Hard To Swallow - Changeling Aspects

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tories
Is hormonereplacementtherapysafefor women?Thecontroversydeepenswith
newrevelationsthat drug companiesexerta powerfulhiddenswayoverthe
scientificliterature on whichGPsrely.RichardGuilliattreports
D
R JOHN EDEN WAS ON HOLIDAY IN TASMANIA
~
when he found out he was under investigation
by the US government. It was just before
Christmas 2008, and Eden - an associate professor at the University of NSW and one of Australia's
leading researchers on women's health - got an email from
a New York Times reporter bearing unpleasant news: the
Senate Finance Committee in Washington had just identified him as one of several researchers who allegedly put
their names to "ghost-written" scientific papers paid forby
-;
the multinational
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drug firm Wyeth Pharmaceuticals.
It was Eden's first intimation of a controversy that
'"- has since swept through
the world of medical research,
taking his reputation along for the ride. Wyeth, it was
claimed, had tried to downplay the dangers of its billionI
I
i
!
selling hormone-replacement
drugs for menopausal
women by secretly sponsoring dozens of scientificarti-
!
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cles that supported the drugs. One of the offending articles had appeared under Eden's name in the prestigious
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American Journal of Obstetrics & Gynecology in 2003.
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THE WEEKEND AUSTRALIAN MAGAZINE I APRIL 3-4 2010
Via a shaky internet connection in Launceston, Eden
watched aghast as headlines such as "Doctor named in US
drug inquiry"circulatedthe internet. ByChristmasEveThe
New YorkTimeswas reporting that the journal that pubI
lished his paper had launched its own investigation. His
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superiors at the university, meanwhile, were seeking an
explanation. "Itwasn't much of a Christmas holiday;'recalls
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the 53-year-old director of the SydneyMenopause Centre.
ii I
Since then the scandal has all but disappeared from
the news here, and even Eden himself was unaware of the
revelations that have followed. For since late last year more
than 1000 documents from Wyeth's internal files have
appeared on the internet, a trove of confidential emails,
memos and reports that lay bare the details of the company's "strategic publications" scheme. They show that
Wyeth orchestrated the production of more than 40 scientific papers - including Eden's - as part of a calculated
strategy to increase sales of its Premarin hormone-replacement drugs. The papers deliberately focused on reassuring
research about the drugs at a time when mounting
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evidence showed that women taking them suffered higher risks of
breast cancer, strokes and heart disease.
To Eden, the documents are both a shock and an embarrassment.
They reveal the full details of Wyeth's role in his paper - and even
show that one of the drug company's senior executives testified that
Eden did not actually write it. That's a claim Eden adamantly denies,
saying he had full control of the article's contents. But he says he now
realises the drug company duped him into helping push its commercial agenda. "I feel stupid - angry," he says. "I look back and ask myself:
How could I have been so naive?"
For a lot of women, the issue has deeper significance, for it goes
to a question that has rattled around medical science for decades.
How safe is hormone replacement therapy (HRT)? And how much
of the scientific literature that doctors rely on to judge such questions is influenced by the hidden hand of the $750-billion-a-year
drug business?
that the company had produced under subpoena as it fought damages
claims brought by women who blame Premarin for their breast cancer.
The University of California has since collated the documents into a
database called the Drug Industry Document Archive.
The documents show that in 1996 - as Wyeth launched its new
menopause treatment Prempro - the company enlisted the help of a
New Jersey medical communications company called DesignWrite,
founded by a former journalist, Mitch Leon. DesignWrite proposed
that its staff work with Wyeth to create a range of research papers on
HRT that would be published in major medical journals in order to
"set the scientific agenda" and "minimize [the] impact of negative
findings': How these papers would be written was described in unequivocal terms. "The first step is to choose the target journal best
suited to the manuscript's content, thus avoiding the possibility of
manuscript rejection," Design Write's proposal stated. "DesignWrite
will then analyze the data and write the manuscript, recruit a suitable
well-recognized expert to lend his/her name as author of the docuA rocky history
ment, and secure the author's approval of its
content:' The ultimate aim was "to establish
JUST AS THE CONTRACEPTIVE PILL FREED
a greater need for estrogen/hormone
generations of women from the tyranny of
replacement therapy while allaying unrealisunwanted pregnancy, menopausal drugs
tic fears that physicians and patients have
have long been sold as female emancipation
concerning the therapy:' Wyeth initially
in a tablet - an antidote to the late-life spec,
hired Design Write to prepare 20 scientific
tre of "the change". Initially prescribed to
papers at a cost of $US464,000.
