FDA Responds to JAMA Studies on Cholesterol Drug Baycol, Reviews Records

Baycol Withdrawal
Bruce Psaty -- a professor of medicine and epidemiology at the University of Washington who served as expert witnesses for plaintiffs suing Bayer over the Baycol withdrawal -- and colleagues said in one of the JAMA articles that Bayer was aware of the risks of Baycol long before it withdrew the drug from the market. Citing internal Bayer documents that became public during the trial, Psaty and colleagues said that the company became aware of the possibility of a link between Baycol and rhabdomyolysis within months of the drug's launch in February 1998. However, the researchers said Bayer acted slowly to confirm the problem or inform doctors. Psaty concluded that under the current system, a pharmaceutical company's "appraisal of (suspected adverse drug reactions) may be influenced by economic considerations." By the time Baycol was removed from the market in 2001, the estimated number of cases of rhabdomyolysis had reached the tens of thousands. As of this fall, Bayer has settled 2,861 lawsuits over Baycol (Kaiser Daily Health Policy Report, 11/23).

FDA Review
During an appearance on C-SPAN on Wednesday, Steven Galson, acting director of FDA's Center for Drug Evaluation and Research, said that Psaty's article alleged that "before the agency was aware of the data, the company knew that the drug was more dangerous than others. If this allegation is correct, the FDA takes it extremely seriously, and we're going to have our criminal investigators look into this." He added, "Right now, we don't really know whether that's true or not. We read about it in this level of detail for the first time" in the JAMA article. FDA spokesperson Kathleen Quinn said, "Bottom line: We have to go back and look at all the data (to) see what we have and compare and make sure we had all we could have -- which we think we did" (AP/Las Vegas Sun, 11/27).

Bayer Response
In the same JAMA issue, attorneys for Bayer said that the company's handling of the Baycol case was "responsible, appropriate and consistently motivated by concern about the safety and welfare of patients" (Kaiser Daily Health Policy Report, 11/23). Bayer also said in a statement that the JAMA article by Psaty "contain[s] no new information regarding Baycol and Bayer's timely reporting of data. Bayer kept FDA fully informed about all pertinent safety information, including adverse event reports. Indeed, an FDA audit of Bayer's post-marketing practices during the time Baycol was on the market demonstrated no deficiencies." The company also said that so far it has paid $1.1 billion, without admitting liability, in out-of-court settlements of cases related to Baycol side effects. Some 7,169 cases are still pending (AP/Las Vegas Sun, 11/27). Bayer last week also launched an advertising campaign to "polish up its image," the Pittsburgh Post-Gazette reports. The print and television ad campaign was launched in Germany and will target U.S. audiences beginning Monday (Shropshire, Pittsburgh Post-Gazette, 11/27).

Graham Under Pressure?
In related news, David Graham, associate director of drug safety in the FDA Office of Drug Safety, said Wednesday that he is facing pressure to change jobs within FDA as a retaliatory measure for his remarks before a Senate Finance Committee hearing on the Vioxx withdrawal (Alonso-Zaldivar, Los Angeles Times, 11/25). At the hearing, Graham said that Merck should have withdrawn Vioxx from the market years earlier and criticized agency actions related to the medication. 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 (Kaiser Daily Health Policy Report, 11/22). In an interview Wednesday, Graham said that FDA Acting Commissioner Lester Crawford on Nov. 9 asked him to consider a new assignment on a team reviewing the workings of the agency. Graham said that he informed Crawford that he was not interested in the new assignment. However, Graham added that he recently heard unofficially that he will be required to accept the new assignment. He said, "What they want to do is move me out of drug safety into the office of the commissioner, where I will basically be exiled and won't be able to do drug research. It's a reprisal." Graham added, "It's a way of neutralizing me so I won't be able to expose any additional drugs" (Los Angeles Times, 11/25). He said he expects to be asked to change jobs as soon as this week (Rubin, USA Today, 11/26).

Response to Graham
Tom Devine -- legal director for the Government Accountability Project -- which is providing legal counsel to Graham, said, "We are hoping to prevent Dr. Graham's exile before it becomes a fait accompli. It is an inexcusable abuse of power that the FDA would sideline (this) scientist." Devine said that soon after Graham retained GAP attorneys to provide legal advice, the group received anonymous phone calls from FDA phone numbers attempting to discredit Graham by accusing him of scientific misconduct (Los Angeles Times, 11/25). "We checked out the allegations (against Graham). They were bluffs that flunked the laugh test," Devine said. FDA in a statement said that the agency "does not condone any form of employee retaliation," adding, "FDA has clearly not discouraged or interfered with David Graham's ability to offer his personal opinion in any public forum he chooses" (Henderson, AP/St. Louis Post-Dispatch, 11/26).

Grassley Requests Probe
Senate Finance Committee Chair Chuck Grassley (R-Iowa) has called on Daniel Levinson, acting inspector general for HHS, to investigate whether FDA officials misused "government resources, including property and time," by using their office phones to make anonymous phone calls questioning Graham's competence. Donald White, a spokesperson for the HHS Office of Inspector General, said that the office would review Grassley's request for an investigation "carefully" but no decision has been made (Pugh, St. Paul Pioneer Press, 11/25).

