The U.S. Food and Drug Administration (FDA) is supposed to ensure the safety and quality of drugs reaching the public, acting on the taxpayers' behalf. As of Friday (February 18), an extraordinary three-day FDA Advisory Committee meeting is finishing, but investigation suggests business interests have superseded public health at the agency.
In a last-minute reversal, the FDA allowed a prominent drug safety scientist to offer testimony about new, unpublished research at extraordinary three-day hearings on the risks and benefits of a controversial class of painkillers known as COX-2 inhibitors.
Dr. David Graham, the FDA's associate safety director, says the agency had attempted to suppress a recent study on the drugs that he conducted with Dr. Gurkirpal Singh of Stanford University.
"They don't want safety information (to go) out to the public," Graham charged in an interview, "because it will only highlight how inadequate their assessment of safety has been before the drugs have gotten onto the market."
The FDA veteran said he was "told in very clear, emphatic and very terse, unfriendly tone of voice and terms, we were not to present these data. These data could not be presented."
Last year, Graham led a study on Merck's Vioxx that indicated 30,000 to 55,000 Vioxx-related deaths in the United States, and more still globally. Similar questions about cardiovascular problems have been raised about Pfizer's Celebrex and Bextra.
In mid-December, U.S. senator Charles Grassley called for an independent commission to review U.S. drug safety policies. Last week, Grassley again made headlines by accusing the FDA's leadership of quashing the new research by Graham and Singh.
Last Wednesday (February 16), Graham said he had received a letter from acting FDA Commissioner Lester Crawford telling him he could testify without fear of reprisal.
The following day, Graham told the committee that he saw a "class effect" of cardiac risk at a higher dosage from COX-2 drugs. "The bottom line conclusion I come to is there doesn't really appear to be a need for COX-2," he said.
The latest study uses the same methodology that Graham perfected in the Vioxx study published in the British medical journal, the Lancet, he told IPS.
Before it was voluntarily withdrawn from the market by Merck last September 30, Vioxx was taken by 80 million people, about 20 million of them in the U.S. Celebrex and Bextra, both manufactured by Pfizer, are reported as having 26 million and seven million global users, respectively.
Repeated telephone calls to Pfizer and the FDA yielded no one available for comment.
Graham and other critics say the agency has a tendency to suppress studies at the most crucial times, only to allow them later to surface.
"We said that we thought this information was absolutely critical to the advisory committee. It spoke about the risks with Celebrex. It spoke about the risks with Bextra," said Graham.
Several similar incidents have occurred in recent months of data suppression by the FDA, including a report linking selective serotonin reuptake inhibitor (SSRI) antidepressants to suicides in young people.
The 15-member FDA committee, whose members are drawn from academia, public health and industry, will ultimately decide whether Celebrex and Bextra should be withdrawn, or whether their warning labels should be strengthened.
Merck & Co. announced Thursday (February 17) that, depending on the advisory committee's findings, it could return Vioxx to the market, citing similar cardiovascular risks with the other COX-2 drugs.
The latest study is "between five and 50 times larger than any other (painkiller) study that's ever been done," Graham said, noting that the accuracy of a study generally increases with its sample size.
"We've looked at most of the non-steroidal pain relievers on the U.S. market. And so we have, I think, a fairly encyclopedic study that documents the levels of risk for many of these drugs," he said.
"The classic approach of industry and FDA has been to do studies that are too small to conclusively identify that a risk is real," he added. "They can conclude, therefore, that there is no risk."
Graham charged that "FDA standards of evidence give drugs and drug companies a free pass on safety."
Currently, about half of the FDA's "human drug" budget is met by the total fees generated by the 1992 Prescription Drug User Fees Act (PDUFA), in which companies pay millions of dollars to have their drugs evaluated by the agency. In some western nations, the drug regulatory bodies are 100 percent industry-funded.
When asked if he saw FDA's problems as stemming from PDUFA, Graham, a 20-year FDA veteran, replied: "This attitude existed before, but what happened with PDUFA in 1992 was it set in motion an external pressure and a dynamic that took this tendency within FDA and made it far, far worse and much more intense."
Many critics also believe that PDUFA heightened a pro-industry bias.
"People know that their salaries are dependent upon the companies that initiate drug testing," said Dr. Sheldon Krimsky of Tufts University in Boston, an ethicist who has studied corporate influence on science. "It has a certain effect on the consciousness of the reviewers. There shouldn't be this supporting role of government by multinationals."
Krimsky says that growing drug industry clout in the U.S. has led to "controlling the research and testing agenda, and to having an effect on regulatory agencies by making sure supportive people are in those agencies."
Control has come with the financing of bio-medical research and the structuring of the studies done to approve the results of that research for the market. Funding processes have been the key mechanisms, including political contributions.
"In the course of the last 30 years, the whole clinical trial process has become a process that the (pharmaceutical) industry has taken more and more control of," the famed British drug scientist and psychiatrist Dr. David Healy -- responsible for Britain banning most SSRI antidepressants for use in young people -- told IPS in an earlier interview.
"They've (the pharmaceutical companies) published as positive trials, trials which everyone else -- when they get to see the raw data -- realise are not positive trials. That actually...it's clear that the drug didn't work, and that it had hazards," Healy told IPS last summer.
His remarks were later echoed by others, including members of Congress, as evidence mounted on the SSRI drugs' connection with violent and suicidal behaviour, especially among children and teens.
Regarding regulators, if Big Pharma "didn't like something about the FDA .... it could change it through direct pressure or through its friends in Congress," charged Dr. Marcia Angell, former editor-in-chief of the prestigious New England Journal of Medicine and a senior lecturer at Harvard Medical School, in an interview last fall with MSNBC.
The pharmaceutical business is becoming "a vertically integrated industry", Krimsky said, which influences "every aspect of drug development" - including physician education, drug promotion, lobbying of government agencies, and consumer advertising.
"There's no other industry in which the manufacturer has such a tight control, and pays for most of the testing that goes on," said Krimsky, who recently published a book entitled, "Science in the Private Interest: How the Lure of Profits Corrupted Bio-Medical Research".
Graham charges that the division of the FDA that pursues drug testing and approval sees its mission as "reviewing and approving as many drugs as it can", with safety a "low priority".
In effect, Graham told IPS, the FDA's Office of Drug Safety is "completely captive" to the Office of New Drugs.
Published studies have claimed that adverse drug reactions appear to be the fourth leading cause of death in the United States. A paper published in the May 2002 Journal of the American Medical Association by scientists from Harvard Medical School also strongly urged physicians not to prescribe newer drugs for their patients where older, proven treatments are available.
Numerous drug industry critics see the need for a "firewall" between drug companies and drug testing.
Graham, Krimsky, and others, including Dr. Curt Furberg, a member of the FDA's Drug Safety and Risk Management Committee, strongly advocate a new, more independent drug safety system, preferably outside the FDA structure completely.
While the FDA has just announced the creation of a new board to oversee monitoring of drugs already on the market, Dr. Sidney Wolfe, director of the non-profit Public Citizen Health Research Group in Washington, was quoted as observing, "In the absence of any fundamental change, it's a cruel hoax."
© 2005 Ritt Goldstein