Tuesday, August 28, 2007

GlaxoSmithKline's Deadly Cover-Up

http://www.alternet.org/workplace/59336/
GlaxoSmithKline's Deadly Cover-Up
By Shelley Jofre, CorpWatch
Posted on August 8, 2007, Printed on August 23, 2007
http://www.alternet.org/story/59336/
A striking young woman with a talent for painting, Sharise Gatchell was
-- like many teenagers -- painfully self-conscious. At 14, she moved
with her family from South Africa to England where at first she found it
hard to make friends. By the age of 16 she was acutely embarrassed that
her periods hadn't started and felt she was sweating excessively. Just
the sort of thing to make adolescence even more painful than usual. Her
mother, Stephanie, took her to see a consultant physician at the local
hospital. Stephanie Gatchell recalls:

"During that consultation she became a bit emotional because she was
explaining to him about the problems she had and how it affected her
social life. Then she started crying and I was amazed. He asked her,
'Sharise, do you sometimes feel like ending it all?', and I couldn't
believe it when she said 'Yes I do.' And then he started talking about
paroxetine and suggesting that she try it."

"Off-label" Prescriptions

Paroxetine -- better known as Paxil in the U.S. -- is an antidepressant.
It is licensed only for adults, but doctors are allowed to prescribe any
medicine if they think it will help their patient, a practice called
"off-label" prescribing. Sharise was not the only teenager getting
paroxetine off-label. Around 7,000 children a year were on the drug in
the UK; and many more in the U.S.

Within days of starting on paroxetine, Stephanie noticed a dramatic
change in her daughter: she became more confident. But with the
confidence came aggression and worse:

"One day in the kitchen her sleeve pulled up slightly and I noticed that
there were cut marks on her left arm. I couldn't believe my eyes. She
was obviously self-harming while she was on the drug, something she's
never ever done before."

Stephanie persuaded her daughter to stop taking paroxetine. But in 2003
Sharise went back on it without telling her mother. When her parents
returned from a weekend break, Stephanie immediately realized something
was terribly wrong:

"I went upstairs before my husband came in, and the moment I got to the
landing at the top and I turned round and looked, she was hanging from
the loft hatch. I tried to revive her, but before I even started I
realized I was too late."

Next to her daughter's suicide note lay a packet of paroxetine.
Stephanie instinctively blamed the drug and now blames herself for
letting her daughter take it. But she couldn't have known what the
drug's manufacturer had known for years.

GlaxoSmithKline Experiments on Children

UK-based GlaxoSmithKline (GSK), the second largest drug company in the
world, which recorded 2006 sales of over $45 billion, had begun a series
of clinical trials in the mid-1990s to test whether paroxetine would
work in depressed children. Paroxetine had already been hailed as a
wonder drug in adults as a treatment for everything from depression and
stress to anxiety and even shyness. By the new millennium 100 million
paroxetine prescriptions had been written worldwide, bringing in $2
billion a year for GSK and placing the antidepressant a close second to
Prozac in popularity.

With the adult market sewn up, the company sought new ways to make money
from the drug, or "life cycle management," as the approach is known in
the pharmaceutical industry. The U.S. Food and Drug Administration
wanted to boost the number of medicines tested for children and had
introduced an incentive that would give companies a six-month extension
on their patent just for carrying out pediatric trials. For paroxetine
alone that would be worth $1 billion. And if GSK could be the first
company to prove its antidepressant was safe and effective for children,
the rewards would be even higher, as paroxetine could become the market
leader.

Hundreds of children were recruited from around the world to take part
in three clinical trials. One group was given the drug, the other a
placebo.
They were randomized controlled trials (RCT) where neither the children
nor their doctors knew whether they were taking the active drug or the
placebo until the end of the study. This is widely accepted as the best
way of working out whether a drug causes a particular effect: the gold
standard in terms of evidence.

But the outcome of these the trials was not what GSK had been hoping
for.
Paroxetine proved no better than placebo. In the biggest trial, Study
329, which was conducted across several sites in the U.S., 11 of the 93
children who took paroxetine developed serious side-effects; seven had
to be hospitalized. Significantly more had self-harmed or attempted
suicide on the drug than on placebo.

