The voluntary manufacturer withdrawal of the COX-2 inhibitor Vioxx (rofecoxib) last fall prompted many critics to question why the agency charged with ensuring the safety of pharmaceuticalsthe U.S. Food and Drug Administrationdid not lead the effort to issue warnings or remove the drug from the market.
By some accounts, the FDA's system for reporting adverse drug reactions is overwhelmed and in need of reform. In addition, the agency lacks the appropriate authority to mandate that drug companies perform postmarketing studies, which could yield valuable safety information. But several new efforts suggest that the landscape for drug safety monitoring is destined to improve: The proposed 2006 federal budget includes a 24% increase in funds earmarked specifically for drug safety, the acting FDA commissioner has announced a broad plan to improve drug safety monitoring at the agency, and Congress is considering legislation that may give the FDA the funding and the authority it needs to ensure the safety of the nation's drug supply.
According to estimates from a 1998 study published in the Journal of the American Medical Association, 100,000 people die in the United States each year from adverse reactions to drugs. Of the 548 drugs approved by the FDA between 1975 and 1999, 8.2% of themincluding five cancer drugsacquired a black box warning, which highlights serious risks, and 2.9% of them were withdrawn from the market.
Before a drug is approved by the FDA, the drug's maker must prove that it is both effective and safe. However, most drugs are tested in, at most, a few thousand people who meet very specific criteria, and the trials are designed to focus on the drug's benefits. Only after a drug is made available to the general public will there be enough people taking it for important but less common adverse events to be detected. Most adverse events that trigger a drug's withdrawal occur in only about one in 50,000 people, said Raymond Woosley, M.D., Ph.D., president of the Critical Path Institute in Tucson, Ariz. "The real problem in safety is often not in the drug but how it is used," he added.
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Health care providers, consumers, and pharmaceutical companies can report adverse events to the FDA through a voluntary reporting system; the agency received 400,000 such reports in 2004. Most of the reports come from health care providers, but about 90% of the time, these are routed through the drug manufacturer before being sent on to the FDA. The adverse events reports are "extremely important to the FDA and public health in general because they tell us the real-world experience of these drugs," said Seligman. They sometimes become one basis for drug warnings, label changes, and withdrawals.
However, the system is not without its problems. The thousands of reports the FDA receives represent at most only 10% of the actual adverse events experienced. The FDA has no way of knowing the total number of people who have experienced an adverse event or even how many people are taking a particular drug. These limitations make it much more difficult to detect problems with drugs and slow the system. For example, for 15 of the most recent drug withdrawals, it took an average of 5.9 years from the initial drug approval to withdrawal, said Woosley.
Using adverse-events reports to detect problems works well for serious, rare events unrelated to the indication of the drug that usually occur soon after someone has started taking the drug, as was the case with Baycol (cerivastatin), a popular cholesterol-lowering drug that was voluntarily pulled from the market in 2001 after 31 deaths from rhabdomyolysis were reported in people taking the drug, said Bruce M. Psaty, M.D., Ph.D., professor of medicine and epidemiology at the University of Washington in Seattle.
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The FDA, however, lacks the federal authority to require companies to perform postmarketing studies for safety or for any other reason. The FDA can request studies, but they are often not completed. The FDA reported in the Federal Register last year that 65% of open postmarketing commitments requested for approved drugs were classified as "pending." Many of these trials appear to not have an assigned start date, so they cannot be labeled as "delayed," said Psaty.
After a drug's approval, the FDA can ask companies to take several actions regarding their drugschange labels to reflect new safety concerns, create a patient registry, conduct patient or physician education, or restrict advertisingbut the agency has no enforcement mechanism for such requests, there are no consequences for ignoring requests, and often lengthy negotiations are required. For example, labeling changes for Vioxx took 14 months before they were made in April 2002. And the FDA has little control over how and in whom a drug is used.
Even FDA scientists are concerned about their ability to ensure a drug's safety after its approval. An internal survey conducted by the Department of Health and Human Services Office of Inspector General in 2002 found that two-thirds of FDA scientists who responded to the survey lacked confidence that the agency "adequately monitors the safety of prescription drugs once they are on the market."
