FDA Advisory Committee Recommends COX-2 Inhibitors Remain on Market

An FDA advisory panel on Friday voted unanimously to advise the agency that all COX-2 inhibitors increase a person's risk for cardiovascular problems, yet a "substantial majority" of panelists recommended that despite the risks, the medications should remain on the market and be accompanied by stronger warnings, the Washington Post reports. The panel's recommendations are nonbinding, but FDA generally follows its advice (Kaufman, Washington Post, 2/19).

The panel, which includes members of the FDA arthritis and drug safety and risk management advisory committees, on Feb. 16 began three days of meetings to examine the safety of COX-2 inhibitors (California Healthline, 2/18).

In its recommendations, the panel "made it clear" that it thought Vioxx, manufactured by Merck, posed a greater risk to consumers than other COX-2 inhibitors and should be tightly restricted, the Post reports (Washington Post, 2/18). The panel voted:

• 31-1 to allow Pfizer to keep Celebrex on the market;
  
  
• 17-13 -- with two votes abstaining -- to allow sales of Bextra, also manufactured by Pfizer, to continue; and
  
  
• 17-15 to allow Vioxx to return to the market (Harris, New York Times, 2/19).

• Banning all direct-to-consumer advertising for COX-2 inhibitors;
  
  
• Adding a "black box" warning for all COX-2 inhibitor labels;
  
  
• Requiring doctors to give patients a written warning that the medications increase a patient's risk of heart attack and stroke;
  
  
• Restricting use of the treatments only to those who have unsuccessfully tried other pain medications; and
  
  
• Placing new warning labeling for nonsteroidal anti-inflammatory drugs such as ibuprofen -- although there was a consensus that some NSAIDs are safer than others (Washington Post, 2/19).

The Philadelphia Inquirer reports that the panel's actions "represented a stunning turnabout" and indicated its "uncertainty about how to interpret clinical trial results showing varying risks."

According to the Inquirer, a "dominant theme was the seeming uncertainty over whether the results of various studies showing health risks were powerful enough to warrant taking the drugs from the market or substantially restricting them." Several patients and doctors said that they "were willing to accept the risk of heart attacks in exchange for relief from arthritis pain," the Inquirer reports (Mondics, Philadelphia Inquirer, 2/19).

Before voting, panel Chair Alastair Wood told members that they were considering the biggest and most complicated prescription drug safety issue to come before the FDA. Wood told reporters following voting that the panel generally agreed that COX-2 inhibitors are valuable but require additional testing and should not be advertised aggressively.

He said, "[T]here are no black-and-white answers" (Washington Post, 2/19). "I think physicians need to be more thoughtful about how they use these drugs in the future. It would be a brave man or woman who started a patient with a clear history of heart disease on these drugs," Wood said.

Cleveland Clinic cardiologist and panel member Steven Nissen said, "We will by our actions today cause a shift in prescribing practices, and I'm not sure it will be toward safer drugs" (New York Times, 2/19). He said, "What we really want is to make sure [COX-2 inhibitors are] available for patients that need [them] and unavailable to patients for whom [they are] inappropriate" (Schmid, AP/Las Vegas Sun, 2/19).

Panel member Michael Domanski of NIH said, "Clearly someone who is leading a poor quality of life (due to pain) and understands the risks is a good candidate (for Celebrex). I don't think we should take this pill out of the hands of doctors" (Alonso-Zaldivar/Gellene, Los Angeles Times, 2/19).

There is "no current timetable on when [FDA] would make a decision," the Washington Times reports (Higgins, Washington Times, 2/19).

John Jenkins, director of the FDA Office of New Drugs, said the agency will weigh the panel's recommendations, adding that the narrow margins of some votes indicate that the agency must carefully evaluate all comments. He said, "Close votes are very challenging to interpret" (Washington Post, 2/19).

Jenkins also said the panel clearly conveyed "that they felt these agents should maybe not be as widely used." Jenkins said, "We heard the message that the committee thought Vioxx had a cardiovascular risk that was perhaps larger or better documented than the others." He said the agency discussed with Merck officials the possibility of bringing Vioxx back to the market (New York Times, 2/19).

Jenkins said the agency is "committed to making a decision in the next several weeks" (Kohn, Baltimore Sun, 2/19).

"Although the votes supported controlled marketing of [COX-2 inhibitors], the sometimes sharply divided panel hardly gave them a vote of confidence," according to the Post.

The vote to return Vioxx to the market "was a vindication of sorts for Merck," but "Vioxx's possible path back to the market remains difficult," the Post reports. If Merck seeks to make such a move, the company must receive FDA approval for revised label information, according to agency officials. Merck representatives said, "[W]e look forward to discussions with the FDA" regarding Vioxx and other COX-2 inhibitors (Washington Post, 2/19).

