American College of Physicians: Internal Medicine — Doctors for Adults ®


Drug-safety issues spur debate over monitoring

Physicians and policy-makers consider how new medications should be watched

From the March ACP Observer, copyright 2005 by the American College of Physicians.

By Gina Shaw

Over the past year, several drugs found in many American medicine cabinets have come under new scrutiny because of risky side-effect profiles. Those profiles have prompted a heated discussion of how U.S. health officials track drug safety—particularly when new drugs now receive faster approval and can reach many more patients through direct-to-consumer marketing.

Policymakers now are debating several possible reforms to boost drug safety monitoring. In January, for instance, legislation was introduced in the Senate that, if passed, would establish a new office of patient protection within the Food and Drug Administration (FDA). That office would be charged with more stringent post-marketing drug surveillance. Other proposals would create an independent drug safety office separate from the FDA and its drug approval process. Experts on both sides of the debate agree that drug safety issues do not end with FDA approval.

"Drug development programs can't possibly identify the risks that will be seen in practice, because the patient populations aren't the same," said Lee S. Simon, FACP, an associate clinical professor of medicine at Harvard Medical School who formerly oversaw pain drug evaluations at the FDA.

"What's more, most drug trials don't have more than 2,500 patients exposed to a particular drug—and it's only at and above 3,000 patients that you can begin to understand risk rates below 0.1%," he said. Only in the post-approval realm, he added, can physicians get to know drugs' effects on patients who have comorbidities or who take other medications. "And that takes time."

That leaves physicians asking: How should doctors make decisions about prescribing newer drugs, and where should they go for evidence-based reviews? (Also see "Drug safety: where to go to get the facts.")

Improving the system

Last fall, the FDA announced plans to bolster its drug safety monitoring program. It is sponsoring an Institute of Medicine report on drug safety that will include recommendations on how to monitor drug side effects more effectively. The report will take at least two years to complete.

The FDA has also established a pilot program to air differing opinions about drug safety and effectiveness within its own Center for Drug Evaluation and Research; that program will include external reviewers. And at press time, the FDA had begun convening advisory group meetings to examine risk management issues related to specific drug classes.

According to a study published in the May 1, 2002, Journal of the American Medical Association, more than 10% of new FDA-approved drugs have serious side effects that go undiscovered during initial testing and marketing. Of 548 new drugs approved between 1975 and 1999, for instance, 56 either acquired a "black box" warning or were withdrawn from the market.

But even those numbers might not tell the whole story, said the FDA's Sandra L. Kweder, ACP Member, deputy director of the Office of New Drugs within the Center for Drug Evaluation and Research.

"In the late 1980s and early 1990s, there was a huge increase in the number of applications for drugs to treat some of the most serious and life-threatening conditions," she said. "In a time like that, you're probably going to see more drugs that have inherently greater risk coming to market, because you're balancing that greater risk against a greater benefit in treating very grave diseases."

When it comes to post-marketing surveillance, the FDA's MedWatch system already receives mandatory adverse event reports from pharmaceutical companies, as well as voluntary reports from providers and patients. Physicians and consumers can report adverse drug effects to MedWatch, either online or by calling 800-332-1088.

Last year, MedWatch received 21,000 voluntary reports from physicians and consumers—about the same number the system has received since it began in 1993. But the lion's share of the 400,000 annual adverse event reports that MedWatch received last year—some 95%—was mandated submissions from the drug companies themselves. (The number of those reports has been rising by about 10%-15% each year.) According to Dr. Kweder, the MedWatch program has seen marked improvement in the quality of the reports it receives—a key factor in improved surveillance.

She also said that it is fair to consider whether the current reporting system by itself is robust enough to appropriately monitor drug safety. The system was, after all, originally designed several decades ago, when drugs were launched and prescribed in very different ways.

"Doctors used to be much more cautious about prescribing new drugs," Dr. Kweder said. "Utilization curves used to be very slow to rise, and it took two or three years for the use of a new drug to increase much." If you look at new products today, she added, you see a very different pattern. "Within months of being launched, their use skyrockets."

With such rapid adoption, is the current system powerful enough to track side effects? "For something that's very rare, it probably is, because these cases stand out," she said. "The hard part is where adverse events might themselves be common conditions, like heart attacks in older people who have arthritis. We need to consider new tools like active surveillance methods and better utilization of managed care databases to help us detect trends in large, stable populations."

