In Bed with Big Pharma? Industry Liaisons Raise Questions at the FDA

"No comment."

That's what the spokesman for a leading academic and member of a Food and Drug Administration (FDA) panel said when asked whether the member's ties to Bayer, the German drug giant, had "affected her judgment in any way regarding her vote on December 8, 2011."

The December 8 vote was to record the views of FDA medical experts on whether the advantages of two best-selling Bayer contraceptive pills and related drugs outweighed the risks of taking them. A “no” vote would have damaged sales and made likely their withdrawal from the U.S. market, where they had become two of America’s best-selling oral contraceptives.

Two other panel members, including the chair, had prior ties to Bayer which they denied had any influence on their vote. A fourth, with ties to a generic manufacturer of the drug under scrutiny, told POGO they too had no bias.

The FDA panel examined studies of the contraceptive and their key ingredient, the synthetic hormone drospirenone, or DRSP. Three Bayer-funded studies had come to the conclusion that the risks were no higher for the pills, known as Yaz and Yasmin, than for other contraceptives. But seven separate studies, not funded by Bayer, had come to the opposite conclusion. Some of these studies rated the risk of Yaz and Yasmin roughly double that of non-DRSP alternatives.

Even more troubling: the FDA panel did not consider an internal Bayer document that was recently introduced as evidence in a federal court proceeding against the company. That document, dating from 2004, features Bayer’s own experts describing its Yasmin contraceptive as having a reported rate of serious “adverse events” that was “10 fold higher” than other contraceptives. The “adverse events” typically involved blood clots, which could become life-threatening if they moved to the lungs or heart.

In 2010, some 2.5 million American women received Yaz, Yazmin and other products containing DRSP, amid thousands of reported cases of blood clots and other problems.

Members of the FDA panel responded to this evidence very differently. Fifteen members voted that the benefits of Yaz, Yasmin, and related contraceptives outweighed the risks. Eleven voted the other way.

However, court documents and other materials obtained by POGO Staff Scientist Ned Feder indicate that four voting members of the FDA panel, including its chairperson, turned out to have prior relationships with Bayer or a company that markets a generic equivalent of Yaz and Yasmin. In one case, the ties involved thousands of dollars in fees, while some of the other panel members had conducted research funded by Bayer or the generic manufacturer. The four all voted in favor of the Bayer pills and related contraceptives, tipping the balance.

Each of the four had evidently told the FDA about their ties to Bayer or other manufacturers, as required. The agency did not object to their voting participation on the panel or make their industry ties public. A transcript of the panel’s deliberations gives no indication that fellow panelists were ever aware of these links as the group spent hours deciding how to deal with the well-documented risks associated with Yaz, Yasmin, and related drugs.

It’s hardly the first time the FDA has confronted charges of bungling conflict of interest issues. In 2004, the FDA struggled with similar criticism after members of another advisory panel voted that the painkiller Vioxx was safe enough to remain on pharmacy shelves. Vioxx was subsequently withdrawn after research demonstrated its link to some 60,000 deaths. It then took until 2008 for the agency to declare that it wanted to be more “transparent” and curtail any “bias” in dealing with conflicts of interest among its medical experts.

As the FDA first green-lighted Yaz in 2001, with Yasmin to follow in 2006, Bayer ginned up hundreds of millions of dollars’ worth of TV and print advertising to highlight the drugs’ role not just in blocking pregnancy, but as a life-style enhancement aimed at younger women trying to curtail everything from acne to severe, pre-menstrual depression.

At one point, Bayer’s claims prompted the FDA to sanction it for deceptive marketing practices and other shortcomings related to the drugs. But that didn’t slow Bayer down, as more than two million American women eventually helped make Yaz and Yasmin the country’s top-selling oral contraceptive and Bayer’s second biggest revenue-grabber, achieving nearly $2 billion in

global annual sales.

“She will be well utilized”

In addition to directing glitzy ads at the public, Bayer was also working hard to win endorsements from the medical community, encouraging doctors to prescribe its pills.

Several members of the FDA advisory panel who would later vote on the future of Bayer’s contraceptives seemed to catch the company’s attention. At least according to court documents, one notable favorite turned out to be Paula Hillard, a Stanford University physician, who seems to have enjoyed a long relationship with Bayer and was seen, according to internal company records, as a “Yasmin advocate.” As long ago as 2003, Bayer was referring to its plans to “educate this Key Opinion Leader,” an apparent reference to Hillard, by discussing with her the risk of blood clots associated with its drug, an issue on which she would later vote in Bayer’s favor while serving on the FDA’s advisory panel.

A variety of Bayer documents covering the period 2008 through the end of 2010 record occasions on which Hillard served, in company lingo, as a “Bayer trained speaker” at medical meetings, not to mention her involvement with “promotional” programs involving Bayer, notably Bayer’s plans for a January 2010 “video shoot with Dr. Paula Hillard to illustrate patient counseling techniques on the safety of YAZ.”

In 2008, an internal document described as a “Bayer Corporate Account Update” hailed her as well. It said:

New west coast speaker… Paula Hillard, MD, recently relocated from Cincinnati, OH to Stanford—this enables us to now have another huge Mirena [also a Bayer drug] and Yasmin advocate here in Nor Cal—she will be well utilized!

“To take the product off the market…not quite sure that’s necessary”

Another panel member who voted in favor of Yaz and Yasmin was Anne Burke, an assistant professor at Johns Hopkins who has acknowledged receiving research funding from Bayer. In the financial disclosure section of a 2008 journal article, Burke disclosed a “conflict of interest” based upon receipt of research funding from Bayer. An internal Bayer document introduced in federal court cites the company listing Burke as a “Bayer contraception expert.” Burke told POGO that she has not received funding from Bayer or a producer of generic equivalents of its contraceptives in several years. She said all of her ties were disclosed to the FDA and that none of them in any way “affect my analysis … nor my decision” when she served on the FDA panel meeting last December.

According to a transcript of that panel’s proceedings, Dr. Burke explained her vote in favor of Yaz and Yasmin by saying:

I don’t think I was expecting it to be more effective than other pills on the market, and while I acknowledge that there does seem to be a moderate increased risk, it’s still lower than the risks of pregnancy. And like some other folks who have spoken, a no vote sounded like it would be—to take the product off the market. I’m not quite sure that’s necessary at this point.

But that wasn’t the way another expert saw it. According to Enrique Schisterman, PhD, senior investigator and chief of the epidemiology branch of the National Institute of Child Health and Human Development, he voted against the drugs because:

there are plenty of other alternatives that do not show any increased risk. One of the main things is do not harm. And even a small excess of risk is no—we shouldn’t take that lightly.

An ounce of prevention

Given what POGO believes are obvious questions about the impartiality of the FDA panel’s recent review of Yaz and Yasmin, Executive Director Danielle Brian and Staff Scientist Ned Feder have written a letter to FDA Commissioner Margaret Hamburg, asking that she set aside the panel’s vote, and convene a new panel without the potential conflicts of interest that tainted the previous review. POGO has also asked Hamburg to ascertain how it happened that four members of the panel disclosed their possible conflicts to the FDA and yet were asked to serve anyway, with no public disclosure.

Looking ahead, POGO asks that when dealing with any question of an FDA expert’s impartiality, the information be made public, and without delay. Finally, POGO asks that the FDA strengthen its new guidelines for dealing with public disclosure of financial conflicts of interest, due out in the near future.