PFPC Daily - December 10, 2004

PFPC Daily - December 10, 2004

Drug Maker Withheld Paxil Study Data

ABC News Uncovers Documents Unknown to Regulators and Many Doctors

ABC News - Dec. 9, 2004

— New documents uncovered by ABC News suggest GlaxoSmithKline,
the maker of the popular antidepressant Paxil, failed to disclose
important information about the possibility of an increased risk of
suicidal behavior in some children taking the drug, as well as
serious withdrawal symptoms when some patients stop taking Paxil.

The new documents obtained by the ABC News program "Primetime Live"
have never before been made public. Earlier this year, the Food and
Drug Administration ordered manufacturers to place a warning in bold
print on antidepressants, alerting consumers that the drugs can cause
suicidal tendencies in children and teenagers.

The FDA's move raised the issue of how much antidepressant
manufacturers knew about this increased risk and when.

While Congress and the FDA have held hearings questioning
GlaxoSmithKline and other drug manufacturers about suppressing
studies that cast their products in a negative light, "Primetime
Live" has obtained actual copies of GlaxoSmithKline reports from its
own internal studies. In these studies, some children showed the same
types of suicidal thoughts and behaviors that parents had for years
claimed their children were exhibiting.

According to these documents, internal studies by GlaxoSmithKline
concluded that Paxil had little or no effect in treating depression
in children and adolescents. And as far back as 1997, the company was
aware of studies reporting suicide-related behaviors in young
patients taking the drug.

In spite of this information, GlaxoSmithKline distributed a memo to
its sales force in 2001 touting the drug's "remarkable efficacy and
safety in the treatment of adolescent depression."

See the memo.
http://abcnews.go.com/images/Primetime/paxil_remarkable.pdf

Additionally, the internal documents reveal GlaxoSmithKline had
scientific evidence Paxil could cause mild to severe withdrawal
symptoms in some patients when they abruptly stopped taking the drug.
A document the company distributed to sales staff referred to
"withdrawal symptoms" and said they included problems like dizziness,
nausea, fatigue, insomnia and nightmares, but advised the sales
representatives to use the less-alarming term "discontinuation
symptoms." The documents suggest GlaxoSmithKline's sales strategy was
to downplay this information in order to maintain its share of the
billion-dollar antidepressant market.

"This is about money," said Rep. Henry Waxman, D-Calif., who is on a
congressional committee investigating antidepressant manufacturers.
"This is not about science, because what they're doing is withholding
the scientific information, suppressing the studies that could have a
negative impact on their sales and their profits."

Drug Maker Under Attack

In addition to the investigation by Congress, the New York attorney
general's office in June of this year leveled charges of consumer
fraud against GlaxoSmithKline. The lawsuit alleged that the drug
giant repeatedly concealed information about Paxil from doctors.

The attorney general's lawsuit noted that GlaxoSmithKline conducted
at least five studies of Paxil's use in children and adolescents, but
the company only published one of these studies — a decision at
the heart of the controversy.

Central to the attorney general's allegations were two Paxil studies
for depression in children and adolescents. ABC News has obtained
original documents from those studies.

In one study, referred to by the company as Study 377, researchers
noted some children exhibiting suicidal behaviors and attempts to
kill themselves. Referring to that study and another, Study 329, an
internal GlaxoSmithKline memo acknowledged that Paxil "failed to
demonstrate a statistically significant difference from placebo on
the primary efficacy measures."

The same internal memo went on to identify a single goal: "to
effectively manage the dissemination of these data in order to
minimize any potential negative commercial impact."

The document recommends that the company not seek government approval
for Paxil's efficacy or safety in treating depression in adolescents
at that time because they believed that they would not get that
approval and "it would be commercially unacceptable to include a
statement that efficacy had not been demonstrated, as this would
undermine the profile of [Paxil]." Finally, the memo concludes,
"Positive data from Study 329 will be published in abstract and a
full manuscript of the 329 data will be progressed."

The results from Study 329 were ultimately published in the Journal
of American Child Adolescent Psychiatry in 2001 with the conclusion
"Paxil is generally well tolerated and effective for major depression
in adolescents."

The New York attorney general criticized the publication of this
article, saying, "Although it allowed the data from study 329 to be
published, GlaxoSmithKline concealed and suppressed studies 377 and
701, which failed to show that [Paxil] was more effective than
placebo in treating [depression] in children and adolescents."
Nonetheless, a 2001 internal memo to the company's sales reps touted
the study as showing Paxil is "truly a remarkable product that
continues to demonstrate efficacy" in adolescents.

See the memo.
http://abcnews.go.com/images/Primetime/paxil_remarkable.pdf

GlaxoSmithKline says its reps were not supposed to discuss the memo
with doctors and notes it was stamped "For representatives'
information only," but the New York attorney general's complaint
charged that the company would only have sent the memo to its reps
"to falsely characterize Study 329 in their communications with
physicians." GlaxoSmithKline later settled the lawsuit, without an
admission of wrongdoing, but paid a $2.5 million fine and promised to
make all of its research available online.

GlaxoSmithKline defends its public disclosures regarding suicide
risks, saying that in each individual pediatric study the numbers
were too small to be statistically significant. GlaxoSmithKline also
claims that it wasn't until data were pooled from all antidepressant
studies that the increased risk of suicide became clear. It and other
drug companies also say there's no way to prove that any individual
suicide-related behavior was caused by the drug and not the patient's
underlying depression.

The makers of Paxil, Effexor and Zoloft said they have not endorsed
the use of their antidepressants in children or adolescents. They
also point out that during their pediatric trials no one actually
committed suicide.

