Can Americans Trust Their Medicine

Can Americans trust their medicine? Dic. 20, 2004

1 hour, 13 minutes ago

By Rita Rubin, USA TODAY

For Susan Ferris, the drug Celebrex has been "a godsend." The 48-year-old South Florida woman has been taking it for her arthritis pain since 2001. She can't tolerate older remedies, such as aspirin or ibuprofen. Since Friday's announcement that Celebrex might be linked to heart attacks and strokes, though, she's not sure what to think. (Story: Some answers for users of Celebrex)

On top of that, she worries about her 58-year-old husband, who has a history of high blood pressure and once had a small stroke. For his arthritis pain, he has taken Celebrex, as well as its cousins Vioxx and Bextra.

Vioxx was pulled from the market Sept. 30 because it increased patients' risk of heart attack and stroke. Bextra's label now bears a new warning against its use in patients who have had heart bypass surgery.

Like the Ferrises, many Americans can't help but wonder whether the doors to their medicine cabinets should carry "proceed with caution" signs. The Food and Drug Administration (news - web sites) has been under attack for its handling of drugs such as Vioxx and suppressing evidence that antidepressants might increase suicidal thoughts in children.

Critics believe the FDA (news - web sites)'s system of regulating drugs is broken. They say the agency approves drugs without thoroughly vetting their safety profile and then fails to keep tabs on unexpected side effects that crop up once a product hits the market.

"Studies are specifically designed to determine whether a drug works," David Kessler, who served as FDA commissioner from 1990 to 1997, said Sunday. "The FDA rarely requires a study specifically designed to answer safety questions."

Another complaint is that the FDA, pressured to get lifesaving drugs to consumers more quickly, rushes drugs to markets. But patients with sore joints - and other medication choices - shouldn't have to tolerate the same level of risk from their pain reliever as, say, cancer patients do with lifesaving chemotherapy drugs, Kessler says.

Sen. Chuck Grassley, R-Iowa, is calling for an independent commission to come up with steps the president and Congress could take to improve drug safety. But President Bush (news - web sites)'s chief of staff, Andrew Card, questioned the need for such a commission on ABC's This Week.

"I support the FDA," Card said. "They do a spectacular job." Deciding whether new drugs should come on the market is "an awesome responsibility," he said. "And (acting FDA Commissioner) Les Crawford is doing a very good job meeting that responsibility."

In response to Card's comments, Sen. Edward Kennedy (news, bio, voting record), D-Mass., attacked the Bush administration Sunday, saying "its record on protecting us from harmful prescription drugs is a catastrophic failure. We need an FDA that looks out for the health of patients and not just the health of the pharmaceutical industry." He said early congressional action on bipartisan reforms is possible.

1 A CNN/USA TODAY/Gallup Poll in November showed that 70% of Americans remain confident in the FDA's ability to ensure prescription drugs are safe, but 37% said their confidence had decreased.

On Friday alone, the FDA and the manufacturers of three disparate drugs announced the discovery of serious problems:

• Pfizer revealed that the National Cancer Institute (news - web sites) had stopped the treatment phase of a trial of Celebrex, its blockbuster arthritis drug taken by more than 27 million U.S. patients since it came on the market in 1998. The study, designed to see whether Celebrex protected against the recurrence of colon polyps, found that participants given the drug were at least 2½ times more likely to have heart attacks or strokes than those who were given a placebo. Pfizer's stock fell just over 11% on the news.

Though the company says it has no plans to pull the drug off the market, it has suspended all direct-to-consumer advertising, spokeswoman Mariann Caprino said Sunday. "We basically want to ensure that time is taken to assess all the new information and understand what it means," Caprino said.

• Eli Lilly said it has added a warning in bold black type to the label for Strattera, used to treat attention deficit/hyperactivity disorder (ADHD) in more than 2 million patients since it was approved in 2002. The warning, based on two reported cases of severe liver injury in patients who took Strattera, states that patients with jaundice or laboratory evidence of liver injury should stop using the drug. Lilly's stock fell about 2½%.

• AstraZeneca informed doctors that a study of Iressa, used to treat recurrences of the most common type of lung cancer, found that the drug did not prolong patients' survival when compared with a placebo. The company said it would stop marketing the drug, which the FDA approved in May 2003. AstraZeneca's stock fell about 7&frac• three• quarters;%.

Major overhaul suggested

Consumers practically need a scorecard to keep up with all the recent revelations about prescription drugs. Some members of Congress, leading scientists and a key FDA insider say these developments point out the need for a major overhaul of how the FDA monitors medications once they come on the market.

