Newly-released court documents gathered as part of a court case against Wyeth (now part of Pfizer) brought by patients who developed breast cancer while taking its Prempro hormone replacement therapy (HT) illustrate how ghostwriting was used to distort or hide scientific evidence and lend clinical credibility to company marketing aims in medical journals and presentations. In “The Haunting of Medical Journals” in this week’s PLoS Medicine, Georgetown physician, researcher and expert witness Adriane Fugh-Berman examined the documents. She found that where company-funded trials and clinical findings are concerned, the marketing tail is still vigorously wagging the dog.

DesignWrite, a medical education and communication company (MECC) was hired by Wyeth to produce large quantities of “authored” papers that touted unproven benefits and later downplayed risks of HT proven in large randomized control trial (RCT) studies. Between 1997 and 2003, Wyeth hired DesignWrite to produce drafts of more than 50 peer-reviewed publications, including at least four primary publications on a Wyeth-funded Prempro trial.

DesignWrite’s ghostwriters also helped “manage” clinicians and thought leaders, ensuring marketing messages remained front and center in published papers, and planned CME events and journal supplements.

“Even though a 1997 DesignWrite proposal admitted that ‘HRT continues to be a drug in search of a disease’” Fugh-Berman writes, “my examination of the available documents indicates that the lack of evidence regarding the prevention and treatment of cardiovascular disease, dementia, and other diseases proved no deterrent to Wyeth/DesignWrite’s promulgation of numerous marketing messages positioning HT as a panacea.”

While this lines up with mounds of other evidence that show companies’ marketing goals running the scientific show, the casualness of the counter-science that was done to keep physicians prescribing HT is newly shocking.

When in 2002 the Women’s Health Initiative, a large RCT, disproved purported cardiovascular benefits previously associated with HT and showed increased risk of breast cancer and stroke, Wyeth commissioned the ghostwriters at DesignWrite to write papers casting doubt on hormone therapy’s role in breast cancer. One Wyeth employee suggested that a journal supplement falsely state that breast cancer associated with the treatment was less virulent. That year, Wyeth management “charged the Publication Committee with increasing the number of positive HRT/Premarin-related publications. They have asked us to publish at least 1 study per month.” The company also flooded medical publications with mini-reviews, editorials, comment, and other booster pieces that did not have to be peer-reviewed, but still packed a clinical punch with physicians.

Physicians, it’s clear from the documents, were only as valuable to Wyeth and DesignWrite as their prescribing pen and their generic credibility. As “authors” who lent their names to ghostwritten pieces, the companies saw them as interchangeable: “I moved Dr. Creasman as an author to the patient ed piece (with Blackwood, Weiss, & Speroff) and left Horwitz and Boman on the basic science manuscript,” one document stated.

This should be insulting to physicians. As a marketing tool, ghostwriting has been implicated in the physician recruitment campaigns around Vioxx, Neurontin and other high-profile drugs stripped of their mystique and safety profiles by sound science.  But as Fugh-Berman and these documents illustrate, the use–and manipulation–of medical journals and clinical evidence to support marketing aims may have become so routine that in some cases, the most reaction Wyeth’s antics stirred was confusion on the part of the token author:

“From what you have written, I would be more of an ‘editor’ rather than the major writer—that is, you guys would be writing the versions—with me ‘altering, editing, etc.? Is that correct?’”

And if this is an outrage to physicians, so should it be to the rest of us. The following is a response from Wyeth’s Gerald Burr to a ghostwriter about whether manuscripts could be reused.

“‘You can’t just put another name on the article, but you can plagiarize the way we did when we wrote papers in college. What you need to do is give your potential authors Karen’s version of the article before the author modified it. Then have your authors modify it for publication under their name. Wyeth owns Karen’s draft, not the final publication.’ Burr supplied five drafts but asked that [a DesignWrite supervisor] Karen Mittleman be notified of the plans for reuse ‘so she can advise if we are going to piss off any of the U.S. authors.’”

Read the full article here.

–Kate Petersen, PostScript blogger

The much-anticipated decision in the case Wyeth v. Levine was announced today, in which the Court rejected, 6-3, the drug industry’s argument that FDA’s approval of a drug’s label should be a shield from liability under state tort law.

We’re as excited as those Legal Eagles over at Prescription Access Litigation, who blogged on the decision here.

Pfizer announced today that it will begin to disclose payments made to physicians in a public online database beginning in the first half of 2010. Not only does this signal another Big (+ Wyeth = Bigger!) Pharma player hopping on the voluntary disclosure train, it would be the first company to post such information including payments to PIs of clinical trials.

