FDA Advisory Committee Meetings on Safety of COX-2 Inhibitors Begin

Merck and Pfizer executives on Wednesday, in the first of three days of meetings on COX-2 inhibitors held by the FDA arthritis and drug safety and risk management advisory committee, provided different opinions on the cause of the increased risk for heart attack and stroke associated with the COX-2 inhibitor Vioxx, which Merck withdrew from the market in September 2004, the Wall Street Journal reports (Wilde Mathews, Wall Street Journal, 2/17).

The committee met amid increased scrutiny of FDA and questions about the safety of COX-2 inhibitors. In addition to the Vioxx withdrawal, FDA recently announced that Bextra -- a COX-2 inhibitor manufactured by Pfizer -- could increase risk for heart attack and stroke, and recent studies have found that the safety concerns associated with Vioxx could apply to all COX-2 inhibitors (California Healthline, 2/16).

The committee will advise FDA on whether to remove COX-2 inhibitors from the market, reduce the dose or duration of use, require more explicit warning labels or limit use of the medications to individuals who have a low risk for heart problems (Schmid, AP/Minneapolis Star Tribune, 2/17). The committee also could request additional studies to "specifically address heart risks," the Chicago Tribune reports (Japsen, Chicago Tribune, 2/17).

Steven Galson, acting director of the FDA Center for Drug Evaluation and Research, in opening remarks at the meeting said that the committee should not only consider safety concerns associated with the COX-2 inhibitors but also the gastrointestinal benefits that the medications provide. The meeting included "considerable discussion" on whether the safety concerns over COX-2 inhibitors arise after months of use or earlier and on the relative risks of older pain medications, such as ibuprofen, naproxen and aspirin, according to the Washington Post (Kaufman, Washington Post, 2/17).

Pharmaceutical Industry Testimony

Merck Research Laboratories Senior Director Ned Braunstein at the meeting said that all COX-2 inhibitors likely increase risk for cardiovascular events, but Kenneth Verburg, a Pfizer vice president, said that the increased risk is "distinct" to Vioxx (Reuters/Arizona Daily Star, 2/17). Braunstein said, "The data strongly suggest it is a class effect" (AP/Minneapolis Star Tribune, 2/17). According to Braunstein, a study that found patients who took Vioxx had more than four times as many heart attacks as those who took naproxen was attributable to a heart protection benefit specific to naproxen.

Verburg provided "lengthy presentations" about the safety of Bextra and Celebrex, a second COX-2 inhibitor manufactured by the company, the New York Times reports (Harris, New York Times, 2/17). He called Celebrex "an effective and safe therapy for arthritis patients." Verburg said that additional studies are needed to determine the safety risks of Celebrex (Baer, Baltimore Sun, 2/17).

Committee Member, Researcher Comments

Committee member Curt Furberg of Wake Forest University said that he was "troubled by some inconsistencies" in documents submitted by Pfizer and questioned "how much trust can we put in these presentations."

Committee member Byron Cryer of the University of Texas Southwestern Medical Center called parts of the Pfizer presentations "misleading."

Cleveland Clinic cardiologist Steven Nissen rejected claims by Merck that the increased cardiovascular risks associated with Vioxx compared with other pain medications were attributable to a heart protection benefit specific to naproxen. He said, "Naproxen would have to be far better than aspirin" in the prevention of heart problems, adding, "This story about naproxen doesn't stand up to any kind of scientific rigor" (New York Times, 2/17).

Committee Chair Alastair Wood of Vanderbilt University said, "I find it worrisome when a drug that is approved to produce a safety benefit results in increased mortality" (Washington Post, 2/17). He added that a more explicit warning label on Celebrex and Bextra would make the medications difficult to market (Mondics, Philadelphia Inquirer, 2/17).

University of Pennsylvania researcher Garret FitzGerald, who has studied COX-2 inhibitors for several years, testified that all of the medications increase risk for cardiovascular events. He said, "It seems to me most rational people would accept a class-based mechanism, as they did for efficacy." FitzGerald also said that a reduction in the dosage of COX-2 inhibitors would not reduce the risk (New York Times, 2/17).

In addition, FitzGerald said that COX-2 inhibitors "afford gastro protection at a small but absolute risk of cardiovascular events." He recommended that physicians prescribe COX-2 inhibitors only to patients who have a low risk for heart problems and who might benefit from gastrointestinal protection (Baltimore Sun, 2/17).

He said that FDA should "leave it to the patient-doctor relationship to define individual behavior" (Wall Street Journal, 2/17). FitzGerald also said that patients should take COX-2 inhibitors for limited amounts of time (New York Times, 2/17).

