FDA Researcher Highlights Safety Concerns of Five Medications During Congressional Hearing on Vioxx

David Graham, a reviewer in the Office of Drug Safety at FDA, on Thursday testified before the Senate Finance Committee that the agency is "feckless and far too likely to surrender to demands of drug makers" and that five prescription drugs currently on the market present significant safety risks to consumers, the New York Times reports. At a hearing on the recent voluntary withdrawal of Vioxx, a COX-2 inhibitor manufactured by Merck, Graham testified that FDA is "virtually incapable of protecting America," adding, "We are faced with what may be the single greatest drug safety catastrophe in the history of this country or the history of the world" (Harris, New York Times, 11/19). Graham said that FDA "as currently configured, is incapable of protecting America against another Vioxx" because of ties between agency reviewers and the pharmaceutical industry (Alonso-Zaldivar, Los Angeles Times, 11/19). FDA "overvalues the benefits of the drugs it approves and seriously undervalues, disregards and disrespects drug safety," Graham said (Wilde Mathews/Won Tesoriero, Wall Street Journal, 11/19). Graham also said that "the new drug-reviewing division that approved the drug in the first place and that regards it as its own child, typically proves to be the single greatest obstacle to effectively dealing with serious drug safety issues" (Rovner, CongressDaily, 11/18). He added, "The scientific standards (the FDA) applies to drug safety guarantee that unsafe and deadly drugs will remain on the U.S. market" (Kaufman, Washington Post, 11/19). Graham said that FDA considers medications safe unless reviewers establish with 95% certainty that they are not, adding, "What it does is it protects the drug," rather than consumers (Henderson [I], AP/Las Vegas Sun, 11/19). He added, "It is important that this committee and the American people understand that what happened with Vioxx is really a symptom of something far more dangerous to the safety of the American people. Simply put, FDA and its Center for Drug Evaluation and Research are broken" (Rubin, USA Today, 11/19). According to Graham, "FDA has let the American people down, and sadly, betrayed the public's trust" (Rovner, CongressDaily, 11/18). He also said that senior FDA officials "did everything in their power to intimidate me prior to my testimony" (Henderson [I], AP/Las Vegas Sun, 11/19).

Vioxx
Graham testified that Merck should have withdrawn Vioxx from the market years earlier and criticized FDA actions related to the medication as a "profound regulatory failure" (Washington Post, 11/19). Graham also said that, based on data from studies conducted by Merck, between 88,000 and 139,000 U.S. residents have experienced heart attacks or strokes as a result of Vioxx. He added that as many as 40% of those patients, or about 55,000, died as a result of Vioxx (Harris, New York Times, 11/19). Graham said, "For the survivors, their lives were changed forever" (Los Angeles Times, 11/19). According to Graham, a Merck study released in 2000 indicated that patients who took Vioxx were five times as likely to experience heart attacks as those who took other pain medications. However, Graham said that when he raised questions about the safety of Vioxx with other FDA officials, he was asked not to express his concerns or revise his conclusions (Mondics, Philadelphia Inquirer, 11/19). Graham said that despite the 2000 study, "the labeling at approval said nothing about heart attack risks" (Los Angeles Times, 11/19).

Safety Concerns About Other Medications
Graham also cited safety concerns about the COX-2 inhibitor Bextra, manufactured by Pfizer, which he said presents cardiovascular risks similar to those of Vioxx; the anti-cholesterol medication Crestor, manufactured by AstraZeneca, which he said is the only such medication to cause acute kidney failure and likely to lead to serious muscle problems; the obesity treatment Meridia, manufactured by Abbott Laboratories, which he said could cause substantial increases in blood pressure; the acne medication Accutane, manufactured by Roche, which FDA has said could cause birth defects; and the asthma treatment Serevent, manufactured by GlaxoSmithKline, which he said could lead to an increased risk in asthma-related deaths and life-threatening episodes. Graham added, "We have case reports of people dying clutching their Serevent inhaler (Harris, New York Times, 11/19). The five medications "already have drawn heightened scrutiny" at FDA and include warnings on their labels about the safety concerns that Graham raised, the Wall Street Journal reports (Wilde Mathews/Won Tesoriero, Wall Street Journal, 11/19). Graham, who has worked at FDA for 20 years, said that in his career he has recommended the withdrawal of 12 medications, only two of which remain on the market (Henderson [II], AP/Las Vegas Sun, 11/18).

