suarez, J. Walkup, B. Waslick; Independent Evaluators: A. Albano, G.
Ginsburg, B. Asche, A. Barmish, M. Beaudry, S. Chang, M. Choudhury, B. Chu, S.
Crawley, J. Curry, G. Danner, N. Deily, R. Dingfelder, D. Fitzgerald, P.
Gammon, S. Hofflich, E. Kastelic, J. Keener, T. Lipani, K. Lukin, M. Masarik, T.
Peris, T. Piacentini, S. Pimentel, A. Puliafico, T. Roblek, M. Schlossberg, E.
Sood, S. Tiwari, J. Trachtenberg, P. van de Velde; Pharmacy: K. Truelove, H.
Kim; Research Assistants: S. Allard, S. Avny, D. Beckmann, C. Brice, B.
Buzzella, E. Capelli, A. Chiu, M. Coles, J. Freeman, M. Gringle, S. Hefton, D.
Hood, M. Jacoby, J. King, A. Kolos, B. Lourea-Wadell, L. Lu, J. Lusky, R. Maid, C.
Merolli, Y. Ojo, A. Pearlman, J. Regan, S. Rock, M. Rooney, N. Simone, S.
Tiwari, S. Yeager.

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6/9/2000 – Prozac Fraud – Motion Filed in Forsyth Case

June 8, 2000
FOR IMMEDIATE RELEASE Baum, Hedlund, Aristei, Guilford & Downey
12100 Wilshire Blvd., Ste. 950
Los Angeles, CA 90025
Contact: Robin McCall
bhagd@…
Day: (800) 827-0087 or (310) 207-3233
Night: (818) 558-5964
www.bhagd.com/media/prozacinformation.html
PROZAC MAKER, ELI LILLY AND COMPANY, COMMITTED FRAUD ON HAWAII COURT BY
CONCEALING CRUCIAL EVIDENCE AT TRIAL, FAMILY IN NEWLY FILED LAWSUIT ALLEGE

June 8, 2000, Hawaii — The plaintiffs in one of the only Prozac cases to
ever go to trial filed a new lawsuit yesterday against the pharmaceutical
giant and Prozac drug maker, Eli Lilly and Company. The new lawsuit
alleges Lilly committed fraud on a Hawaii Court by concealing potentially
damaging patent language for a new and improved Prozac during their civil
trial last year over Prozac’s alleged role in their parents’ deaths. That
trial ended in a verdict in Lilly’s favor. (An appeal is currently pending
in the Ninth Circuit Court of Appeals.)

The plaintiffs, Susan Forsyth, of California and her brother, William
Forsyth Jr., of Maui, have requested that the verdict be set aside based on
the alleged fraud. The Forsyths’ first suit alleged that, while under the
influence of Prozac, their father, a successful businessman and retiree
living on the island of Maui, stabbed his wife (their mother) to death and
then committed suicide by impaling himself on a kitchen knife after being
on Prozac for 10 days.

The new lawsuit alleges that, “unbeknownst to plaintiffs or their counsel
at the time that case went to trial, Eli Lilly and Company had recently
agreed to pay $90 million for exclusive rights to a patent for a new
formulation of the Prozac molecule which would reduce the following
side-effects of the original Prozac: “nervousness, anxiety, insomnia, inner
restlessness (akathisia), suicidal thoughts, self mutilation [and] manic
behavior,” the very side effects which plaintiffs’ claimed occurred with
their father and resulted in the brutal deaths of both parents.

MORE – MORE – MORE

The new suit alleges that an “in-house patent lawyer for Eli Lilly and
Company sat mutely in the courtroom during key portions of the Forsyth
trial without advising the Court or opposing counsel of these facts or
correcting the mis-impression created by Eli Lilly and Company’s trial
counsel and its witnesses.”

Attorney, Karen A. Barth, of the Los Angeles law firm, Baum, Hedlund,
Aristei, Guilford & Downey, represents the Forsyths along with Andy Vickery
of the Texas firm, Vickery & Waldner. Karen Barth stated of the new action:

“It is incredible that, on the one hand, Lilly vehemently argues to a
federal judge and jury that Prozac does not cause suicide and/or violence
(or akathisia which is a known precursor to suicide) while on the other,
pays $90 million for a patent for a ‘new and improved Prozac,’ which
clearly acknowledges Prozac’s propensity to increase the risk of suicide
and violent behavior and to cause akathisia! Lilly has consistently blamed
the individuals taking Prozac for these adverse reactions rather than
acknowlege any connection to Prozac.

“The new patent is an admission by Eli Lilly that the original Prozac
causes these side effects. If Lilly denies this, they’ve paid $90 million
for an invalid patent. (For a patent of a new product to be accepted, it
must be something new and useful. The ‘useful’ part of this patent is
reduced side effects.)”

