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DO DRUG AUTHORS WRITE, OR SIGN OFF?

Articles in journals influence doctors to prescribe drugs. But sometimes, the drugmaker is driving the story content.

Documents recently released in federal court cases against the drug company Wyeth have exposed one of the dirty secrets in the world of medical journals: the widespread practice of ghostwriting.

While doctors are named as the authors of articles about treatments and diseases, behind the scenes are paid writers who are largely responsible for crafting the pieces.

Not only is the ghostwriter on the payroll of a drug company with interests in the topic, the company often reviews the manuscript before the physician sees it.

With publication in a peer-reviewed journal, the physician enhances his reputation and resume. The drug company gets its marketing message across by a supposedly unbiased author.

Meanwhile journal readers - doctors and their patients - have no inkling of the drugmaker's role in shaping the information.

A growing number of critics, including Sen. Charles Grassley, are demanding that industry financial ties to journal articles be disclosed. Many journals now require authors to identify anyone who contributed to an article and their financial sponsorship.

"There ought to be clear rules: Write your own paper, no guest authorship, no ghostwriting," said Dr. Marcia Angell, Harvard professor and former editor of the New England Journal of Medicine. "And there should be a decisive and painful response (by journals and medical schools) when the rules are broken. Now the response is just a tap on the wrist and hand-wringing."

A Wyeth spokesman brushed off the controversy.

"Why are you doing a story about ghostwriting?" asked Wyeth's Doug Petkus. "Did the doctor agree to the content? Did he approve it? That's the key."

In the Wyeth documents, one of the dozens of doctors whose name appeared on ghostwritten articles was Dr. James Fiorica. At the time, he headed the gynecologic oncology program at H. Lee Moffitt Cancer Center and was a professor at the University of South Florida in Tampa.

Fiorica, who also was a paid Wyeth speaker, dismissed the extensive role the drugmaker played in formulating articles that appeared under his name.

"I wouldn't allow my name to be on something that I didn't feel comfortable with, and with the literature supporting," he said. "I try to be as actively involved as much as I can."

- - -

In the late 1990s, Wyeth's hormone treatments for menopausal symptoms, including hot flashes and night sweats, were the most-prescribed drugs in America. The estrogen drug Premarin and the estrogen-progestin combination, Prempro, were on their way to $2 billion a year in sales.

But there were increasing concerns about links between hormone use and breast cancer, and evidence was emerging that the drugs did not prevent heart disease, an off-label use for which they were widely prescribed.

The drug company was not about to let its valuable franchise be undermined. Internal corporate documents released last month in connection with more than 8,700 lawsuits against Wyeth tell the story.

In 1997, Wyeth hired DesignWrite of Princeton, N.J., to create a public relations campaign to tout the benefits and "diminish the negative perceptions" of hormone replacement therapy among health care providers.

In its confidential proposal to Wyeth, DesignWrite explained how it would use research articles and journal supplements to "position the product appropriately to influence prescribers."

"The first step is to choose the target journal best suited to the manuscript's content, thus avoiding the possibility of manuscript rejection," the proposal said.

"We will then analyze the data and write the manuscript, recruit a suitable well-recognized expert to lend his/her name as author of the document and secure his/her approval of its content. After the client (Wyeth) has reviewed and released the manuscript for submission, DesignWrite will see it through the necessary production stages."

By 1999, DesignWrite had generated a dozen journal articles for Wyeth. It proposed writing 20 more articles in 2000 and 2001, for a fee of $500,000.

Among these were articles by Fiorica. A "Strategic Publication Plan Tracking report" at DesignWrite had this note after a couple of Fiorica's articles: "Author requested editorial support."

One article under Fiorica's name, "Mammographic Breast Density and HRT," argued that although hormones made breast tissue denser, it was not more difficult to detect breast cancer.

Several versions of the manuscript were sent to Fiorica for review. In 2001, the piece was rejected by a peer-reviewed journal, Mayo Clinic Proceedings. It was published a year later in Menopausal Medicine, a medical newsletter - funded by Wyeth.

- - -

In addition to ghostwriting journal articles, DesignWrite coordinated Wyeth's role in continuing medical education courses, or CME. Drug companies regularly fund such courses, which provide required credits to practicing physicians. To prevent bias, there is supposed to be a firewall between the drugmaker and the company it pays to organize the course.

But court documents show the firewall was virtually nonexistent during development of a course on "Postmenopausal Hormone Therapy and Breast Health: A review for clinicians," first offered in October 2001.