Physician, FDA Comments

Physicians at the meeting "attacked Merck and FDA for waiting 14 months to put a warning label on Vioxx after studies picked up potential cardiovascular problems -- and for making the label too vague for doctors," the Sun reports. Physicians also said that FDA and Merck did not adequately track patients who ended treatment with Vioxx in clinical trials because of adverse reactions (Baltimore Sun, 2/17).

FDA Medical Officer Lourdes Villalba, who supervised the application for market approval for Vioxx, said that agency officials were not "sleeping behind the wheel; we were actually engaged in reviewing a lot of data" (Washington Post, 2/17). She added that FDA officials first had to place the data on Vioxx "into context" (Baltimore Sun, 2/17).

James Witter of FDA presented "mixed data" on Celebrex that did not indicate a "clear signal of cardiovascular risk," the Journal reports (Wall Street Journal, 2/17).

Future Meetings

Merck on Thursday likely will present to the committee data on etoricoxib, a COX-2 inhibitor currently in development. Novartis likely will discuss the experimental COX-2 inhibitor lumiracoxib (CQ HealthBeat, 2/17).

David Graham, associate director for science and medicine at the FDA Office of Drug Safety, also will testify before the committee (Boston Globe, 2/17).

In addition, committee members likely will hear presentations from researcher John Abramson, who is expected to "lay blame" on medical journals for failure to warn about the increased risk for cardiovascular events associated with Vioxx, the Boston Herald reports (Strahinich, Boston Herald, 2/17).

Galson said that FDA would act on the recommendations of the committee within several weeks (Washington Post, 2/17).

Editorial, Opinion Piece

New York Times: If the FDA Drug Safety Oversight Board "is intended to be the [Bush] administration's primary solution for the glaring weaknesses," in the agency's "ability to protect patient from adverse effects that show up only after a drug is widely used, it will fall woefully short," according to a Times editorial. The editorial notes that the agency has promised to make information about safety available to the public, a move that "should go a long way toward breaking the inertia that typically paralyzes the agency while it waits to accumulate conclusive evidence." The editorial concludes that what the agency lacks is "is a firm commitment to strengthen [its] power ... to act against" unsafe drugs already on the market (New York Times, 2/17).
Henry Miller, Washington Times: The United States "needs improved pharmacovigilance ... not by creating a new independent agency, but by fixing the FDA," Miller, a physician and former FDA official, writes in a Washington Times opinion piece. Miller adds that "we need to encourage physicians to report side effects ... contract with organizations that treat large patient populations to monitor and report adverse events ... [and] share data with foreign regulators." He suggests that the United States "consider some variation of the U.K.'s 'yellow card' system," through which health care providers report adverse events to federal regulators (Miller, Washington Times, 2/17).

Broadcast Coverage

CBS' "Evening News": The program includes comments from Graham (Attkisson, "Evening News," CBS, 2/16). The complete segment is available online in RealPlayer.
CBS' "Evening News": The program includes coverage of the FDA meetings (Kaledin, "Evening News," CBS, 2/16). The complete segment is available online in RealPlayer.
CNN's "Live Today": The program includes comments from Merck Chair and CEO Raymond Gilmartin and arthritis patients (Feig, "Live Today," CNN, 2/16). The complete transcript is available online.
CNN's "Paula Zahn Now": The program includes comments from Dr. Chris Pappas of St. Luke's Episcopal Hospital, pharmaceutical industry whistle-blower David Franklin, U.S. Attorney Mike Sullivan, Duke University physician Peter Kussin and CNN medical correspondent Dr. Sanjay Gupta (Griffin, "Paula Zahn Now," CNN, 2/16). The complete transcript is available online.
NPR's "Morning Edition": The program includes discussion on the FDA meetings (Knox, "Morning Edition," NPR, 2/17). The complete segment is available online in RealPlayer.
WBUR's "The Connection": The program includes comments from Jerry Avorn, a professor at Harvard Medical School, and Ken Kaitin, director of the Tufts Center for the Study of Drug Development and associate professor of medicine at Tufts University (Gordon, "The Connection," WBUR, 2/16). The complete segment is available online in RealPlayer.
WBUR's "Here & Now": The program includes comments from Marc Kaufman, a Washington Post reporter; Dr. Jeffrey Drazen, editor of the New England Journal of Medicine; and Karen Keyser, an arthritis patient scheduled to testify at the FDA meetings on Thursday (Young, "Here & Now," WBUR, 2/17). The complete segment is available online in RealPlayer.

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