IF YOU FOUND yourself on the jury for Weiss v. Wyeth or Kendall v. Wyeth or any of the 1,500 other v. Wyeth cases on the docket at the Philadelphia Court of Common Pleas right now, you’d probably get to know some major characters in this courtroom drama quite well. There would be Tobi Millrood, a lean-framed pharmaceutical litigator with an intense blue-eyed gaze behind square specs. He would tell you that Collegeville-based Wyeth spent years pushing its hormone replacement therapy drug Prempro for unsafe long-term use, overstating its benefits and understating its risks. You’d meet Heidi Hubbard, maybe the least scary lawyer working for any pharmaceutical company anywhere, with a sweet, clear voice and big eyes. She’d say that science is unable to pinpoint the exact causes of breast cancer, and thus “It is a misrepresentation to say that hormone therapy causes breast cancer.” There’d also be Esther Berezofsky, another prominent pharmaceutical litigator and a former clinical psychologist with a slight New York accent and swingy blond hair who’d tell you that the history of HRT is a history of misleading women, misleading physicians, misleading the public. There’d likely be Joe Camardo, a wiry gray-haired doctor who’s the senior vice president of Wyeth’s medical affairs, who says, “We constantly reevaluate our position in our drugs. We believe in this drug,” and you’d also probably hear from his colleague, bird-like Ginger Constantine, a women’s health exec and clinical researcher who calmly insists that hormone therapy drugs are and have been the most studied drugs in the country, and that science has always been Wyeth’s number one pursuit. She’d invoke a list of studies to prove this.
If you were on a jury, you’d be in a crossfire. And you’d probably be hoping that somewhere in all this talk, the scientific data would just speak for itself. But then you’d find that with Big Pharma, it’s damn near impossible to separate the science from the marketing from the law from the lengths to which a drug company goes to get us our drugs (its drugs). That this is especially true in the case of Prempro. And that this is what it boils down to, and why it matters:
Joy Henry, of Henry v. Wyeth, a 75-year-old from Camp Hill, wears a prosthesis in place of her left breast. She would tell you it never occurred to her — nor, she thinks, to her doctor — that taking Prempro would do anything but help her. And that she wishes she could go back and make another decision, knowing what she knows now.
PREMPRO IS THE offspring of Premarin, the matriarch of the drug family that comprised Wyeth’s top sellers from 1994 to 2001. For years, the Premarin family dominated the hormone therapy market, earning the company as much as $2 billion a year while relieving millions of women of their most wretched menopausal symptoms. And Prempro seemed like a wonder drug: Not only could it curb debilitating hot flashes, but it was also thought to prevent osteoporosis and lower the risk for heart disease — the number one killer in women over 65.
But in 2002, everything changed. A long-term government-sponsored study of the drug ended abruptly when researchers found that not only did Prempro not offer any heart benefits; it actually slightly increased the risk of heart attacks, embolisms and strokes. And then there was the clincher: breast cancer. The study, part of a larger effort called the Women’s Health Initiative (WHI), showed a 26 percent increase in risk for breast cancer over the general population.
Millrood saw the report. He did the math: “It didn’t take me long to figure out that with the millions and millions of prescriptions written, the number of women who could have suffered from breast cancer at the hands of Prempro could be staggering.” It took him one day to file the first lawsuit in the country against the drug. The papers picked up the filing. “Within three weeks,” Millrood remembers, “my office fielded 3,400 calls from women. These women weren’t fearful that they were going to develop breast cancer. Most already had it.” By the end of the year, he had nearly 500 cases.
Today there are almost 9,000 cases filed nationwide against Wyeth for Prempro — about 1,000 of them Millrood’s. In seven years, only a handful of them have been heard (more on that later). But in Philadelphia alone, nearly 1,500 trials — a new round of which got under way in mid-September — will ask thousands of Philly jurors to decide whether Wyeth is responsible for case after case of breast cancer in women who took its drug. Including that of Joy Henry, who is a former business owner, who is a widow and mother, who swallowed Prempro for eight years, and who eventually had her left breast removed along with her tumor.
