WASHINGTON – A debate over how the Food and Drug Administration responds to newly discovered risks in drugs escalated yesterday, as an FDA official criticized his agency's approach and raised concerns about a handful of medications already on the market.
David Graham, associate director for science and medicine in the agency's drug-safety office, told the Senate Finance Committee that his agency discounts recommendations from its own safety researchers and doesn't give sufficient weight to safety concerns once drugs are approved.
Some other witnesses echoed his critique at the hearing, which focused largely on the history of Vioxx, a painkiller with $2.5 billion in annual sales that was withdrawn by Merck& Co. on Sept. 30 because it was tied to an increased risk of heart attack and stroke with long-term use.
Dr. Graham, who said he clashed with FDA officials about his conclusions on Vioxx's safety, cited five other drugs that he believes require stronger regulatory action: Pfizer Inc.'s Bextra, a painkiller in the same class of medications as Vioxx; Crestor, a cholesterol drug made by AstraZeneca PLC; Meridia, Abbott Laboratories' obesity drug; Accutane, an acne drug made by Roche Holding AG and available generically; and Serevent, an asthma medicine from GlaxoSmithKline PLC.
Those drugs already have drawn heightened scrutiny of the FDA as well as the attention of consumer advocates and some regulatory agencies abroad. The companies that make those five drugs defended their products, most of which already have warnings on their labels about the safety issues he raised.
Although Dr. Graham's sharp criticism of his agency and his public warning about specific drugs was unusual, his concerns about the FDA's drug-safety policies reflect a longstanding tension within the agency. It has been accused of both dragging its feet in getting some drugs to market – a complaint heard regarding approvals of some AIDS medicines, for instance – and of moving too quickly to accommodate new drugs backed by big pharmaceutical companies.
Sandra Kweder, deputy director of the FDA's office of new drugs, who testified on behalf of the agency, said the drug-review divisions of the FDA "work extremely closely with our colleagues in drug safety" and scientific disagreements are dealt with properly. But, she added, "There is clearly concern that somehow the system is not working as well as it could. ... We need to address that."
In an interview, Steven Galson, acting director of the FDA's drug center — of which the drug-safety office is a part — said that each of the five drugs "does have safety issues that need to be addressed and discussed," and added that he feels the agency is "on top of them."
The Vioxx withdrawal — which has driven Merck stock down to about $27 a share from the prior $45 — is adding new weight to the idea that the FDA should develop an independent process for overseeing drugs once they are on the market, to help it strike a balance between the benefits offered by important new treatments and the sometime-serious side effects.
Finance Committee Chairman Charles Grassley, an Iowa Republican, said he supports greater independent authority for the office that oversees drugs' safety after they go on the market. "I intend to keep pressing for reforms inside the FDA," he said during yesterday's hearing. "An independent office of drug safety would be a positive change."
The FDA's Dr. Kweder said the agency has commissioned an outside review of how it handles drug safety and "we look forward to change if that is deemed needed."
The broader theme of the FDA's handling of drug safety provided a backdrop for testimony that centered mostly on Vioxx. Two academic researchers offered a detailed timeline of the growing evidence of concerns about the drug, drawing largely on Merck and FDA documents that have been previously reported. Questions about the drug's cardiovascular safety arose before it went on the market in May 1999. "The failure to conduct large long-term safety studies subjected millions of patients over four years to a drug whose safety had been questioned by the FDA even before its approval," said Gurkirpal Singh, an adjunct clinical professor of medicine at Stanford, who was testifying by a live video hookup.
Ray Gilmartin, CEO of Merck |
Raymond Gilmartin, chief executive of Merck, said at the hearing that his company acted responsibly by studying Vioxx extensively, disclosing data about the drug and pulling it from the market when the latest results appeared to demonstrate increased risk. "Merck puts patients first," he said.
Dr. Graham has in the past clashed with other FDA scientists who have disagreed with his interpretations of data, and he has raised early alarms internally on drugs that were eventually pulled from the market because of their risks. In his testimony yesterday, he argued that FDA is "incapable of protecting America against another Vioxx," and the FDA's drug center "overvalues the benefits of the drugs it approves and seriously undervalues, disregards, and disrespects drug safety." The FDA divisions that review drugs for approval become too attached to them, he said.
Dr. Kweder yesterday defended the agency's handling of Vioxx and other safety matters. The agency "pursued ... vigorously" a label change that added cardiovascular concerns to Vioxx's label in 2002, she said: "We did not sit back."
The agency's Dr. Galson said that the office of drug safety is already separate from the review divisions — though it doesn't have independent authority over drugs — and "we think it would be really dangerous to separate the assessment of benefits of drugs too much from the assessment of risks."
Separating the FDA's drug-review divisions from its post-approval safety oversight wouldn't be simple to implement. Currently, the drug-review divisions generally oversee labeling and other decisions even after the medicines go on the market, with the drug-safety office in an advisory role. Doctors in the review divisions, which are made up of medical specialists, are often the most familiar with how a drug works and where it fits in clinical practice. They are used to relying on placebo-controlled trials, the "gold standard" of scientific evidence, to make their approval decisions.
However, once a drug is approved, the FDA typically has to rely largely on reports of incidents that come in through its "adverse event" reporting system. By some estimates, that system captures just 10% of the problems. Sometimes, the agency does studies such as one Dr. Graham worked on, which troll through large databases for trends. The FDA can't order a drug maker to do another safety trial after the product is approved, though it has strong indirect influence.
There has long been concern — sometimes expressed by FDA officials — that the agency has limited resources to detect safety problems once a drug is approved. The other question, raised by Dr. Graham, is whether the FDA acts aggressively enough to obtain data and respond to the safety information it does get.
In defending the other drugs mentioned in Dr. Graham's testimony, GlaxoSmithKline said Serevent "is safe and effective when used appropriately" according to labeling guidelines, and has a "black box" warning on its label. A spokeswoman for Abbott said that Meridia is one of the few effective drugs available for treating obesity and has been "extensively studied" in more than 12,000 patients. A Pfizer spokeswoman said that a recent analysis had found no increased cardiovascular risk in Bextra.
A spokeswoman for AstraZeneca said Dr. Graham's comments were "inconsistent with past statements of the FDA" and the drug's safety profile is "comparable" to competing drugs. A Roche spokeswoman said that the company and other manufacturers are working on a new registry to monitor Accutane prescriptions: "It's a high priority for all of us," she said.
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