Don't put this organization on a pedestal they don't deserve.

By far not a prefect system, 75% of all drugs do not make it through trials.  Where are all the poor patients who took trials that got no benefit now? Wait... one right here! Me! I'm not saying all trials are bad but someone has to be the paitents that did not get helped.  How do you know that person will not be you?

FDA Drug Approval Process under Scrutiny

The U.S. Food and Drug Administration (FDA) is facing renewed criticism over the process by which it approves drugs for market. Recent reports indicate many drugs are approved before they are proven safe, and problems with the agency's structure and processes prevent it from fulfilling its mission. Subsequently, Congress has started using its oversight powers to scrutinize the agency, and the clamor for FDA reform is growing louder.

The Federal Food Drug and Cosmetic Act requires FDA to ensure the safety of new drugs before the agency approves the drugs for market. However, operating within a provision of the law, FDA often approves drugs before safety is established. The agency then requires drug manufacturers to further study drugs while they are on the market. These "post-marketing commitments" serve to streamline the drug approval process.

FDA recently revealed that many of the post-marketing commitments go unfulfilled. On Feb. 2, the agency published a report in the Federal Register detailing the progress of post-marketing commitments, which in Fiscal Year 2006 numbered 1,259. As The NewStandard reported, FDA said drug companies "had yet to initiate 71 percent of outstanding 'post-market' safety evaluations." Meanwhile, only 11 percent have been submitted. These drugs remain on the market, yet neither FDA nor drug makers have proved their safety.

Congress also recently expressed concern over the FDA drug approval process. On Feb. 13, the House Committee on Energy and Commerce's Subcommittee on Oversight and Investigation held a hearing titled "The Adequacy of FDA Efforts to Assure the Safety of the Drug Supply." The hearing occurred in response to recent regulatory failures that allowed dangerous drugs on the market, such as the highly publicized Vioxx incident.

Hearing witnesses testified that the FDA drug approval process is subject to industry influence and that agency managers sacrifice sound science in the name of expeditious approval. Ann Marie Cisneros, a clinical researcher, accused the pharmaceutical company Aventis of being complicit in a fraudulent clinical research project which Aventis had sponsored.

The testimony of Dr. David B. Ross, a physician and former FDA pharmaceutical reviewer, told the story of the antibiotic Ketek. Dr. Ross claimed Ketek was approved despite persistent warnings of its danger: "FDA managers were so bent on approving Ketek that they suppressed evidence of fraud and pressured reviewers - including myself - to change their reviews."

The criticism leveled at FDA is not new. The Government Accountability Office (GAO), the investigative arm of Congress, issued a report in March 2006 identifying significant gaps in FDA's ability to monitor and regulate post-market drugs. The GAO report mentioned organizational structure, insufficient oversight and poor data availability as some of the major problems facing FDA. GAO recommended Congress expand FDA's regulatory authority for post-market drugs.

In September 2006, the National Academy of Sciences Institute of Medicine also identified problems at FDA. Most notably, "FDA and the pharmaceutical industry do not consistently demonstrate accountability and transparency to the public by communicating safety concerns in a timely and effective fashion."

The mounting evidence in the case for FDA reform increases the likelihood of congressional action. Congress will likely take up the renewal of the Prescription Drug User Fee Act (PDUFA), which is set to expire this year. The legislation gives FDA the authority to require drug manufacturers to pay fees that the agency then uses to conduct drug reviews. In his proposed FY 08 budget released in early February, President George W. Bush called for new industry fees to further finance FDA. User fees from regulated companies would account for 21.3 percent of FDA's budget and pay for nearly 60 percent of reviews, according to USA Today.

FDA critics are skeptical of the industry-paid user fees. In the House hearing, Dr. Steven E. Nissen, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic Foundation, chastised PDUFA: "We started down the wrong pathway when we said that the regulated industry was going to pay the FDA to regulate itself."