IT WASN’T VERY long after the WHI study was published — immediately after her doctor found her breast cancer — that Joy Henry was taken off Prempro. Shortly thereafter, she had a mastectomy. “The pain was terrible, for four months almost unbearable,” she says. Six years later, “It still hurts.” She’s a mild woman, sharp but gentle, with a soft voice and a slow cadence that rises and falls as she describes how her husband (who died last winter) was as panicked — “devastated, really” — as she was about her diagnosis. Under a cloud of dark hair, her face doesn’t really look 75, but her body — fine-boned and delicate — has been ravaged by disease. She can’t drive long distances — the seatbelt is agonizing. She takes pills for the back pain caused by her change in posture. So roundly terrible was her recovery that she decided against a surgery to reconstruct her breast, even though “It’s depressing living with such major discomfort, and with my disfigured body. Depressing, disgusting, embarrassing.” Medical science can’t prove it, but Henry’s convinced it all started with Prempro.
In fact, much of Prempro’s own story begins where medical science left off — and social science took over. What started in 1942 as an estrogen pill designed to treat the hot flashes and vaginal discomfort that make life hellish for some menopausal women blossomed into a full-fledged cultural phenomenon, complete with celebrity endorsements.
By the mid-1970s, millions of women were prescribed Wyeth’s estrogen drug, Premarin, each year. About half of all menopausal American women were using hormone replacement therapy; its popularity increased until 1975, when the estrogen in Premarin was shown to drastically increase the risk of endometrial cancer. Sales fell, hard. Two decades later, the company unveiled Prempro, which added the hormone progestin (a synthetic version of the body’s natural progesterone) to Premarin to ward off endometrial cancer; the FDA approved it in late 1994. But there was a condition — a post-marketing study would have to assess breast cancer risk, which, even after testing, was still an X factor. Prempro remained on the market for seven profitable years, right up until WHI revealed its disturbing news in 2002.
After that, Prempro got additional FDA-mandated black-box warnings (the most severe warnings a drug label can contain) emphasizing the newly reported risk of breast cancer — a risk that increases with each year of use — as well as a warning that HRT should not be used to prevent heart disease. Wyeth sent out 500,000 “Dear Doctor” letters. Prescriptions dropped precipitously. Meanwhile, WHI researchers planned a follow-up study: In 2006 and again this year, they reported that U.S. breast cancers decreased directly in step with the decline of hormone therapy.
But the Prempro saga is incomplete without the story of medicinal marketing at its finest (or its worst).
Mona Lisa smile on her lips, supermodel Lauren Hutton sits, leaning forward, hands folded. “I take an active interest in my health,” say the words floating above her head in the magazine. “That’s why I asked my doctor about the consequences of estrogen loss at menopause.”
In the 2000 ad, Hutton — stunning at 57 — is surrounded by advertising copy reporting everything any study had looked at with respect to menopause: “Brain: For the past 10 years, research has explored the questions surrounding the consequences of menopause and cognitive functioning, memory, and Alzheimer’s disease.” “Teeth: Research continues to explore the association between tooth loss and menopause.” And so forth. “Talk to your doctor,” the ad urges the reader.
There were other spokeswomen, like Patti LaBelle, and other advertising channels, too, throughout the years. There was Seasons, Wyeth’s free magazine sent primarily to Premarin users (circulation: 1 million). There were the brochures in doctors’ lobbies, declaring “Menopause isn’t gone in a flash — its debilitating consequences can affect the rest of your life.” Welcome to prong 1 of HRT marketing: Direct to Consumer.
It’s been effective. A draft of a 1998 internal marketing presentation tracking “the success of changing the HRT paradigm” showed just how drastically Wyeth thought the public’s perception of the drugs changed in a decade. A drawing of a scale represents the public perception in the 1980s. “Perceived risks” are on its left side, weighing it down heavily: breast cancer, endometrial cancer. On the right are the “perceived benefits”: relief of vasomotor symptoms (hot flashes). The risks outweighed the benefits. But in the Prempro 1990s, the lone perceived risk — breast cancer — appears to carry little weight compared to the benefits side of the scale, heavy with the many perceived uses for HRT: vasomotor symptoms, osteoporosis, cardiovascular disease, Alzheimer’s, colon cancer, macular degeneration, osteoarthritis.
That only the first two conditions shown were scientifically accepted and FDA-approved uses of HRT? Well, in advertising, as they say, perception is reality.
And the really smart stuff — the kind of marketing that Nike and Coca-Cola wish they dreamed up — is marketing that doesn’t look like marketing at all. Prong 2.
Some years after Premarin had been linked to endometrial cancer, research found that the drug helped to reduce postmenopausal bone loss. Estrogen helped prevent osteoporosis! It was good news. Wyeth promptly launched a public-awareness campaign regarding osteoporosis and its treatment — neither of which were, at the time, hot topics in women’s health. (Mission accomplished.) Then came the formation of the National Osteoporosis Foundation, to which Wyeth was a contributor. In 1988, Premarin was granted FDA approval to put “prevention of osteoporosis” on its label. By the early ’90s, Premarin — which, even before Prempro, was often being used in tandem with progestin to protect against endometrial cancer — was back on top.