The BBC (British Broadcasting Corporation) obtained confidential case
reports from Study 329 which detail what happened to them:

"[13 days after starting paroxetine] the patient became very angry. He
punched pictures, broke glass and sustained lacerations that required
six sutures... he expressed hopelessness and possible suicide thoughts."

"The patient began exhibiting symptoms of disinhibition, grandiosity and
expansive mood around week four [after eight weeks] the patient became
agitated and said she would kill herself."

"[11 days after starting paroxetine] the patient was hospitalized for
psychosis with auditory hallucinations and superficial cuts."

Yet this was a drug that was supposed to make children happier and
reduce the risk of suicide.

The company knew it had a problem. In an internal memo to senior
executives in 1998 the product director for paroxetine admitted:

"The results of the studies were disappointing. The possibility of
obtaining a safety statement from this data was considered but rejected.
Consultation of the marketing teams confirmed that this would be
unacceptable commercially."

In other words, publishing the data in full would undermine the drug's
safety profile and put profits at risk. It took five years for this
information to reach the public domain and only then as a result of the
BBC investigation. In the intervening years doctors continued to
prescribe a drug to tens of thousands of vulnerable children, ignorant
of the fact that it had not been shown to work and was harmful to some.

Lawsuits Reveal Questionable Paper Trail

This has been described by British psychiatrist Dr. David Healy as "the
biggest medical scandal since thalidomide." Dr. Healy, rather than the
regulatory authorities charged with monitoring the safety of medicines,
was instrumental in uncovering the evidence at the heart of the scandal.
It was a series of U.S. legal actions that led Dr. Healy, as an expert
witness, and the legal team with whom he was working, deep into GSK's
secret archives, where they found a series of damning internal
documents.

What this paper trail reveals is how the company, with no hope of
obtaining a children's license, devised a back-door method of marketing
paroxetine for childhood depression. In came the spin-doctors to bury
the inconvenient facts and spread the good news to doctors around the
world that paroxetine was safe and effective for children.

Drug companies discovered long ago that doctors are much more likely to
be persuaded by their peers than by the hard sell of sales reps. So GSK
built a business relationship with several leading academics to write
articles and speak at conferences, effectively selling paroxetine for
the company. They are known in the trade as "Key Opinion Leaders."

Internal company documents reveal that Professor Martin Keller, Chair of
Psychiatry at Brown University in the U.S., was one of the company's
leading Key Opinion Leaders. He was named as the author of Study 329.
But the documents cast doubt on whether he actually analyzed the data
himself and wrote the final paper. In a memo, Professor Keller thanks a
ghost writer for the initial preparation of the study manuscript -- a
ghost writer who works for a medical public relations company hired by
GSK:

"You did a superb job with this. Thank you very much. It is excellent.
Enclosed are some rather minor changes from me."

It is clear from the internal correspondence that the ghost writer was
making some important decisions about how to present the data for
publication. At one point a senior GSK executive comments that: "It
seems incongruous that we state that paroxetine is safe yet report so
many Serious Adverse Events."

GSK suggests to the public relations person that she make clear
paroxetine may have caused all 11 of the serious side-effects. But the
final article
says: "Of the 11 patients, only headache (1 patient) was considered to
be related to the treatment."

The paper never states clearly how many children became suicidal, nor
does it explore whether the drug was to blame. Instead, it concludes
that paroxetine is "generally well-tolerated and effective".

The next step in GSK's marketing plan was to get the study published.
Doctors rely on medical journals to give them advice they can trust. The
first journal GSK approached spotted flaws in the study and rejected it.
So the company sent it to the premier children's mental health magazine,
the Journal of the American Academy of Child and Adolescent Psychiatry.
Its peer reviewers also spotted the flaws, as is clear from their
confidential
comments:

"Overall. Results do not clearly indicate efficacy, authors need to
clearly note this."

"The relatively high rate of serious adverse effects was not addressed
in the discussion."

"Given the high placebo response rate, are [these drugs] an acceptable
first-line therapy for depressed teenagers?"