In addition to PDUFA reauthorization, two Senate bills aim to enact reforms within FDA. A bill introduced by Sens. Charles Grassley (R-IA) and Christopher Dodd (D-CT) would separate FDA's drug safety office from its drug approval office, thus elevating FDA reviewers to the same status as managers who approve drugs, according to Congressional Quarterly (subscription). In an attempt to improve post-market regulation, a bill introduced by Sens. Edward Kennedy (D-MA) and Michael Enzi (R-WY) would focus more on the drug safety processes as they are currently used. Both bills are currently in committee.

It is unclear whether the drug approval process at FDA will be subject to reform. However, with the safety of many post-market drugs unknown, the issue is unlikely to go away. In his testimony, Ross chided his former employer: "Overall, there is a culture of approval [at FDA.]" He indicated that approval, not safety, is the top priority, adding, "If you can get a product on the market...then you find some way of doing it."

Report faults FDA oversight of drug trials

Fri Sep 28, 2007 12:13pm EDT

WASHINGTON (Reuters) - A report to be released on Friday finds the U.S. Food and Drug Administration does very little to ensure the safety of patients who help test drugs in clinical trials, The New York Times reports.

It quotes Daniel Levinson, the inspector general of the Department of Health and Human Services, as saying FDA officials do not know how many clinical trials are being conducted and have audited fewer than 1 percent of the testing sites.

FDA inspectors often show up long after the tests have been completed, the Times quotes the report as saying.

HHS is the parent department of the FDA, which, among other duties, approves new drugs. Clinical trials -- those involving real human patients -- are a key part of this approval process.

But the FDA has been accused of lax oversight of drug trials in general. The agency has said it lacks the resources to do the job properly.

It has 200 inspectors who are responsible for 350,000 testing sites, the Times said.

The report found that top drug officials in Washington downgraded negative findings from these inspectors 68 percent of the time.

The FDA disqualified researchers from conducting further clinical trials 26 times from 2000 to 2005 and disqualified their data twice, although it found serious problems at trial sites 348 times, the newspaper quotes the report as saying.

Levinson recommended that the agency create a registry of all continuing clinical trials.

President George W. Bush signed a measure into law on Thursday that will give the FDA more power and money to do this as part of better policing of reports of dangerous side effects from prescription drugs after they reach the market.

The legislation is largely a response to a string of drug safety controversies, including the 2004 withdrawal of Merck & Co Inc's widely used arthritis pill Vioxx after it was linked to heart attacks and strokes

Key Problems With the FDA

Problem: Pressure From the IndustryThere's pressure to speed decisions, and there's pressure to soft-pedal problems. That means drugs may go on the market without adequate vetting -- or follow-up. Critics of the FDA like to say it's the best agency the pharmaceutical industry can buy. That's a political jab, and agency advocates say it's unfair. "The extraordinary efforts of these committed staff members are the very reason further catastrophic food-and-drug events have been averted," an otherwise scathing review by the FDA's Science Board concluded last November.

But most agree that there's at least a problem of perception, and perhaps more than that, caused by the growing chunk of the agency's budget that comes directly from drug companies. Industry dollars now pay for more than half of the FDA's drug-review budget; in five years, that proportion is expected to jump to 70 percent.

Called user fees, this $400 million a year is designed to speed decisions on applications for new drugs. "User fees seem to save taxpayers money," says Susan Wood, PhD, the former assistant commissioner for women's health at the FDA and now a professor of public health at George Washington University. "But they undermine public confidence in the FDA's independence and impose time pressures that could end up costing lives."

Faster approval of drugs, of course, is a very good thing if you need a lifesaving medicine. Many patients are clamoring for that speed. Review times have been cut from 27 months to less than a year. Vioxx was fast-tracked in just six months. But some argue that the pendulum has swung too far. "A lifesaving drug should be sped along," says Steven Nissen, MD, chair of the department of cardiovascular medicine at the Cleveland Clinic and a frequent advisor to the FDA. "But with user fees, we've pressed the accelerator on all drugs, and that's a mistake."

Here's the danger: "The easiest way to make those deadlines is not raise too many questions and just accept what the drug companies say about safety," says former FDA drug reviewer David Ross, MD. Too often, Dr. Ross says, reviewers tell their FDA supervisors that a drug doesn't work or has a major safety problem and "managers come up with contrived reasons to approve the drug anyway." He says the standards of safety and efficacy have slipped to the point that the drug reviewers "can end up approving almost anything."