When Prempro was launched, CEO Bob Essner spoke to a roomful of Wyeth-Ayerst sales associates. “We can make real the full promise of HRT to create in the near future a world where the majority of women will start HRT at menopause and continue on it for the rest of their lives,” he said.
The drug’s label, however, suggested the exact opposite ideal, advocating for the lowest effective dose for the shortest period of time. Essner noted in his speech that his words were the paraphrased hopes a former director of the National Institutes of Health had once expressed for the future of HRT — and besides, Wyeth lawyer Hubbard adds, this meeting was a sales rally, a pep talk of sorts for the troops, not a literal directive. Physicians would get their prescribing information not through Wyeth representatives, but through labels — labels that have always been FDA-approved.
But according to court testimony, the troops were indeed selling the idea of “Prempro for life” to doctors — and not just for hot flashes. Heart disease, Alzheimer’s … it was all fair game for salespeople doing their job, even though neither of those uses was affirmed by the FDA. And in the case of heart disease, the claim of protection was later proven wrong.
THE BURR IN Prempro’s saddle has always been the breast cancer risk. It started the same day the drug was approved, with the FDA noting: “The true effect of HRT on breast cancer incidence and mortality must be considered the most important safety issue.” The agency required that breast cancer studies continue.
Wyeth lawyers and researchers insist that previous testing on the estrogen-plus-progestin combination (E+P) that makes up Prempro was extensive, but as late as 1995, the company’s own sales training booklet noted that there were no large-scale, long-term studies to support the safety and efficacy of the combined hormone regimen (though the next sentence muses, “The perception of Ob-Gyns is that the continuous combined regimen of estrogen and progestin is a well-studied, safe regimen”).
“The FDA okayed it,” Millrood says, “because they felt there was a need for the drug. And they trusted that the company would abide by scout’s honor — that they’d seriously approach the breast cancer issue, that they would tell people to use it, for now, only for the short term.”
The plaintiffs’ counsel are adamant that Wyeth could have, should have, done more — more testing, more warnings — especially in light of “red flags, which were everywhere,” Millrood says. Red flag: A 1989 article, “The Risk of Breast Cancer after Estrogen and Estrogen-Progestin Replacement,” published in the New England Journal of Medicine and reporting slightly increased risk of breast cancer with estrogen, possibly increased with the added progestin. Wyeth advised its sales force: “Under no circumstances should you initiate discussions concerning this study. If asked about the study, be factual. You should continue to present the benefits.”
Through the years, the company also considered how it might manage the media. Confidential memos highlighted by the plaintiffs discussed how to “downplay the value of” a 1996 study that found breast cancer among lean women using E+P, advocating a “dismissive strategy” that would suggest the media was “inappropriately creating a public health scare.” “Dismiss and distract,” read the handwritten scrawl. “We must be prepared to deal with press so headlines do not read ‘WARNING,’” said another. There would be op-eds placed in media, and an education campaign, spearheaded by the National Council on Aging, to raise “awareness and concern about various age-related diseases to neutralize fear of breast cancer.” Wyeth contends that these cited directives were drafted by outside consultants, and that the company didn’t follow the advice, for the most part.
But the question, muffled as it may have been, didn’t go away. In 1990, the International Agency for Research on Cancer (IARC) was considering classifying estrogen as a carcinogen of the breast. Wyeth — which at this point listed the possible link on its own label — formed a task force of doctors to help inform the IARC, so that it wouldn’t define a definitive relationship between the two.
The company line is clear: Wyeth maintains it always made sure the labeling on the drug was accurate, reflecting everything that evolving science knew about the drug.
The label — sure. But there are so many other ways of getting the message out.
"GHOSTWRITING" — THAT’S WHAT the media’s been calling it. Big Pharma got blasted in August by the New York Times over how pharmaceutical companies — Wyeth being the lead example — apparently pay employees of medical-writing firms to draft scientific articles that promote company viewpoints. The articles are then sent to doctors involved in the research who read and attach their names to said articles, so that other doctors assume they’re perusing work written by fellow physicians, with no mention of the pharmaceutical companies’ role in it all.
