[NYAPRS Enews] FW: Promise of Smoking Remedy Chantix Turns to Ashes for Some

[Harvey Rosenthal]

With Pfizer, FDA Shunning Tests on Mentally Ill, Promise of Smoking
Remedy Chantix Turns to Ashes for Some

By Lilly Fowler <http://www.fairwarning.org/writer/lilly-fowler/>   Fair
Warning December 15, 2010 

<http://www.fairwarning.org/wp-content/uploads/2010/12/Ware-300x300.jpg>
Late one morning in June 2008, 57-year-old Southern California real
estate agent Linda Ware was driving with her cousin along a desert
highway when she began hallucinating. Envisioning in the distance a sign
that read "God Is in the Realm," she pulled over suddenly and ordered
her cousin out of the car. Then, just as abruptly, Ware burst out
laughing and pulled back onto the road again.

Although Ware suffered from depression, as her daughter Cary Ussery
related, she'd never acted like this. A few days earlier, however, she
had started taking Chantix, a pill meant to help her quit smoking by
suppressing the effects of nicotine on the brain.

The day after the driving incident, a family friend found Linda Ware
slumped by her bed, dead from a fatal cocktail of prescription drugs, a
suicide note at her side.

Tragedy has plagued Chantix ever since it was approved in May, 2006,
even as the drug has helped some smokers kick the habit. By mid-2009,
the U.S. Food and Drug Administration had received reports of nearly 100
suicides, 200 attempted suicides and close to 5,000 serious psychiatric
events overall. Hundreds of reports of side effects have continued to
stream in this year.

A review of the drug's history shows that Pfizer Inc., the giant
pharmaceutical company that makes Chantix, failed in its years of
clinical trials to test the product on the mentally ill or those with a
recent history of depression - even though millions of smokers suffer
from psychiatric problems. Moreover, FDA regulators approved Chantix
after a speeded-up "priority review" process, and did not request a
follow-up study on mentally ill patients using the medication, even
though the agency's own safety reviewer reported that the exclusion of
such smokers may have undermined the clinical trials.

It wasn't until three years later, after thousands of reports of serious
side effects, that the FDA told Pfizer to conduct trials including
people with a history of mental illness. The agency then also slapped a
so-called black box warning, the FDA's strongest alert, on the
medication.

The controversy over Chantix's side effects, particularly for smokers
with mental health issues, has triggered a torrent of lawsuits. About
1,000 such cases have been filed in federal court, and plaintiffs
lawyers say they anticipate bringing forward more than 1,000 additional
suits. There also are scattered cases in state courts in New York,
Illinois and elsewhere. Plaintiffs in more than half of the cases claim
the drug led to suicides or suicide attempts, and many say they suffered
psychosis, blackouts, aggression, diabetes or other problems. No cases
have yet been tried or settled.

The plaintiffs lawyers argue that Pfizer, the world's largest
pharmaceutical company with sales this year of more than $60 billion,
neglected to test Chantix adequately before its release, deliberately
hid evidence of serious side effects and failed to sufficiently warn
consumers about its risks. Pfizer has turned over to plaintiffs lawyers
more than six million pages of documents under a protective order that
bars their public release.

Pfizer, for its part, defends Chantix and says it "acted responsibly and
appropriately at all times in connection with the development, approval,
and marketing" of the drug. The FDA, likewise, says it acted properly in
approving the drug, despite the problems that emerged after it went on
the market.

"The agency does not feel any mistakes were made," said FDA spokeswoman
Sandy Walsh."We can never speculate as to what may happen with a drug
once it goes into widespread use after approval."

The FDA's failure at the outset to require Pfizer to include the
mentally ill in its research, however, points to a potentially serious
flaw in the agency's regulation of drug safety for these particularly
vulnerable consumers. Although the mentally ill commonly are excluded
from drug clinical trials, they account for a disproportionate number of
smokers and are a key part of the target market for smoking cessation
treatments.

Their exclusion baffles experts such as Dr. Karen Lasser, a Boston
University researcher who has studied the link between mental illness
and smoking. "You need to think about who is going to be taking the
drug," she said.

Paul Thacker, a former Senate Finance Committee investigator who has
written about FDA decision-making, agreed. "If you're not thinking in
that way," he said, "then you're not doing your job."

Back when Chantix was approved, Pfizer officials figured they had a
potential major new star in their portfolio. With nearly 70 percent of
the estimated 45 million smokers in the U.S. hoping to quit, the market
appeared to be vast. Sales quickly zoomed to $883 million in 2007, which
turned out to be the drug's peak year. (During the first nine months of
this year, sales totaled $522 million.)

Chantix, which is sold as a pill, works by taking the pleasure out of
smoking by interfering with the way nicotine ordinarily affects the
brain. At the same time, it spurs the release of dopamine, which helps
control the brain's pleasure centers the way smoking usually does.

