Menopause: The Scandal (Part Two)

In part one of this post, I introduced some of the admittedly controversial issues surrounding the use of hormone replacement therapy in menopausal women, and I pointed out that the proper forum for scientific debate and medical education is in journals and medical meetings. Furthermore, in order for us to trust the integrity of this education, it should not be funded by the pharmaceutical industry. Let drug companies fund research and advertising all they want--but scientific debate among doctors should be completely independent of a promotional agenda.

This sounds obvious but the current system of CME all too often turns a blind eye to what has become a constant stream of artful transgressions of this principal. Journal supplements have become a key promotional strategy for drug companies seeking to influence prescribing behavior. This fact is hardly news, and such corrupted supplements are a dime a dozen to this day. What is unusual about Dr. Fugh-Berman's recent article about the marketing of Premarin is that she reveals a smoking gun--that is, documentation from Wyeth and DesignWrite showing that the CME was planned with an explicitly promotional intent.

The trail of evidence begins with a proposal for Wyeth submitted by DesignWrite, entitled "Premarin Publication Program" (yes, the pdf is available from the Drug Industry Document Archive at UCSF, and it makes for pretty creepy bedtime reading). On page 3 of the proposal, DesignWrite tells Wyeth exactly what it plans to do in order to get more doctors to prescribe Premarin:

"The specific objective of this program is to 1) increase physician awareness on the multitude of benefits that hormone replacement therapy provides for postmenopausal patients, 2) diminish the negative perceptions associated with estrogens and cancer, and 3) blunt the competitive threat of raloxifene, a selective estrogen receptor modulator, expected to be approved early next year for osteoporosis."

Ghost-writing is big business. Wyeth paid DesignWrite $25,000 per Premarin-boosting article and ended up paying the company several million dollars between 1997 and 2003. They paid a particularly big chunk of cash, $413,140, for a CME meeting and journal supplement. DesignWrite apparently loves producing CME supplements for companies, because, as they say in their publication plan,

"The value of journal supplements is that it allows you to better tailor your marketing message since it is a manufacturer-sponsored publication form. Additionally, reprints of supplements may be purchased and distributed widely among health care professionals via sales representatives and direct mail."

DesignWrite put on a 2001 meeting of Wyeth's hired guns in order to provide content for the supplement. They helpfully produced this outline of what each article should say--basically, they all minimized concerns that HRT causes breast cancer.

Eventually, the supplement was published in 2001 by the journal Women's Health in Primary Care and Wyeth mailed it to 128,000 physician, bought 1,500 additional copies for its sales force, and distributed the supplement to media and “select thought leaders”. In her article, Fugh-Berman publishes a pretty damning table comparing each carefully crafted marketing message with a corresponding sentence as it was published in a CME article. And of course, each article has an identified academic "author," with the actual writer having been an employee of DesignWrite in each case.

All in all, this is a nauseating example of the use of accredited CME to manipulate doctors.

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.

Harvard's Top Neurologist Just Says "No" to Commercial CME

In a piece of extraordinarily good news for those of us promoting industry-free CME, one of Harvard's top neurologists, Martin Samuels, announced a new company, Lighthouse Learning, that will refuse any commercial funding for continuing medical education courses.

The Boston Globe broke the story in this article on their front page, which is in itself significant. It means that mainstream journalists understand that the funding of medical education is no longer an arcane topic that is of interest only to a few insiders.

The Globe's Liz Kowalczik quotes Dr. Samuels thusly:

“Doctors have lost confidence in [continuing medical education] and the public has lost confidence,’’ said Samuels, who sees patients at Brigham and Women’s Hospital, where he heads the neurology division. “The feeling is that everything is tainted. We simply must have a new way of doing this.’’

Dr. Samuels' statement is particularly convincing because he used to be involved in the very industry-funded system that he is now spurning. Until recently, Samuels was the head of the neurology course of Pri-Med, an industry-funded MECC that puts on well-attended CME courses throughout the country. (Here's a link to their upcoming course in Boston). In January 2008, I blogged about Dr. Samuels' lecture at an ethics meeting at Harvard Medical School. Clearly, he was already ambivalent about industry funding of CME, calling for the the abolition of industry-sponsored satellite symposia at major medical meetings, while still defending the ability of Pri-Med to maintain a firewall between promotion and education. Evidently, his experiences with Pri-Med since then have proven to him that such a firewall is easily breached.

