Menopause: The Scandal (Part One)

Are rooms too hot for you? Are you sweating when everyone else is staying cool? Is sex not what it once was? If so, you may be entering menopause, and Wyeth, along with several other pharmaceutical companies, may have just the drug for you. The trouble is that the side effects, such as breast cancer and heart disease, may not be worth the cure.

Hormone replacement therapy (HRT) used to be tremendously popular, and Wyeth's Prempro (a combination of estrogen and progesterone) was at the top of the heap. That is, until preliminary results of the Women's Health Initiative were announced in 2002. Thus began the long saga of re-evaluating the science behind HRT, the latest installment of which is a fascinating and rather disquieting article just published in PLOS: The Haunting of Medical Journals: How Ghostwriting Sold “HRT," by Dr. Adriane Fugh-Berman.

A little background first. HRT came into vogue over the last couple of decades as a way of decreasing some of the nuisance symptoms of menopause (such as hot flashes and vaginal dryness) as well as potentially preventing more serious diseases of older age, such as heart disease, cancer, osteoporosis, and dementia. In the 1990s, the NIH funded placebo controlled clinical trials of HRT in order to determine once and for all whether HRT actually did improve outcomes for post-menopausal women. The largest part of the Women's Health Initiative study enrolled 16,000 postmenopausal women between the ages of 50 and 79 (average age was 63). These women were randomized to either Prempro or placebo, and were followed for an average of about five years.

But in 2002 the study was halted. Why? Because a preliminary analysis of the data showed that women in the Prempro group had increased risks of breast cancer, heart disease, stroke, and pulmonary embolism. But this group also showed a decreased risk of colon cancer and hip fracture (Rossouw J et al., JAMA 2002;288:321-333). And for those women who were less than five years postmenopausal, Prempro actually reduced the heart disease risk.

The WHI results were therefore somewhat mixed, but they nevertheless led to significant decline in prescriptions of HRT to all women, particularly those who are post-menopausal. Many reasonable doctors have been skeptical of the results of the WHI, and there is plenty of room for debate.

While Dr. Fugh-Berman clearly believes that the dangers of HRT usually outweigh the benefits, her recent article is not really about the scientific merits of either argument. It is about something that I think anybody would regard as scandalous--the fact that marketing executives have become central participants in medical debates. Fugh-Berman shows convincingly that Wyeth used marketers and ghost-writers to manipulate medical opinion, with the result that doctors are making critical prescribing decisions based on the "medical" opinions of business school graduates.

Because of her legal consultation in a suit against Wyeth, Fugh-Berman had early access to thousands of documents implicating the company in deceptive marketing techniques. These documents are now public.

Her article is a guided tour of the worst of worst.

Most of the documents relate to Wyeth's work with DesignWrite, a medical education and communications company (MECC) that specializes in using medical education to help companies market their drugs. The documents showed that DesignWrite told Wyeth that it would “position the product [Prempro] appropriately to influence prescribers.” The strategy was to make sure that plenty of Prempro-friendly papers were published in medical journals.

Let's take a little step back here. The nature of science is skepticism and debate. Prempro is presumably neither "good" nor "bad." Well-informed physicians differ on the significance of the risks and on which women are reasonable candidates for the drug. Medical journals and scientific meetings are the appropriate forums for airing these opinions. If a physician wanted to write a paper defending Prempro because she truly believed that the concerns have been overblown, nobody would have a problem with it. Even if she didn't have time to write it herself, and paid a medical writer to write the first draft, that would be legitimate, as long as the medical writer were acknowledged.

But this is not the process of medical discourse that we are talking about here. Wyeth decided that it simply didn't have the time to wait for physicians to decide on their own that Prempro was such a valuable drug that it needed defending. It's not that there weren't plenty of doctors who sincerely believed in Prempro. It's just that they didn't see the issue as being so scientifically important that they would devote their time to writing papers about the issue. Clearly, they needed some nudging.

This was exactly DesignWrite's job. Their medical writers would write a paper that emphasized Prempro's advantages while minimizing its side effects. DesignWrite would then search for key opinion leaders who they believed were already concerned that HRT was getting a bad rap. To such KOLs, they would say, essentially, "Doctor, we know you are concerned about the underuse of HRT. We have written a first draft of a paper outlining these issues. Would you like to review it? In return for your help, we will make you the sole author of the paper, and we will make sure it gets into a prestigious journal. Whadaya say?"

