WASHINGTON — Patients nationwide are being injured and killed because doctors routinely are prescribing drugs in ways never certified safe or effective by the Food and Drug Administration, a six-month Knight Ridder investigation has found.
Over the last year, 115 million such prescriptions were written, nearly double the number of five years ago, the newspapers' analysis of prescriptions for a sample of top-selling drugs found.
The investigation discovered that the practice, called off-label prescribing, is often driven by questionable research, aggressive drug-company marketing and cavalier doctors, and condoned by tepid regulators.
"Sometimes it may help, sometimes it may do more harm than good and sometimes it may kill people," said Dr. Arnold Relman, a former editor of the prestigious New England Journal of Medicine.
Knight Ridder reviewed 15 top-selling classes of drugs and found that some, such as cholesterol medicines, rarely are used as unapproved treatments. But three-quarters of anti-seizure medications are prescribed off-label for such things as depression and hot flashes and to help people lose weight. Nearly two-thirds of antipsychotics were prescribed off-label, including for insomnia and attention deficit disorder. And about one-quarter of the prescriptions for antidepressants were for unapproved uses such as pain and premature ejaculation, according to the analysis of proprietary prescribing data routinely used by the pharmaceutical industry.
The data, generated by Versipan of Yardley, Pa., is based on the health-information company's monthly survey of 3,400 doctors with office-based practices, as well as information the company collects from retail pharmacies. Verispan uses their responses to project national numbers.
Dr. Raymond Woosley, the vice president of health sciences at the University of Arizona, said off-label prescribing puts patients at greater risk than when doctors followed a drug's FDA-approved directions.
"I have no doubt about it," said Woosley, who also is the director of one of the national centers for drug research established by the federal government. "The caveat is we can't quantify it."
For patients with rare, intractable or fatal illnesses, off-label prescribing is sometimes appropriate. In other cases, there may be gold-standard studies backing an off-label use. But doctors routinely are choosing unapproved therapies that are questionable at best and lethal at worst.
The practice is legal, widely accepted and defended by doctors and the American Medical Association — but it's taking a toll. Victims of off-label prescribing have suffered heart attacks and strokes, had permanent nerve damage or lost their eyesight. Most of those Knight Ridder interviewed never were told that the FDA hadn't approved their treatments.
Dr. Nancy Nielsen, an elected official of the American Medical Association, doesn't think doctors have been "cavalier" about off-label prescribing. "They have been in meetings," she said. "They know it works."
But individual doctors — untrained in the basics of drug therapy — usually aren't in a good position to gauge whether off-label treatments really are working, if there's a placebo effect or whether the patients simply got better on their own, experts say.
History is filled with examples of doctors who were convinced that an off-label therapy was safe and effective, only to be proven disastrously wrong. In the 1990s, there was the off-label diet-drug combo Fen-Phen, widely prescribed until some patients began suffering from a rare heart-valve disease.
More recently, there was the rampant off-label prescribing of hormone replacement therapy in the belief that the drugs would protect women from heart disease, breast cancer and Alzheimer's. The Women's Health Initiative, a government-run study that some doctors consider controversial, has found that the therapy actually increases the risk of getting these diseases.
While respecting the right of doctors to practice medicine as they see fit, records show that the FDA has been concerned about off-label prescribing for years.
FDA Commissioner Mark B. McClellan, a physician, said in an interview that 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.
Yet the agency has done little over the years to curb the practice, and it recently has sought public comment on whether drug makers should have more leeway to market unapproved uses of their drugs. The move was prompted by court rulings that the agency says have eroded its power.
"They certainly are backing off," said Dr. Michael Wilkes, the vice dean at the School of Medicine at the University of California, Davis, who studied off-label promotions for the FDA in the 1990s.
Doctors are free to prescribe as they wish, but the FDA prohibits drug-makers from marketing unapproved treatments. Since 1998, the agency has cited companies nearly 70 times for improperly promoting their drugs that way, a review of records shows. But getting around FDA marketing rules isn't difficult. The agency acknowledges that it's impossible to police the millions of conversations between drug companies and doctors.
Drug makers universally deny that they push off-label uses at doctors.
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. But FDA officials said in a court deposition that the rule hadn't been enforced.
The agency often has faltered in finishing what could be simple fixes to help consumers. For example, it repeatedly has backed away from plans, dating to 1979, to ensure that people get basic information about their drugs when they pick up prescriptions at the pharmacy. While most people do get leaflets with their prescriptions, most of them are part of an industry-run voluntary program — and last year, the FDA said half of those leaflets didn't meet agency standards.
The result is a system in which companies can get a drug approved for one treatment v then sell it for all sorts of off-label uses.
Consider Topamax, a drug the FDA approved in 1996 as a supplemental treatment for epilepsy.
Topamax has several potentially serious side effects. It often causes numbness and tingling in the hands and feet. It can cause depression and kidney stones. It can slow thinking and impair memory. It can cause vision problems, including a form of glaucoma that can result in blindness.
To stop seizures, the FDA deemed these risks acceptable.
In 1998, Topamax was prescribed only for seizures, Knight Ridder's analysis of prescription data found. But in the past year, 79 percent of Topamax prescriptions were for illnesses and conditions the drug hasn't been approved to treat, the analysis showed. Doctors are prescribing it for patients with migraine headaches, schizophrenia, bipolar disorder, depression, pain and nerve damage.
Over the last year, Knight Ridder found, doctors wrote 586,000 Topamax prescriptions to treat bipolar disorder, a condition involving alternate bouts of depression and mania.
"Topamax is no better than a placebo," said Dr. Joseph Goldberg, a research scientist at Zucker Hillside Hospital on Long Island, N.Y., who published a review of epilepsy drugs as treatments for bipolar disorder earlier this year while at Cornell University. "It's giving an ineffective treatment for a potentially life-threatening illness. It would be like giving Tylenol for pneumonia."
The drug's maker, Johnson & Johnson, has asked the FDA to approve its use for migraines. Goldberg said that even studies by Johnson & Johnson found that it didn't work to treat bipolar disorder. As a result, company spokeswoman Lesley Fishman said, the drug maker didn't seek FDA approval for treating that condition.
Carolyn Bartley nearly went blind in June 2000 a week after she began taking Topamax, which her psychiatrist prescribed as a treatment for bipolar.
"Everywhere I looked, it was like a watercolor painting — and somebody had smeared it," said the 44-year-old Annapolis, Md., bookkeeper. Laser surgery reduced the pressure in both eyes and restored her sight. In 2001, Johnson & Johnson sent a letter to doctors warning about the kind of sudden glaucoma Bartley experienced.
Bartley's psychiatrist, Dr. Parviz Sahandy, said he hadn't researched the medical literature on Topamax, but that he considered it effective for bipolar disorder about 50 percent of the time.
(Researcher Tish Wells contributed to this article.)