Drug Safety System Sharply Criticized

The Food & Drug Administration's program for ensuring drug safety has serious structural and regulatory shortcomings, according to many speakers at the Institute of Medicine'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 FDA's purview that compromise drug safety.

An IOM 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 actually fill their prescriptions.

The IOM study was prompted in part by the high-profile withdrawals of the best-selling 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 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 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 promises by the drugmakers to perform additional safety studies after the medications are placed on the market.

But one drawback to this faster approval scheme, Woodcock said, is that, 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 advertising. Despite these factors, she said, the drug withdrawal rate has remained steady, while the speed at which they are withdrawn has increased.

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, "we do not have a detailed understanding of who 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 effects from a drug and subgroups most likely to benefit from the drug would improve safety, she said. "Currently, no entity--government or otherwise--is charged with evaluating the comparative safety of drugs and the long-term outcomes of therapy."

Steven Galson, acting director of FDA's Center for Drug Evaluation & Research, noted that the agency made several changes recently to improve its drug safety system. One change set up a program for adjudicating differences in opinions about pharmaceuticals among FDA professionals. Another established a quasi-independent drug safety oversight board.

FDA is responsible for only part of the drug safety system, Galson pointed out. "It regulates companies, but states are primarily 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 IOM 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 conduct studies when problems first arise and heavily fine those companies that fail to comply, he said. "This IOM study is important, but we shouldn't wait months or possibly years for a study when we can fix known problems now."

Currently, according to an FDA report published Feb. 18 in the Federal Register, drug companies benefiting from FDA's accelerated approval process have not conducted the postmarketing studies requested by the agency on a timely basis, Vaughan said. "Sixty-eight percent of the postmarket approval safety studies that companies promised to conduct had not even been started. The drug industry sees FDA as a paper tiger. FDA needs the authority to require these studies and impose penalties that will get some action on the backlog."

ONE THING FDA should do is strengthen its Office of Drug Safety, Vaughan said. "We need a drug safety board that is not necessarily outside FDA but that gets respect." The current Office of Drug Safety has about 100 employees and a budget of only $30 million. Last year, it had to review about 473,000 adverse drug reaction reports.

IOM should also consider the issue of how to communicate with patients about drugs, Vaughan said. "So many people are baffled by the warnings issued about drugs," he said. One way to provide greater clarification of drug safety would be to require comparative trials, he explained. Drugmakers should be required to compare a new drug not only with a placebo, but also with existing treatments for the same condition, he said. "Patients and health care providers would benefit from knowing whether a new drug is both safer and more effective than older drugs for that condition."

In many cases, even when accurate information about a drug is known, the drug is still misused, said John A. Gans, chief executive officer of the American Pharmacists Association. "The vast majority of drugs are put in the hands of patients, and they make drugs work or not work," he said. "The reality is that self-care is important," he said. The inhaler used incorrectly, for example, will not work. This means that the health care community needs to partner with patients much more carefully to ensure that drugs and devices are used properly, Gans explained. "We hear information that 50% of prescriptions are not filled. That is an outrage."

Information also takes a long time to disseminate among physicians, Gans said. For example, "We learned early on that ACE [angiotensin-converting enzyme] inhibitors help diabetics, but it took 17 years for this information to be incorporated into standard practice."

The highly publicized withdrawals of Vioxx and Bextra have eroded public confidence in drug safety, said David Borenstein, a member of the board of directors of the American College of Rheumatology. "We need an improved system for postmarket surveillance of pharmaceuticals. 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 efforts 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 IOM committee is likely to recommend sweeping changes, particularly related to postmarket drug surveillance. Public interest in the IOM meeting was high. At least one more public session will be held before the IOM report is issued next year.