FACT SHEET FOLLOWS

YOU CAN FIND THE NEW COMPLAINT AT:

WWW.BHAGD.COM/MEDIA/PROZACINFORMATION.HTML

# # # The Forsyths lawsuit contains the following claims, among others:

1. Under the influence of Prozac, the Forsyth plaintiffs’ father stabbed
their mother numerous times before impaling himself on a kitchen knife.
When the Forsyth children sought justice for these wrongful deaths in this
Court, Eli Lilly and Company repeatedly represented to this Court and to
its Jury that suicide is not a side effect of Prozac, and that Mr. Forsyth
could not have had a drug-induced “akathisia” because this condition
requires both “inner” feelings of restlessness and outward manifestations
of motor movement.

2. Unbeknownst to plaintiffs or their counsel at the time that case went to
trial, Eli Lilly and Company had recently agreed to pay $90 million for
exclusive rights to a patent for a new formulation of the Prozac molecule
which would reduce the following side-effects of the original Prozac:
“nervousness, anxiety, insomnia, inner restlessness (akathisia), suicidal
thoughts, self mutilation [and] manic behavior.”

3. In-house patent counsel for Eli Lilly and Company sat mutely in the
courtroom without advising the Court or opposing counsel of these facts or
correcting the mis-impression created by Eli Lilly and Company’s trial
counsel and its witnesses. Under the prevailing case law in this Circuit,
this conduct constitutes a “fraud on the Court” and mandates that the
Court’s prior judgment be set aside. See Pumphrey v. K.W. Thompson Tool
Co., 62 F.3rd 1128 (9th Cir. 1995) (affirming trial judge’s decision in
independent action to set aside defense verdict and judgment in products
liability, wrongful death, case based on fraud on the court).

14. Several months prior to the trial of the action, Lilly purchased the
exclusive license to U.S. Patent No. 5,708,035 (“the patent”) from
Sepracor, Inc. (fn3 Sepracor Inc. is a specialty pharmaceutical company with
a unique strategy to develop and commercialize potentially improved versions
of widely-prescribed drugs referred to as Improved Chemical Entities (ICEs).
Sepracor’s ICE Pharmaceuticals are differentiated, proprietary, single-isomer
or active-metabolite versions of currently marketed drugs.) The patent
abstract states: “A method and composition are disclosed utilizing the pure
R(-) isomer of fluoxetine which is a potent antidepressant and appetite
suppressant substantially free of adverse effects.” As further explained in
the Background section of the patent: “This invention relates to a novel
composition of matter containing optically pure R (-) fluoxetine. This
composition possesses potent antidepressant and appetite suppressant activity
as a serotonin uptake inhibitor while avoiding the usual adverse effects
associated with the racemic mixture of fluoxetine.” The adverse effects
listed include thoseexact same adverse effects that were at issue in trial
of the action, i.e.,
akathisia and suicidal thoughts and behavior, and mutilation; side effects
which Lilly consistently and repeatedly told the Court and jury did not
exist. As set forth below, such a position by Lilly during the trial of
the action was a fraud on this Court.

15. Though, during discovery of the underlying case, Plaintiffs
specifically asked for such information such as that contained in the
patent, Lilly never supplemented its discovery responses to provide such
information.

16. In December 1998, Lilly entered into an agreement to pay approximately
$90 million for the exclusive license to U.S. Patent 5,708,035. A true and
correct copy of the patent [is] available online from the U.S. Patent Office
at www.uspto.gov. On its company website at www.lilly.com, Lilly announced
its intention to market this new type of Prozac. [ ]

17. As exclusive licensee, to enforce patent rights against third parties,
Lilly must necessarily stand in privity with the inventors with respect to
their representations to the Patent Office, particularly representations
about “usefulness” which could affect the validity of the patent. See e.g.
Abbott Laboratories v. Diamedix Corp., 33 U.S.P.Q.2d 1771, 47 F.3d 1128
(Fed.Cir. 1995). (fn6 A licensee who is adverse to the inventor or
patent owner can challenge the validity of the patent. Lear, Inc. v.
Adkins, 395 U.S. 653 (1969). But to enforce the patent, Lilly must
necessarily accept the fact that its statutory usefulness hinges on
reducing these side effects of Prozac.)

18. Further, Lilly acknowledged, adopted and ratified the information
contained within the patent in its 1999 Annual Report: “And, pending U.S.
Federal Trade Commission approval, we’re in-licensing Sepracor’s
R-fluoxetine, a compound that may offer broader efficacy and fewer side
effects than existing therapies.” (Emphasis added).

19. Under the Patent Act there are two essential requirements for
patentability of an invention, i.e. it must be both “new” and “useful.” 35
USC §101. As the patent itself demonstrates, fluoxetine is a racemic
mixture or stereo-isomer. What this means in lay terms is that the Prozac
molecule is like a pair of gloves, with both a right hand and a left hand.
The patent discloses a method for separating the stereo-isomer and creating a
one-handed or R(-) version of fluoxetine, i.e. with only one of the two
isomers. This is what is “new.”

