"Thousands of doctors prescribed the drugs
for millions of women on that basis," he says, adding that
studies later contradicted the belief. "It will be very
interesting to see whether the courts are able to connect the
dots and make it clear whether this was a kind of medical
ventriloquism on Wyeth"s part."
Prempro is a combination of Premarin, an
estrogen drug derived from the urine of pregnant mares and first
approved by the Food and Drug Administration in 1942, with an
additional hormone, progestin.
Part of the Premarin saga shows how a drug
maker successfully and cannily expanded a franchise whose central
ingredient is horse estrogens into a billion-dollar panacea for
aging women. Yet several hundred pages of court documents also
raise questions about another aspect of Premarin"s trajectory:
how Wyeth worked over decades to maintain the image and
credibility of its hormone drugs even as the products were
repeatedly under siege.
Pfizer representatives say court documents
paint an
unfair picture of Wyeth"s practices and that plaintiffs" lawyers
have cherry-picked documents for out-of-context comments to sway
juries.
Still, the documents offer a snapshot of
Wyeth"s efforts. Taken together, they depict a company that over
several decades spent tens of millions of dollars on influential
physicians, professional medical societies, scientific
publications, courses and celebrity ads, inundating doctors and
patients with a sea of positive preventive health messages that
plaintiffs" lawyers say deflected users" attention from cancer
concerns.
Even as evidence mounted of an association
of the drugs with cancer — first in the 1970s with Premarin
and endometrial cancer, then in the 1990s with Prempro and breast
cancer — Wyeth tried to contain the concerns, the court
documents show. (A note handwritten in 1996 by a Wyeth employee
responding to a new report of breast cancer risks associated with
hormone therapy said: "Dismiss/distract.")
In 2002, researchers halted the largest
clinical trial ever conducted of women"s health because
participants who took certain combined hormones had an increased
risk of breast cancer — as well as a higher risk of heart
attack, stroke and blood clots in the lungs — compared with
those taking a placebo.
Other parts of the same federal study,
called the Women"s Health Initiative, later found that hormone
drugs increased the risk of dementia in a subset of participants,
those age 65 and older.
Sales of Wyeth"s hormone drugs peaked at
about $2 billion in 2001, but after results of the 2002 study
came out sales plummeted.
Pfizer is now fighting the Prempro
litigation along with lawsuits over its progestin drug, Provera.
Mr. Loder, the Pfizer spokesman, says Pfizer and Wyeth had fully
informed patients, doctors and regulators of the risks of their
menopause drugs, based on the best available science at the time
of the disclosures.
"They provided accurate warnings, performed
studies on benefits and risks, and kept the F.D.A. fully
informed," he says.
But last month, a federal appellate court
in St. Louis ruled in the case of a plaintiff named Donna
Scroggin that Wyeth"s inaction over accumulating evidence —
and the company"s attempts to mitigate cancer concerns by trying
to undermine unfavorable scientific reports — could allow a
jury to find Wyeth guilty of malicious conduct and award punitive
damages.
For its part, Pfizer contends that two
state judges in Pennsylvania have reached the opposite
conclusion: that juries should not be allowed to award punitive
damages because there was insufficient evidence of corporate
misconduct.
Whichever direction the different cases
ultimately follow, the court papers associated with them
illustrate a pattern in the history of hormone therapy. First,
many doctors enthusiastically prescribe hormone therapy drugs.
Then a few researchers publish studies cautioning about risks,
causing sales to fall. And finally, some doctors start
prescribing a new iteration of hormone drugs.
For example, Prempro now comes in lower
doses. Prempro labels say the drug should be prescribed for the
shortest duration appropriate for the treatment goals and risks
of the individual woman; previous labels on Wyeth"s hormone drugs
for decades gave the same advice. The current label also says
that using estrogens, with or without progestins, may increase a
woman"s chance of heart attack, stroke, breast cancer and blood
clots.
Menopausal hormone therapy has long been
pitched as a way to stave off what some doctors viewed as the
undesirable aspects of female aging.
In the popular 1966 book "Feminine
Forever," Dr. Robert A. Wilson, a gynecologist, used disparaging
descriptions of aging women ("flabby," "shrunken," "dull-minded,"
"desexed") to upend the prevailing idea of menopause as a normal
stage of life. Women and their physicians, Dr. Wilson wrote,
should regard menopause as a degenerative disease that could be
prevented or cured with the use of hormone drugs.
"No woman can be sure of escaping the
horror of this living decay," Dr. Wilson wrote. "There is no need
for either valor or
pretense. The need is for hormones."
Premarin had been available for decades,
but Dr. Wilson"s book propelled the idea of hormone "replacement"
into the popular consciousness and onto physicians" prescription
pads. The revivifying drugs promised to inhibit the ravages of
time on the appearance and the psyche, Dr. Wilson
wrote.