No one can say that moving drugs more quickly from the laboratory to the pharmacy always puts Americans at risk. But there is a smoking gun: an alarming spike in adverse drug reactions reported to the FDA recently, from 267,000 in 2000 to over 471,000 in 2006. And the number of reported deaths has nearly tripled, from 5,519 to 15,107. That's only part of the story: The agency estimates that it learns of fewer than one in ten drug reactions.

Janet Woodcock, MD, the FDA's deputy commissioner and chief medical officer, flatly denies that user fees and sped-up approvals compromise safety. "The FDA is legendarily tough -- our requirements are viewed as a really tough bar to get over."

"The review standards have not changed one bit since the introduction of user fees," says Alan Goldhammer, PhD, deputy vice president for the Pharmaceutical Research and Manufacturers of America, the drug industry lobby. "We've been careful never to compromise the independence of the FDA. Congress would not permit it."

Nevertheless, says Dr. Woodcock, "I understand that there's a perception problem."

What's Being Done
Congress slightly increased the FDA's drug safety budget last year but accomplished that mostly by boosting user fees once again. To help offset that influence, and enable the FDA to tackle all its other responsibilities, reformers say Americans should pay 3 cents a day to fund the agency, rather than the 1.5 cents we now pay. The agency's Science Board argues, "That's a great price to pay for the assurance that our food and drug supply is, indeed, the best and safest in the world."

Problem: Safety of New DrugsWhen the FDA approves a drug or medical device, staff scientists must, in effect, make a judgment call about its safety. They're relying on industry studies that usually follow between 600 and 3,000 people, often for just a few months. Those small clinical trials are designed to measure a drug's safety and effectiveness in a targeted group of patients -- not the dangers the drug might pose when it's taken by people with a wide variety of backgrounds and health conditions. "If it kills one in 2,000 people, or makes one go blind, you may not see that in the trial," says Drummond Rennie, MD, a deputy editor of The Journal of the American Medical Association (JAMA) and a professor of medicine at the University of California, San Francisco. "You start adding that up, and that's ten in 20,000 going blind, and that's a lot of people."

Those risks are revealed only after a medicine goes on sale and has been used for months or years by hundreds of thousands or even millions of people. Keeping track of those reactions is called post-market surveillance, and experts say it's one of the most important phases of drug testing. Historically, user fees were not allowed to go toward checking the safety of drugs once they were on the market. And until now, those follow-up reports haven't been mandatory. A 2006 report found that 65 percent of the studies that drug firms promised to conduct in recent years hadn't even begun.

What's Being Done
Congress authorized the FDA to spend $25 million from user fees this year to improve drug safety. But agency insiders say that's not nearly enough. "You've still got a mismatch," says Hubbard, who is now a senior advisor for the Alliance for a Stronger FDA, a group that includes seven former agency commissioners and three former Secretaries of Health and Human Services. "You still have all this effort going into getting the drugs on the market, and not much going into making sure they're safe once they're out there."

On that issue, Congress got tough last year. The FDA can now require companies to trace the long-term effects of their drugs. If firms renege, they face stiff fines, up to $10 million for repeat offenses.

Another crucial reform: Companies can no longer treat the results of clinical trials as trade secrets. Until this year, a manufacturer could cherry-pick what it revealed -- publishing a favorable study in a medical journal and sticking less rosy findings in a drawer. A report in the January New England Journal of Medicine revealed that one-third of antidepressant drug trials are not published, which can mislead doctors into thinking the drugs are more effective than they really are.

Here, too, Congress has drawn the line: Companies must post results of clinical trials on a public database, ClinicalTrials.gov, within one year of their completion. Independent experts should soon be able to evaluate the findings and better inform doctors and consumers about what the studies mean. Unfortunately, companies can wait three years to post summaries written for the general public.

That new measure of openness draws kudos from Dr. Woodcock, the FDA deputy commissioner. "People volunteered for those trials, and their lives may have been altered as a result," she says. "They deserve to know that their information has contributed to society." Having such full disclosure about a treatment or device is the only way to know what medical research means for all of us.

