GOVERNMENT & POLICY tising. Despite these factors, she said, the drug withdrawal rate has remained steady, while the speed at which they are withdrawn has increased.
DRUG SAFETY SYSTEM SHARPLY CRITICIZED Speakers at Institute of Medicine meeting cite serious problems with FDA's monitoring system BETTE HILEMAN, C&EN WASHINGTON
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HE FOOD & DRUG ADMINISTRA-
tioris program for ensuring drug safety has serious structural and regulatory shortcomings, according to many speakers at the Institute ofMedicine's (IOM)June 8 meeting to examine the U.S. system for ensuring the safety of approved drugs. Almost none of the speakers said the system is working well and needs only minor changes. And some identified important problems outside FDAs purview that compromise drug safety An I O M committee has been charged by FDA with scrutinizing the entire health care system as it relates to drug safety It is examining the role of health professionals, hospitals, and patients in ensuring drug safety as part of the U.S. health care delivery system. It is considering patient education and compliance, and even statistics on whether patients actuallyfilltheir prescriptions. The I O M study was prompted in part by the high-profile withdrawals of the bestselling arthritis drugs Vioxx and Bextra and revelations that some widely prescribed antidepressants, such as Paxil, increase suicidal behavior in children. The conclusion that can be drawn from most of the presentations at the public meeting is that the current FDA system 36
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for ensuring drug safety was not designed well in the first place and wasn't intended to cover many aspects of pharmaceutical safety, such as whether patients use drugs as directed. Janet Woodcock, FDA acting deputy commissioner for operations, testified that "the system has broken down to some extent." She explained that the drug review process speeded up after z passage of the Prescription § Drug User Fee Act in 1992. « PDUFA allows drugs for | life-threatening illnesses to § be approved more quickly £ by FDA in exchange for g promises by the drugmak- sj ers to perform additional u safety studies after the medications are placed on the market. But one drawback to this faster approval scheme, Woodcock said, is that, Vaughan since 1992, many fewer drugs have had a safety track record from marketing abroad before they were sold in the U.S. At the same time, more patients are being exposed to new drugs as a result of massive promotional efforts by companies, especially direct-to-consumer adver-
THE CURRENT drug safety system has both strengths and weaknesses, Woodcock said. Manufacturers who hear of drug-related adverse events must report them, whereas physicians' reporting of adverse events is voluntary "The system is quite good at picking up rare serious adverse events, like liver failure, after drugs are marketed," she said. But it is poor at recognizing increased frequency of common diseases, such as heart attacks, because these diseases occur so frequently in the general population. Also, the system is not designed to detect adverse side effects that occur in the very old or in people taking multiple drugs, she explained. "Current drug therapy is fundamentally a trial-and-error process," Woodcock observed. At the time of approval, 'Sve do not have a detailed understanding ofwho should take the drug and who should not," she said. "Each year, adverse drug events cause about 100,000 deaths and a huge number of hospitalizations." Many adverse drug reactions are preventable, she explained, because they are known side effects. Woodcock told the committee that some partial solutions to drug safety problems would be to decrease medication errors through greater use of automation, to identify adverse drug reactions by surveying electronic medical records from managed heath care organizations, and to look for adverse side effects that occur in nursing homes. In the future, using genomic and other tools to identify patients at high risk for side ef-
Woodcock
fects from a drug and subgroups most likely to benefit from the drug would improve safety, she said. "Currendy, no entity—government or otherwise—is charged with evaluating the comparative safety of drugs and the long-term outcomes of therapy" WWW.CEN-0NLINE.ORG
Steven Galson, acting director of FDAs drugs, Vaughan said. "So many people are Center for Drug Evaluation & Research, baffled by the warnings issued about noted that the agency made several drugs," he said. One way to provide greater changes recently to improve its drug safeclarification of drug safety would be to rety system. One change set up a program quire comparative trials, he explained. for adjudicating differences in opinions Drugmakers should be required to comabout pharmaceuticals among FDA propare a new drug not only with a placebo, fessionals. Another established a quasi-inbut also with existing treatments for the dependent drug safety oversight board. same condition, he said. "Patients and health care providers would benefit from FDA is responsible for only part of the knowing whether a new drug is both safer drug