Even though Pfizer is proposing a higher reporting threshold of $500, which would miss out on a healthy portion of payments like meals, the move takes more wind out of the already drooping sail of an argument the industry is hammering Massachusetts regulators with: that disclosure of clinical trial payments is Fatal to Business (especially, to hear them tell it, the Massachusetts Convention Industry).

It’s worth remembering Eli Lilly already discloses consulting and advisory payments on its website, and had pledged to widen that disclosure to match the Physician Payments Sunshine Act by 2011 (go here to read about other company promises) – so it could be said that Pfizer’s announcement is a case of the Great One-Up. But coming now – as Massachusetts Dept. of Public Health continues to come under industry fire for drafting regs that would require companies to do as Pfizer is doing – the move is significant.

As Newton’s First Law of News requires, the wires also brought this not-so-great report out of Minnesota indicating that the ethics chair and outgoing dean of the University of Minnesota Medical School, Dr. Deborah Powell, has significantly weakened recommendations by her own conflict of interest reform committee, which handed in a bold and comprehensive draft COI policy earlier this academic year.

According to the Minnesota Daily, which received a copy of the unreleased draft, “key elements of the task force’s recommendations, believed by some to be among the most needed changes, are notably absent from Powell’s draft, among them a recommendation to sever financial ties between industry and continuing medical education programs.”

Among those nips and tucks Dean Powell made to the committee’s recommendations? Yep, research:  “The task force recommended that faculty fully disclose the source of research funding as well, particularly those with clinical trials funded by industry,” but such disclosure didn’t make it into the new draft, either.

“They gutted it,” Center for Bioethics professor Carl Elliott told the Daily. Another Minnesota faculty member, Gary Schwitzer, a health journalist who has been a strong voice in calling for the separation of pharma money and faculty, told the paper he had not seen the latest draft at all, and American Medical Student Association Scorecard Director Gabriel Silverman said that the draft changes would take his read on the policies from strong to “borderline.”

Dean Powell, whose leadership of the task force was already marred by reports that the co-chair she named, Dr. Leo Furcht, was sanctioned for violating the university’s old conflict of interest policies, will step down as medical school dean but continue to chair the ethics reform committee, according to the Daily.

In a week where spending your taxpayer dollars on bad investments suddenly sounds like a ‘rescue plan,’ read this: the FDA spent a chunk of their not-so-spare change  (OK, so $300,000 is a lot less than $700 B) to hire a PR firm to “create and foster a lasting positive public image of the agency for the American public,” the Washington Post revealed this week. Instead of issuing the request for bids required for federal government work, a former public affairs executive for a medical-device firm now working for the FDA orchestrated a no-bid contact through Alaska Newspapers, Inc, which isn’t subject to government bidding requirements because of its special status. 

So are we more enraged at the fact the agency went the good ol’ boys route and circumvented the rules process to find the best and lowest-cost bidder, or that even as the chronically under-funded agency was asking Congress for more dollars to shore up its crumbling safety and oversight divisions, it was working this hard and shelling out this much to shine up the story in tomorrow’s social studies books? Right now, we’d say it’s a coin toss.

Putting ADHD drug ads in timeout

The FDA has warned five drugmakers about false or misleading advertisements of five ADHD drugs, according to the Bureau of National Affairs Health Care Daily Report. “The FDA sent letters to Eli Lilly and Co., Mallinckrodt Inc., Novartis Pharmaceuticals, Johnson & Johnson, and Shire Development.” One of them was a video testimonial by Extreme Celebrity Home-giver Ty Pennington for Shire’s Adderall XR, an unapproved ad the FDA says overstates efficacy but which company officials claim was never supposed to leave the Shire website, where the side effects, dosage and indications were plain for all to see.

The pre-emption question

As the Supreme Court’s November date with pre-emption case Wyeth v. Levine nears, this Boston Globe editorial argues the evidence has shown that the FDA approval process requires “insufficient proof” of drugs’ safety “and then does not recognize their harmful effects quickly enough.” The Globe continues: “the Supreme Court has no business depriving patients of their recourse to courts.”

Pharmalot’s Ed Silverman has made his site the one-stop shop for all things pre-emption. Check out his syllabus here.

Media matters

And in this week’s Journal of the American Medical Association, researchers from Harvard Medical School and Cambridge Health Alliance look at news reports on industry-funded pharmaceutical studies in the mainstream media and found that about 40% of 300 major news stories failed to mention the source of the study’s funding. 