There is no evidence that DesignWrite offered these doctors any money for their services. There was no need to. The payoff was much greater than a couple of G's. They were offering a guaranteed publication in a prestigious journal, along with the many perks that flow from that, such as academic promotion, media interviews, invitations to speak at top medical conferences, paid consultancies and speaking gigs from pharmaceutical companies, and lucrative invitations from MECCs to write and teach industry-supported CME programs.

Basically, these papers are career rocket fuel for KOLs. Who could refuse such an offer?

In Part Two: Fugh-Berman names names, and calls out some sleazy CME.

University of Wisconsin + Wyeth = Biased CME

In the fall of 2002, the Women’s Health Initiative stopped its NIH-funded clinical trial of hormone replacement therapy, because women randomized to receive hormone therapy (estrogen + progesterone) had more breast cancer, heart disease, and strokes than those not taking the drugs.

This presented Wyeth, the manufacturer of the implicated drug Prempro, with a problem: a potentially catastrophic loss of income.

They responded the way drug companies generally respond when their product is shown to be hazardous. They ramped up their marketing. They criticized the methods of the study. They emphasized the need to weigh risks vs. benefits.

And, according to this riveting article from the Milwaukee Journal Sentinel, Wyeth deployed an army of ghostwriters and academics to create a one-sided $12 million CME program which is under investigation by the Senate Finance Committee.

According to the article, Wyeth hired a marketing communications company called DesignWrite which teamed up with UW Medical School to create an organization they named “The Council on Hormone Education.” This council was composed of 40 academics in the field, 34 of whom had ties financial ties to Wyeth.

It is unclear if the members of the council actually created any course content or if they simply were paid to put their names on CME articles written by DesignWrite ghostwriters. At any rate, the council stamped its name on 16 CME newsletters, the stated goals of which were "to develop and disseminate balanced, accurate, timely and consistent information about hormone therapy" so doctors could "better serve women."
The newsletters included articles such as "A Perspective on WHI (the Women's Health Initiative)," "Choosing the Right Therapy for Postmenopausal Osteoporosis" and "Sexual Desire Disorder in the Postmenopausal Woman."

Sounds pretty academic.

But when John Fauber and Susanne Rust, the investigative reporters, showed the materials to independent experts in the field, here were the reviews:

--Jacques Rossouw, chief of the Women's Health Initiative branch of the National Institutes of Health said, according to the paper, that “the views expressed in the course are not those of the general scientific community and are not suitable for a university medical education course.” "There is a history of this kind of thing from Wyeth," Rossouw said. "The materials regurgitate lines that I have heard and read many times, and I have come to believe (though I do not know) that this is part of an overall marketing strategy to the profession. It is not good science because it fails to strive for any kind of balance."

--Raymond Gibbons, a professor of medicine at the Mayo Clinic and former president of the American Heart Association, “said he also found material relating to heart disease one-sided. He noted that the materials inappropriately gave observational data equal weight to rigorously done, randomized clinical trials. ‘It's a lot of post hoc analysis,’ he said. ‘I don't see the other side of the argument.’"

-- Marcia Stefanick, an investigator with the Women's Health Initiative, told the Journal Sentinel that “since the results of the first large clinical trial on hormone therapy were released in 1998, drug companies have been trying to minimize the concerns….They are very eager to keep coming up with ways to show it isn't harmful….There is this constant attempt to get women back into it."

--Anthony Scialli, an adjunct professor of obstetrics and gynecology at Georgetown University's School of Medicine, put it simply: "It is pure, undisguised marketing.”

And what is the University of Wisconsin, the ACCME-accredited sponsor of the program, saying and doing? First, they immediately pulled the program from their website after the Journal Sentinel started asking inconvenient questions. Second, an apparently very embarrassed George Mejicano, who is director of UW’s CME programs, is not giving the straightest of answers. For example, when asked if the course had received criticism, he is quoted as answering: “Yes and no. It’s complicated.”

It’s not really so complicated. UW took in $1.5 million from Wyeth to help them advertise Prempro in the guise of CME. Money clarifies the mind and sharpens incentives.

Meanwhile, UW is involved in several other ongoing big ticket CME initiatives. These include:

--Pfizer’s $12.3 million smoking cessation program. Pfizer happens to make Chantix, an embattled smoking cessation drug.

--Boehringer Ingelheim’s program on restless leg syndrome . The company happens to make Mirapex, a drug for RLS.

-- Bayer HealthCare Pharmaceutical’s course on premenstrual dysphoric disorder. Bayer happens to make Yasmin, an oral contraceptive being touted as a good treatment for…yes, premenstrual dysphoric disorder.

If you want to enjoy these advertisements, you’d better get on it. I’ll wager that the chastened university will be soon be shutting down these websites as well!