The advice from the panel was "not good news for Pfizer," which "had come into the advisory committee with a strategy to deny almost entirely the notion that Celebrex increased the risks of heart attacks and strokes and to suggest that any evidence linking Bextra to such risks was shaky and irrelevant," the New York Times reports.

John LaMattina, Pfizer's president of global research and development, said that the company would not advertise Celebrex or Bextra in the next few weeks. He said, "Then after that, we will discuss with FDA what we should and shouldn't do" (New York Times, 2/19).

Pfizer Medical Director Gail Cawkwell said, "We're very pleased that the FDA has reaffirmed the importance of Celebrex and Bextra for pain and inflammation" (Baltimore Sun, 2/19).

Sen. Chuck Grassley (R-Iowa) said, "I remain troubled by FDA's reluctance to be fully transparent. ... Specifically, FDA should value the science of its own employees at least as much as the science presented by drug companies" (Washington Post, 2/19).

Gurkirpal Singh, a senior researcher at Stanford University who co-wrote a study with FDA safety officer David Graham that showed Vioxx carried increased cardiovascular risks, said, "I am surprised. We discussed study after study. But at the time of the vote, the data didn't seem to make a difference."

Public Citizen Director Sidney Wolfe said, "It's inexcusable. These drugs should be off the market. These drugs have unique cardiovascular risks and no unique benefits."

Graham said, "Safety has been trumped" (Baltimore Sun, 2/19).

Several newspapers recently published feature articles related to the FDA advisory committee's decision on COX-2 inhibitors. Headlines appear below.

• Baltimore Sun: "New Drug Panel Has Challenges Before It" (Bell, Baltimore Sun, 2/19):
  
  
• Chicago Tribune: "Flaws in Drug Agency Put Consumers at Risk" (Graham/James, Chicago Tribune, 2/20);
  
  
• Chicago Tribune: "Drug Ad Limits Could Spread" (Japsen, Chicago Tribune, 2/22);
  
  
• Chicago Tribune: "FDA Cut Off Critic's Access to Drug Database" (Kotulak, Chicago Tribune, 2/20);
  
  
• Newark Star-Ledger: "Experts To Review Data on Pain Pills" (Schwab, Newark Star-Ledger, 2/21);
  
  
• Newark Star-Ledger: "Merck Faces Hurdles on Its Victory Lap" (Silverman, Newark Star-Ledger, 2/22);
  
  
• Long Island Newsday: "Drug Decisions Cause Outbreak of Shock" (Ricks, Long Island Newsday, 2/20);
  
  
• New York Times: "A Reminder That No Drug Is Risk-Free" (Berenson/Feder, New York Times, 2/19);
  
  
• USA Today: "Rheumatologists Outvote Drug Safety Specialists" (Rubin, USA Today, 2/21);
  
  
• USA Today: "Return of Vioxx Would Be Unusual, Not Unprecedented" (Schmit, USA Today, 2/22);
  
  
• Wall Street Journal: "Merck, Pfizer Face Advertising Obstacle" (Hensley et al., Wall Street Journal, 2/22);
  
  
• Wall Street Journal: "A Vioxx Comeback Could Tilt Balance in Merck Litigation" (Martinez, Wall Street Journal, 2/22); and
  
  
• Wall Street Journal: "Where Findings on Painkillers Leave Patients" (Winslow et al., Wall Street Journal, 2/22).

• NPR's "All Things Considered": The program includes discussion on the hearings (Silberner, "All Things Considered," NPR, 2/18). The complete segment is available online in RealPlayer.
  


• NPR's "All Things Considered": The program includes discussion on the hearings (Ludden/Knox, "All Things Considered," NPR, 2/19). The complete segment is available online in RealPlayer.
  


• NPR's "Weekend Edition Saturday": The program includes discussion on the hearings (Simon/Silberner, "Weekend Edition Saturday," NPR, 2/19). The complete segment is available online in RealPlayer.
  


• CNN's "Live From": The program includes discussion of the hearings (Cohen, "Live From," CNN, 2/18). The complete transcript is available online.
  


• CNN's "Live Saturday": The program includes comments from Dr. Peter Kim, president of Merck Research Labs, and Dr. Lee Simon, a Pfizer clinical adviser (Koppel, "Live Saturday," CNN, 2/19). The complete transcript is available online.
  


• WAMU's "The Diane Rehm Show": The program includes comments from Dr. Jerry Avorn, professor of medicine at Harvard Medical School and chief of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital in Boston; Alan Goldhammer, associate vice president for regulatory affairs at the Pharmaceutical Research and Manufacturers of America; and Marc Kaufman, a Washington Post reporter (Roberts, "The Diane Rehm Show," WAMU, 2/16). The complete segment will be available online in RealPlayer after the show.