Nevertheless, the journal published the study. Who knows how many child
and adolescent psychiatrists around the world were influenced by the
article's misleading conclusion?

At the same time, another of GSK's PR people was saying in an internal
memo:

"Originally we had planned to do extensive media relations surrounding
this study until we actually viewed the results. Essentially the study
did not really show paroxetine was effective in treating adolescent
depression, which is not something we want to publicize."

Objective Medical Opinion?

When I first started looking at Study 329 for the BBC in 2002, I was
confused about its findings. The published article's conclusions seemed
at odds with the details of the study. I went to Philadelphia to
interview one of the authors and came across another of GSK's Key
Opinion Leaders -- Dr.
Neil Ryan, an eminent child psychiatrist at the University of
Pittsburgh. He was speaking at an American Psychiatric Association
symposium sponsored by GSK but I had no reason at that time to think he
was anything other than independent.

Dr. Ryan told the audience that paroxetine was effective for children
with depression. He didn't mention anything about the apparent high rate
of psychiatric side-effects of paroxetine in Study 329. But the more I
studied the data, the more convinced I became that paroxetine was
causing serious problems for some kids who took it. When I returned to
Britain, I pursued him by telephone but he refused to talk to me about
it.

Fast forward four years, when the internal GSK documents revealed what
had actually been going on behind the scenes. Dr. Ryan had been asking
the company that sponsored his research how he should deal with my
awkward questions, emailing all my correspondence to them. In one email
he said:

"I'll call you again later today and you can advise on how might be best
to handle this."

GSK denies that it promoted paroxetine for off-label use through Key
Opinion Leaders or any other route, laying the responsibility firmly at
the door of individual clinicians.

A statement issued by the company reads: "Any decision to prescribe a
medicine outside its authorized indications, in the EU or the U.S., is
made by a doctor on the basis of his/her clinical judgement and the
interests of their patient."

But where do doctors get the information from that gives them the
confidence to prescribe off-label? From medical journals and
conferences.

It was the documents that in the end exposed the Key Opinion Leaders and
the drug company. Without the U.S. legal action we would have been none
the wiser. The drug is now effectively banned in the UK for use in
under-18s and in the U.S. it carries a "black box" warning about the
risk of suicidal behaviour.

This drug was GSK's golden egg for many years and a lucrative business
was built around its promotion. So it is perhaps not surprising the
company dismissed my investigation as media scaremongering. What is
surprising, though, is how many doctors on both sides of the Atlantic
who claim to practice evidence-based medicine still refuse to
acknowledge the damage the drugs can do -- even though the evidence
comes from GSK's own RCTs and the company's internal correspondence
clearly shows how they tried to cover it up.

Sales Affected by Warning Labels

Dr. Mike Shooter, former President of the Royal College of Psychiatrists
and a child psychiatrist who used to prescribe paroxetine, says:

"I personally felt cheated and heaven only knows what the children,
adolescents and their parents and their doctors on the other end of that
felt. Very much the same. This has huge implications, right through
medicine."

Professor Keller and Dr. Ryan seem unabashed by their role in the
scandal. A few months ago Professor Keller co-authored another paper, on
the impact of media reporting on prescribing. Rather than exploring how
those conducting the trials overlooked the damage to children caused by
the drug, he and his co-authors expressed concern that prescriptions of
antidepressants to children have declined sharply in the U.S. since the
addition of the black box warning -- as if the increased risk of
suicidal behaviour on the drugs wasn't something that should affect
prescribing.

The FDA is now considering whether to remove the black box warning on
paroxetine and other similar antidepressants because it is scaring
doctors.
In the UK, the regulatory authorities are investigating whether GSK
acted fraudulently in its conduct over Study 329. Theoretically,
criminal charges could be brought, but the medicine's regulator is
fully-funded by the drugs industry, so don't hold your breath.

Meanwhile, Stephanie Gatchell and her husband have moved away from the
home that holds so many awful memories, to start a new life in Ireland.
They can't forgive GlaxoSmithKline for concealing what it knew about
paroxetine:

"I can't understand how they could possibly be so devious, and all just
because of profit. I think the decision-makers in that company should be
brought to justice. They have a lot to explain."

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