The pharmaceutical industry is working with the FDA to consider routes to more robust surveillance, said Alan Goldhammer, PhD, associate vice president for regulatory affairs with the Pharmaceutical Researchers and Manufacturers Association (PhRMA), a trade group.

"Just recently, the FDA and representatives from PhRMA member companies convened a workgroup that prepared a report on how to use data-mining techniques to take advantage of large databases, like the FDA reporting system," Dr. Goldhammer said. At the same time, PhRMA members are awaiting the release of new FDA guidance on pharmacovigilance and risk management. "We want to make sure we can detect signals about adverse events early, analyze them and validate them," he said.

However, it remains to be seen whether more stringent surveillance would remain part of the FDA. Some experts, including Eric B. Larson, FACP, Chair of the College's Board of Regents and director of the Center for Health Studies at Seattle's Group Health Cooperative, think an independent drug safety office is the better way to go.

"Post-marketing surveillance and safety shouldn't be coupled with the current drug approval process," said Dr. Larson. Otherwise, he pointed out, the same agency responsible for approving a drug's licensing and labeling is put in the awkward position of having to actively look for evidence that it made a mistake. "That means," he said, " they have to prove themselves wrong."

But for Harvard's Dr. Simon, creating a much more powerful group within the FDA makes more sense. "You can't separate safety surveillance from efficacy," he said. "If you aren't studying relative benefit as well as relative risk, then you have no balance. You can't understand the risks of a drug without studying them in the context of benefits."

A conservative approach

Where does this leave physicians when it comes to prescribing new therapeutics? In some cases, physicians say they have good reasons for adopting a new drug quickly.

"With a medication that's a new revelation, that's going to make a major impact on medical care because there's nothing else like it, I'm likely to be an earlier user," said David W. Potts, FACP, an infectious disease specialist in Townville, S.C. With such a drug—like a new antiretroviral that might work for AIDS patients who are resistant to other medications—Dr. Potts said he tells patients what is and isn't known about it, and then "keeps an eye out for the unexpected."

The same holds true for physicians treating patients with advanced disease. "If we're dealing with a curable malignancy, oncologists will still use a standard-of-care drug that has been out for awhile, unless it's in the context of a clinical trial," said Tanya L. Repka, FACP, an oncologist in Duluth, Minn., and former Governor for the Minnesota Chapter. "For patients with advanced disease on their second, third or fourth-line chemotherapy, we're willing to try a number of different things to help them live better and longer."

But like prudent purchasers who wait a year or two to see what kinks show up in a new model car, many internists say they're in no rush to prescribe the latest medication, particularly if it is newly added to an established drug class.

"There really are very few breakthroughs that a physician needs to adopt quickly," Dr. Larson said. "I tend to be a late adopter, especially when the drug is simply a variant on an existing class of drugs that is already pretty good. If a medication is working well for a person, I don't feel obligated to change to the next new drug."

When it comes to prescribing, Dr. Larson said he continues to follow a principle he learned in medical school: " 'Don't feel like you need to know all the drugs of a class, but learn one or two—and learn them well,' " he said. "In your reading and in your surveillance, pay attention to those particular drugs."

Physicians have, however, complained for several years that it's getting harder to hold that cautious line. For one, media coverage of newly approved drugs is often medically incomplete, if not downright inaccurate.

And drug-company spending on direct-to-consumer advertising has more than tripled between 1997 and 2003, when it hit $3.3 billion, according to Connecticut-based pharmaceutical and health care consultant IMS Health. Many physicians think that kind of promotional muscle drives inappropriate patient demand. A study published in the Jan. 25, 2005, Archives of Internal Medicine, for instance, found that close to 75% of patients prescribed COX-2 inhibitors were in fact at low risk for gastrointestinal problems.

According to some physicians, the current high visibility of drug safety concerns might make it easier to convince patients to take a more conservative approach to new drugs. At the same time, some doctors say that headlines may be scaring some patients away from drugs they need.

"I have a neighbor, a very intelligent person, who's now reluctant to take any prescription medication because he's afraid of the side effects," said South Carolina's Dr. Potts. "So he's not getting the care he needs to treat his high cholesterol and blood pressure."

Evidence-based reviews

To better track drug safety, as well as efficacy and cost, large health systems are creating their own review programs. The pharmacy and therapeutics committee of Seattle's Group Health, for instance, conducts an evidence-based review of any new drug proposed for its formulary—and makes that information available to its network physicians.

Boston-based Partners HealthCare recently formed a system-wide outpatient drug committee to examine and classify new drugs. Partners is also starting work on a single, network-wide system for reporting adverse drug events.

