DOUBLE-DUTY DRUGS

By Christine Gorman

Heather Trebilcock has never smoked a cigarette. So she certainly never thought she would be putting nicotine directly into her blood--or that she would be grateful for its presence. But when Trebilcock developed severe abdominal cramps and diarrhea two years ago and starting losing weight--dropping 20 lbs. in three weeks--she knew she had to do something. Her doctor in Des Moines, Iowa, thought she might have colitis, a painful inflammation of part of the large intestine. In her case, however, standard treatments for the disease didn't work , and her condition deteriorated.

Desperate for relief, and facing the possibility of radical surgery, Trebilcock went to the Mayo Clinic, where Dr. William Sandborn offered an unusual treatment. He gave the 23-year-old college student a nicotine patch as part of a study to determine its effect on colitis. Normally prescribed to help smokers kick the habit, these patches release a predetermined amount of nicotine through the skin into the bloodstream, where it eases the craving for cigarettes. Physicians have known for some time, however, that nicotine also seems to quiet the symptoms of colitis. So, although the Food and Drug Administration has not approved the nicotine patch for the treatment of colitis, Sandborn thought it might just do the trick. It did. "It was like a miracle drug," Trebilcock says. Within two weeks her condition began to clear up. Now, she says, "I'm back to normal."

Using a drug to treat a disorder for which it was not intended--a practice known as off-label prescribing--may sound like dangerous medicine. But it is surprisingly widespread and has become a hot issue, both in the medical community and in the U.S. Congress. The American Medical Association estimates that 40% to 60% of all prescriptions in the U.S. are written for drugs being used for something other than their approved purpose. Now drug companies have started campaigning for the right to promote their products' unofficial benefits, and their lobbying effort is likely to be well received on Capitol Hill.

Why is off-label prescribing so common? Chiefly because pharmaceutical companies are reluctant to invest the time and expense to get FDA clearance on new uses for an established drug--especially when the drug's safety has already been proved. Says Dr. Martin Raber, physician in chief of the M.D. Anderson Cancer Center in Houston: "It is accepted practice that once a drug is FDA-approved it can be freely used." But the FDA gets nervous when a drug's unapproved uses overshadow its original purpose. Retin-A cream, for example, was approved by the FDA for the treatment of acne in 1971, but then, much to the FDA's consternation, it was widely prescribed to smooth wrinkles caused by aging and overexposure to the sun.

This shadowland of medical practice didn't start to attract public scrutiny until off-label prescribing became the treatment of choice for people suffering from AIDS or advanced cancers. "When it comes to treating cancer, things are much more liberal than in other areas of medicine," says Dr. Thierry Jahan, an oncologist at the University of California at San Francisco. "There's an element of desperation. So you try a lot of combinations of drugs that are already on the market while waiting for new drugs to become available."

The issue was thrust into the spotlight--and controversy--two weeks ago when it was reported that the anticancer agent Methotrexate can be used in conjunction with an anti-ulcer drug to safely and effectively induce abortion.

Doctors take a chance whenever they depart from FDA-approved uses of powerful drugs. Should something go wrong, a patient could successfully sue for malpractice. Paradoxically, there are situations in which a patient might also sue if the physician fails to prescribe a drug for off-label use. Take Lyme disease. Scientists have shown that the most effective cure for the tick-borne malady is treatment with one of two antibiotics, amoxicillin or doxycycline. Neither is approved for that use, but the drugs have become such standards of care that a doctor might be considered negligent for not using them.

Because drug companies may not advertise unapproved uses, physicians usually learn about them by following new studies in the medical trade press or peer-reviewed research journals. Many of those studies are funded by drug companies. Sometimes researchers stumble upon unexpected uses by noting interesting side effects during clinical trials. In 1987, for example, a year before Prozac was approved for alleviating depression, scientists observed that many patients lost weight while taking the drug. Word got out, and now some physicians prescribe Prozac to treat obesity as well.

