FDA Silenced Expert on Safety Warnings for Vioxx, Sen. Grassley Says

Several weeks before Merck pulled its arthritis drug Vioxx from the market for safety reasons, FDA officials "silenced" an agency researcher who concluded that high doses of Vioxx should not be prescribed or used because it increased the risk of cardiovascular problems, Senate Finance Committee Chair Chuck Grassley (R-Iowa) said Thursday, AP/Long Island Newsday reports. David Graham, associate director for science in FDA Drug Center's Office of Drug Safety, was lead author of a study that examined records for 1.39 million Kaiser Permanente patients, including 26,748 who took Vioxx and 40,405 who were on Pfizer's Celebrex. The study found that high doses of Vioxx, or rofecoxib, tripled risks of heart attacks and sudden cardiac death (Henderson, AP/Long Island Newsday, 10/7). Graham planned to present the findings at an epidemiology conference Aug. 25, but his supervisors said the results were "too preliminary" and recommended that the study be submitted first to a medical journal so it could undergo peer review or be presented at the conference with an alternative FDA opinion, according to the Denver Post (Mulkem, Denver Post, 10/8).

Revisions to the Conclusion
On Aug. 12, Anne Trontell, an official in Graham's office, wrote in an e-mail to another official that the study's recommendation was "unnecessary and particularly problematic" because FDA funded the study and Graham also might be asked to present "alternative FDA opinion" on the drug, the Wall Street Journal reports (Wilde Mathews, Wall Street Journal, 10/8). She added that Merck should be notified about the study results before they became public "so they can be prepared for extensive media attention that this will likely provoke" (AP/Long Island Newsday, 10/7). The following day, John Jenkins, director of FDA's office of new drugs, wrote that Graham's conclusion uses "pretty strong language since, to my knowledge, FDA is not contemplating such a warning or labeling." Jenkins suggested that the conclusion be changed to read, "[T]his and other studies suggest an increased risk of AMI (acute myocardial infarction, or heart attack) with rofecoxib use and should be considered by prescribers when making individual treatment decisions" (Wall Street Journal, 10/8). However, Graham said in an e-mail response to supervisors, "I've gone about as far as I can without compromising my deeply held conclusions about this safety question. I've also shared with you the perspectives of my co-authors, and I think it's safe to say they share these same conclusions" (Denver Post, 10/8). When the study was presented Aug. 25, the abstract said, "[T]his and other studies cast serious doubt on the safety of rofecoxib" at doses exceeding 25 milligrams "and its use by physicians and patients" (Wall Street Journal, 10/8). When Graham submitted a revised, final version to FDA on Sept. 30, FDA's announcement of the study's release did not mention specific data on cardiovascular risks, according to the Denver Post (Denver Post, 10/8).

Grassley Questions FDA's Actions
Grassley on Thursday compared Graham's experience to that of Andrew Mosholder, another FDA scientist whose research on the link between antidepressants and suicidality in children faced resistance
from superiors at the agency, the Post reports (Washington Post, 10/8). "Dr. Graham described an environment where he was 'ostracized,' 'subjected to veiled threats' and 'intimidation,'" Grassley said in a statement after committee investigators interviewed the researcher. He added, "Merck knew it had trouble on its hands and took action. At the same time, instead of acting as a public watchdog, [FDA] was busy challenging its own expert and calling his work 'scientific rumor.'" The Senate Finance Committee is one of three congressional committees examining FDA's actions. In addition, the Government Accountability Office has expanded its investigation of FDA's conduct in regard to Mosholder and the risks of antidepressants to include its handling of Vioxx studies (AP/Long Island Newsday, 10/7).

FDA's Response
Steven Galson, acting director of FDA's drug center, said Grassley's accusations are "baloney," adding that Graham's study was undergoing the same review process as any other research on major drug-safety issues (Kaufman, Washington Post, 10/8). That review is "more rigorous" than standard scientific reviews," FDA officials said in a prepared statement (AP/Long Island Newsday, 10/7). Galson said Graham changed the conclusion "on his own" but that the revisions did not alter "the thrust of the report" (Wall Street Journal, 10/8). FDA's statement also said Graham did not submit his completed report to his supervisors until Sept. 30. Galson said FDA officials had been "frustrated by Graham's inability to produce the data he promised," the Washington Post reports. "We were waiting all summer, but he missed his deadline," Galson said (Washington Post, 10/8).

Pfizer Defends Safety of Celebrex
In related news, Pfizer officials on Thursday defended the safety of its drug Celebrex after a New England Journal of Medicine editorial released online Wednesday suggested that all COX-2 inhibitors might increase risk of cardiovascular problems, the Philadelphia Inquirer reports (Philadelphia Inquirer, 10/8). Garret FitzGerald, a professor of cardiovascular medicine at the University of Pennsylvania School of Medicine, wrote that physicians should not prescribe COX-2 inhibitors to patients with high risk for heart disease without additional evidence to confirm the safety of the medications. He added that clinical trials of all COX-2 inhibitors have indicated the medications cause some increased cardiovascular risk. FitzGerald recommended that pharmaceutical companies that manufacture COX-2 inhibitors should have to provide additional evidence to prove the safety of the medications (Kaiser Daily Health Policy Report, 10/7).

Celebrex Is 'Different'
Joseph Feczko, Pfizer's president of global development, said, "[T]here's an accumulation of cardiovascular data that proves [Celebrex is] different" than Vioxx. Celebrex's chemical structure differs from that of Vioxx, which Pfizer officials said suggests "it would not have the same side effects," the Inquirer reports (Philadelphia Inquirer, 10/8). Celebrex, which had sales of $1.5 billion during the first six months of the year, is Pfizer's fifth-largest seller. The company also manufactures Bextra, another COX-2 inhibitor (Los Angeles Times, 10/8).

Broadcast Coverage
Several broadcast programs reported on Vioxx:

ABCNews' "World News Tonight": The segment includes comments from Graham (Stark, "World News Tonight," ABCNews, 10/7). A related ABCNews story is available online.
APM's "Marketplace": The segment includes comments from Frank Palumbo of University of Maryland School of Pharmacy; Barbara Ryan, pharmaceutical industry analyst with Deutsche Bank; and Eric Topol, a cardiologist at the Cleveland Clinic (Palmer, "Marketplace," APM, 10/7). The complete segment is available online in RealPlayer.

PBS' "Nightly Business Report": The segment includes comments from Anthony Butler, pharmaceutical industry analyst with Lehman Brothers; Thomas Girardi, an attorney at Girardi & Keese representing former Vioxx patients against Merck; Paul Sader, former Vioxx user who filed a lawsuit against Merck two years ago; and Victor Schwartz, attorney with Shook, Hardy & Bacon (Kangas/Woods, "Nightly Business Report," PBS, 10/7). The complete transcript is available online.