Researcher regrets ghostwritten hormone therapy review

What drives someone with a strong scientific reputation to cut a secret deal with a drug company for ghostwriting help just to have one more paper published?

Let's ask.

Dr. John Eden is the founder and director of the Sydney Menopause Centre, part of the New South Wales Health Department. He is a researcher with a long publication list. The University of New South Wales publication, Uniken, called Eden, who is an associate professor there, "the face of reproductive endocrinology in Australia."

With some papers that have been cited more than 400 times, there is no doubt that Eden has had a big impact in that field.

His reputation suffered a serious blow in December 2008 when Duff Wilson wrote a piece for The New York Times that revealed that Eden had signed his name to a paper ghostwritten by Wyeth, maker of hormone replacement therapy (HRT) powerhouse Prempro.

Eden did not talk to Wilson at the time. So Antidote emailed Eden to see what he might say now. He was surprisingly forthcoming and said he regrets the decision.

"We academics are under some pressure to 'publish or perish,'" Eden wrote. "Performance evaluation of at least Australian academics includes the number and quality of publications per year. In retrospect, I was probably naïve and I wouldn't do it now."

Wyeth had long planted ghostwritten research papers in major scientific journals to subtly steer doctors toward its therapies by either highlighting a particular diagnosis, promoting a particular therapy or downplaying side effects. These papers often did everything but use the brand name of the drug to market a particular pill. Wilson, using documents released by Sen. Charles Grassley's office, wrote:

Wyeth executives suggested that Dr. Eden write such a paper in 2000, according to the documents, and had the outline and draft manuscript written for him. The Archives of Internal Medicine rejected the paper before it was published in The American Journal of Obstetrics and Gynecology - with no mention of Wyeth or DesignWrite connections.

Eden told Antidote that he had made it clear to the American Journal of Obstetrics and Gynecology (AJOG) that he had help writing the paper, although he did not specify Wyeth's involvement.

"In retrospect, I might have taken disclosure further and highlighted that the medical writers were engaged by a third party, but their role was facilitation and they had no undue influence on the final outcome," Eden wrote. "The first draft was based on papers that I had written and talks that I had given during the 1990s and in 2000. It took a further three years to finalize the paper for submission to AJOG. All medical papers undergo rigorous peer and editorial review before being accepted for publication. I stand by the paper, which made a substantial contribution to the HRT debate. In fact, it was the Editor's Choice article for that edition of the Journal."

The timing of the paper was great for Wyeth. In 2001, Prempro and Wyeth's other hormone pills were responsible for $2 billion in U.S. sales, 15% of Wyeth's business. The following year, the researchers behind the federally funded Women's Health Initiative halted a major HRT study because it found that women taking HRT suffered significantly higher rates of heart disease and cancer than those who did not. Sales of Prempro fell off a cliff.

Now, in May 2003, Eden, a well regarded expert in hormone therapies, was going right to the heart of the HRT debate. The paper was titled "Progestins and breast cancer," and it essentially asked whether drugs like Prempro increase breast cancer risk. Eden answered emphatically: "no."

"To date, there is no definitive evidence that progestins act in the pathogenesis of breast cancer," says the abstract.

The debate over the role of progestins in breast cancer has been fierce, with some studies suggesting high doses of progestins as a therapy for breast cancer and others taking a more cautious view. The contrast can be seen in two papers in the same issue of Gynecological Endocrinology in December 2001. The American College of Obstetricians and Gynecologists recommended in a journal paper that women continue to be prescribed HRT as late as March 2002, just before the WHI study was halted.

But after the WHI study, the tone among researchers started to change. A paper in the journal Breast Cancer Research said in October 2002, "It is now established that the most commonly prescribed estrogen-progestin replacement therapy regimen significantly increases breast cancer risk."

This is why Eden stressed to Antidote that his work on the paper in question was completed prior to the WHI study.

"If you look at the actual paper, you will note that the Journal received the paper 9 July 2002 - ironically the day before the release of the Women's Health Initiative (WHI) preliminary results," he wrote. "This confirms that my article was not written in response to WHI. When I revised the paper in response to the editorial and reviewers' remarks I then added some comments about WHI. My paper clearly reported the WHI (Women's Health Initiative) research showing an increased risk of breast cancer associated with more than 5 years use of the Wyeth HRT oestrogen-progestin product."

When Antidote asked Eden if he was concerned at the time that he was writing a review paper that ran counter to the prevailing thought, he answered, "not at all."

"The nature of scientific enquiry is to always ask questions and not just accept the status quo," Eden wrote. He added, "My core hypothesis for the last decade or so, is that HRT doesn't cause breast cancer but might activate a small (even undetected) tumour, making it grow faster. Also, it seems clear to me (then and now) that not all progestins are the same with regard to their impact on breast cancer risk. As we have shown moderate-high dose progestin actually decreases breast cancer recurrence. And the French have shown that a moderate dose of norethisterone given to women with cystic breasts, reduced their risk of breast cancer. Unfortunately, I don't expect that we will ever get a trial directly comparing different progestins and their impact on breast cancer risk (as I called for in the opening abstract section)."

With more ghostwriting cases coming to light every day, it is hard to know how to read the publication history for a something like HRT. How do we trust medical journals that did not think to ask who was funding the "writing assistance" that was acknowledged in the author's notes? If a report in a journal is "peer reviewed" by physicians who have been working as a consultant for a drug company, can we expect that the reviewers' opinions are unclouded? Should the research history of doctors like Eden and Dr. Gloria Bachmann be reviewed in light of their heretofore secret work for drug makers or should we assume that they wrote everything else themselves?

I appreciate Eden's candor and his willingness to admit a mistake. But health writers and watchdogs have a lot more work to do in teasing out the effects of ghostwriting in medicine. Let me paraphrase Eden's ghostwritten paper: To date, there is no definitive evidence that these doctors were acting independently and producing scientific work that was purely in the best interest of patients.