"We are essentially no better off than we were in the days of snake-oil salesmen," FDA whistleblower David Graham said in an interview Sunday.

Already, those familiar with the FDA have some ideas about how to revamp the agency.

"Structurally, the FDA is flawed," says Wayne Ray, a Vanderbilt University epidemiologist who does consulting work for the agency.

One problem, Ray says, is that a large chunk of FDA's funding comes from "user fees" paid by the very companies seeking the agency's permission to market new drugs. That financial support from industry can't help but make the agency look favorably on new drug applications, he says. "I'm not just blindly critiquing the industry," Ray says. "We do need a watchdog to protect the public."

Currently, the FDA's Office of New Drugs, which reviews companies' applications to bring drugs to market, and Office of Drug Safety, which monitors drugs once they're on the market, are both part of the agency's Center for Drug Evaluation and Research, or CDER. That's too close for comfort, Ray and other FDA watchers say.

2 "In a sense, the FDA and the industry are kind of like the parents of the drug, and they are the ones who decide what's going to happen next," Ray says. "They may be very well-meaning about it, thinking this is a good drug, it has benefits, but they're not looking at it impartially. When there are serious doubts raised about safety, you need an impartial look."

One approach: Set up an FDA Office of Postmarket Surveillance to monitor not only drugs but also medical devices and biologics - products such as vaccines - says longtime FDA critic Sidney Wolfe, director of the Public Citizen Health Research Group. The office should be independent of CDER and the FDA divisions that review new product applications, Wolfe says.

For now, he says, "when push comes to shove, they (FDA) side with the industry over and over again." For example, at the very least, he says, the FDA should have required a boxed warning - the strongest type of warning possible - about cardiovascular risk on the Vioxx and Celebrex labels.

Tough times for FDA

It hasn't been a good autumn for the FDA, the drug industry or their constituents and customers. It started when Merck pulled Vioxx, its blockbuster arthritis drug, from the market. A company- sponsored study had found that colon-polyp patients who took the drug for a year and a half were about twice as likely to suffer a heart attack or stroke as those on placebo.

Pfizer, which issued three press releases affirming the safety of Celebrex after Vioxx's exit, says it has no plans to withdraw it. Crawford says the FDA has not yet made a decision on Celebrex's fate but is "leaving open all regulatory options as we move forward." Meanwhile, he says, doctors should consider prescribing alternative treatments.

Celebrex generally appeared to be safe in previous studies, although none lasted more than a year. On average, patients in the cancer institute polyp trial had taken the drug for 33 months before treatment was halted over safety concerns.

And with both Celebrex and Vioxx, patients at high risk for a heart attack or stroke were for the most part excluded from the pre-market clinical trials. Yet, in the real world, arthritis patients tend to be older and, therefore, at a higher risk for cardiovascular problems.

In October, Pfizer revealed plans to conduct a study comparing Celebrex with a placebo in more than 4,000 osteoarthritis patients at high risk for cardiovascular disease. But, in the press release announcing the study, Joseph Feczko, president of worldwide development at Pfizer, focused on the possibility that Celebrex's anti-inflammatory effects might actually protect the hearts of individuals with coronary artery disease, not harm them.

Eric Topol, cardiology chairman at the Cleveland Clinic, says that study should have been done a few years ago, when research first hinted at a connection between Celebrex and cardiovascular problems.

Now, with all the recent negative publicity, Pfizer might have a hard time recruiting patients at high risk for heart disease or stroke for a Celebrex study, Topol says.

Wolfe puts it more bluntly: "Those trials would be extremely unethical studies to do. Those drugs are dead in the water."

In a press release Friday, Pfizer noted that its own long-term colon polyp trial, similar in length to the cancer institute study, has found no difference in heart attacks or strokes between the Celebrex and placebo groups.

3 But that doesn't lessen the significance of the cancer institute's findings, says University of Pennsylvania pharmacologist Garret FitzGerald. "The absence of evidence is not the evidence of absence," FitzGerald says. "The detection of risk in a controlled trial is infinitely greater evidence than the failure to detect it."

Doubts about other drugs

In mid-November, Graham told the Senate Finance Committee, which Grassley chairs, that he's concerned about the safety of five other drugs on the market as well: Accutane for acne, Bextra for arthritis, Crestor for high cholesterol, Meridia for weight loss and Serevent for asthma. The makers of all five have vigorously defended their safety.