ameliorate the hot flushes and mood swings
One ofWyeth's senior marketing execuof menopause, HRT was embraced by many
tives, Jamie Durocher, has since elaborated
women as a proverbial elixir of youth that
on how the program worked while testifying
was said to improve skin, pep up sex, make
bones sturdier and ward off heart disease
in an Arkansas courtroom in 2007. Durocher
said Wyeth staff typically came up with the
and senility. The US author Gail Sheehy capsubject matter of the various articles based
tured her generation's evangelical enthusion their scientific knowledge; DesignWrite
asm for the drugs in her best-selling 1992
would then prepare an outline, send it to a
book The Silent Passage.
scientist who had been targeted as the evenThe rocky history of these drugs is inextual author, and then "move towards prepartricably tied up with drug giant Wyeth ing a draft based on the author's guidance':
recently acquired by pfizer for $US68 billion
- which marketed the blockbuster menoWyeth had no problem finding willing
participants,
because many clinicians
pause treatment Premarin. Launched in the
In July 2002 a major US
already had close ties to the company and
early '40S by Wyeth's sister company Ayerst
were keen proponents of HRT. Like many
Laboratories, Premarin became the beststudy concluded that women
drug companies, Wyeth funnelled millions
selling drug in the US after the publication
on Prempro had a 26 per
of dollars to scientists conducting clinical
of Feminine Forever, a hit 1966 book by New
cent higher risk of breast
trials ofits drugs; it also funded major womYork GP Robert Wilson. Wilson pronounced
cancer... The announcement
en's health organisations such as the North
that menopause was a disease and estrogen
was
a
disaster
for
Wyeth,
was the cure which would transform women
American Menopause Society. ByDecember
whose menopause drugs had
from shrivelled "castrates" into late-bloom2000, Wyeth had 41 papers in production,
just
reached $US2 billion
some of them with authors marked as "to
ing roses. Only after his death was it revealed
in sales
be decided". The papers were targeted at
that Ayerst had helped finance his work.
more than two dozen science journals, and
Sales of estrogen drugs slumped in the
their prospective authors included some of the world's most highlate '70Safter it was discovered they caused uterine cancer, but their
profile researchers into menopausal drugs.
popularity surged again after scientists discovered that administering
Dr John Eden came to Wyeth's attention because his clinical
an additional hormone, progesterone, solved that problem. Sales
studies of women being treated for breast cancer at the Royal Hospispiked even further in the late '80S when Wyeth - by then fully merged
tal for Women in Sydney suggested that high doses of progestin - the
with Ayerst - began heavily promoting HRT as a preventative for
extra hormone in Wyeth's new drug Prempro - could actually reduce
osteoporosis, prompting doctors to recommend long-term use of the
recurrence of the disease. This appeared to contradict studies that
drugs to promote longevity.
With 70 per cent of the market, Wyeth's m~nopause drugs were
showed progestin increased the breast cancer risk. In June 2000
approaching annual sales of $USl billion in 1996. But by then the
Wyeth flew him to New York to present his research at a companycompany had'a new problem - the year before, a survey of more than
hosted symposium, and at dinner on the opening night he met the
80,000 USwomen published in The New England Journal of Medicine
Wyeth marketing executive Mark Barbee. A month later, Barbee
had shown that those on HRT suffered a significantly higher inciemailed Eden to say that the Australian's research was "invaluable to
t- dence of breast cancer. The finding appeared to confirm a long-standus as we move our business forward", offering the assistance of a
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writer to turn the presentation into a published paper.
ing fear about the drugs which Wyeth needed to neutralise. The plan
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Eden says today that he had no idea that Wyeth was in the process
it came up with would ignite the controversy that has engulfed Dr
o
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0..
of financing more than 40 such papers. "If I had any idea, I would
John Eden and dozens of other leading menopause researchers.
have said, 'Forget it';' he asserts. Like many researchers, he was used to
The.full details have only become available since last year, when
getting editorial assistance from librarians and university staff, and he
US courts began releasing hundreds of internal Wyeth documents
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THE WEEKENDAUSTRALIAN MAGAZINE / APRIL 3.4 2010
Eden's paper was still being assessed by that journal when a bombhad accepted honoraria from drug companies for many years. He says
shell landed on the world of menopause research: in July 2002 the US
Wyeth's offer did not strike him as untoward.