"We want it to be electronic, convenient and easy to analyze, as well as accessible across all of Partners HealthCare," said Thomas H. Lee, FACP, president of the Partners system. Implementation, he said, is one or two years off. "Then we can pool data from across hospitals."

The Agency for Healthcare Research and Quality also plans to begin drug reviews for effectiveness and risk. Last December, the agency announced a new $15 million initiative to review interventions—including prescription drugs—for the top 10 conditions found among Medicare beneficiaries, including stroke, arthritis, pneumonia, diabetes and ulcers. The review should be completed by mid-2006.

And since 2001, the Oregon Evidence-based Practice Center at Oregon Health & Science University in Portland has conducted drug-class reviews. Its drug effectiveness review project now has posted assessments of 21 drug classes, from ACE inhibitors to urinary incontinence drugs, on its Web site; it expects to review another four. About a dozen state Medicaid programs, including those of Oregon, Washington and Idaho, as well as employee benefits groups, subscribe to the center's services, but its final reports are free.

"We want these reports to address questions that clinicians would care about, not questions tailored to what the literature happens to have studied," says Mark Helfand, ACP Member, the center's director. He notes that reports cover safety as well as efficacy.

"Our goal," he said, "is to define the strengths and limitations of the evidence for people making decisions about these drugs."

Gina Shaw is a freelance health care writer based in Montclair, N.J.


Drug safety: where to go to get the facts

What's the best way to learn more about the potential risks of a newly approved therapy?

Start with something simple, experts say: the label. That might sound obvious, said Lee S. Simon, FACP, an associate clinical professor of medicine at Harvard Medical School and a former official with the Food and Drug Administration (FDA). But in practice, he finds that many doctors don't bother to read new drug labels, even though it's the one place where they can find adjudicated information as well as warnings, precautions and safety signals.

"I lectured at a New York specialty hospital on risk management and post-marketing vigilance, and out of 35 people in the audience, eight raised their hand when I asked if they read new drug labels," he said. "At a national pain forum with 1,000 attendees, I asked the same question, and there couldn't have been more than 50 hands raised."

Beyond reading labels, monitoring journals and networking with colleagues, physicians can tap into other drug information sources. Here are a few that physicians recommend:

  • The Medical Letter. This independent, peer-reviewed, advertising-free newsletter offers critical evaluations of virtually all new agents, as well as reviews of older drugs when new information becomes available. "It's a very good source for unbiased information about new therapies," Dr. Simon said. Subscriptions cost $76 a year for print only or $89 for print, online and Palm OS handheld editions. You can subscribe online or by calling 800-211-2769.

  • The Prescriber's Letter. Edited by pharmacists, this is another independent, non-advertising supported newsletter. The monthly publication is augmented with more in-depth "Detail Documents" available 24 hours a day. Arthur D. Silk, FACP, an internist in Garden Grove, Calif., said he likes its broad approach and the "rumor vs. truth" section.

    "They do discuss rumors of dangers, he said, "and they have Web links to more detailed information." The Prescriber's Letter also issues supplemental materials, like patient education handouts about drugs in the news. A subscription costs $88 for print, online, and Palm or PocketPC handheld access. Subscribe online or call 209-472-2240.

  • Drugs@FDA. This section of the FDA's Web site is particularly helpful to physicians who want more detailed information about the trials leading up to a drug's approval, said Mark Helfand, ACP Member, director of the Oregon Evidence-based Practice Center at Oregon Health and Science University. Choose a drug, select "approval history and related documents," and you will often find a "Review" section that contains statistical, pharmacological and medical reviews.

  • "Worst Pills, Best Pills." A Web site and annual guide written by Public Citizen's Health Research Group, Worst Pills is "a bit iconoclastic and confrontational," said subscriber Eric B. Larson, FACP, a Seattle internist and Chair of the College's Board of Regents. "But they are looking out for problems caused by drugs, and that's something doctors can learn from." The site advises physicians to wait seven years before prescribing new drugs that are not true breakthroughs.

  • The Wall Street Journal. According to Dr. Silk: "They tend to get their medical articles right, more often than the rest of the mainstream media, and they expand on them. I find it quite a good source of medical information."

  • While this medical information Web site gets advertising support, it offers free access as well as useful reviews like the "New Drugs of the Year" series, taken from the Journal of the American Pharmacists Association. Dr. Simon said he also recommends its "ask the experts" series for questions on specific drugs.


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