WASHINGTON — In 1962, a Congress horrified that thousands of European babies had been deformed by the medication thalidomide ordered the Food and Drug Administration to make sure the same thing never happened in America.
Congress gave the FDA the power to assess the safety and effectiveness of all drugs before they could be sold on the U.S. market.
Forty years later, however, an ever-growing segment of the American pharmaceutical business is eluding that rigorous scrutiny. Millions of patients are being given drugs by their doctors that the FDA hasn't approved for treating their particular illnesses. Off-label prescribing, as it's called, puts patients at risk while offering no assurance the drugs will work.
And while the FDA has argued in court that the "risk to the public from unproven uses of drugs and devices is both real and substantial," the agency rarely has tried to curb it. When it attempted to do so in the 1990s, its efforts fizzled.
Now as the phenomenon soars — Knight Ridder found that off-label prescribing for a sample of top-selling drugs has nearly doubled in the last five years — the Bush administration has opened the door to doing even less to stop it.
Saying recent court rulings have eroded its power, the FDA has sought public comment on whether drug makers should have more leeway to market the unapproved uses of their profitable drugs. Overseeing the effort is a Bush appointee who, before coming to the FDA, helped sue the agency over its marketing and advertising restrictions.
"They certainly are backing off," said Michael Wilkes, the vice dean at the School of Medicine at the University of California, Davis. He studied off-label promotions for the FDA in the 1990s.
In part, the agency is handcuffed by a conflicted mandate from Congress. The FDA is trying to do many things: Get powerful drugs to market while protecting the public, respect the First Amendment while regulating drug advertising and let doctors practice as they see fit — except when they make dumb errors. Given the rapidly growing number of drugs in the marketplace, prescribing is far more complicated for doctors today.
"There's some limit to what the federal government should do, I think, because it's not going to be effective," said Dr. Janet Woodcock, the director of the FDA's drug division. "You can't just Band-Aid and patch something that has systemic, underlying problems."
But it's also clear that the agency hasn't followed through on its limited efforts to reduce the risks of off-label drug sales:
- Under FDA rules, if a drug maker knows a drug is being used for off-label purposes, it's required to come forward with evidence supporting those unapproved uses. FDA officials said in a court deposition that the rule had not been enforced.
- After the FDA took a major drug company to court in 1993 and won a hefty payment for overt off-label sales pitches, its commissioner vowed to use such sanctions again to control illicit marketing. But FDA officials could point to no other case since then when they have.
- Last year, the FDA issued 28 violation letters for improper drug marketing, down from 158 in 1998. The agency said it would need nearly twice as many people to adequately police the industry's 37,000 advertisements and other promotions each year.
- Twenty-four years ago, the FDA said it wanted to ensure that patients got useful, easy-to-understand information about the drugs they took. Most still don't.
The bottom line for consumers: Beware.
"We as patients have got to raise the questions ourselves and take care of our own selves," said Jere Goyan, who was FDA commissioner from 1979 to 1981.
The drug Kristen Pettijohn took was called Avelox. It's part of a family of antibiotics called fluoroquinolones.
Those powerful but risky drugs are intended for patients who are fighting particular bacterial bugs. But they're widely prescribed off-label for less serious illnesses, sometimes even to treat viruses, which can't be killed by antibiotics.
A study this year funded by the National Institutes of Health reviewed 100 emergency room prescriptions for fluoroquinolones and found that only 19 were written for appropriate conditions and only one was given in the correct dose and for the proper duration.
The FDA long has been aware of the possibility that Avelox could be misused.
Just before it approved Avelox in 1999, a member of the agency's expert review panel — Robert Danner, a critical care expert at the NIH _ offered a warning: "This is exactly the kind of place that you get into trouble. I am absolutely convinced that the drug will be used differently once it's marketed frequently."
Avelox was approved, however, and marketed hard by Bayer Corp. In 1999 and 2001, the FDA admonished company officials for encouraging unapproved uses.
This past May, Pettijohn, a gregarious 23-year-old nursing student from Batesville, Ind., who recently had gotten engaged, picked up the persistent cold that had been running through her family. "Her version was a little worse than ours," said her father, Gary Pettijohn. "I would say it was moderate at best."