Of course, reporters aren’t alone – recently, major medical journals have been discovered to have missing disclosure statements from industry-funded authors, and Congressional queries have found giant gaps in payment disclosures by university researchers. When it comes to disclosure, these researchers seem to be asking that the fourth estate go first.

UMN ponders new stronger COI policy

Minnesota Public Radio revealed leaked recommendations by a University of Minnesota medical school task force on new conflict of interest policies. The recommendations called for health care providers to disclose to patients any interest they have in companies whose products they prescribe them, developing a conflict of interest website, a complete phaseout of industry funding for continuing medical education, and a requirement that all physician-industry relationships be disclosed (currently, only payments above $10,000 are required to be reported). The University received a D on the American Medical Student Association scorecard for its current policies earlier this year. Here’s the AP follow-up.

Cephalon settlement calls for disclosure

As part of $444 million in settlements of whistleblower lawsuits related to illegal off-label marketing, Cephalon is the first drugmaker to enter into a corporate integrity agreement that will require it to disclose prominently payments to physicians and amounts on its website; the move comes a week after Eli Lilly and Merck announced they will voluntary disclose such payments beginning next year; two years ago, five medical device makers began to disclose such payments under a similar settlement agreement to Cephalon’s.

Find out more at Marketwatch and Wall Street Journal Healthblog.

A market research survey of 180,000 docs conducted in the fourth quarter of 2007 found that 19 percent of responding physicians said they refused to see drug reps, no matter what. That sounds like good news, until you get to the part where 73 percent will see a detailer “at any time of day, any day of the week.”  But give that the survey conductor, SK& A Information Services, is a healthcare marketing firm, we can’t blame them for some spin. [Disclaimer: this short article does not make clear what percentage of the 180,000 docs called responded.]

Such data may have played a role in this: PhRMA, the trade association for American pharmaceutical manufacturers, says it’s taking another look at its sales and marketing tactics. The trade association has taken some flak for its 2002 *voluntary* code of ethics, which was widely heralded by the medical community as a little better than no code at all.

Sen. Herb Kohl (D-WI), a co-sponsor of the Physician Payments Sunshine Act, sounded a bit skeptical about what such discussions might lead to.

“I would be pleased if the pharmaceutical industry seriously strengthened their self limitations,” Kohl told the AP. “However, if their voluntary approach hasn’t worked over the past six years, I’m unsure whether it would work now.”

In the other house of Congress, Rep. Henry Waxman announced that in his digging he’s discovered a meeting the pharma representatives had with the FDA in April that led to the FDA’s guidance that would allow sales reps to show doctors journal articles on off-label use as part of their pitch. Waxman leaked that in November, and we’re keen to see what comes of this latest development.

State of the States

Tomorrow, the New York State Assembly hears three bills on pharmaceutical reform: one would require public disclosure of gifts from pharmaceutical companies to prescribers, another would prevent companies from selling prescriber data without his/her consent, and a third would create a mandatory state clinical trials registry housed at DHS. RxP, AARP, NLARX, National Physicians Alliance and others will be testifying in support – we’ll keep you posted.

And yesterday, the New York Times ran this damning piece about how the top-tier spinal implant researchers are also top-circle investors in the companies of devices they are researching. As for the rest, you probably know it already…(since this story is on top of most e-mailed at nytimes.com). If not, read this.

A triad of good editorials appeared recently in (chronological order) the Grand Forks Herald (registration required), Beloit Daily News, and the St. Cloud Times, concerning the recent news that a group of Minnesota and Wisconsin hospitals and clinics were shipping their pharma freebies (and conflicts) off to Cameroon. The St. Cloud Times specifically cites the Physician Payments Sunshine Act as a measure worth consideration to curb the marketing influence pharma currently wields over medicine.

This piece from the Barre Montpelier Times-Argus looks how some of the state’s mental health advocacy groups are swearing off pharma, and how much salt one should take with reports like Mental Health America’s annual depression and suicide state ranking (Cheer up Utah!), once the backer (Wyeth) is factored into to the picture.

“The mantra in Vermont and the United States that this is unrestricted money is a myth,” Ken Libertoff told the Times-Argus. “It really has distorted treatment and advocacy in the field.”

Libertoff runs the Vermont Association for Mental Health, which forewent pharmaceutical grants last year. He said he’d begun to feel that accepting the industry backing was changing the nature of his organization’s advocacy work. Wisconsin isn’t doing so hot when it comes to following up or following through on medical complaints. Just eight percent of medical complaints filed between 2002 and 2006 were acted on by the board of medical licensure.

Scrutiny of such investigations has been growing, perhaps in the wake of a New York Times report last May that documented a Minnesota psychiatrist who’d been repeatedly sanctioned by the medical board continued to consult for pharmaceutical companies.