National Institutes of Health announced it was abandoning a major
DesignWrite was a one-stop shop - it drafted, edited and revised
study of 16,000 women taking Prempro because they were suffering
manuscripts for scientists, then provided them with a complete packsignificantly higher rates of breast cancer, strokes and heart disease.
age of material to expedite publication, including template letters
The Women's Health Initiative study concluded that women on Premaddressed to the target journals and the suggested names of peerpro had a 26 per cent higher risk of breast cancer, 29 per cent more
reviewers. If queries were raised in the peer-review process, Designheart attacks and double the rate of blood clots.
Write would perform rewrites. All the time, the company was liaising
The announcement was a disaster for Wyeth, whose menopause
with Wyeth to ensure the papers suited the company's commercial
drugs had just reached $US2 billion in annual sales. The worldwide
needs. In one email a Wyeth executive urged the company to find
alarm it sparked was exemplified by the front-page headline in Sydadditional scientists who would be "advocates" for its drugs; another
ney's Daily Telegraph, which urged "CALLYOUR GP': Not only were
Wyeth staffer suggested "repurposing" some papers to help improve
the breast-cancer risks of HRT confirmed, the purported long-term
market expansion in South America.
benefits of the drugs were thrown into question.
The Eden paper is cited in a trail of Wyeth documents that
In late 2002, Eden quickly revised his paper to take in the new
provide a case study of how the process worked. Shortly after Wyeth
findings. Unbeknown to him, Design Write's staff were scrutinising it
flew Eden to New York in June 2000, the company's marketing staff
to look for "anything that the client [Wyeth] might have an issue
met with Design Write and - according to the minutes of that meet.
with".The final paper argued that there was
ing - "John Eden was suggested as the author
1
no definitive evidence linking progestins to
of a breast cancer paper questioning the role
breast cancer - a message Wyeth must surely
of progestin as a causative factor". After Eden
have thought timely. It was published in May
accepted Wyeth's offer of a writer's assist2003, as the Editor's Choice article in the
ance, Design Write hired a young West Coast
American Journal of Obstetrics & Gynecolmicrobiologist, Caron Pruiett, to write an 8ogy. In a notation at the end, Eden acknowl10page manuscript entitled Breast Cancer &
edged the "editorial assistance" of Karen
Progestins, based on an outline and bibliogMittelman and Stephen Parker, but failed to
raphy provided to her. Pruiett, who at that
mention that they worked for DesignWrite,
time worked in a laboratory examining cator that Wyeth had paid for their work.
tle faeces and wrote science papers to sup"I look back now and I think, 'Why did I
plement her income, was instructed to pay
do that?'" he says, admitting it was an error
particular attention to "why progestins may
of judgment. "I wrote the paper, I acknowlnot be responsible for the incidence of breast
edged the two people who helped me. My
cancer in hormone replacement therapy
mistake was not mentioning that they were
(HRT) users".
funded by Wyeth:'
DesignWrite paid Pruiett $US3000 for
her work, which resulted in an ll-page "draft
Laughing off the scandalI
outline" with 70 footnotes. But the draft
JOHN EDEN WAS NOT ALONE IN FAILING TO
paper caused some disquiet inside Wyeth: at
acknowledge Wyeth's contribution to his
a meeting in July 2001, DesignWrite agreed
to revise it after concern was raised about
paper - other researchers recruited into the
DesignWrite hired young
company's "strategic publications" program
"[the] message with respect to pipeline prodmicrobiologist Caron Pruiett to
did likewise. As a result, little was known
ucts". At another meeting a month later it
write a manuscript entitled Breast
about it until December 2008, when the US
was decided the draft would be reviewed by
Cancer & Progestins, based on an
Senate Finance Committee released a raft of
Wyeth's marketing department before being
outline and bibliography provided
sent to Eden.
internal
Wyeth documents it had obtained
to her. Pruiett at that time worked
as part of an investigation into medical
Shown a copy of Pruiett's draft paper,
in a laboratory examining cattle
ghost-writing. Among them were details
Eden says he has no recollection of ever seefaeces
and wrote science papers
about the Eden paper.
ing it, although more than half of it later
to supplement her income
At the time, Eden refused to comment
appeared in his published paper. Heacknowlother than to say he stood by his article.
edges, however, that DesignWrite may have
Wyeth dismissed the headlines, saying it had exercised no control
prepared the first draft based on the PowerPoint slides from his New
over the content of the articles and had not paid the researchers for
York presentation. "What happened was that the draft would come
them. Some of those researchers have since laughed off the contro[and] I would say, 'No, this is wrong, move this around, do this, do
versy. Dr Leon Speroff, a former professor of obstetrics at Oregon
this: and send it back;' he recalls.
