Withheld Study on Vioxx Published This Week in the Lancet

The COX-2 inhibitor Vioxx, which Merck withdrew from the market in late September 2004 over potential safety risks, could have resulted in as many as 140,000 heart attacks, many of which were fatal, according a study previously withheld by FDA and published on Tuesday in the journal Lancet, the Los Angeles Times reports (Maugh, Los Angeles Times, 1/25). At a Senate hearing on Vioxx last November, David Graham, associate director for science in the FDA Office of Drug Safety, testified that Merck should have withdrawn the medication from the market years earlier and criticized agency actions related to the treatment. He also said that FDA "as currently configured, is incapable of protecting America against another Vioxx" because of ties between agency reviewers and the pharmaceutical industry. Graham testified, based on data from studies conducted by Merck, that 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. According to Graham, FDA previously would not allow him to publish the study on Vioxx, and agency officials sent e-mails to Lancet to persuade the editors not to publish the research. Steven Galson, acting director of the FDA Center for Drug Evaluation and Research, at the hearing criticized the study as "irresponsible" and "junk science." However, FDA on Jan. 3 approved the study for publication (Kaiser Daily Health Policy Report, 1/4).

Study Details
For the study, Graham and colleagues analyzed data from more than 1.4 million California residents who took anti-inflammatory medications from 1999 to 2004 (Whalen, Wall Street Journal, 1/25). About one million study participants took ibuprofen; 40,000 took Vioxx; 435,000 took naproxen; and 27,000 took Celebrex, a COX-2 inhibitor manufactured by Pfizer. Researchers found 8,143 cases of serious heart disease and 1,508 deaths among study participants (Los Angeles Times, 1/25). According to the study, participants who took Vioxx had a 34% higher risk for heart disease than those who took other anti-inflammatory medications (Wall Street Journal, 1/25). The study also found that the risk for death was "substantially higher" for participants who took Vioxx, the Los Angeles Times reports. In addition, the study found no increased risk for heart disease or death among participants who took Celebrex. Researchers extrapolated the results of the study to estimate the 88,000 to 139,000 cases of heart disease attributable to Vioxx (Los Angeles Times, 1/25). In an interview, Graham said, "FDA had responsibility for regulating this drug, and they didn't do what they should have. I believe the FDA ... views industry as its client and not the public and that what happened with Vioxx is an example of that" (Kotulak et al., Chicago Tribune, 1/25).

Merck Response
A Merck spokesperson called the conclusions in the study about the safety risks of Vioxx "speculation." He said a separate study that prompted Merck to withdraw Vioxx from the market indicated that participants experienced an increased risk for heart attacks and strokes only when they took the medication for 18 months and found no difference in the mortality rate among participants who took Vioxx compared with those who took a placebo. In addition, he said that the effect of Vioxx on cardiovascular health "can only be made on a case-by-case basis" (Wall Street Journal, 1/25).

Study Author Name Removed
Authors of a separate study published last year in the journal Circulation that found Vioxx could increase risk for heart disease have alleged that Merck officials forced one researcher to remove her name from the study, according to an opinion piece published in the most-recent edition of the Archives of Internal Medicine, the AP/Las Vegas Sun reports. In the opinion piece, written by study authors Jerry Avorn of Harvard University and Daniel Solomon of Brigham and Women's Hospital, Solomon identified the researcher as Merck epidemiologist Carolyn Cannuscio. According to Solomon and Avorn, when the study results were finalized, Merck required Cannuscio to "remove her name from the article immediately prior to publication." They added, "Even after funding and agreeing with the design of the study, Merck publicly discredited our findings" (Tanner, AP/Las Vegas Sun, 1/24). Avorn said, "FDA has become a little bit too beholden to the drug companies and is either unwilling, afraid or unable to get them to do the safety studies that need to get done once there's a signal that there may be a problem" (Chicago Tribune, 1/25). Merck spokesperson Anita Larsen said that Circulation and Merck policies allow the company to remove the names of authors from studies "if the authors draw conclusions that are not supported by the data." According to Larsen, Cannuscio agreed with the decision by Merck to have her name removed from the study. Cannuscio declined to comment on the issue (Tanner, AP/Las Vegas Sun, 1/24).

Public Citizen Petitions FDA To Ban Celebrex, Bextra
Public Citizen on Monday petitioned FDA to remove Celebrex and Bextra, a second COX-2 inhibitor manufactured by Pfizer, from the U.S. market over concerns that the medications increase risk for heart disease, the AP/Las Vegas Sun reports (AP/Las Vegas Sun, 1/24). In the petition, Public Citizen wrote, "If a drug offers no unique benefit compared to other drugs for treating the same problem (in this case arthritis and pain) but subjects patients to unique risk, it must be removed from the market" (Chicago Tribune, 1/25). An FDA spokesperson said that the agency will "review the petition carefully." A Pfizer spokesperson in a statement said that the company "remains confident in its COX-2 medicines as important treatment options that provide necessary pain relief for patients around the world." An FDA advisory committee meeting on COX-2 inhibitors is scheduled for Feb. 16-18. The Pfizer spokesperson called the meeting an "appropriate setting" to raise concerns about Celebrex and Bextra (Wall Street Journal, 1/25).

Reaction to Recent Study Examined
The Washington Post on Tuesday examined reaction to a study published Monday in the Archives of Internal Medicine that found many patients who would "have done just as well on older, cheaper medications" were prescribed COX-2 inhibitors, in part because of how pharmaceutical companies marketed the treatments. According to the study, Merck in 2000 spent $161 million to market Vioxx. A Merck spokesperson defended company marketing practices, which he said are "aimed at ensuring that our product communications are fair and balanced and consistent with FDA labeling." In addition, the Merck spokesperson said that the company trains employees to ensure that advertisements are "consistent with both our standards and our policies" (Kaufman, Washington Post, 1/25).