Vioxx's exit left Celebrex and Bextra, also marketed by Pfizer, as the only so-called COX-2 inhibitors on the U.S. market. (Merck sells another COX-2 inhibitor, Arcoxia, in dozens of other countries, but the FDA has put Merck's application on hold for now.)

Just a week before Friday's revelation about Celebrex, Pfizer and the FDA announced a new warning in bold black type - not as strong as a boxed warning - for Bextra's label because two studies had shown an increased risk of heart attacks or strokes in heart bypass surgery patients who took the drug. Public Citizen on Friday called for both drugs to come off the market.

And, in a letter in this week's New England Journal of Medicine (news - web sites), Ray and two Vanderbilt colleagues urge doctors to stop prescribing Bextra "except in extraordinary circumstances." The reason, they write: Doubts raised about Bextra's safety "constitute a potential imminent hazard to public health and thus require action." If they'd known about the Celebrex colon polyp study when they wrote the letter, says co-author Marie Griffin, they would have cautioned against prescribing that drug as well.

"Let's just not use these drugs until we know they're safe," says Griffin, an internist. "We're not saying we know that they're dangerous for healthy people. We're just saying let's wait until we have more data."

No drug is totally safe, Ray acknowledges. "Any use of medication is a trade-off between benefits and risks," he says. "When a drug comes on the market, we have good evidence that the benefits will outweigh the risks. Even just substantial doubt about safety can kind of tip that balance."

Ironically, the main selling point of COX-2 inhibitors has been that they're safer - at least on the digestive tract - than older nonsteroidal anti-inflammatory drugs, or NSAIDs, such as ibuprofen (Motrin and Advil) or naproxen (Aleve). The FDA allowed Merck to claim that Vioxx was gentler on the stomach than naproxen, but many patients might be surprised to learn that Pfizer has never conclusively demonstrated the gastrointestinal superiority of Celebrex over any NSAID.

"That was the dirty little secret all along with Celebrex," says FitzGerald, who first suggested more than five years ago that all COX-2 inhibitors raise the risk of heart attack and stroke because they cause platelets to clump together and form blood clots.

Still, Susan Ferris says she'll continue to take Celebrex, at least until her doctors' appointments next month. She has inflammatory bowel disease, which, she says, is exacerbated by the older NSAIDs. Her bowel disease is in remission, and, as far as her doctors know, her heart is fine. "I will stop the medication when my doctors tell me to or the information gets to the point where I feel it will do more harm than good," Ferris says.

Problems with studies

4 The problem is that doctors and patients often can't make informed decisions because the appropriate studies haven't been done, Griffin and others say.

Clinical trials conducted to gain FDA approval usually involve only several thousand patients studied for a relatively short period of time.

Don't look for any quick fixes, says pharmacologist Raymond Woosley, vice president for health sciences at the University of Arizona. He says the U.S. system of regulating prescription drugs is broken beyond repair. "Any patches that we try to put on that system are likely to make it worse," he says.

Though many critics say the FDA is too quick to approve drugs, Woosley argues that it's often too slow, discouraging pharmaceutical companies from investing in innovative research that might benefit relatively few patients. For example, he worries that drugmakers won't capitalize on what is known about the human genome by developing medicines tailored to individuals' genetic makeup.

Woosley's medical school and its partners, the FDA and the Stanford Research Institute, have established a new institute whose goal is to accelerate drug development. "I'm not talking about shortcuts," Woosley says. "We just have to stop making drug companies waste money on science that is out of date. A great example is how Alzheimer's drugs are being developed."

To test whether the drugs work, researchers are studying the speed of patients' mental decline, a process that can take years, Woosley says. But PET or MRI scans of subjects' brains could provide preliminary answers in a matter of weeks, he says. Post-marketing studies, which are rarely conducted these days, could answer whether the brain-scan changes translate into a slower mental decline.

Clearly, with speedier approval comes the need to limit drugs' use and monitor them more intensely, Woosley says. With that in mind, he says, the FDA might have to ban direct-to- consumer advertising for brand-new drugs. Such ads have led doctors to prescribe COX-2 inhibitors to patients who had little to gain from taking them, he says.

"I don't think Celebrex or Vioxx should be pulled," Woosley said Sunday. "The problem was there were millions of people taking them who shouldn't have been."

Electronic patient databases, such as those maintained by HMOs, could help the FDA keep abreast of what happens after drugs come on the market, Woosley says. "Right now," he notes, "the drugs are on the market, but nobody learns anything until there's a great signal that they're killing people."

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