FDA Has Requested Black Box Warnings For Two Diabetes Medications, Agency Commissioner Says At House Committee Hearing

Main Category: Diabetes
Also Included In: Cardiovascular / Cardiology
Article Date: 11 Jun 2007 - 2:00 PDT

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FDA has requested a black box warning for the labels of the type 2 diabetes medications Avandia, manufactured by GlaxoSmithKline, and Actos, manufactured by Takeda Pharmaceuticals, because of increased risk for congestive heart failure associated with the medications, agency Commissioner Andrew von Eschenbach announced on Wednesday at a House Oversight and Government Reform Committee hearing, the New York Times reports. FDA issued the request on May 23, according to von Eschenbach. FDA previously had not made the request public (Harris, New York Times, 6/7).

FDA last month issued a public safety warning about Avandia in response to a study published on the New England Journal of Medicine Web site. For the study, Steven Nissen and Kathy Wolski of the Cleveland Clinic analyzed the results of 42 previous studies of Avandia that involved 27,843 participants.

The study found that 86 participants who took Avandia experienced a heart attack, compared with 72 of those who did not take the medication, a statistically significant 43% increased risk. In addition, the study also found that 39 participants who took Avandia died from cardiovascular events, compared with 22 of those who did not take the medication, an almost statistically significant 64% increased risk.

FDA and GSK disclosed that, according to a meta-analysis of previous studies conducted by the company in August 2006, participants who took Avandia had a 31% increased risk for cardiovascular events. However, FDA did not take regulatory action on Avandia because of clinical trial data submitted to the agency last August. The data from the trial, which involved 30,000 patients, found that participants who took Avandia had no increased risk for cardiovascular events (Stein, Washington Post, 5/22).

GSK on Tuesday published interim data from a company study on the NEJM Web site. The data indicated no increased risk for cardiovascular events associated with Avandia (Saul/Harris, New York Times, 6/6).

Warning Details
The request from FDA for a black box warning for the labels of Avandia and Actos involved only increased risk for heart failure associated with the medications, not increased risk for heart attacks (Alonso-Zaldivar, Los Angeles Times, 6/7). Von Eschenbach said that "these drugs were being prescribed to patients with significant heart failure," despite current warnings on the labels of the treatments (Rubin, USA Today, 6/7).

He said that FDA has not reached a conclusion about whether Avandia and Actos increase risk for heart attacks and continues to analyze related trial data. An FDA advisory committee this summer plans to address the issue (Cohen, Newark Star-Ledger, 6/7).

GSK, Takeda Response
GSK spokesperson Nancy Pekarek said that the company is "in discussions with the FDA about label changes" for Avandia but has "not agreed to any wording" (Newark Star-Ledger, 6/7).

Moncef Slaoui, chair of research and development at GSK, said, "The most important message today for the committee and the public is this: The cardiovascular profile of Avandia is comparable to that of the two other oral anti-diabetes medicines that are most widely used" in the U.S. (Lopes, Washington Times, 6/7). According to Slaoui, GSK has conducted 116 trials of Avandia that have involved more than 52,000 patients (Vollmer, Raleigh News & Observer, 6/7).

Takeda officials in a statement said that the company has entered discussions with FDA to develop a black box warning for the label of Actos to "heighten awareness of the risk" for heart failure. However, Takeda officials said that they support the "safety and efficacy of Actos when used according to its label," adding that trials have found no increased risk for heart attacks associated with the medication (Newark Star-Ledger, 6/7).

Congressional Response
Rep. Henry Waxman (D-Calif.) said, "FDA dropped the ball" in efforts to ensure the safety of Avandia (Raleigh News & Observer, 6/7). Avandia is "a case study of the need for reform of the nation's drug safety laws," Waxman said, adding, "Millions of diabetics who have taken Avandia have not been well-served by our regulatory system" (Los Angeles Times, 6/7).

During the hearing, "Republicans accused Democrats ... of needlessly scaring patients and of vilifying a company when it wasn't at all certain that" safety risks exist, according to the Baltimore Sun (Rockoff, Baltimore Sun, 6/7). Rep. Darrell Issa (R-Calif.) accused committee Democrats of "politicizing science," adding, "This does look like in fact that this was a political concoction to anecdotally go after a company, and I object to it" (Harris, New York Times, 6/7). Issa said, "There is not a clear and present danger with Avandia" (Washington Times, 6/7).

Legislative Possibilities
Waxman prior to the hearing said that he would introduce a bill (HR 1561) as an amendment to legislation to reauthorize the Prescription Drug User Fee Act to improve FDA oversight of prescription drug safety (Armstrong, CQ HealthBeat, 6/6). Among other provisions, the legislation would allow FDA to require pharmaceutical companies to conduct studies of the safety of new medications after they reach the market (Edney, CongressDaily, 6/6).

Waxman said, "FDA needs the will, the resources and the authority to be a more effective watchdog of drug safety" (Stein, Washington Post, 6/7).

However, von Eschenbach said that FDA requires additional funds, not additional authority, to ensure prescription drug safety. According to von Eschenbach, proposals that would separate the prescription drug approval and medication safety functions of FDA are "more destructive than constructive" (Harris, New York Times, 6/7).

Opinion Piece
Lawmakers should question the "methods and motives" of Nissen, who bypassed FDA and began "strategizing" with Rep. Henry Waxman (D-Calif.) "well before rushing to save the public from cardiovascular Armageddon" with the publication of his study on the safety risks of Avandia, Peter Pitts, president of the Center for Medicine in the Public Interest and a former FDA associate commissioner, and Robert Goldberg, vice president of the center, write in a Washington Times opinion piece. According to the authors, Nissen "has positioned himself as the nation's de facto drug regulatory czar," but he "has his own credibility gap to deal with."

The authors write, "Nissen regularly claims that the pharmaceutical industry hypes the value of new medicines while soft-pedaling or not publishing safety problems. Yet he had hawked early clinical results of several drugs such as ones he had been paid to study, including some that ended up causing heart attacks and kidney failure." The authors write, "For someone who is concerned about the appearance of impropriety, Dr. Nissen's conduct is characterized by a series of uncomfortable coincidences," adding, "Most involve putting his career ahead of the safety of patients" (Pitts/Goldberg, Washington Times, 6/6).

Broadcast Coverage
Several broadcast programs on Wednesday reported on the hearing. Summaries appear below.

• ABC's "World News": The segment includes excerpts of testimony from the hearing (Stark, "World News," ABC, 6/6). Video of the segment and expanded ABC News coverage are available online.
  
  
• CBS' "Evening News": The segment includes comments from Rep. Chris Cannon (R-Utah); von Eschenbach; Waxman; Nissen; and GSK CEO Jean-Pierre Garnier (Andrews, "Evening News," CBS, 6/6). Video of the segment is available online. The program also included a profile of Nissen (Cordes, "Evening News," CBS, 6/6). Video of the segment is available online.
  
  
• NBC's "Nightly News": The segment includes comments from Nissen, Waxman, Bruce Psaty of the University of Washington, Garnier and von Eschenbach (Costello, "Nightly News," NBC, 6/6). Video of the segment is available online.
  
  
• NPR's "All Things Considered": The segment includes comments from Waxman, Issa, von Eschenbach and Nissen (Silberner, "All Things Considered," NPR, 6/6). Audio of the segment is available online.
  
  
• PBS' "Nightly Business Report": The segment includes comments from von Eschenbach; Buse; Slaoui; and Chris Viehbacher, president of U.S. pharmaceuticals at GSK (Gersh, "Nightly Business Report," PBS, 6/6). A transcript of the segment is available online.

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