Early in the morning of May 15, Pettijohn's mother took her to an emergency room. Going there, Pettijohn told her mom, would be quicker than waiting for an appointment with their family physician.
Forty-two minutes later, Pettijohn was on her way to the drugstore. The doctor had diagnosed her with acute bronchitis and prescribed Avelox. The potent antibiotic's label says it's approved for cases of chronic, or long-term, bronchitis, and only after blood tests have been taken to identify the bacteria causing the problem. Her medical records show no blood work was done.
That was a Thursday. By Sunday, Pettijohn was nauseated and suffering abdominal pain. Her mother packed a plastic bag with the remaining Avelox pills and took her to the hospital.
Over the next five days, Pettijohn was incoherent. She had a burning rash and her skin began peeling off. She slipped into a coma, resting on an air bed, totally wrapped as though she were a severe burn patient.
By Wednesday, a doctor approached Gary and Ruth Pettijohn.
"Our problem just got twice as difficult," he said. "She has two life-threatening conditions simultaneously."
Pettijohn's liver was in full failure, and she was experiencing a form of Stevens-Johnson syndrome, a rare and extreme drug reaction mentioned on the Avelox label.
She had a liver transplant on Friday. The doctors reported that her old liver had turned to mush and fallen apart in their hands.
Soon after the operation, Pettijohn had a heart attack, then another. Her death certificate cited Avelox as the prime contributing factor in her death.
The hospital had no comment about her death. Bayer had no comment beyond saying the death "was promptly and accurately reported to the FDA," and that it thinks its antibiotic should be prescribed only for approved conditions.
As Congress reworked the nation's drug-safety laws after thalidomide, it sought to create a regulatory system that guaranteed that the drugs Americans used were safe and effective.
Lawmakers in 1962 worried that drug makers might be tempted to get a medication approved for one use and then promote it for others. "The initial claim would tend to be quite limited," said a group of senators led by the late Tennessee Democrat Estes Kefauver. "Thereafter, the sky would be the limit. Extreme claims of any kind could be made."
Congress told the FDA to require stringent tests before a drug could get to market. Once a drug passed, a company could advertise it only for the approved uses.
The FDA began reviewing all the drugs that had been on the market as of 1962, when the new approval rules kicked in. Of 3,443 drugs commonly prescribed, 1,124, or one-third, were deemed useless and taken off the market, FDA records show.
Even though that shows that doctors often can't judge drugs' effectiveness, the FDA largely has stayed out of the doctor's office.
The agency's rules say it can require a drug company to prove that an off-label use is safe and effective. The FDA has said that a drug's "actual use" by doctors can show a drug maker's "intent" in selling it.
However, asked in a lawsuit deposition in 1996 if the FDA had ever considered using the option of requiring proof of off-label effectiveness, the agency's Dr. Robert Temple replied: "We think about this all the time. We just don't know quite how to do it."
Knight Ridder found that the off-label use for some drugs is as high as 90 percent of all prescriptions sold for it.
Off-label uses became a concern in the 1990s, under the activist tenure of then-Commissioner David A. Kessler, who noted that "medical history is replete with examples of products and procedures that were based on medical anecdote, not evidence, and were thought for years by most clinicians to be effective, but later turned out to be useless and sometimes even dangerous."
In 1991, the FDA established a task force to examine off-label uses of drugs and medical devices.
The agency also found that drug companies often had no incentive to evaluate the merits of off-label prescribing because they might discover that their drugs didn't work when prescribed off-label and sales would suffer, according to a review of FDA records.
The drug makers, which are among the most profitable industries in the United States, know they can continue to get off-label sales without going through the expense of proving a drug's effectiveness for the off-label use to the FDA.
Also interfering is the patent protection process. Once a drug's patent lapses, there's little financial interest in taking on the added costs of new FDA application.
Based in part on the work of the off-label task force, the FDA attempted a host of fixes. But a decade later, those efforts largely have fallen short:
- One push was to have companies apply for FDA approval for popular off-label treatments. While the effort initially produced more applications, the numbers have been dropping. From 1998 to 2002, the number of approvals for new uses of existing drugs went from 74 to 39, according to the FDA.