The course was based on presentations made by six academic physicians during an "Expert Panel on Breast Health and HRT" at the Four Seasons Hotel in Philadelphia. E-mails and handwritten notes show that while DesignWrite fretted the details like gifts for the presenters ("Can we get a discount on the Coach Travel Wallet?" asked DesignWrite's Bernadette Janas), little was done without consulting Wyeth ("Meet w/Mark [Barbee, Wyeth product manager] again - planning meeting," Janas wrote.)

Documents show Wyeth had a role in choosing speakers, including Fiorica as chairman. ("YES," Janas wrote in all capital letters after getting the Moffitt doctor's agreement.) Wyeth and DesignWrite chose the topics to be discussed and sent reading material to participants beforehand.

Per its agreement with Wyeth, Rosie Lynch, DesignWrite's vice president, wrote that the company took responsibility for "writing and editing the papers as shown in the outline." DesignWrite's proposed charge for producing an introduction and four scientific articles: $100,000.

In a flurry of e-mails, Wyeth executives reviewed and edited manuscripts even before they had been seen by the physicians who would be identified as authors. The ties between topic and expert were so flexible that a month after the meeting, DesignWrite e-mailed Wyeth about switching authors on manuscripts.

One of the speakers was thrilled with the results. Dr. Leon Speroff, then a professor at Oregon Health and Science University in Portland, shot an e-mail back to DesignWrite after receiving a draft of its manuscript.

"You did a super job of writing this paper - succinct and makes the points very well," wrote Speroff, whose article was on the "inconsistency in studies" showing a link between breast cancer and hormone therapy.

Fiorica was named as author of the introduction and two articles, which were e-mailed for his review several months after the meeting. He said recently he was comfortable with the process.

"It's very unlikely I'd let anything go through that I didn't feel captured what was said at the meeting or in the literature," he said. "Whether it's coming from me or from someone else doesn't matter as long as the content is accurate."

Michael Platt, president of DesignWrite, said his company "stands by the medical and scientific accuracy and validity of every article in which it has participated."

Though the CME was officially accredited by the University of Wisconsin Medical School, documents show that the school had no involvement in the project until just weeks before the manuscripts went to press. The university received $1.5 million through Wyeth's Council on Hormone Education for sponsoring CME courses on hormone therapy through 2006.

The UW faculty member who reviewed the CME material for bias, Dr. Julie Fagan, told the Milwaukee Journal Sentinel last month that she first learned of Wyeth's involvement in the process during a court deposition in June 2009.

Because the named authors were all distinguished and well-published, Fagan said, "I, like doubtless many readers, assumed they had written the articles themselves. I probably should have been more skeptical going into the project."

Wyeth's spokesman, Petkus, said the pharmaceutical company's role in the course work was clearly disclosed. "We did not control or direct the content of this CME program,'' he said.

The course material, which was sent to 128,000 doctors, carried this disclaimer on the index page: "The opinions expressed in the articles that appear in this supplement are those of the authors and do not necessarily reflect those of ... Wyeth-Ayerst Laboratories."

- - -

At times, DesignWrite wrote so glowingly of hormone therapy's benefits that it even made a Wyeth executive cringe.

Reviewing Fiorca's introduction to the CME course, Jamie Durocher, then group product director at Wyeth, worried that physicians would be turned off by too boosterish an approach.

"I think certain revisions are necessary to unobtrusively acknowledge the conflict of recent years (without being negative)," she wrote, referring to growing concerns about the risks of hormone therapy.

The ghostwritten introduction, meanwhile, emphasized potential benefits of hormone therapy, from improved sexual function to lower risk of Alzheimer's disease.

Wyeth's Durocher also recognized that the company had to be sensitive about the breast cancer issue. While the company insisted studies were inconclusive, it claimed the benefits of hormones outweighed "the small potential for increased risk of breast cancer."

Editing the "patient question-and-answer" section of the CME, Durocher admitted that, for many women, "any risk of cancer is perceived as too much."

"It may be helpful to also mention ... that women on HRT who do develop cancer have a less virulent cancer and a better outlook for recovery," she suggested. Her statement appeared nearly verbatim in the patient handout, which was approved by Fiorica and the other experts.

Fiorica defended his work with Wyeth as part of his role as a department head at a well-known cancer center.

"When I was at Moffitt, I'd chair panels," said Fiorica, 52, who is now medical director of the Women's Cancer Care program at Sarasota Memorial Hospital. "My focus is breast cancer, so a lot of times if questions come up, they'd ask me."

Though he has been paid to speak on behalf of Wyeth as well as several other drug companies, Fiorica said the money doesn't influence his message.

"My purpose is to educate physicians regarding a particular topic about what's current in the literature," he said of the Wyeth-funded courses. "It doesn't matter who pays for it. The literature is the literature."

