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.
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. This is all true if you replace hormones with actual hormones, not synthetically and chemically changed hormones.
“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 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.
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. Because these drugs were not bioidentical hormones and do not behave the same when taken orally and are chemical mistakes of the actual hormone.
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 are getting hormones "replaced" which is not the case with drugs like Premarin or Prempro.
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.
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.