Not true, insists the Wyeth camp. Steve Urbanczyk, Hubbard’s co-counsel, admits to a “strategic publications development committee” that determines where there are holes in the literature regarding science that’s related to Wyeth drugs. “The topics are strategically chosen,” he says, “but the literature is balanced and scientific. Wyeth pays firms to help doctors publish articles that are beneficial to other doctors.” It’s just like in post-WHI 2003, he says, when doctors were terrified of any use of progestin: “We see something like that, and we think it’s a good idea to put out a full review of all the science.”
But the Wyeth paper trails look damning. They look, in fact, like a third prong of HRT marketing. Consider the 2002 memo from a manager at DesignWrite, a medical-writing firm in Wyeth’s employ, to Wyeth’s “Menopausal Health Pub Management,” discussing the firm’s then-president of women’s health care, Mike Dey, who “has charged the Publication Committee with increasing the number of positive Premarin-related publications (Mike would like us to publish at least one study per month). This increase in publications is necessary to challenge the media’s recent focus on the … negative information on HRT.”
There are also the Publication Plan Tracking Reports, a detailed compilation of dozens of Wyeth-planned HRT articles. The invasion at Normandy wasn’t this strategically organized. The committee designed a chart of neat boxes: first the topic of the message to be conveyed (i.e., “Breast Cancer Message”), then the narrower theme/title of the article (i.e., “Is There an Association Between Hormone Replacement Therapy and Breast Cancer?”). (The answer in the published paper? “Difficult to evaluate.”) Then: who will actually write the paper; the “confirmed author” whose byline will appear; the date the paper is due; the due dates for multiple revisions between the writer and Wyeth and the “confirmed author.” Then come the target date and the journal for publishing. The chart shows article after article: Accepted. Check. Published. Check.
YOU PROBABLY HAVE Wyeth to thank for much of what’s in your medicine cabinet right now. Your Advil. Your Dimetapp. Your Centrum and Anbesol and Robitussin. Then there are the prescription drugs, heavy hitters like the antidepressant Effexor; Zosyn, the hospital antibiotic for drug-resistant bacteria; Prevnar vaccine to protect children from diseases — like meningitis — that are parents’ worst nightmares; Enbrel for crippling rheumatoid arthritis. And somewhere in Wyeth’s sprawling pharmaceutical headquarters in Collegeville, medical scientists are working with the World Health Organization on a drug that fights river blindness, which currently threatens the eyesight of 100 million Africans. They’ve donated the drug for clinical trials, and vow to give it away — not sell it — should it prove effective.
Buzz among the 5,000 area employees these days isn’t about that, however, or Prempro, or even the recent ghostwriting exposés (though thanks to the publicity, it looks like regulations against that practice are forthcoming), but about the $68 billion Pfizer buyout of the company scheduled to go down this month. (Pfizer itself just handed over $2.3 billion to settle federal charges for alleged marketing excesses in selling one of its own drugs, the painkiller Bextra.) The future of Wyeth as Wyeth is still a bit uncertain.
The future of Prempro, in contrast, seems pretty stable, no matter what the juries decide. Doctors in some 85 countries continue to prescribe it for hot flashes. “Most women aren’t looking at hot flashes forever,” says Edith Mitchell, a medical oncologist at Jefferson. “I think that short periods of hormones in patients, just to relieve symptoms, are okay.” Hers is a common opinion in a post-WHI world; last year, Prempro made $1.1 billion.
And now, to determine whether Wyeth did know about — or could have known about — the drug’s risks to women like Joy Henry is to sort through the quagmire of science and marketing and clinical researchers who really do want to help people, and that is the job of juries. Thus far, 23 out of 31 cases set for trial have been resolved favorably for Wyeth; the company has settled five, and several are on appeal. Little is certain.
Except this: The Philadelphia judge who basically invented mass tort pharmaceutical litigation — Sandra Mazer Moss — has made it her court’s mission to get through this docket and hear all 1,500 Philly-based trials. There might even be cases tried in groups. “The plaintiffs are due their day in court,” Moss says. “And so are the defendants. That is justice. Even one-tenth of a courtroom in your lifetime is better than nothing because you’re dead.”
If you were on the jury, you’d likely hear that Moss — who came to this court’s bench in January — arrived too late for the 205 women who died still waiting for their cases to come to trial. If you were on the jury, you’d hear that WHI’s lead researcher thinks 200,000 women who got breast cancer in the past decade have long-term hormone therapy to thank for it. If you were on the jury, you’d hear that Wyeth did everything a responsible drug company can possibly do in getting out a drug whose benefits still outweigh its risks.
Of course, if you’re not on the jury, you might never hear any of that. You might just be a patient.