Angell, the Harvard professor and author of The Truth about Drug Companies, feels differently. "The pharmaceutical industry has no business being involved in the education of physicians regarding the products they make," she said. "It's impossible to have industry funding without industry influence."

- - -

In summer 2002, just as Fiorica's ghostwritten article was published, Wyeth got bad news.

One arm of the government's huge Women's Health Initiative, or WHI, study of hormone therapy was stopped early when it became clear that women on estrogen and progestin had greatly increased risk of breast cancer, heart attacks, strokes and blood clots.

Wyeth's sales of Prempro plummeted 60 percent. The drugmaker also started seeing a flood of lawsuits from women saying the drug was responsible for their breast cancer.

Dr. Jacques Rossouw, who heads the WHI, sponsored by the National Institutes of Health, said Fiorica should have been aware of evidence discrediting his thesis that hormone therapy did not impair detection of breast cancer.

"He didn't know our data yet, but there was enough evidence already that showed quite clearly there was an underdiagnosis of breast cancer in women taking hormone therapy because of the increase in breast density," Rossouw said. "It obscures the ability to make the diagnosis."

Fiorica recently defended the article, which also was part of the CME coursework. "The published data presented was relevant at the time of the presentation in 2002," he said.

The arm of the WHI study that involved women on estrogen only, or Premarin, was halted in February 2004 after similar increased risks were shown for stroke and blood clots.

Fiorica remained on Wyeth's Council on Hormone Education, offering continuing education courses to physicians, until 2006. He declined to say if his opinions on the risks of hormone therapy have changed in light of the WHI data.

"That's a whole different discussion," he said, before declining further interviews.

Speroff, the physician who had applauded DesignWrite's ghostwriting effort, remains a strong believer in Wyeth's products. "There's growing support once again for multiple health benefits of hormone replacement therapy," said Speroff, now retired.

That reaction puzzles Rossouw, whose WHI studies of more than 27,000 women ages 50 to 79 have provided the most conclusive results so far on risks of hormones.

"There's room for legitimate disagreement regarding the interpretation of the data," Rossouw said. "But when I read what these people write and say, I wonder if they've actually read the data."

Times researcher Shirl Kennedy contributed to this report. Kris Hundley can be reached at khundley@sptimes.com or (727) 892-2996.

* * *

FAST FACTS

Tracking the data on hormone therapy

1998: The Heart and Estrogen/Progestin Replacement Study (HERS) of 2,763 postmenopausal women with heart disease finds that the drugs did not prevent further heart attacks or deaths from heart disease. Hormones also increased the risk of blood clots.

2002: The Women's Health Initiative study of women on estrogen and progestin is stopped early after the trial, which included 16,608 women ages 50-79, found an increased risk of heart disease, stroke, blood clots and breast cancer.

2003: WHI study finds twice the risk of dementia in women 65 and older taking estrogen/progestin.

2004: WHI halts a study of 11,000 women taking only estrogen after finding they had an increased risk of stroke and blood clots and no benefit from the hormones regarding heart disease, breast cancer or colorectal cancer. Based on these findings, the WHI recommended that hormone therapy should not be used to prevent heart disease, a common off-label use.

2008: WHI researchers find combined estrogen plus progestin hormone therapy appears to increase the risk that women will have abnormal mammograms and breast biopsies, and may decrease the effectiveness of both tests for detecting breast cancer.

2009: Responding to a significant drop in breast cancer cases since 2002, a WHI follow-up study confirmed that the risk of breast cancer associated with estrogen plus progestin use goes down significantly once these hormones are stopped. Researchers also found that the increase in breast cancer risk seen with longer use of estrogen plus progestin is even higher than previously estimated. A woman continuing combination hormone therapy after about five years doubles her annual risk of breast cancer.

Source: www.nhlbi.nih.gov/whi

Risks and benefits of hormone therapy

The Women's Health Initiative study found that compared with the placebo ...

Estrogen plus progestin resulted in:

- Increased risk of heart attack.

- Increased risk of stroke.

- Increased risk of blood clots.

- Increased risk of breast cancer.

- Reduced risk of colorectal cancer.

- Fewer fractures.

- No protection against mild cognitive impairment and increased risk of dementia (study included only women 65 and older).

Estrogen alone resulted in:

- No difference in risk for heart attack.

- Increased risk of stroke.

- Increased risk of blood clots.

- Uncertain effect for breast cancer.

- No difference in risk for colorectal cancer.

- Reduced risk of fracture.

(Findings about memory and cognitive function are not yet available.)

Source: www.nhlbi.nih.gov/whi

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