Graham Study
In related news, e-mails between FDA officials and the editor of the journal Lancet, "sugges[t]" that the FDA "took the unusual step" of calling the editor about the credibility of the findings of a scientific study on Vioxx performed by Graham, USA Today reports (Rubin, USA Today, 11/29). Graham has alleged that agency officials delayed and criticized the results of a study he conducted that found that high doses of Vioxx tripled patient risk for heart attack and sudden cardiac death. Graham planned to present the study at an epidemiology conference on Aug. 25, but his supervisors said that the results were "too preliminary" and recommended that he first submit them to a medical journal for peer review or present them at the conference with an alternative FDA opinion. Graham also submitted the study to the Lancet for peer review (Kaiser Daily Health Policy Report, 11/18). The Lancet had planned to post the study on its Web site on Nov. 17, but Graham said he pulled the paper "at the last minute because he feared for his job," USA Today reports.

E-Mails
Graham decided to pull the paper following a series of e-mails he received from Lancet editor Richard Horton, USA Today reports. According to the e-mails, Galson called Horton on Nov. 12 to inform him that FDA had not cleared Graham's paper for publication. In a follow-up e-mail, Galson referred to a review of Graham's study by Ann Trontell, deputy director of the FDA's Office of Drug Safety, that referred to "potential charges of data manipulation" in Graham's study. Graham said he addressed the concerns raised by Tontell. In an e-mail to Galson on Nov. 14, Horton said that he was "taken aback" by Galson's phone call. He also said that raising the possibility that a scientist manipulated data "is an extremely serious allegation. One could read such an allegation as an attempt to introduce doubt into our minds about the honesty of the authors -- doubt that might be sufficient to delay or stop publication of research that was clearly of serious public interest." On Sunday, Galson said, "We didn't make any efforts to block publication in the Lancet, adding, "What we did is let the Lancet know that the paper was submitted in violation of the agency's clearance process." In a statement, Crawford said that Galson contacted Horton "out of respect for the scientific review process" (USA Today, 11/29).

FDA Reform Efforts Face Obstacles
The idea of an independent FDA office to monitor drug safety "is already running into obstacles on Capitol Hill," the New York Times reports (Gay Stolberg, New York Times, 11/25). In their editorial last week, JAMA editors recommended a major overhaul of the drug-safety monitoring system, including new oversight requirements and the establishment of an independent safety review board to monitor post-market problems in newly approved products. Many of the recommended changes would require congressional approval (Kaiser Daily Health Policy Report, 11/23). Grassley has said he supports the creation of an independent drug safety monitoring office. On Wednesday, he said a bill that would create such an office could be ready as early as February, although he predicted that the legislation would face a difficult road because of resistance from the pharmaceutical industry and FDA. Senate Health, Education, Labor & Pensions Committee Chair Judd Gregg (R-N.H.) said, "Another layer of bureaucracy at the FDA is probably the last thing we need," adding that the Vioxx withdrawal was one of "a couple of high visibility mistakes" that have been "blown out of proportion," the New York Times reports. Gregg said, "Congress has a tendency in a situation like this to jump on the bandwagon and beat the drums loudly," adding that reform efforts should focus instead on giving FDA the resources it needs to review and approve new medications. Sen. Edward Kennedy (D-Mass.), who is drafting drug safety legislation, predicted that reform bills would receive "bipartisan support," noting that "the FDA gold standard has been tarnished" (New York Times, 11/25).

Other Related Stories

• Baltimore Sun: The Sun on Sunday looked at the "growing number of critics" who say FDA requires "major changes" in its organization and operations, possibly including a new finance structure for FDA and increased regulatory powers for the agency after a drug is approved (Kohn, Baltimore Sun, 11/28).
  
  
• Christian Science Monitor: The Monitor on Thursday looked at the "growing conflict over drug safety" and FDA's relationship with the drug industry (Marks, Christian Science Monitor, 11/26).
  
  
• Los Angeles Times: The possibility of reforming FDA through legislation currently is uncertain but "should become clearer" by early 2005, the Los Angeles Times reports (Alonso-Zaldivar, Los Angeles Times, 11/26).
  
  
• NPR's "Weekend Edition Saturday:" The program included an interview with former FDA commissioner David Kessler about complications with Vioxx and other drugs, and the agency's drug approval process (Simon, "Weekend Edition Saturday," NPR, 11/27).
  The complete segment is available online in RealPlayer.
  
  
• Richmond Times-Dispatch: The Times-Dispatch on Sunday examined the "long list" of personal injury attorneys who have placed advertisements seeking plaintiffs for Vioxx-related lawsuits. According to the Times-Dispatch, the "challenge" for these lawyers is "to distinguish the curious and the gold-diggers from those who truly have been injured" (Cooper, Richmond Times-Dispatch, 11/28).
  
  
• Washington Times: The Washington Times on Thursday looked at the "[m]any arthritis sufferers" who took Vioxx and are now "having trouble" finding an effective alternate treatment (Howard Price, Washington Times, 11/25).
  
  
• Washington Times: The Washington Times on Saturday examined JAMA's editorial. Dr. Al Sears, director of the Florida-based Center for Health and Wellness, said the editorial shows FDA has "lost credibility" in its post-approval review process after becoming "too dependent on the drug companies" (Howard Price, Washington Times, 11/27).