FDA Testimony
According to the New York Times, the testimony from Graham and the subsequent criticism of his allegations by other FDA officials "was a rare public airing of tensions that have simmered in the agency for decades" between those who support reduced review times for new prescription drugs and the use of pharmaceutical companies as partners in the process and those who consider such companies "antagonists needing to be curbed." Sandra Kweder, deputy director of the FDA Office of New Drugs, said, "My personal view is that our system works very well," adding that many new medications on the market "have ongoing concerns about particular aspects" of their safety (Harris, New York Times, 11/19). Kweder testified that she has "no reason to believe that set of five drugs" cited by Graham as unsafe "is specifically more concerning than other drugs we are looking at." Kweder added that the estimates made by Graham on Vioxx-related deaths were based on a statistical calculation and did not represent "real deaths." She said, "I believe Merck acted responsibly once the problem was recognized." She also said the potential cardiovascular risks found in study results available to FDA prior to the approval of Vioxx were not adequately significant to raise concerns (Los Angeles Times, 11/19). She added that "there is no magic formula" used by FDA to determine which medications present the most safety risks (Henderson [II], AP/Las Vegas Sun, 11/18). Kweder said that she hopes IOM in a planned evaluation of FDA will recommend the separation of agency drug safety and approval divisions. She added that FDA plans to "implement a program for addressing differences of professional opinion" (CongressDaily, 11/18). "There is clearly concern that somehow the system is not working as well as it could. ... We need to address that," Kweder said (Wilde Mathews/Won Tesoriero, Wall Street Journal, 11/19). Steven Galson, acting director of CDER at FDA, said that five medications cited by Graham as unsafe "do have special safety issues, but they're under evaluation, and we're watching them carefully" (Henderson [I], AP/Las Vegas Sun, 11/18). He added that the medications "are all approved and are safe and effective like other drugs that are approved, recognizing that safe does not mean risk-free." Galson said that the estimates made by Graham on Vioxx-related deaths and injuries are "irresponsible" and "constitute junk science" (Harris, New York Times, 11/19).

Pharmaceutical Industry Testimony
The pharmaceutical companies that manufactured the five medications cited by Graham as unsafe "defended their products vigorously" and said that they were "surprised" by his testimony, the Washington Post reports (Washington Post, 11/19). AstraZeneca spokesperson Emily Denney said that FDA has not indicated any "major concern regarding Crestor" and the testimony from Graham on the medication was "inconsistent with past statements from the FDA and our understanding of its current view of the safety and efficacy of Crestor." Roche officials said that the company has acknowledged the safety risks of Accutane and that the medication is under an FDA-approved risk-management program. "This drug is extremely beneficial as long as it's used safely and appropriately," Roche spokesperson Carolyn Glynnane said. Susan Bro, a spokesperson for Pfizer, said that a recent study that found Bextra does not increase patient risk for serious cardiovascular events and that the medication is safe and effective when taken as indicated. Tim Lindberg, a spokesperson for Abbott, said, "Science continues to support the safe use of Meridia to treat obesity." GlaxoSmithKline officials said in a statement that the company "stands firmly behind" Serevent, adding, "Any issues concerning mortality associated with Serevent have been fully considered by the FDA, resulting in a black box warning that was included in the medicine's label in August of 2003" (Silverman, Newark Star-Ledger, 11/19).

Gilmartin Testimony
According to Merck Chair and CEO Raymond Gilmartin, "Given the availability of alternative therapies and the questions raised by the data, withdrawing Vioxx was consistent with an ethic that has driven Merck actions and decisions for more than 100 years." (Henderson [II], AP/Las Vegas Sun, 11/18). Gilmartin said that results of the studies on Vioxx were not as definitive as Graham indicated in his testimony, adding that several of the studies were epidemiological reports based on reviews of medical records rather than clinical trials. He added that Merck withdrew Vioxx from the market about one week after a study presented in September provided conclusive evidence that Vioxx caused an increased risk for cardiovascular events (Philadelphia Inquirer, 11/19). "Merck believed wholeheartedly in Vioxx. I believed wholeheartedly in Vioxx," Gilmartin said, adding, "In fact, my wife was taking Vioxx until the day we withdrew it from the marketplace" (Los Angeles Times, 11/19). He said that heart attacks "occur throughout the population" and that FDA found the cardiovascular risks of Vioxx "for any one individual was very small." Gilmartin also testified that no "reliable estimates" exist on the number of patients killed or injured as a result of Vioxx. He added that the estimates made by Graham were "just speculation" (Schwab, Newark Star-Ledger, 11/19).