As the popularity of estrogen grew, an
increasing number of women developed cancer of the uterine
lining, the endometrium. In 1975, an F.D.A. panel concluded there
was a link between Premarin and endometrial cancer. The company
then sent a letter to doctors trying to mitigate such concerns,
documents show.
"Dear Doctor," wrote Dr. John B. Jewell, at
the time the medical director of Ayerst, the Wyeth predecessor.
"It would be simplistic indeed to attribute an apparent increase
in the diagnosis of endometrial carcinoma solely to estrogen
therapy." Women may still receive "proven benefits," he wrote, by
using "the lowest maintenance dose needed to control the
menopausal symptoms." He added that the company planned to study
the issue further.
F.D.A. officials then met with company
officials, saying they were "incensed" that the letter was
"intended to obfuscate the issues," according to a 1976 memo
signed by the F.D.A. and the company. The F.D.A. said it would
issue a bulletin saying there was a clear link between estrogen
therapy and endometrial cancer. In 1976, the maker of Premarin
added a warning to the label about the risk of endometrial
cancer.
But the company never conducted further
studies on the risk of developing endometrial cancer, according
to the St. Louis appeals court decision.
The company instead focused its risk
research on the possibility of breast cancers associated with
hormone replacement therapy. But two studies published in the
mid-1970s in The New England Journal of Medicine reported that
taking estrogen therapy had increased the risk of endometrial
cancer by at least five times.
Reports in 1975 about endometrial cancer
"resulted in a precipitous decrease in estrogen use," according
to a history of hormone therapy in The American Journal of
Medicine in 2005.
In 1980, researchers at Boston University
Medical Center estimated that the use of hormone therapy had
caused more than 15,000 cases of endometrial cancer in the United
States between 1971 and 1975 alone.
"This represents one of the largest
epidemics of serious iatrogenic disease" — meaning disease
caused by physician-administered treatments — "that has
ever occurred in this country," the authors wrote. (Mr. Loder
said Pfizer was not familiar with that report.)
Today, physicians prescribe Premarin to
women who have had hysterectomies and therefore are not at risk
for endometrial cancer.
BY the mid-1990s, after a few studies had
reported a protective effect of hormone drugs on the heart, Wyeth
had begun to reposition menopausal hormone therapy as a
preventive health choice that could help inhibit heart disease
and other maladies, according to court documents.
That marketing
strategy coincided with the introduction of Wyeth"s new
combination hormone drug Prempro, which included a progestin
hormone to keep estrogen from causing excessive cell growth in
the uterine lining.
In one commercial from a Wyeth research
institute, the model Lauren Hutton runs down a beach and warns of
the health risks of estrogen loss.
"My doctor said if you don"t replace
estrogen that you lose at menopause, your risk for certain
age-related diseases could increase," Ms. Hutton said in the
commercial. In a voice-over, a narrator told viewers about
studies looking into the connections between menopause and heart
disease, memory loss and sight loss.
"Believe me," Ms. Hutton said, "the time to
protect your future is now."
Sally Beatty, a spokeswoman for Pfizer,
said this was a "help seeking" ad, of the type encouraged by the
F.D.A. She added that the promotion did not mention any specific
drugs, not did it suggest that drugs could cure the ailments
described.
The labels for Premarin and Prempro at the
time said the drugs were approved to treat moderate to severe
symptoms of menopause like hot flashes, night sweats and vaginal
dryness and to prevent osteoporosis.
But Wyeth also positioned its menopausal
hormone drugs as having larger protective benefits, court
documents show.
Wyeth used proxies to promote a wide range
of health benefits from hormone therapy, paying millions of
dollars to influential doctors and medical groups and helping
them develop abstracts for medical conferences and articles for
medical journals, according to court documents.
The company also paid $12 million to
sponsor continuing medical education programs from 2002 through
2006 at the University of Wisconsin, Madison. The programs,
including an assertion that the Women"s Health Initiative and
another heart-risk study "miss the mark on quality of life,"
reached thousands of doctors.
Doctors were aware in the 1990s that
hormone therapy could increase a woman"s risk of breast cancer,
says Dr. Carol Bates, the director of the primary care program at
Beth Israel Deaconess
Medical Center in Boston.
But based on the results of observational
studies that had been published, many physicians, herself
included, believed that the drugs" ostensible ability to reduce
heart attacks and perhaps Alzheimer"s
would outweigh a breast cancer risk, she says.
"In the 1990s, there was actually
tremendous pressure to put women on hormone therapy, and it came
from a good place," Dr. Bates says. "But it was taken a bit to
the extreme."
Hormone therapy — aimed at the
symptoms it effectively treats and with full disclosure about its
possible risks — has many advocates. Dr. Lynne T. Shuster,
the director of the women"s health clinic at the Mayo Clinic in
Rochester, Minn., says such regimens can be very worthwhile for
treating hot flashes, night sweats and vaginal dryness associated
with menopause.