Academy bristles at OIG report

And in a follow-up to last week’s article on the OIG report that the NIH has taken a hands-off approach to monitoring conflicts of interest, the Chronicle of Higher Education takes its turn. With a definite dog in this fight (since the NIH has said universities should police their own grantees), the Chronicle doesn’t pull punches when it comes the research monolith in Bethesda.  “In harmony with its distaste for the police function,” the Chronicle writes, “NIH takes a minimalist approach to checking on conflict of interest among its grantees — so minimalist, that any less would be none.” Ouch.

From the blogs:

Here is Howard Brody’s attempt to keep his argument against conflicts of interest on track, and why it’s not akin to hating capitalism….Just in case you were confused.

At the Carlat Psychiatry Blog, Dr. Carlat has an email exchange with American Journal of Psychiatry editor Dr. Robert Freedman that leaves him baffled. Us too.  First, Freedman disclosed an unpaid relationship with investigators, then in an email to Carlat, said it was just in case he had to contact pharmaceutical investigators…in the future. Is that like the Boy Scout Motto for conflicts of interest? 10 yards, 10 years: a modest proposal

And what would Superbowl week without a football-related pharma story? After all, PostScript is headquartered in Patriot Nation. So in the spirit of all that side-effect-induced suspense between downs, this Boston Globe column suggests we take the next decade off the pharma ads during sports programming.

Right now, Dr. Daniel Carlat’s article, “Dr. Drug Rep,” is sitting atop the vaunted Most E-mailed list on nytimes.com.  Featured in Sunday’s New York Times Magazine, Dr. Carlat’s narrative recounts his year as a paid speaker for Wyeth Pharmaceuticals and its depression drug, Effexor.  Carlat, a psychiatrist with a practice in Newburyport, MA and author of a great blog, spins an intriguing tale complete with dialogue, disillusionment, and Broadway glitz in four parts.  If you haven’t already read it, chances are someone has sent it to your inbox.

No doubt: We are a list-crazed culture. From the fatalistic travel book series 1000 Places to See Before You Die to the Seven Habits of Highly Effective People to Casey Kasem’s American Top 40, we are a people in love with the list.  And “Most E-mailed” at nytimes is no exception, showing a real-time ranking of the stories being sent (and to extrapolate, being read) most frequently from the New York Times website.  “Most E-mailed” has been elbowed as an echo-chamber metric, perhaps most charmingly by The Onion, which reported in April that the coveted top-ten was tearing the New York Times newsroom apart.

But despite this and other “real news” criticisms, nytimes.com “Most E-mailed” has become the sidebar to watch for what people are talking about around the web-based water-cooler.

And what they are talking about today is Carlat’s “Dr. Drug Rep.”  Over every other Times news story.  We read this as a really good sign that pharmaceutical influence on doctors—the economics of it, the tactics, the pervasiveness (Carlat cites a report that estimates about 25 percent of U.S. physicians receive money for speaking about or helping to market drugs)—is at the top of readers’ minds.  And though we’re biased, we think that’s where it should be.

The blogosphere is also a-flutter with Carlat’s confessional (the story is currently at #8 on the Times Most-Blogged tab), and is yielding some interesting side stories, including a comment on Pharmalot from an ex drug rep who says that some pharmaceutical reps just go through the motions of setting up speaking engagements and ‘ghost-dinners’ under pressure to spend their speaking budgets. More blogs here, here, and here.

All of this buzz comes along as more and more legislation is being introduced at the city, state, and federal level to alter the way drug companies court and co-opt doctors.  Recent headliners include the Physician Payments Sunshine Act, similar legislation slated to be introduced in the House, Maine’s data-mining restriction bill, and the Safe Rx Act being considered by the D.C City Council.  It’s a natural feedback loop, and the volume is growing. 

Does all this add up to our nation taking stock, just as Carlat did, about the ethics and consequences of our relationship with medicine and the pharmaceutical industry, and the relationship we permit between the two?  Perhaps.  Or perhaps it’s too a big leap to see the patchwork of moves by individual, corporate, academic, and public healthcare stakeholders as the actions of a united, albeit clumsy, moral agent.  Either way, it seems we can read the growing policy and media attention—measured in bills and newspaper inches and airtime—like a loudening macro version of the silent internal dialogue Carlat describes having with his conscience after each Wyeth talk he gave. 

It will be interesting to follow this story and see whether this interplay among policymakers, press and the public concludes, as Carlat’s tale did, in a collective, incremental “No Thanks.”