Other Testimony
According to the Wall Street Journal, other witnesses at the hearing "echoed" the criticisms of FDA made by Graham (Wilde Mathews/Won Tesoriero, Wall Street Journal, 11/19). Bruce Psaty, a medical professor at the University of Washington, and Gurkipal Singh, a Stanford University researcher, agreed with Graham that FDA should separate the agency offices on drug safety and approval (CongressDaily, 11/18). Psaty said that Merck was aware as early as November 1996 that Vioxx caused an increased risk for cardiovascular events. "For Vioxx to be used safely, the potential cardiovascular risks need to be defined clearly so that physicians and patients can be informed about the risks as well as the benefits of therapy," Psaty said. Singh testified that FDA was aware of the safety risks of Vioxx in 1999, prior to the approval of the medication, based on small studies that would have prompted "many scientists" to consider the results "an early warning sign." Singh added, "It is my opinion that at this point in time, larger and more definitive studies should have been done before the drug was approved" (Los Angeles Times, 11/19). He said, "The failure to conduct large long-term safety studies subjected millions of patients over four years to a drug whose safety had been questioned by the FDA even before its approval" (Wilde Mathews/Won Tesoriero, Wall Street Journal, 11/19). However, Singh said, "I was warned that if I continued in this fashion, there would be serious consequences for me. I was told that Dr. Lewis Sherwood, a Merck senior vice president and a former chief of medicine at a medical school, had extensive contacts within academia and could make life very difficult for me at Stanford and outside" (Harris, New York Times, 11/19).

Lawmaker Reaction
Sen. Jeff Bingaman (D-New Mexico) said, "The culture within the FDA, being one where the pharmaceutical industry, which the FDA is supposed to regulate, is seen by the FDA as its client instead." Bingaman added that President Bush should appoint a new FDA commissioner; Lester Crawford currently serves as acting commissioner (Henderson [II], AP/Las Vegas Sun, 11/18). Finance Committee Chair Chuck Grassley (R-Iowa) said that although an "awful lot of red flags" were raised prior to the withdrawal of Vioxx, FDA officials dismissed the concerns of agency reviewers. (Henderson [I], AP/Las Vegas Sun, 11/18). Grassley said that might propose legislation that would make independent the FDA drug safety office, which currently reports to the office that approves medications. "It doesn't make any sense from an accountability standpoint to have the office that reviews the safety of drugs that are already on the market to be under the thumb of the office that put the drugs on the market in the first place," Grassley said (Los Angeles Times, 11/19). He also said that FDA might have "allowed itself to be manipulated by Merck on labeling changes" for Vioxx in 2002 (Cohen, Newark Star-Ledger, 11/19). He added, "One of my concerns is that the FDA has a relationship with the drug companies that is too cozy." Grassley also criticized Crawford for his apparent efforts to "intimidate" Graham before the hearing (CongressDaily, 11/18). Grassley said, "What's come to light about Vioxx since Sept. 30 makes people wonder if the FDA has lost its way when it comes to making sure drugs are safe" (Cohen, Newark Star-Ledger, 11/19). According to the Newark Star-Ledger, "Not everybody on the panel was so critical," such as Sen. Orrin Hatch (R-Utah), who is "a longtime supporter of the pharmaceutical industry." Hatch said that Gilmartin "acted responsibly" (Schwab, Newark Star-Ledger, 11/19).

Other Related Articles

• The New York Times reports that the hearing represented "a dress rehearsal" for testimony that Gilmartin could have to provide in Vioxx-related lawsuits and that "he had a relatively good day" (Berenson, New York Times, 11/19).
  
  
• USA Today examined the safety history of the five medications approved by FDA that Graham cited as unsafe (Szabo/Rubin, USA Today, 11/19).
  
  
• The results of a study of COX-2 inhibitors in mice "suggest that chronic use" of the medications could "undermine the protection against heart disease that premenopausal women get from natural levels of the hormone estrogen," the Journal reports (Winslow, Wall Street Journal, 11/19).

Broadcast Coverage
Several broadcast programs reported on the Vioxx hearing:

• Stark , "World News Tonight," ABCNews, 11/18.
  
  
• McKenzie, "World News Tonight," ABCNews, 11/18.
  
  
• Attkisson, "Evening News," CBS, 11/18. The segment is available online in RealPlayer.
  
  
• Reid "Nightly News," NBC, 11/18. The segment is available online in RealPlayer.
  
  
• Heath, Nightly Business Report, 11/18. A transcript of the report is available online.
  
  
• Rovner, "All Things Considered," NPR, 11/18. The segment is available online in RealPlayer.
  
  
• Silberner, "Morning Edition," NPR, 11/19. The segment is available online in RealPlayer.