Downplaying Withdrawal Symptoms

Paxil belongs to a class of antidepressants known as selective
serotonin reuptake inhibitors, or SSRIs. Like other SSRIs, Paxil can
cause withdrawal symptoms when patients stop using the drug. Until
2001 there was no clear warning or precaution in the prescribing
information provided to doctors by GlaxoSmithKline.

In prescribing information up to December 2001, the company only
mentioned "withdrawal syndrome" as a rare potential side effect
associated with the nervous system, but without explaining what
"withdrawal syndrome" is. GlaxoSmithKline also mentioned spontaneous
reports of "discontinuation symptoms," but explained these reports
"may have no causal relationship with the drug."

But "Primetime Live" discovered an internal safety review dating from
1997 that provided scientific evidence from GlaxoSmithKline studies
of withdrawal effects caused by Paxil. There was never any mention of
these studies and the specific results in any of the official
prescribing information made available to American doctors and
patients.

Starting in December 2001, GlaxoSmithKline included a precaution to
make doctors and patients aware of some possible "discontinuation"
side effects affecting "2 percent or greater" of patients based on
studies.

According to the 1997 review, one study found that 25 percent of
patients taking Paxil in one experienced discontinuation symptoms
(vs. 5.9 percent for patients taking a placebo). In a study of
patients with major depression, 42 percent of the patients taking
Paxil experienced one discontinuation symptom.

GlaxoSmithKline told "Primetime Live" that "most of the individual
studies have been made public either through publication in a
peer-reviewed journal or presentation at a major medical meeting."
But none of the medical experts contacted by "Primetime Live" knew
about this data, and GlaxoSmithKline did not make those publications
or presentations available, despite repeated requests.

Despite these studies, these documents reveal that GlaxoSmithKline
instructed its sales force to downplay or minimize the negative
effects of discontinuing Paxil from doctors.

A 1998 "business plan guide" for sales reps instructed them to
"minimize concerns surrounding discontinuation symptoms." Sales reps
were also told to explain to doctors that the "discontinuation
incident rate is two in 1,000 patients." This rate is markedly
different from the results of the studies in the safety review
published nine months earlier.

See the Business Plan Guide.
http://abcnews.go.com/images/Primetime/paxil_bpg.pdf

In a company-sponsored education program for sales representatives,
"withdrawal syndrome" was clearly defined as "a class effect that can
occur when an SSRI is stopped abruptly. Symptoms may include
asthenia, flu-like symptoms, fatigue, dizziness, nausea, and sleep
disturbances (insomnia, vivid dreams or nightmares)." However, the
next direction recommended reps avoid using the term: "instead of
'withdrawal syndrome,' which implies addictive properties, try to
refer to this phenomenon as 'discontinuation symptoms.'"

One vivid reminder of the importance of Paxil to GlaxoSmithKline is
found on a May 1997 sales memo. Sales reps are reminded, "Let's face
it in the end. [sic] The only thing the anxious and agitated patient
will be saying is: 'Where's my Paxil!!!!!!'" The comment is
illustrated by a cartoon of a screaming woman.

See the May 1997 sales memo.
http://abcnews.go.com/images/Primetime/paxil_wheresmy.pdf

As if to underscore the importance of Paxil to GlaxoSmithKline,
another company sales document graphically explained why
discontinuation is an issue. The answer: $1 billion, the total sales
of Paxil and Seroxat (a related SSRI) as of September 1997. This
statement is illustrated by a large, black money bag.

See the "money bag" memo.
http://abcnews.go.com/images/Primetime/paxil_moneybag.pdf

A Publishing Coincidence

In a 1997 memo, a public relations firm working for GlaxoSmithKline
drafted a letter on the topic of discontinuation symptoms that was
apparently intended for publication by a company spokesperson or
possibly a physician.

The memo explained that "complete duplication will look fishy if we
decide to submit both. Are there other references we could draw on
for the various drugs? At the very least, we can't have the
references appear in the same order." The draft letter listed three
physicians as the intended senders, including Dr. Bruce Pollock of
the University of Pittsburgh.

A letter by Pollock appeared in the October 1998 issue of the Journal
of Clinical Psychiatry. Although Pollock's letter was not the same as
what the PR company drafted, it made nearly every point in the draft
— almost in the same sequence.

See the PR company's draft letter and Dr. Pollock's letter to the
journal.
http://abcnews.go.com/images/Primetime/paxil_pollock.pdf

Pollock, who was on the company's advisory board at the time, told
"Primetime Live" he wrote the published letter and stands by its
accuracy. He did say, however, he "could imagine a scenario where a
representative from the makers of Paxil said, 'Could you make this
point?'" because it was well-known that he had studied Paxil in
elderly patients. But he denied that he had any knowledge of
intentions to use his letter in a marketing plan, or that he had any
knowledge of the draft letter prepared by the PR firm that included
his name.

This published letter resurfaced once again in the internal
memorandum obtained by "Primetime Live." The company's 1998 business
plan guide for sales reps cited Pollock's letter as "an effective
tool for addressing discontinuation."

GlaxoSmithKline declined to comment on these documents, saying "it is
difficult to respond to court documents taken out of context." In
court, they have said they provided adequate and complete warnings to
physicians about the risks of withdrawal. In a letter to "Primetime
Live," they also said the majority of patients who experience any
symptoms have mild to moderate symptoms that are usually
self-limiting within two weeks.

ABCNEWS' Greg Fisher, Kate Sheekey, Kim Launier and Marc Lallanilla
contributed to this report.

SOURCE:
http://abcnews.go.com/Health/story?id=311956&page=1