Problem: Sloppy Record KeepingFor an organization whose core function is gathering and analyzing crucial facts quickly, the FDA's partially computerized database "is like something that came off the ark," says Dr. FitzGerald, the Penn pharmacologist and agency advisor.

Companies are required to tell the FDA about any severe reactions they learn of, and do so within 15 days if the injuries are life-threatening. And the agency operates a website called MedWatch (http://www.fda.gov/medwatch/), where doctors (and patients) can download a form to report problems. But few physicians bother to use it. The result: Only a small fraction of adverse reactions get passed on. Even more important, the FDA doesn't have the time or money to make sense of the information it does receive.

The agency is notified of half a million problems each year, a third of them serious, says Dr. Woodcock. Most of those reports arrive via paper fax and have to be sorted by hand. More worrisome, the FDA's skeleton staff of 35 report analysts have only eight minutes to read even the most serious case, says Hubbard, who tracked such things as associate commissioner.

"We've never had enough resources to really do the job and hire the staff," says Dr. Woodcock, who has been at the FDA for two decades. "And it's not that we didn't try."

What's Being Done
Congress has responded, telling the agency to invest several million dollars to connect to large medical-records databases run by the Veterans Health Administration, Medicare and HMOs. Using these databases will allow the FDA to better track and analyze adverse drug side effects. That means the FDA will know much sooner if a newly marketed drug needs to be relabeled or pulled off the market, even whether one medication works better than another. And thanks to Congressional intervention, the agency will now be able to make label changes quickly, without prolonged negotiations with the drug companies.

Who's minding your food? Surprise! It depends At least 15 government agencies are responsible for safety inspections The Associated Press updated 9:41 a.m. ET, Tues., Feb. 24, 2009

WASHINGTON - So, a guy walks into a restaurant. Who makes sure his food is safe?

It depends on what he eats.

A cheese pizza that arrived at the restaurant frozen? The Food and Drug Administration is in charge of inspecting it.

A frozen pepperoni pizza? That's the Agriculture Department.

A fresh pizza, made at the restaurant? Both departments would be responsible for the original ingredients, if the pizza has meat on it. What if he eats eggs? It depends whether the eggs are inside the shell, in liquid form or have been processed. Fish? Some fish is inspected by the Commerce Department.

The FDA bears the brunt of food safety oversight, a mission called into question in the wake of a massive recall of peanut products. But at least 15 government agencies have a hand in making sure food is safe under at least 30 different laws, some of which date back to the early 1900s.

It's a convoluted system.

"There is no one person, no individual today who is responsible for food safety," said Rep. Rosa DeLauro, D-Conn. "We have an immediate crisis which requires a real restructuring."

DeLauro and Sen. Dick Durbin, D-Ill., have been proposing an overhaul of the nation's food safety structure for more than a decade. There might now be the political will to do something following the outbreak of salmonella traced to peanuts blamed for sickening 600 people and killing at least nine others.

‘Can't have two systems'
They may be making headway. President Barack Obama's new agriculture secretary, Tom Vilsack, said he supports creating a single, combined food safety agency. It's a major break from his predecessors.

"You can't have two systems and be able to reassure people you've got the job covered," Vilsack said.

Such a radical overhaul would be difficult. Many in the food industry have long opposed any changes, fearing increased oversight could cut into profits. Allies in Congress have resisted new laws.

But resistance appears to be softening, the result of high-profile outbreaks of foodborne illness from domestic and foreign food sources.

Industry is open to change, said Scott Faber, a top lobbyist for the Grocery Manufacturers Association, which represents large food and beverage companies.

"The food industry recognizes that we need to give FDA new powers and new resources to address new challenges," Faber said.

Businesses are concerned about reorganizing the entire system. The priority should be strengthening the current agencies before rearranging them, he said.

The old system is an overlapping patchwork of inspections. Both the Agriculture Department and the FDA inspect shipments of imported food at 18 U.S. ports of entry. Sometimes, the FDA stores products at Agriculture Department warehouses, where they wait to be inspected by the FDA because agriculture employees aren't allowed to inspect them.

The two agencies also differ on how frequently they inspect businesses. Meat inspectors visit processing facilities daily in most cases, while FDA inspects much less frequently.