Health Sciences University, told Milwaukee's Journal Sentinel newsWhat he didn't realise, he says, is the role Wyeth had played in
paper he saw nothing wrong with putting his name to a paper written
formulating the paper and monitoring its contents. "They certainly
by Design Write's staff. "If you don't like the way it works;' he said,
never made it clear that they were going to read the paper;' he says.
"that's your business:' Speroff's paper was a critique of the evidence
"Whether they made suggestions or not I don't know - I don't want to
linking HRT with breast cancer; DesignWrite's internal files indicate
know,to be honest - but the fact that this Design Write were giving it
it was written by a staff member with a PhD in dietary science. In May
to [Wyeth's] people to look at - I'm offended. I'm highly offended:'
2001, Speroff sent her an email saying: "You did a super job of writing
DesignWrite's files show its staff working closely with Eden over a
this paper - succinct and makes the points very wel!:'
period of more than a year, sometimes suggesting changes and offerAnother high-profile expert involved in Wyeth's program was the
ing to carry out edits. A November 2001note reads: "manuscript sent
author aQd New York University professor Lila Nachtigall. She denied
to author for review"; the following month Eden sent revisions back
her paper was ghost-written but commented that the Senate's investiand in March 2002 he submitted the paper to the Archives of Internal
gation "kind of makes me laugh".
Medicine in Arizona. When the journal rejected the article, DesignOthers are not so sanguine. Professor Alastair MacLennan of the
Write sent Eden a new covering letter, this time addressed to the
University of Adelaide was co-editor of the journal Climacteric in 2000
American Journal of Obstetrics & Gynecology in Ohio.
APRIL3-4 2010 / THE WEEKEND AUSTRALIAN MAGAZINE 15
--
--
when Professor Rogerio Lobo of Columbia University submitted a paper
nately it's fanned by some doctors. 1mean, the number of women I've
to him for publication. The article, which listed the British researcher
talked to who say, 'I was told my HRT gave me breast cancer' ... These
Or Mark Whitehead as co-author, argued that low-dose HRT therapy
are the things women are told, and that spreads through the populahas "tremendous potential" for improving women's health. It was one
tion." The result, he says, is that many women with severe and debiliof many papers Wyeth paid for as it prepared to launch a low-dose
tating symptoms are not getting treatment.
HRT pill. Lobo emphatically denies the paper was ghost-written. But
But Or Andrew Penman, CEO of the NSW Cancer Council, points
Climacteric, which published the paper in 2001, has launched an
out that the risks are cumulative, so that a woman on HRT for 10years
investigation after MacLennan became aware of several documents
doubles her risk of breast cancer. That is not trivial, he says, and the
on the Drug Industry Document Archive, among them a 26-page draft
nine per cent decline in breast cancer which has been recorded since
of the article which Design Write sent to Lobo in November 2000.
women began shunning the drugs in 2002 supports that. Asked about
MacLennan is no longer an editor of Climacteric and says he is
Wyeth's financing of scientific papers on HRT safety, Penman says the
reluctant to comment until the matter has been fully investigated.
"review" papers of the type Wyeth paid for are often influential because
But he has proposed that it publish a discussion of the broader issue
their authors have an eminence in their respective fields. ''It's not for
of "parties with vested interests" potentially influencing the content
me to judge the merits or motivations that lay behind anyone of these
of papers. "Ifthe veracity of the authorship is in doubt the new editors
articles," he says. "But it does raise the issue of whether the process of
and the editorial board may choose to publicly withdraw the Climacscientific publication has been used for proprietary purposes:'
teric and Index Medicus [the index of medical scientific journal arti,The revelations about Wyeth follow other pharmaceutical
.
cles] record of this publication;' he says.
industry scandals, most recently when
Or John Eden, meanwhile, says he feels
Merck & Co was shown to have promoted
like an "idiot" after The Weekend Australian
its anti-arthritis drug Vioxx by secretly
Magazine showed him documents detailing
financing a journal, The Australasian JourWyeth's hidden role in his paper. "Tome, this
nal of Bone &Joint Medicine, which was full
is clear-cut - they had an agenda and they
of pro-Vioxx articles. It has since been
made me part of their agenda without telling
revealed that five other journals published
me ... It goes toward integrity and we acaby the prestigious Elsevier company were
demics take that really seriously. Looking
financed by drug companies. Public health
back, I'm embarrassed to think I didn't realexperts in the US have decried such pracise that. I was deceived:'
tices, saying they call into question the
The embarrassment for Eden is comreliability of the scientific literature on
pounded by the testimony of Wyeth's Jami~
which many GPs base their decisions.