I'm going to assume that M/C Communications, the parent company of Pri-Med, is not terribly happy about this turn of events. According to the Globe, "M/C Communications said its model allows it to reach thousands of doctors with affordable programs. " Talk about a lame defense. In not even addressing the central issue here--that industry funding inevitably biases CME--M/C has essentially admitted that they are a marketing company. If they had been honest they would have said that "its model allows it to promote the sponsor's products to thousands of doctors with affordable programs."

Here is Lighthouse Learning's official press release announcing its launch.

Stephen Stahl + Lurasidone: The Hired Guns Come to Town

Just when you thought we had reached the point of antipsychotic supersaturation, yet another me-too drug is edging its way into this $20 billion market. The drug is Lurasidone, and the company is Sunovion (formerly Sepracor). FDA approval is likely by the end of this year, and in anticipation Sunovion has begun a marketing blitz, tossing so much money at hired guns that it looks like confetti. And where there is drug company money to be had, Stephen Stahl is never far behind.

Lurasidone is simply another antipsychotic—no more, no less. The two major clinical trials (Pearl 1 and Pearl 2) have shown inconsistent efficacy results, high rates of side effects such as akathisia (restlessness), parkinsonism (tremor and stiffness), and sedation, and apparent inferiority to Zyprexa. Like several of the newer antipsychotics (such as Ability, Geodon, and Fanapt), Lurasidone causes little weight gain and few metabolic abnormalities. With no clear advantages over its many competitors, Lurasidone will succeed or fail based purely on the strength of its promotional campaign.

Which is why Sunovion has hired the impresario of drug company-funded education, Stephen Stahl, as their chief hired gun.

Stahl is the driving force behind a road show of Sunovion-funded “programs” entitled “Schizophrenia: Building Awareness—Advancing Understanding.” I first started receiving flyers for these lectures in July, and I get a new one every week or so. I’ve scanned some of them into my computer and have posted them on Evernote here.

The most recent promo piece came a couple of days ago, in the form of an email from Stephen Stahl himself. It started this way:

"To my fellow Boston area Psychopharmacologists:

Just a head's up about a local educational program I hope you can attend related to schizophrenia. The content is based both upon my textbook, Stahls Essential Psychopharmacology, and two cases from my private practice.”

Obviously aware of the increasing skepticism about pharma funding of physician education, Stahl addresses the issue head on: “ Although supported by Pharma and not CME (a new company Sunovion with a drug in the pipeline is the sponsor), there is no mention of any product here, just information on disease state, what I think is a very a cool update (understandable) on genomics, neuroimaging and the prodrome related to schizophrenia, and illustrated after the first didactic lecture with two cases taken from my practice.”

While I applaud Stahl’s transparency, I think he misunderstands the problem with pharma-funded programs. Their deficiency has nothing to do with the fact that they mention their drug, or any other drug. Why would a busy psychiatrist attend a half-day program on antipsychotics in which “there is no mention of any product”? In fact, we want to hear plenty about products. We look to experts like Stahl (and others on this tour, such as Leslie Citrome, Henry Nasrallah, Andrew Cutler, and Steve Potkin) to help us navigate the increasingly confusing terrain of antipsychotics.

We want them to talk about products, and we want specific recommendations. What is their first choice of antipsychotics and why? What are their second and third choices? What do they think about the increasing popularity of conventional antipsychotics? In their heart of hearts, do they really think that Lurasidone is worth choosing over its competitors? Shouldn’t we be hesitant to try me-too medications, when others of equal efficacy have long track records and clinical experience?

I predict that none of these experts will address these painfully obvious questions. Because if they did, they might let it slip that risperidone is their drug of choice. Or Abilify. Or Trilafon. Or Some Other Drug That Is Not Lurasidone.

Instead, audience members will hear about purely hypothetical mechanisms of action, many of which will be presented in such a way that Lurasidone will appear to have a "potential" advantage over its competitors.

This, after all, is the marketing strategy that Stahl has pioneered. Keep the audience mesmerized with colorful cartoons of fancy mechanisms of action that have no proven connection to the drug’s clinical action. Then say that because of these mechanisms of action, the sponsored drug “might” or “should” or “could potentially” or “will theoretically” be the best thing since Fridays.

Yesterday, Stahl’s CME company, NEI, sent me a free booklet, “Psychosis and Schizophrenia: Thinking It Through.” Like his road show, this book is funded by Sunovion, and it contains a coyly phrased endorsement of Lurasidone that is vintage Stahl: “Actions at 5HT7 and 5HT1A receptors suggest potential antidepressant and pro-cognitive actions, but this requires confirmation in clinical trials and real world clinical experience” (page 43).

Sorry for the poor review, Steve. But as Randy Jackson says on American Idol, “I’m just tryin’ to keep it real, dog.”