- An attempt to revise the prescribing labels for doctors has dragged on for more than 10 years. The agency says its labels are confusing even for doctors, and that fixing them could reduce medication errors.
- Proposals to give patients more meaningful drug information have been stalled even longer. The FDA repeatedly backed away from plans, dating to 1979, to ensure that all patients get basic information about the drugs they buy. Opposition has been fierce. Doctors have argued that the information would frighten patients unnecessarily. Today, most of the leaflets patients get about drugs are part of an industry-run voluntary program. The quality of the information they provide varies widely, with only about half of the leaflets studied meeting FDA goals for usefulness, according to an FDA-commissioned study announced last year.
- Proposals to restrict drug makers' efforts to get around the ban on promoting off-label drug uses ran into a blizzard of legal challenges by the Washington Legal Foundation, a free-market advocacy group. On free-speech grounds, the courts turned away many of the FDA's arguments; U.S. District Judge Royce Lamberth said the "FDA exaggerates its overall place in the universe."
Helping the Washington Legal Foundation make its case was Daniel Troy, a prominent First Amendment and corporate lawyer. Today, Troy is chief counsel of the FDA, a Bush administration appointee who has started a process that could substantially rewrite the FDA's rules on commercial speech, including those regulating off-label drug promotions.
The pharmaceutical industry has jumped on the opportunity, pushing the agency to relax some of its restrictions on promoting off-label uses. Consumer groups, such as Public Citizen Health Research Group, and many congressional Democrats say to do so would invite disaster.
FDA Commissioner Mark B. McClellan, a physician, said the agency would like to see more evidence submitted about off-label uses, stressing that it was important for such treatments to meet the "gold standard" of FDA approval.
To help curb risky off-label prescribing, he wants to improve the FDA's system for reporting drugs' side effects, and he wants better information in the hands of doctors and consumers. The effort to rewrite the labels doctors read will be finished "in a matter of months," he said. "I think we can do much better than we have."
The FDA has had some success using its authority to get the pharmaceutical industry to study drugs' affects on children and put that information on the label. Those efforts, begun in the 1990s and involving congressional and agency action, have produced some results, although they recently have been set back in court.
In many ways, the FDA's 1962 mandate to determine whether drugs are safe and effective is irrelevant in today's market, in which some off-label treatments have become so widespread that they're now considered the standard of care.
Amiodarone — under the brand name Pacerone — was the drug taken by George Cox, a Buckner, Mo., man who lost nearly all his sight, and by Martha Andreasen of Bowie, Texas, who's struggling with lung damage.
Amiodarone can have a devastating effect on the lungs: As many as 17 percent of patients in some studies experienced lung damage, and about 10 percent of them died. Patients taking the drug have suffered thyroid, liver and eye problems, including blindness. The FDA approved it only as a drug of last resort for patients with a life-threatening heart condition called ventricular tachycardia.
In 1999, Cox, now 75, was given amiodarone for atrial flutter, a heart condition that isn't life-threatening. He got the prescription a full decade after the FDA began telling the drug's makers to stop promoting it as something other than a last-resort drug.
Andreasen also was given amiodarone off-label. She had atrial fibrillation, a common heart problem similar to atrial flutter. Like many patients, she said she was never warned of the drug's risks or that her prescription was off-label. Her pharmacy leaflet mentioned nausea and dizziness, but not death from lung problems.
Today, Andreasen is tethered to an oxygen tank each night, and at age 54 she's already made her funeral arrangements. She's homebound and doesn't have the strength to clean her house, a humiliating letdown for a woman who's been a member of her town's Young Homemakers club for 30 years. Since she was dropped by her husband's health insurance, the Andreasens now pay $800 a month for high-risk insurance and co-payments. Their dining room table sits atop plywood because they can't afford to finish a repair to the floor.
"The FDA is supposed to protect the general public from situations such as this _ or so I thought," Andreasen said.
Since at least 1988, the FDA has warned two drug companies to stop false and misleading promotions that downplayed amiodarone's risks while suggesting it as a first-line therapy. The agency sent letters to amiodarone makers in 1989, 1992 and 1998. "Your firm has an intolerable record of compliance with the law," read the 1989 letter to Wyeth, one of the amiodarone makers.