And some users agree.
Irene Fisher, a kitchen and bath designer
in Baldwin, N.Y., says she has been taking Prempro for 16 years
to control hot flashes and night sweats.
"I always feel good when I take it," she
says. The benefits are worth a small risk, Ms. Fisher says,
adding that she has an annual mammogram to check for breast
cancer and that "I think you have to know your own
body."
But many women were not so fully informed
in the 1990s.
In 1996, for example, a federal study
reported that breast cancer risk may have been "substantially
underestimated." Wyeth reacted with plans to dismiss it as "just
one more paper," and try to "overshadow" it by directing
journalists to other studies, according to documents cited in the
court of appeals decision in Missouri.
In 1997, Wyeth began working with
DesignWrite, a company in Princeton, N.J., that is paid by drug
makers to develop manuscripts for publication in medical
journals. The specific objective of a publication plan for Premarin
was to "increase physician awareness on the multitude of benefits
that hormone replacement therapy provides" and "diminish the
negative perceptions associated with estrogens and cancer,"
according to a 1997 DesignWrite proposal prepared for
Wyeth.
Over the next decade, Wyeth paid
DesignWrite to prepare at least 60 articles for publication in
medical journals on the potential benefits of hormone therapy for
cardiovascular disease, Alzheimer"s disease, diabetes, colon
cancer, vision loss and other health problems, the court
documents show.
In response to an e-mail query, Michael
Platt, president of DesignWrite, wrote that the articles were all
medically and scientifically accurate and valid and peer
reviewed.
But Wyeth"s and DesignWrite"s effort hit an
obstacle in 2002 when researchers reported the results of the
Women"s Health Initiative.
The National Institutes of Health
ultimately decided to start using the term "menopausal hormone
therapy" instead of "hormone replacement therapy," says Marcia L.
Stefanick, a professor of medicine at the Stanford University
medical school who was principal investigator on the Women"s
Health Initiative study at her institution.
While the drugs are effective at treating
symptoms like hot flashes, she says, the word
"replacement" implies that women need hormone drugs after
menopause. "But there is no good evidence that women need this
after menopause," Professor Stefanick says.
In 2003, Wyeth added a "black box" warning
to the label saying Prempro should not be prescribed to prevent
cardiovascular disease.
The same year, the F.D.A. approved a lower
dose version of Prempro so women would have more
options.
Today, many doctors who once offered
hormone therapy to women without symptoms like hot flashes limit
the use of the drug to those with symptoms, prescribing low doses
for a short time.
"Right now, the big difference is we do not
recommend hormone therapy for good health or health promotion or
anti-aging," says Dr. Shuster of the Mayo Clinic.
And even with lower-dose hormones, doctors
do not have a uniform view on what constitutes the optimal
duration.
Dr. Adriane Fugh-Berman, an associate
professor at the medical school of Georgetown University,
considers both Premarin and Prempro examples of drugs that gained
widespread popularity before science had established the full
extent of their risks.
"Where there has always been a push is
where there isn"t data," says Dr. Fugh-Berman, who has been a
paid expert witness for plaintiffs in the hormone litigation.
"Now, low-dose hormones are being pushed."
Like Dr. Wilson, the gynecologist in the
1960s who identified the evils of menopause, contemporary voices
are advocating hormones as an anti-aging treatment.
The actress Suzanne Somers, for example,
has identified her own lineup of maladies, which she calls the
Seven Dwarves of Menopause: "Itchy. Bitchy. Sweaty. Sleepy.
Bloated. Forgetful. All Dried Up."
In books with titles like "The Sexy Years"
and "Ageless," Ms. Somers has promoted the use of "bio-identical
" hormones, which can be prescribed by doctors in customized
doses and can be prepared individually by pharmacies.
But Dr. Shuster of the Mayo Clinic says the
hormones have not been extensively studied for safety and
efficacy. And, unlike branded hormone therapy, she says, they
have not been approved by the F.D.A.
Women, Dr. Shuster says, should not assume
that compounded hormones are safer than F.D.A.-approved
menopausal hormone drugs. Nevertheless, with sales of more than
two million books, Ms. Somers has become a menopause guru to
millions.
"I think I had a lot to do with making the
word "menopause" mentionable," Ms. Somers, 63, said in a phone
interview last week. She said the compounded hormones were safe,
and she sent some articles from medical journals to back up her
point.
In fact, much of Ms. Somers"s description
of menopause as a deficiency that can be rebalanced with hormones
sounds like a modern take on "Feminine Forever."
"Hormones," Ms. Somers said last week, "are
the juice of life."
This article, , first appeared in The New
York
Imagen
Prempro.
Autor:
Dr. Félix E. F.
Larocca
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