Most manufacturers of prepackaged, open-faced meat sandwiches, for example, are inspected daily by the Agriculture Department. But add a second piece of bread to make it a traditional sandwich and the FDA takes over. That means inspections probably happen once every five years, according to a study by the Government Accountability Office.

The GAO, the investigative arm of Congress, recommended two years ago that Congress re-examine the system. It said 76 million people are sickened by foodborne illness each year and 5,000 die.

But few changes have been made. And despite the salmonella outbreak, even the lawmakers urging changes say a streamlined new agency is unlikely any time soon.

A flurry of food safety bills have been introduced in Congress. Many would strengthen FDA's oversight rather than creating a single lead agency. DeLauro's bill would not combine agencies onto one. It would divide the FDA in two, separating the agency's drug oversight and food safety duties.

"We have a crisis at the moment. Let's try to address that," DeLauro said.

U.S. Food and Drug Administration
FDA Consumer magazine
January-February 2002
Table of Contents

Why Drugs Get Pulled Off the Market By Michelle Meadows"But aren't drugs supposed to be safe?"According to Janet Woodcock, M.D., director of the Food and Drug Administration's Center for Drug Evaluation and Research (CDER), people tend to ask that question a lot when a drug is taken off the market. The FDA's mission is making sure that drugs are "safe and effective." So what does "safe" really mean?When it comes to any drug, "safe" means that the benefits of the drug outweigh the risks for the population the drug is intended to treat and for its intended use. "Safe does not mean harmless," Woodcock says. "Every drug comes with risks, and our tolerance for risk is higher for drugs that treat serious and life-threatening illnesses. There is no question that cancer drugs can be highly toxic. But they also save lives." (Flalady-There is no proof cancer saves lives. It can extend lives not cure cancer.)If the FDA decides that a drug's benefits outweigh its risks, the agency approves the drug for marketing. Approved drugs continue to be evaluated through postmarketing surveillance--a system that monitors a drug's safety on an ongoing basis. Postmarketing surveillance seeks to identify problems that weren't observed or recognized before approval and any problems that might arise because a product isn't being used as anticipated. (flalady -hurt how many people for how long?)The goal is to catch any bad news right away so that the FDA and drug companies can act quickly and communicate new risk information to consumers and doctors. CDER evaluates required reports from drug companies, which must promptly pass on any report they receive of a serious adverse reaction that isn't already described in the drug's labeling. CDER also relies on MedWatch, the system through which consumers and health professionals voluntarily report adverse events associated with all products the FDA regulates.When the FDA receives reports of significant new adverse events, the agency evaluates them for their seriousness and the likelihood that they were caused by the drug. To the extent possible, the agency also considers how the toxicity compares with other treatments for the same disease. Ultimately, of course, the critical question is: Do the benefits of this drug still outweigh its risks for the population described in the labeling? In many cases, that question cannot be answered immediately, and more reports must be considered. Sometimes, the impact of labeling revisions needs to be assessed. (Flalady-this could take years to get if off the market!)Usually, when important new risks are uncovered, the risks are added to the drug's labeling and doctors are informed of the new information through letters and other education. It's only rarely that the approval decision on a drug needs to be reassessed and changed. A conclusion that a drug should no longer be marketed is based on the nature and frequency of the adverse effect and how the drug compares with treatment alternatives.When the FDA believes it is clear that a drug no longer has a place in treatment, it will ask the manufacturer to withdraw the drug voluntarily.(See "Safety-Based Drug Withdrawals (1997 - 2001).") Companies have agreed to withdraw the drug in all cases except one--the case of an antidiabetic drug called phenformin, which was taken off the market in 1976 as an imminent hazard, despite the company's objections. If a company does not agree, the FDA can bring formal procedures to require withdrawal. (flalady-the drug manufacturer must VOLUNTARILY pull the product and what loose millions?)At first glance, one might assume that every time a drug comes off the market, it means that somewhere along the way somebody made a horrible mistake--that the drug never should have been on the market in the first place. But FDA experts say that would not be correct. Most often, the withdrawal occurs because of adverse effects that were not seen prior to marketing. Sometimes, there was no clue at all. In other cases, one can see hints of the problem