20. What the patent claims as “useful” is the propensity of the new R(-)
fluoxetine molecule to reduce side effects. The side effects which the
patent claims will be reduced include: “nervousness, anxiety, insomnia,
inner restlessness (akathisia), suicidal thoughts, self mutilation [and]
manic behavior.”

21. A Lilly in-house patent lawyer was present in the courtroom during
portions of the trial of the Forsyth case, including the opening statements
and some of the testimony. Although he did not appear as trial counsel,
he was nonetheless an “officer of the court” for fraud on the court
purposes. See Pumphrey, supra at 1132.

22. In the trial of the wrongful death case, Lilly defended against the
general causation contentions, i.e. that Prozac causes some people to
become violent or suicidal, by arguing that any violent or suicidal
thoughts experienced by people on Prozac was because of their underlying
depression or other life “stressors.” It specifically and repeatedly
represented in both testimony and argument that treatment emergent
suicidality was not a side effect of Prozac.

23. Neither Mr. Norman nor other Lilly counsel ever brought it to the
attention of the Court or Jury that Lilly had agreed to pay $90 million for
a patent, whose validity hinges on the truthfulness of the notion that
“akathisia, suicidal thoughts [and] self-mutilation” are side effects of
Prozac. Rather, they allowed the mis-impression to continue.

29. Lilly is no stranger to claims that it has “protected Prozac”, inter
alia, by conduct which could be branded as a “fraud on the court.” Potter v.
Eli Lilly & Co., 926 S.W.2d 449Ky.1996) was a writ of prohibition case
against Judge John Potter, the trial judge of the first Prozac/wrongful death
case to go to trial in this country. The case resulted in a defense verdict.
Judge Potter entered a final judgment which stated “dismissed pursuant to
jury verdict.” However, when he learned later that there had been a
mid-trial secret settlement, that evidence had been withheld from the jury,
and that the attorneys for both parties had misrepresented facts to him
concerning their dealings, Judge Potter issued a show cause order, requiring
the parties to demonstrate why the judgment should not be modified to read
“dismissed as settled.” The judgment was ultimately
corrected to “dismissed as settled” as Judge Potter had proposed in the
first place.

The Kentucky Supreme Court, citing Hazel-Atlas Glass Co. v. Hartford Empire
Co., 322 U.S. 238 (1944) held that, not only did the judge have the right,
but, indeed, he had the duty to investigate a potential fraud on his court.
It wrote:

“there was a serious lack of candor with the trial court and there may
have been deception, bad faith conduct, abuse of the judicial process or
perhaps even fraud.” Id. at 454.

See also Winkler v. Eli Lilly & Co., 101 F.3d 1196, 1203 (7th Cir. 1996).

30. Plaintiffs did not discover the fraud on this Court until it came to
their attention via a May 7, 2000 article in the Boston Globe newspaper
entitled “Prozac Revisited”.

32. One of two things must be true. Either “inner restlessness
(akathisia), suicidal thoughts, [and] self-mutilation” are side effects of
the original Prozac, or Lilly has paid $90 million for an invention that
is not “useful” and a patent that is not valid. But regardless of which
one it is, by knowingly adducing evidence and making arguments which
created a false impression, and knowingly withholding the patent from
discovery supplementation, Lilly has perpetrated a fraud upon this Court.

33. Thus, based upon the foregoing, a fraud was committed on this Court. The
nature of this fraud was such that it harmed “the integrity of the judicial
process” within the meaning of Pumphrey v. K.W. Thompson Tool Co., 62 F.3rd
1128, 1132-33 (9th Cir. 1995).

34. Accordingly, the Judgment entered in the action entitled Susan K.
Forsyth, individually and as Personal Representative of the Estates of
June M. Forsyth and William D. Forsyth, and William D. Forsyth, Jr. v. Eli
Lilly and Company, Case No. 95-00185ACK should be set aside and a new trial
should be ordered.

PRAYER

WHEREFORE, Plaintiffs pray judgment against defendant Eli Lilly and
Company, as follows:

1. That the Judgment entered in the action entitled Susan K. Forsyth,
individually and as Personal Representative of the Estates of June M.
Forsyth and William D. Forsyth, and William D. Forsyth, Jr. v. Eli Lilly
and Company, Case No. 95-00185ACK be set aside and a new trial ordered.

2. An award for reasonable attorneys’ fees, including all attorneys’
fees incurred in the trial of the action entitled Susan K. Forsyth,
individually and as Personal Representative of the Estates of June M.
Forsyth and William D. Forsyth, and William D. Forsyth, Jr. v. Eli Lilly
and Company, Case No. 95-00185ACK.

3. An award of costs incurred in the underlying trial and herein;

4. An award of such other and further relief as the court deems just and
equitable.

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