Thursday, September 23, 2010

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.


Deborah Emin said...

This practice is so widespread and filters into the writing of laws as well. It has been shown that many lobbyists are involved in writing the legislation that will regulate their clients' actions.
Years ago, while a patient of a psychopharmacologist I was paid to help him write about an anti-depressant. While we were putting together the copy he was on the phone with the drug company's marketing department. I kept fighting to put the side effects of the drug on the copy that was going to patients and they were strongly advising him not to put it in. He finally had me write it and they flatly refused to add it. This type of flattening of any normal balance of what is right for the patient or the citizen is universal and a testament to how far out of control the greed in this country has gone.
Thanks to writers like Dr. Carlat we are beginning to have some reasonable discussion of these issues.
Deborah Emin, Publisher
Sullivan Street Press, Inc.

SteveM said...

Re: "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."

I like to look for subtexts in these dialogs. How about this one?

Pharmaceutical marketing has made therapy options a zero-sum game. The maladies of aging; heart disease, cancer, osteoporosis and mental decline can be countered and in some cases reversed with diet, aerobic exercise, resistance training, active mental stimulation and some simple supplements like, fiber, calcium and fish oil.

I'm not a physician. But it seems that what may be appropriate therapy for a menopausal woman prior to and even concurrently with pharmacotherapy would be a consultation with a nutritionist, a gym membership, enrollment in a foreign language course and a trip to the supplement aisle at her local Costco.

Of course that same guidance may apply to many who are suffering from less than acute psychiatric disturbances. But how many psychiatrists actually explicitly prescribe non-pharmaceutical solutions?

Unfortunately, the physician and DTC marketing promise of a quick fix and severely understated side effect information have shoved common sense self-help and non-medical therapies into a dark corner.

This holistic disconnect is actually pretty amazing and disheartening at the same time.

BTW: About fish oil and the GSK product Lovaza currently being marketed hard, see this:

Only in America...

Marilyn Mann said...


"The maladies of aging; heart disease, cancer, osteoporosis and mental decline can be countered and in some cases reversed with diet, aerobic exercise, resistance training, active mental stimulation and some simple supplements like, fiber, calcium and fish oil."

This seems like an overstatement. Can you be more specific about what specific benefits you are claiming for each of these interventions?

A recent meta-analysis found that calcium supplements significantly increase the risk of heart attacks.

Boland et al., Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010; 341:c3691

SteveM said...

Re: Marilyn Mann

Thanks for the reference. You learn something new every day. I see that the paper was recently published. As I mentioned, I'm not a physician. So made my point about calcium supplements based on physician recommendations that I had read about.

Apart from that, people who engage in healthy activities tend to get healthier. Exercise strengthens the cardio-vascular system, resistance training strengthens muscles and increases bone density, active learning enhances mental acuity and supplements prudently taken can offer additional benefits. Aren't those generally true?

Wouldn't someone feel less fatigued if she exercised? Physically stronger if she weight trained? Less lonely if she were in a class learning with others?

So it surprises me that positive activities are not more explicitly prescribed by health care professionals. I.e., rather than just weakly suggested as an aside when the patient is ambling out the door.

petrossa said...

Why nobody pays attention to andrenopause HRT is beyond me.

The infinitesimally weak relation between prostrate cancer and testosteron causes many a midlife crisis to develop.

Adrenopause is easily on par with menopause in it's negative effects but men are just supposed to live with it.

Also it causes that one monthly treatment for a man costs about 400% more and are never reimbursed by healthinsurance in any country i know of.

That's the real scandal. Focus on that.

Marilyn Mann said...


I agree that exercise has many benefits, intellectual activity and education has some benefits. However, supplements each have to be individually evaluated in clinical trials before I can endorse them. Some supplements *have* been evaluated and no benefit has been found. So I cannot endorse supplements in general any more than I can endorse prescription drugs in general. And remember supplements are a very big business and are often advertised in a very misleading way.

I agree that fish oil has been shown to have benefits for cardiovascular disease in people with cardiovascular disease or risk factors for cardiovascular disease. I'm not aware that fish oil has been shown to have such benefits in the general population. In fact, a large NIH-funded trial is being run through Brigham and Women's and is testing that very question. The same trial is testing vitamin D for prevention of chronic diseases.

I am not against people taking moderate doses of fish oil and vitamin D, for instance, while we wait for the results of that trial. I just think it behooves us not to make overly exuberant claims for their benefits. We have tested vitamin E, B vitamins, vitamin A, etc., and have not found benefits and in some cases have found harms. So we need to be cautious.

I also think it is important to recognize that many people have a healthy lifestyle and do everything right and still get cancer or heart disease or Alzheimer's disease or whatever.


Marilyn Mann said...

I decided to come back and give an example of why I am wary of supplements. A 2007 meta-analysis that was published in JAMA found that "treatment with beta carotene, vitamin A, and vitamin E may increase mortality."

Bjelakovic, et al. Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis. JAMA. 2007;297:842-857.

Anonymous said...

What do people think about bio-identical compounding creams? Are they considered safe? This is what I use.