in retrospect, but not the serious events that eventually led to the withdrawal.Many complex factors go into making judgments about benefits and risks, and into ultimately deciding whether a drug should be taken off the market. Here are some major issues, often overlapping, that weigh into the decision-making process. Rare, Unpredictable Problems Most drugs on the market are well-tolerated and their adverse effects are known. Known side effects cause more injuries and deaths than unrecognized side effects. But some problems happen so infrequently that they can't be seen or predicted before a drug gets on the market. Serious drug-induced liver disease, for example, is the leading single reason drugs have been pulled from the market. But it is rare, occurring at a rate of 1 in 5,000 to 1 in 10,000 exposures or less. This will not show up in clinical trials, which will pick up relatively common problems."If we want reasonably rapid access to needed drugs, it's not practical to require that they be tested in 15,000 to 30,000 people, which is what you'd need to be reasonably sure you saw even one case that occurs at a rate of 1 in 5,000 to 10,000," according to Robert Temple, M.D., director of the FDA's office of medical policy. "And the case would need to be recognized as drug induced," he says. So drugs are typically tested in several thousand subjects, allowing detection of relatively common serious adverse events, such as those affecting 1 in 1,000 people. This practical size of clinical trials means we can't know everything about a drug when it gets on the market. Rare events will only surface when the drug is used in larger numbers of people. Temple says, "Sometimes less severe events that are seen in trials can be used to predict the occurrence of rare, more serious events, but that is not always the case, and such predictions have considerable uncertainty."The number of subjects in clinical trials is increasing in some areas of drug development, says Peter Honig, M.D., director of the FDA's office of drug safety. "But the numbers will never be large enough to eliminate the need for postmarketing surveillance." The FDA is working on ways to better predict rare events, especially those related to the liver and heart. But some uncertainties will always be there, including the possibility of rare characteristics that make some people particularly susceptible to an adverse reaction. More Toxic than Expected There are also times when a drug's toxicity is known, but the drug turns out to be more toxic than the clinical trials suggested, which again may only be seen when the drug is used in larger numbers or in different ways.Initially approved in 1997, Baycol (cerivastatin) was a member of a class of cholesterol lowering drugs known as "statins." Baycol and the other five drugs in its class--Lipitor (atorvastatin), Lescol (fluvastatin), Mevacor (lovastatin), Pravachol (pravastatin), and Zocor (simvastatin)--have all been associated with rare reports of rhabdomyolysis, a condition that causes marked breakdown of muscle cells and can sometimes lead to fatal kidney failure and other problems.Knowing this about the statin drugs, the FDA made sure to look for the problem when deciding to approve Baycol. But the agency didn't find unusual risk associated with the drug at that time. "In its first few years, Baycol had a small market share," says Sandra Kweder, M.D., acting director of the FDA's office of review management. "But when FDA approved a higher dose of the drug after initial marketing, use of the drug grew and we could see clearly that Baycol caused the problem more frequently than the other drugs in its class." Problems with Baycol were reported most frequently when it was used at higher doses, when used in elderly patients, and particularly, when used with another lipid-lowering drug called Lopid (gemfibrozil). Baycol was voluntarily withdrawn in the summer of 2001. When Safer Options Are Available When the FDA approved Seldane (terfenadine) in 1985, the drug became the first prescription antihistamine to relieve allergies without causing drowsiness--a side effect that can cause accidents and injuries. A few years after approval, it was discovered that Seldane could cause fatal heart rhythm irregularities when it was used together with drugs that slowed its elimination from the body, or in patients with liver disease.Major efforts to warn against use in such patients were partly successful, but fatal rhythm abnormalities continued to be reported. According to Temple, removal of the drug was considered, but that would have left only one non-sedating antihistamine, so Seldane remained available."But the equation shifted when Allegra came on the market in 1997," Temple says. "Allegra provided exactly the same benefits of terfenadine but without the risk of the potentially fatal heart condition." So the new availability of Allegra (fexofenadine) weighed heavily in the decision to withdraw Seldane. Dangerous Combinations Like Seldane, a heart drug called Posicor (mibefradil) posed problems mainly when used with other drugs. Although Posicor itself did not have unusual toxicity, it was taken off the market