March 9, 2012
Margaret Hamburg, M.D.
Food and Drug Administration
10903 New Hampshire Ave
Silver Spring, MD 20993-0002
Re: FDA Review of Drospirenone (DRSP)-based Oral Contraceptives
Dear Commissioner Hamburg:
We are writing to follow up on our meeting with you in December and to express our strong concerns about the December 8, 2011 FDA joint meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee. This Advisory Committee meeting reviewed new data on drospirenone (DRSP), an artificial hormone that is in several very popular oral contraceptives, such as Yaz and Yasmin.
As we mentioned in our meeting with you, there were several irregularities that seem to have resulted in a vote that was interpreted as being in favor of keeping these contraceptives on the market, although there is strong evidence that they are less safe than more than a dozen other, less expensive and equally effective oral contraceptives that are readily available.
The committee members were asked to vote on whether “the benefits of the DRSP-containing oral contraceptives for prevention of pregnancy outweigh their risks.” After voting 15 to 11 that the benefits outweighed the risks, each Advisory Committee member explained his or her vote. Those who voted “no” explained that safer oral contraceptives were available. Almost all the 15 who voted “yes” indicated they voted on a comparison of risks and benefits of DRSP oral contraceptives compared to pregnancy, rather than on whether the risks and benefits of DRSP-containing oral contraceptives outweigh the risks and benefits compared to other oral contraceptives.
For example, panel member Elaine Morrato voted “yes” but said “However, if the standard is to make a comparative, which we-I just compared it in the absolute sense. I would agree that I didn’t see any benefit of the product that’s well demonstrated for Yasmin, perhaps for Yaz. And so if the regulatory standard would be that you’d have to demonstrate a comparative benefit, then I would vote no.”
That explanation would change the vote to 14 “yes” and 12 “no.” Three panel members who voted that the benefits outweighed the risks expressed strong concerns and said they were not sure the benefits outweighed the risks compared to other oral contraceptives.
Julia Johnson voted “yes” and said “I am significantly concerned regarding the most recent FDA study…I would like to see comparison with another U.S. study. I think that’s absolutely critical. I do not think there is one advantage for this pill over any other for use for women. If indeed there is truly an increased risk, then I would vote differently.”
Sean Hennessey voted “yes” and said “It was a difficult vote. I think that the drug ought to be rarely used and probably not first line….I think that it’s possible that future studies will show comparative benefit in terms of PMDD and acne versus other agents. But I’m agnostic as to whether those benefits exist right now.”
Anne Burke voted “yes” and said “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.”
Two of those three, Julia Johnson and Anne Burke, were subsequently reported in the Wall Street Journal as having had substantial conflicts of interest on the issue because of financial associations with Bayer, the manufacturer. Although those financial ties were recent, they were apparently not counted by the FDA as conflicts because they were more than 12 months prior to the meeting. Two other committee members that voted “yes” also had financial ties to Bayer. In contrast, committee member Dr. Sidney Wolfe was not allowed to vote because of “intellectual conflicts of interest” that were based on his previously expressed strong concerns about Yaz and Yasmin.
Aside from the committee members already mentioned in this letter, there appear to be at least seven others who were practicing OB/GYNs: Eve Espey, Geri Hewitt, Paul Hillard, Melissa Gilliam, Kathleen Hoeger, Valerie Montgomery Rice, and Bob Wild. All seven physicians voted “yes” according to the transcript. Given that practicing OB/GYNs routinely prescribe oral contraceptives, and that these physicians have likely made a decision to either prescribe or not prescribe/stop prescribing DRSP-containing OCs prior to the meeting, this certainly raises an intellectual conflict of interest as great as that attributed to Dr. Wolfe. Had they been ask to participate in the panel but not vote, as Dr. Wolfe was, this clearly would have resulted in a majority vote that the benefits do not outweigh the risks.
The different handling of the financial conflicts and the intellectual conflicts regarding prescribing decisions and publicly expressed concerns clearly biased the vote. Had Dr. Wolfe voted “no,” and had at least one of the three panel members who expressed strong concerns (two of whom had financial ties) voted “no” on the more specific question of whether the benefits outweigh the risks compared to other OCs, the vote would have been 14 “no” and 13 “yes.” If all the members with financial conflicts of interest and Sidney Wolfe (because of his intellectual conflict) had not been allowed to vote, even keeping the no votes of the other seven prescribing OB/GYNs, the final vote would have been 11 to 11 if one counts Dr. Morrato’s vote as a yes despite her explanation, and 12 to 10 against the pills if her vote had been counted as a “no” because of her explanation.
Obviously, we can’t predict how people would have voted with different wording, and only Elaine Morrato made it clear that she would have voted “no” instead of “yes.” However, the vaguely (and we believe inappropriately) worded question and the difference in how conflicts of interest were handled raises very serious questions of bias.
When oral contraceptives first became available, comparing risks and benefits of oral contraceptives to pregnancy was the right question. Now, however, there are more than two dozen choices of oral contraceptives, and it is important to consider their risk-benefit profiles when drospirenone oral contraceptives are being reconsidered.
We urge you to re-examine the policies that resulted in the bias on this panel, and for FDA to consider those biases in its future decision regarding oral contraceptives containing drospirenone. We thank the FDA for its support for a well-designed study of the risks of drospirenone and strongly believe that the results are persuasive that lives will be saved if these oral contraceptives are removed from the market.
Susan Wood, Ph.D., Jacobs Institute of Women’s Health
Diana Zuckerman, Ph.D., National Research Center for Women & Families
Cynthia Pearson, National Women’s Health Network
Judy Norsigan, Our Bodies Ourselves
The Honorable Tom Harkin
The Honorable Barbara Mikulski
The Honorable Rosa DeLauro
Dr. Janet Woodcock