"The current systems for drug safety are inadequate to protect the health of the public," said Psaty. Woosley agreed, saying, "We have all these drugs prescribed and no feedback."
Since the Vioxx withdrawal, the FDA has announced several changes aimed at improving the agency's drug safety efforts. In November, Acting Commissioner Lester Crawford, D.V.M., Ph.D., announced his five-point plan for drug safety, which included appointing a permanent director to the Office of Drug Safety. (The office has been headed by an acting director since October 2003.) "Hopefully we'll be able to get someone in there in the next few months," Steven Galson, M.D., acting director of FDA's Center for Drug Evaluation and Research, said at a recent meeting of the FDA's Science Board Advisory Committee.
The FDA is also sponsoring an Institute of Medicine study of the drug safety system. In April, the IOM announced its initial list of committee members, which included Psaty, but meetings have yet to be scheduled and no deadline has been set for issuing a report.
In February, the FDA announced several more actions aimed at improving drug safety, including the proposal for a new Drug Watch Web page that would help the FDA disseminate information about emerging drug safety issues that are under evaluation by the FDA. The FDA has published a draft guidance for the creation of the new Web page in the Federal Register and is accepting comments until August.
Perhaps more notable was the creation of a Drug Safety Oversight Board to oversee drug safety issues within CDER, including the Drug Watch program. The board, which was named on May 18, will be led by the deputy director of CDER and includes several representatives from a variety of FDA centers and offices, and one representative each from the National Cancer Institute and the Department of Veterans Affairs. Board members from the FDA who made decisions about particular drugs under review will not be able to vote on decisions related to those drugs. However, when the plan was submitted to the FDA's Science Board, several committee members questioned whether there should be some kind of outside independent oversight for the Drug Safety Oversight Board.
Psaty also questioned the independence of the new board, calling it a "shuffling of a few chairs." However, restrictions on federal advisory committees have made it difficult for the FDA to bring in people from outside government to sit on the Drug Safety Oversight Board.
"What's needed is a transparency that we don't have right now," said Alastair J. J. Wood, M.D., associate dean and professor of medicine at Vanderbilt University in Nashville, Tenn. He has suggested creating an independent drug safety board that would work something like how the National Transportation Safety Board works in relation to the Federal Aviation Administration.
Wood has also suggested implementing a phased approval process and extending patent exclusivity if a pharmaceutical company demonstrates their drug has a conclusive benefit or conducts safety studies. "Incentivize people to do things rather than regulate them," he said.
Others have suggested setting up a system similar to the United Kingdom's Yellow Card Scheme in which health care professionals are encouraged to report all adverse reactions to drugs and that monitors newer drugs more intensely. There has also been interest among U.S. pharmacists in developing a system for them to report adverse events, but there is no model for compensating them for the additional work, Galson told the Science Board.
On April 27, Sens. Charles Grassley (R-Iowa) and Christopher Dodd (D-Conn.) introduced legislation that would create a Center for Postmarket Drug Evaluation and Research, which would report directly to the FDA commissioner. The new center would have five times the budget of the current Office of Drug Safety and new authorities. The center director would be able to require postmarket safety studies, require that companies make changes to drug labels, restrict the use of high-risk drugs and alert consumers to these risks, and recommend that the FDA commissioner withdraw a drug when necessary. For the first 2 years after a drug's approval, advertising would have to include a disclaimer stating that the drug's safety risks are not fully known. In addition, the center would be able to fine pharmaceutical companies up to $2 million if they fail to comply with decisions. The FDA had no comment on the legislation.
How much, if any, of this actually becomes law remains to be seen. There are concerns that some of the limits on advertising might violate the First Amendment. And Sen. Mike Enzi (R-Wyo.), who chairs the Senate Health, Education, Labor, and Pensions Committee that will probably consider the bill, has publicly expressed concern that the new center would put too much emphasis on the risks of drugs and not enough on their benefits.
But the biggest problem in health care may not be drug safety, said Woosley. The public does not appreciate that "more people die from not having a drug than from drugs."
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