Durocher before the Arkansas District Court
Pfizer, which bought Wyeth last year,
in 2007. Asked who wrote the Eden paper,
defends Wyeth's publishing activities as
she replied: "The manuscript was written, as
"responsible" and denies the articles on HRT
we've seen, by a medical writer, but based on
were ghost-written. "Medical writing comOr Eden's agreement with the outline a,ndthe
panies assisted authors only in drafting
subject matter. And of course, Or Eden had
manuscripts, and authors themselves had
''';:",~
reviewed the full manuscript, made changes
total control of the content of these papers,"
:..§ ""~,
to the manuscript ... and obviously states
says spokesman Christopher Loder. He adds
that this is his manuscript."
that since last year pfizer has begun fully
Eden rejects that ,account, saying the
disclosing its financial relationships with
paper is entirely grounded in his work and
"Theyhad an agenda and they
physicians, medical organisations and
he had no contact with anyone from Wyeth
patient advocacy groups. Loder does not
made me part of their agenda
during its preparation. A comparison of
respond directly to Eden's claim that Wyeth
without telling me ... Itgoes
Design Write's draft version and the final
deceived him, although he notes that Eden
toward integrity and we academics
published paper shows they are substanstands
by the contents of his article.
take that reallyseriously. Looking
tially different, and the American Journal of
pfizer
is now fighting a raft of lawsuits in
back, I'membarrassed to think I
Obstetrics & Gynecology informed Eden two
the
US
from
women who developed breast
didn't realise that"
Or John Eden (above)
weeks ago that its investigation had concancer while taking Premarin or Prempro.
Some of those cases have been settled out of
cluded it was not ghost-written, was unbiased and was of high scientific quality. "This is one of the best papers
court, others the company has lost - although it has announced
I've ever written;' he says. "I had control. But from my perspective,"
plans to appeal. Meanwhile, sales of HRT drugs have plummeted
he adds, "it's tainted."
since 2002 and some have been taken off the market.
For researchers such as Eden, the US litigation casts a long shadow.
Dissenting opinions on HRT
"My research budget is smaller than it's ever been;' he says. "No one
IN FEBRUARYTHE NATIONAL INSTITUTES OF HEALTH IN THE US
wants to fund HRT research; it's a problem, it really is."In his younger
reaffirmed its finding that the risks of HRT outweigh the benefits,
years in academia, he remembers, colleagues spurned the "dirty
saying new analysis showed it doubled the risk of heart disease within
money" of the drug industry, but over the past 20 years it has become
two years. The announcement followed an earlier bulletin which
a hallmark of the synergy universities encourage their staff to pursue.
stated that "overall risks, including risks of stroke, blood clots and
The week before our interview, he had flown to a drug-industry sponcancer, remain high':
sored conference in Florence, using an air ticket provided by a drug
..
"
Eden is one of many menopause clinicians who argue that those
company. "I'm an expert in my field. I need to interact with these com-§
::> risks have been grossly exaggerated. The NIH study, he points out,
panies," he says. "My group here takes part in these very, very imporE
0;>
'"
tant large clinical trials. I have to have relationships with them:'
" showed that breast cancers increased by only eight women per 10,000
E
per year; this was widely publicised as a 26 per cent increase (from 30
Not long after the Wyeth ghost-writing scandal broke, Eden made
'"
..."
to 38 women per 10,000), leaving many women with the mistaken
a personal resolution to donate all his drug industry honoraria to
belief that they have a 26 per cent chance of getting breast cancer.
charity. Now he's wondering whether that's enough. "How do you
"Women were absolutely terrified," he says. "And often unfortutrust them?" he asks. "Well, trust is gone:'
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THE WEEKENDAUSTRALIAN MAGAZINE / APRIL 3-4 2010