FDA Officer Says Conflicts of Interest Compromise Agency
November 19, 2004A veteran Food and Drug Administration safety officer Thursday told a Senate hearing inquiring into the abrupt recall of the arthritis drug Vioxx that five other widely used drugs should be either withdrawn or sharply restricted because they have dangerous side effects.
Describing the agency that he works for as incapable of stopping dangerous drugs from coming to and staying on the market, David Graham, associate director of the Office of Drug Safety, told the senators that the FDA's role in reviewing and approving new drugs sometimes conflicted with its duty to address safety issues.
Asked by Sen. Jeff Bingaman, D-N.M., to identify the five drugs, Graham hesitated and then listed them to the startled hearing room: the popular cholesterol-lowering drug Crestor, the weight-loss drug Meridia, the painkiller Bextra, the acne medication Accutane and the asthma medication Serevent.
Each poses different issues, Graham said in answer to questions from senators, but all require more aggressive action by the FDA.
AstraZeneca's Crestor, he said, poses risks of kidney failure and a rare muscle disease; Abbott Laboratories Inc.'s Meridia is of little use and has cardiovascular side effects; Roche's Accutane can cause birth defects if used by pregnant women; Pfizer's Bextra carries cardiovascular risks similar to those linked to Vioxx; and GlaxoSmithKline's Serevent increases the risk of dying of asthma. The makers of all five drugs later defended their products vigorously.
Dr. Steven Galson, acting director of the FDA's Center for Drug Evaluation and Research, said the agency already had taken steps to alert consumers to those drugs' safety concerns. That includes heightened warnings for Serevent; a tougher risk management plan to ensure pregnant women don't use Accutane, and an upcoming advisory committee hearing regarding Bextra.
A 20-year veteran of the FDA, Graham has played a significant role in the withdrawal of nine drugs over the past decade, and his highly unusual attack on his own agency astonished many in the room. He called the FDA's handling of Merck & Co.'s Vioxx which he said should have been pulled from the market years ago the most distressing episode of all and a "profound regulatory failure."
"I would argue that the FDA as currently configured is incapable of protecting America against another Vioxx," Graham said in his scathing assessment. "The scientific standards (the FDA) applies to drug safety guarantee that unsafe and deadly drugs will remain on the U.S. market."
Citing estimates he said were based on the results of Merck's own clinical trials, Graham said between 88,000 and 139,000 Americans had probably had heart attacks or strokes as a result of taking Vioxx, and that 30 to 40 percent had probably died.
Graham also contended that FDA had an inherent conflict of interest that triggered "denial, rejection and heat" when safety questions emerged about products it had approved.
Graham's sentiments were endorsed at the hearing by two other drug safety experts, but they were disputed by a ranking FDA official as "not the FDA that I know."
Sandra Kweder, deputy director of the Office of New Drugs, said the agency was dedicated to protecting consumers and that drug safety was at the heart of its activities. She acknowledged, however, that "clearly, there's concern by the public and this committee that the system isn't working as well as it should, and we need to address that."
Asked about the five drugs that Graham identified as needing immediate action, Kweder said, "I don't have reason to believe that set of five drugs gives more reason for concern than any other set."
Graham's revelations and criticisms were at the center of the hearing called by Sen. Charles Grassley, R-Iowa, chairman of the Senate Finance Committee and an increasingly sharp critic of the FDA. Following Graham's comments, Grassley pointedly warned agency officials against disciplining Graham in any way.
Grassley also suggested that an independent board of drug safety may be needed to ensure the safety of medications after FDA approval. An "awful lot of red flags" were raised before Vioxx was withdrawn, said Grassley, and the agency disdained, rather than listened to, its own reviewers.
Merck CEO Raymond Gilmartin came to the defense of the FDA and his company's actions in dealing with the issues around Vioxx, a heavily advertised and hugely profitable drug until it was abruptly recalled in September. He said the company had no scientific reason to withdraw the drug until it heard clear negative results reported by the safety monitoring committee of a clinical trial. At the time, Gilmartin said, his own wife was regularly taking the drug.
"Throughout Merck's history, it has been our rigorous adherence to scientific investigation, openness and integrity that has enabled us to bring new medicines to people who need them," Gilmartin said. "I am proud that we followed that same rigorous scientific process at every step of the way with Vioxx."
One of a class of painkillers known as COX-2 inhibitors that are widely used by arthritis sufferers, Vioxx was introduced in 1999. It was withdrawn after researchers halted a clinical trial because patients taking Vioxx were experiencing twice as many heart attacks and strokes as patients taking a placebo, but witnesses testified there had been suggestions of possible cardiovascular risks going back the mid-1990's.
Officials of the companies whose drugs were cited by Graham all said they were surprised by his testimony. Carolyn Glynn, a spokeswoman for Roche, said it had long recognized that Accutane required special handling because of its known connection to birth defects.
AstraZeneca, the maker of Crestor, said in a statement that "to date, the FDA has not given the company any indication of a major concern regarding Crestor, and the comments today are inconsistent with past public statements from the FDA."
Abbott Laboratories issued a statement defending its weight loss drug Meridia. "Obesity remains one of the leading health epidemics in the U.S., and Meridia is one of the few effective drugs that are currently available," it said.
GlaxoSmithKline stood by its asthma drug Serevent, saying it was "safe and effective when used appropriately."
Pfizer spokeswoman Susan Bro said its Cox-2 drug, Bextra, "has been found safe and effective when used as indicated." She noted that the company had already "committed to conducting further studies to confirm the longer-term cardiovascular safety profile."
Five drugs cited by a Food and Drug Administration official as the worst examples of those that remain on the market despite safety concerns:
- Accutane, a treatment for severe acne linked to birth defects and foetal death when used by pregnant women.
- Bextra, a painkiller found in a recent study to more than double the risk of heart attacks and strokes among patients with heart disease.
- Crestor, an anti-cholesterol drug linked to a muscle-destroying side effect and acute renal failure.
- Meridia, an obesity treatment linked to heart problems and, among pregnant women, stillbirths, miscarriages and birth defects.
- Serevent, an asthma medication that a study in England linked to increased deaths.