in 1998 because of its interactions with at least 25 drugs. It markedly increased the blood levels of those drugs, leading to potentially fatal side effects of the other medications.When Posicor was first marketed in 1997, its labeling warned of possible interactions with three drugs. Two more drugs were later added, but reports of interactions and resulting adverse reactions with even more drugs kept coming. There was concern over whether it was realistic to expect physicians to be able to use Posicor safely, given the many drugs it interacted with. In the absence of any special benefit of Posicor compared to other members of its class, such as effectiveness in people who don't respond to other treatments, the FDA concluded that the drug should be removed from the market.When taken at a higher than recommended dose and when taken with other drugs, Hismanal (astemizole), another non-sedating antihistamine approved in 1988, posed risks similar to Seldane. The drug was withdrawn in 1999, as safer alternatives became available.Beginning about 1990, many potentially harmful interactions between drugs and even between drugs and foods (such as grapefruit juice) were noted with Seldane and other drugs. The discovery led to greater attention by the FDA and drug manufacturers to such interactions before drugs are marketed, Temple says. This represents a significant enhancement of safety assessment. Improper Use The term "safe" also depends on whether a drug is used according to the labeling. This is why the FDA makes sure labeling and advertising for prescription drugs are accurate and balanced--presenting both the benefits and the risks.The major problem with Duract (bromfenac), a nonsteroidal anti-inflammatory drug, was that the directions were not followed. The pain drug was withdrawn in 1998 after liver failure occurred in patients who took the short-term treatment for pain for more than the 10 days recommended in the labeling. Clinical trials indicated that a higher incidence of elevated liver enzymes was associated with longer use. Duract's manufacturer, Wyeth-Ayerst Laboratories, Philadephia, added a new warning (Continued from page 14) to the labeling and sent letters out to doctors, but reports of long-term use of the drug continued. When Other Risk Management Options Fail The day you hear news about a drug coming off the market, it may appear to be a sudden, drastic step. But several other options to manage risks usually have been attempted before that point. The main risk management tools employed by the FDA are education through letters to health-care professionals (known within the FDA as "Dear Doctor" letters) and labeling changes, such as new warnings, sometimes boxed in black for emphasis. Also used are required Medication Guides, labeling specifically for patients that emphasizes significant risks and advises patients how to detect or avoid them. In some cases, a drug is labeled as "second line," meaning it is to be used only in patients for whom other treatments fail. In other cases, a drug that is known to be dangerous is still made available under certain circumstances through what's known as restricted distribution (see box).Sometimes these risk management techniques are effective, and other times they aren't. "We have our anecdotes, but there is little systematic study on the effect of drug labeling changes on physician behavior," says Temple.Labeling changes were a partial success with the allergy drug Seldane. Studies showed use of Seldane with inappropriate drugs declined almost 90 percent, but that left considerable exposure to the dangerous combinations, some of which could be lethal.The label of the heartburn treatment Propulsid (cisapride) was changed several times in 1998. The FDA cosponsored a study to evaluate the effect of various regulatory actions, and found that the percentage of patients inappropriately exposed to the drug was unchanged."We know that the farther out we are from the initial approval, the less likely we are to change behavior," Woodcock says. "Once a prescribing pattern has been established, it's hard to change it."Clearly, the more special care that is required, the more physicians must remember, and the more we need other safeguards like spotting dangerous combination uses at the pharmacy level, the more of a challenge risk management becomes. "We do consider whether we are being unreasonable in our expectations, but sometimes that can't be known beforehand," Temple says.Currently, the FDA is involved with several drug safety initiatives, including revamping the drug labeling for physicians to create a highlights section, a relatively short section that will describe the most critical information. Better education is a high priority. "We're looking into better ways to educate the public and doctors about changes in risk information, and to get information out faster," says Honig.But FDA experts say the agency can't do it alone. The FDA judges drug risks for a population, doctors judge risks for individual patients, and patients judge the risks they'll take based on personal values. Ultimately, drug safety requires involvement of all parts of the health system.