The pressure to innovate is strongest for conditions without known treatment. In the past few years, thousands of people prone to violent behavior have become able to live outside mental institutions thanks to drugs called beta-blockers, which are normally prescribed for cardiac conditions. Apparently beta-blockers can soothe an overactive nervous system in the same way they quiet a racing heart. But their use for mental disorders is strictly off-label. "There are no FDA-approved drugs to treat violent and aggressive behavior," says Dr. Stuart Yudofsky of the Baylor College of Medicine in Houston.

Probably the one drug that is most famous for doing double, triple and maybe even quadruple duty is aspirin. Not only has it been relieving headaches for nearly a century, but doctors are now fairly confident that taking an aspirin every other day can reduce the risk of heart attack in many people. And last week Harvard researchers reported the best evidence to date that long-term use of the drug--for 20 years or more--may cut in half a person's risk of developing colon cancer.

Aspirin, of course, is not a prescription drug and therefore is not closely regulated by the FDA. (In fact, considering how little is known about how it works, some drug experts doubt that aspirin would ever make it through today's strict approval process.) Pharmaceutical firms argue that the FDA should loosen its grip on both on-label and off-label prescribing. Last month Senator Connie Mack of Florida, a cancer survivor, introduced a bill that would loosen the reins on off-label promotions, allowing drug companies to send doctors copies of peer-reviewed articles about their products' unofficial uses . "The argument is often made that doctors can read these articles themselves," says Steve Berchem, a spokesman for the pharmaceutical industry. "But doctors don't have time to read every journal and find the articles that might be applicable to their patients."

As might be expected, officials at the FDA are not sure the proposal is a good idea. "The journals are not always right," argues William Schultz, one of the agency's deputy commissioners. And there is nothing to stop companies from sending only those articles that mention their products favorably and omitting negative reports. The worst outcome, say critics, would be if manufacturers used the relaxed rules to adopt a sort of bait-and-switch research program. They could, for example, seek approval from the FDA for an indication that is easy and inexpensive to prove but not widely useful. Then they would be free to market their drug for more common and complicated conditions without having to pursue the more rigorous research. "If you switch it around, [the drug companies] won't test," Schultz says. "The doctors won't know what works, and insurers won't know what to reimburse."

Deciding who pays for unapproved uses is, in fact, a growing problem. For years insurers have recognized the importance of off-label prescribing and have agreed to reimburse patients for their prescriptions. Now many cost-conscious managed-care firms have started to clamp down on off-label reimbursements--especially if the medication is particularly expensive. "A physician and patient can argue with the insurer," says Dr. Howard Ozer, director of the Winship Cancer Center at Emory University in Atlanta. "But if it goes on for too long and the patient can't pay for the drug out of his own pocket, he can die before the approval can be obtained."

Even when it isn't a matter of life and death, the new reimbursement policy can hurt. In a study published last year, a team of researchers that included Dr. Daniel Present of Mount Sinai Medical Center in New York City reported that the antirejection drug cyclosporine, usually used for transplant patients, helped patients with colitis. After the study was completed, he prescribed the immunosuppressive drug for one of his patients, who had a similar condition called Crohn's disease, only to learn that her health-maintenance organization would not pay for it. The woman's father finally had to put her in the hospital and pay $10,000 for the treatment out of his own pocket. Although her condition improved within days, the HMO still refused to reimburse her. "They say they won't pay because cyclosporine isn't approved for Crohn's," says an exasperated Present. "I ask them, 'Well, what is?' We know we can get sued. We know we have to fight the HMOS. But we also have to do what's best for our patients."

Trusting someone to do what's right can be hazardous. But doctors have traditionally been given a lot of latitude when it comes to deciding what drugs to prescribe, and in the gray area of off-label medicine, the benefits of letting them continue to use their best judgment is probably worth the risk.

--Reported by Nina Burleigh/Washington, Deborah Fowler/Houston, Lawrence Mondi/New York and Tara Weingarten/Los Angeles

With reporting by NINA BURLEIGH/WASHINGTON, DEBORAH FOWLER/HOUSTON, LAWRENCE MONDI/NEW YORK AND TARA WEINGARTEN/LOS ANGELES