Wyeth's promotions continued. From 1999 to 2002, a slick magazine-style brochure that Wyeth paid for proclaimed "Amiodarone From Last to First-Line Antiarrhythmic Therapy" on its glossy purple cover.
Wyeth spokesman Doug Petkus said the brochure was educational, not promotional. Regardless, Wyeth no longer is doing any promotion of its amiodarone drug, Cordarone, because its patent protection has expired.
After Cox lost most of his sight, his Missouri pharmacist gave him Wyeth's "First-Line" brochure, and he passed it on to the FDA in 2001.
The agency wrote back, saying it can "take action when unapproved (off-label) uses become widespread or endanger the public health," but until last month it had done little to try to curb the widespread off-label prescribing of amiodarone.
In the last year, doctors wrote nearly 2.3 million off-label amiodarone prescriptions, according to Knight Ridder's analysis. That's 82 percent of all the prescriptions for the drug.
In response to Knight Ridder's findings, the FDA's Woodcock said the agency would require that all amiodarone prescriptions be accompanied by an FDA-approved patient guide to ensure that consumers know exactly what the drug is approved for and what its dangers are. Patients will get the guides starting early next year.
"What you brought to the table was the extent of off-label use and some specific patient experiences of not getting all of the information about this drug," Woodcock said.
"Obviously this drug is a very risky drug," she said.
While many cardiologists defend amiodarone's off-label use for atrial fibrillation, a recent NIH study challenged their long-held beliefs.
Called AFFIRM, the study concluded that patients taking drugs such as amiodarone to control their hearts' rhythm experienced more side effects and hospitalizations than those given safer drugs to control how fast their hearts beat. For all its extra risks, amiodarone was no more effective.
Dr. Claude Lenfant, the recently retired director of NIH's National Heart, Lung and Blood Institute, said amiodarone didn't appear to be the best treatment for many patients with atrial fibrillation. But changing a doctor's practice "takes place very, very slowly."
"I personally feel there's a system failure," he said.
Even when it's aggressive, the FDA has been unable to stem off-label prescribing.
For more than a decade, the FDA has tried to corral the use of Accutane — a drug for severe forms of acne — which can cause birth defects.
As early as 1990, a frustrated FDA official wrote that "intensive regulation has not, cannot and will not achieve the Agency's goal of eliminating pregnancy exposure to Accutane." At the time, the official estimated that 90 percent of Accutane's use by women was off-label, typically for mild acne that can be treated with safer drugs.
Even tough new warnings on the drug's label about suicide, psychosis and depression didn't stop sales.
According to an internal company sales plan for 2001, drug maker Roche concluded that despite extensive media coverage about those new dangers, "prescribers were apparently unmoved by this information."
In 2002, the same FDA official made another estimate that 90 percent of Accutane use was off-label. The company disputes the FDA estimate. ___
Thalidomide's entry into the U.S. market shows how physicians and the drug industry consider the FDA irrelevant.
The drug was approved in 1998 for a leprosy-related skin condition that's virtually nonexistent in the United States.
After studies showed that the drug might be useful for treating multiple myeloma, a form of cancer, Celgene Corp. aggressively sold that idea to doctors.
One company sales representative went further, telling an oncologist that the drug, marketed as Thalomid, is "good for weight loss," could be used "as an appetite stimulant" and is a "great drug for feelings of general well-being," according to an FDA document describing the sales pitch.
When the doctor asked whether the FDA had approved Thalomid for those uses, the sales rep said, "No, but do you want some material anyway?"
In 2002, the FDA told Celgene that its existing data on multiple myeloma wouldn't be enough to win the agency's approval. The earliest the company says it might seek authorization as a treatment for that form of cancer is 2005.
Today, 70 percent of Thalomid uses are for multiple myeloma, while only 1 percent are for its approved leprosy condition. Celgene, in filings with the Securities and Exchange Commission, declared: "We may not be able to attain or maintain profitability" if physicians prescribe Thalomid only for patients who are diagnosed with leprosy. ___
(Researcher Tish Wells contributed to this report.)