Pfizer launched Chantix with a news release spotlighting the dire
statistics on quitting smoking: less than 7 percent of smokers who try
to quit on their own make it past the one-year mark. In contrast,
clinical trials showed that about 22 percent of Chantix users who took
the drug for three months were able to abstain from smoking for a year
or more.

The company early on promoted its product through a series of TV, print
and online ads that, without mentioning Chantix or its side effects,
sought to sell people on the idea of quitting smoking. The "My Time to
Quit" campaign was intended to draw smokers to a website
<http://www.mytimetoquit.com/sites/mttq/pages/index.aspx>  [3] that,
after providing quick facts about kicking the habit, tiptoed to
information about the drug. Overall, Pfizer has spent about $300 million
on advertising for Chantix, according to the Nielsen Co., a media
information business.

Pfizer also spread its influence by paying doctors to give talks to
other physicians on smoking cessation techniques while also giving funds
to universities. The University of Wisconsin-Madison said the company
has given it more than $3 million, mainly for continuing medical
education courses it offers on smoking cessation.

The multi-pronged promotional effort by Pfizer eventually addressed
rising concerns about the drug. In 2008, Joseph Feczko, then Pfizer's
chief medical officer, wrote an opinion piece in the Wall Street
Journal. Headlined "Smoking Has Side Effects Too," the piece tried to
offset the negative publicity about Chantix with a reminder on the
hazards of smoking. It also explained how regulators and drug companies
conduct follow-up research, and alert the public, after they receive
reports of serious side effects.

Along the way, a controversial tack Pfizer took to push its product was
a study written by a team of employees headed by Kathryn E. Williams,
then part of the company's Global Research and Development unit. The
study
<http://www.pharmalot.com/wp-content/uploads/2008/06/chantix-l-term-stud
y.pdf>  [4], which was published in 2007 in the journal Current Medical
Research and Opinion, deemed Chantix safe for long-term use. (Labeling
on the drug prescribes a 12-week course of treatment, but the study
looked at consumers who used Chantix for a year.)

The article, however, was flawed in that failed to provide statistical
analysis to back up the claim, according to Dr. John Spangler, a smoking
cessation expert at Wake Forest University's School of Medicine. He
wrote to the journal to complain, noting that the numbers actually
indicated Chantix patients were 2.5 times more likely to suffer a
serious adverse event than those on a placebo.

"I don't know what they were trying to accomplish," Spangler said in a
recent interview. "A faulty study has been included into the world's
medical literature." Pfizer declined to comment on the study.  The
journal, for its part, said via email that the article "underwent
rigorous and independent peer review, and full disclosure of the
authors' employment and funding was made."

Other studies have demonstrated that Chantix has helped some smokers,
but often is no better than other options for quitting. For instance, a
study
<http://thorax.bmj.com/content/early/2008/02/08/thx.2007.090647.abstract
>  [5] published in in the journal "Thorax" in 2008 showed that Chantix
works better than the nicotine patch for some people, but not for
others. Other researchers have concluded that nicotine gum is just as
effective as Chantix.

What's more, most people who give up smoking quit cold turkey, without
medication. A 2006 survey of more than 8,000 smokers by the National
Cancer Institute found similar success rates among those who used
medication in trying to quit and those who didn't. The figures showed
that 16 percent of the non-medicated group abstained from smoking after
nine months, versus 14 percent for the group using medications.

Still, experts such as Lirio Covey, a professor of clinical psychology
at Columbia University who worked on early studies of Chantix, say the
FDA's approval of Chantix made sense. "Some people really have a hard
time stopping smoking. Chantix does have some utility," Covey said. "I
would say that it's a pretty good drug, but it's not the first resort"
for treatment.

For Covey, who said she has received close to $80,000 from Pfizer this
year to study the effects on mood of smoking cessation, the key facts
are these: millions have taken Chantix to stop smoking, and the number
of people who suffered severe side effects is relatively small. In her
estimation, the benefits of the drug outweigh the risks. She also
believes it's still not clear if the side effects are the result of the
drug or nicotine withdrawal.

But questions about why Chantix's safety wasn't fully evaluated extend
back at least to May, 2006, when the FDA's safety reviewer for the drug,
Dr. Howard Josefberg, submitted his report
<http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021928_s000_Chan
tix_MedR.pdf>  [6] to the agency. He endorsed approving Chantix, but
found that Pfizer's clinical trials may have been "too carefully
screened." He noted that the studies excluded people treated for
depression over the previous 12 months as well as "those with histories
of panic disorder, psychosis or bipolar disorder."

"The patient population studied, then, may not represent the true target
population should varenicline be approved," added Josefberg, using the
generic name for Chantix.

The report by Josefberg, who declined to be interviewed for this story,
indicated that three or four people died out of the roughly 5,000
smokers treated with Chantix in clinical trials. FDA researchers,
however, said all of the fatalities appeared to be unrelated to the
drug.