safety system, Galson pointed out. and more effective than older drugs for "It regulates companies, but states are prithat condition." marily responsible for regulation of pharmacies, physicians, and hospitals." One important question the IOM committee ought to consider is: "Should FDA have authority for provisional approval of drugs?" Galson said. "This might ensure that manufacturers' promises to do postmarketing studies are fulfilled." Bill Vaughan, senior policy analyst for Consumers Union, told the I O M panel that it should make interim policy recommendations to Congress "that will ensure fundamental drug safety reforms now." Congress, he said, should require drugmakers to make public all clinical trials. It should also require drug manufacturers to Goldhammer Gans conduct studies when problems first arise and heavily fine those companies that fail In many cases, even when accurate into comply, he said. "This I O M study is imformation about a drug is known, the drug portant, but we shouldn't wait months or is still misused, saidJohn A. Gans, chief executive officer of the American Pharmapossibly years for a study when we can fix cists Association. "The vast majority of known problems now." drugs are put in the hands of patients, and Currently, according to an FDA report published Feb. 18 in the Federal Register, they make drugs work or not work," he said. "The reality is that self-care is important," drug companies benefiting from FDA's ache said. The inhaler used incorrectly, for excelerated approval process have not conample, will not work. This means that the ducted the postmarketing studies rehealth care community quested by the agency on needs to partner with paa timely basis, Vaughan tients much more caresaid. "Sixty-eight percent fully to ensure that drugs of the postmarket api< and devices are used propproval safety studies that ei erly Gans explained. "We companies promised to hear information that 50% conduct had not even ofprescriptions are not been started. The drug filled. That is an outrage." industry sees FDA as a Information also takes paper tiger. FDA needs a long time to disseminate the authority to require among physicians, Gans said. For examthese studies and impose penalties that ple, "We learned early on that ACE [anwill get some action on the backlog." giotensin-converting enzyme] inhibitors help diabetics, but it took 17 years for this ONE THING FDA should do is strengthen information to be incorporated into stanits Office of Drug Safety Vaughan said. "We dard practice." need a drug safety board that is not necessarily outside FDA but that gets respect." The highly publicized withdrawals of The current Office of Drug Safety has Vioxx and Bextra have eroded public conabout 100 employees and a budget of only fidence in drug safety, said David Boren$30 million. Last year, it had to review about stein, a member of the board of directors 473,000 adverse drug reaction reports. of the American College of RheumatolIOM should also consider the issue of ogy. "We need an improved system for how to communicate with patients about postmarket surveillance of pharmaceuti-
it drug "Current therapy is fundamentally a trial-and-error dprocess."
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cals. The MedWatch system {under which consumers, drugmakers, and health care professionals report problems to FDA] is haphazard," he told the committee. "We believe an independent surveillance system with enforcement powers should be independently managed outside FDA and industry," he said. Also, "we need a revised system for educating patients about the benefits and risks of drugs." The Pharmaceutical Research & Manufacturers of America (PhRMA), which represents major drugmakers, supports ef-
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Galson forts to improve safety regulations that do not interfere with patient access or with physicians' practice of medicine, said Alan Goldhammer, associate vice president for regulatory affairs at PhRMA. "New safety initiatives should address the postapproval period," he said. "Changes to the preapproval process are unnecessary and would unduly burden and delay new drug development." No one should lose sight of the fact that the overwhelming majority of medications are administered safely to tens of millions of Americans each day, he said. "Companies maintain large pharmacovigilance and epidemiology divisions whose sole responsibility is to monitor the safety of their drugs, and the resources required for this are not trivial," he said. Pharmaceutical companies are the stewards of their products and have liability concerns, so they have incentives for collecting safety information, he explained. Despite Goldhammer's assurances, most speakers made clear that there is widespread dissatisfaction both inside and outside FDA with the current drug safety system. Consequently, the I O M committee is likely to recommend sweeping changes, particularly related to postmarket drug surveillance. Public interest in the I O M meeting was high. At least one more public session will be held before the I O M report is issued next year. • C&EN
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