Still, one death in particular piqued the interest of scientists. A
white male in his 60s who took the drug for close to six months took his
own life. "Patient 103510121069 represents the most potentially
concerning case," Josefberg wrote. He "committed suicide by hanging
27-days after completing the 24-week varenicline treatment." The patient
had a history of severe depression but neglected to share his troubled
past with those screening patients, according to FDA documents.

More than 80 other Chantix patients in the trials reported serious side
effects. In one case, a 46-year-old white female, who stopped taking the
drug after a week, arrived at work speaking incoherently, confronting
colleagues, and overturning furniture, according to FDA documents. She
was hospitalized for acute psychosis. Later reports indicated the
patient had some history of psychotic behavior, but had failed to tell
investigators, according to FDA documents.

All told, Josefberg concluded that there was no clear connection between
Chantix and any deaths or serious adverse events, psychiatric or
otherwise. He recommended the FDA approve the drug with a warning that
alerted users to side effects such as potential heart problems, nausea,
insomnia and abnormal dreams, while adding that the trial data was far
from conclusive on the drug's cardiovascular effects.

The routine exclusion of mentally ill subjects from clinical trials,
researchers say, is justified in certain cases. Sometimes the subjects
are too sick to consent to participate. Mentally ill patients may also
fail to follow the proper dose regimens or other instructions. In
addition, including people with mental or other health problems in drug
research can complicate evaluating the results of a medication.

Yet many experts argue that excluding the vast numbers of Americans who
are mentally ill from the trials leaves in doubt the real world effects
of drugs on many people who may be vulnerable. According to the National
Institute of Mental Health, 26 percent of Americans 18 and older, or
close to 60 million people, suffer from a diagnosable mental disorder in
a given year. About 6 percent suffer from a serious mental illness.

Beyond that, the mentally ill account for a big proportion of American
smokers. A report this spring from the U.S. Centers for Disease Control
and Prevention <http://www.cdc.gov/nchs/data/databriefs/db34.htm>  [7]
found that 43 percent of adults with depression smoke, versus 22 percent
of other adults.

Boston University's Lasser, in a recent analysis relying on the broader
definition of mental illness, concluded that people with such disorders
represent about 40 percent of all smokers.

Raymond Lorenz, the author of a recent paper
<http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=2829
>  [8] on Chantix and the mentally ill and a faculty member at Auburn
University's pharmacy school, said more research is needed to gauge the
risks that psychiatric patients face when they take the medication.
Still, he wrote that excluding the mentally ill "seems to be a glaring
oversight" in Pfizer's trials before the FDA approved Chantix.

The FDA could have, but didn't, ask Pfizer to conduct additional
research - in this case, research including mentally ill smokers -
immediately after Chantix was approved. The agency sometimes does that
as a compromise, to ensure that medications reach patients without extra
years of delays, while keeping an eye on a drug's side effects after it
comes into widespread use.

By late 2007, however, the parade of Chantix warnings and restrictions
by federal authorities had begun. That November the FDA issued a warning
<http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm10903
2.htm>  [9] that some patients taking Chantix reported having suicidal
thoughts. Two months later, the agency ordered revised labeling
indicating that Chantix's safety for mentally ill patients was not
established. Other federal agencies also took action, including the
Federal Aviation Administration, which banned pilots and air traffic
controllers from using Chantix.

Finally, in July, 2009, the FDA came around to fully embracing testing
Chantix on the mentally ill. "We are going to require that they study
folks that have mental health disorders," said  Dr. Curtis Rosebraugh,
an FDA drug evaluation official, in a telephone conference call media
briefing
<http://www.fda.gov/downloads/NewsEvents/Newsroom/MediaTranscripts/UCM17
1035.pdf>  [10]. "There is a disproportionate amount [of them] that
smoke and they would be potentially exposed to this drug. We have no
idea if that subgroup population is at higher risk or not and so we do
want to get some sense of that."

Chantix users like Brandon Campbell already have a sense of that.

In July 2007, Campbell, a 33-year-old IT technician at Duke University
Hospital, gave the drug a try after enrolling in an employee wellness
program to quit smoking. Although Campbell, like Ware, had a history of
depression, there was no indication as yet that the safety of the drug
had not been established in people like him. Soon after finishing the
recommended 12-week course of treatment, Campbell recalls, he started
experiencing severe symptoms. He felt disconnected from reality, had
trouble remembering things, and became emotionally unstable-breaking
down over trifles. He also contemplated suicide. He'd been depressed
before, sure, but had never felt, as he put it, like driving over a
cliff.

The problems persisted. This past summer, Campbell said, he sat in his
garage in Durham, North Carolina, with the doors shut tight and the car
running, hoping to die. Then the police started beating on the door, and
he was rushed to the hospital. Campbell still smokes and says he still
wants to quit, but he's exceedingly wary of trying any more
pharmaceuticals. "It's like playing Russian roulette," he says.

________________________________

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http://www.fairwarning.org/2010/12/chantix/

 

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