Chances are that you -- or people you know -- have left the doctor's office at some point with a drug prescription that didn't jibe with the use approved by the Food and Drug Administration.
Although many patients are unaware of it, physicians often prescribe drugs for a disease, or at a dose, or for a patient type that's different from what the FDA has sanctioned.
But exactly what information are doctors basing these treatments on?
Although off-label prescribing is a legal and common practice, the evidence supporting these treatments can vary widely in quality.
Off-label treatments can be grounded in top-notch research comparable to the rigorous studies that the FDA would demand. But some experts say doctors are too often influenced by information from poorly designed studies, drug firm handouts, or a company sales rep buying them a fancy lunch.
"Bearing in mind that some off-label use is perfectly justifiable, it is fair to say that much of it is not justifiable," said Dr. Jerry Avorn, a pharmacology professor at Harvard Medical School and author of the book "Powerful Medicines," which calls for changes in prescribing patterns. "If there is not evidence presented to the FDA about a given indication, it certainly is a user-beware situation."
Before a drug can be prescribed at all in the United States, the manufacturer must convince the FDA that it is both safe and effective in at least one disease. These days, any potential new drug must undergo a demanding sequence of tests to win FDA approval, often starting with test-tube studies and animal trials.
If all goes well, the experimental compound moves to the next stage -- clinical trials using human subjects, the most costly and time-consuming part of the FDA approval process.
Many drugs fail before the final phase, which is usually a large-scale, carefully controlled study to evaluate the drug's effectiveness. That kind of trial is considered the "gold standard" of proof for a drug's value.
Once the trials are completed, FDA experts in toxicology, pharmacology, experimental design and other disciplines pore over the manufacturer's data to assess whether the touted benefits of the drug candidate are significant or just a statistical fluke.
They also weigh the benefits against the risks. Even if a drug relieves symptoms, it may not be worth the exposure to substantial side effects unless the disease it treats could cause even greater harm. Many drugs that once looked very promising have failed at some stage of the FDA's review.
Given a drug's painstaking path to approval in even a single disease, many Americans are surprised to learn what happens once a new medicine enters the U.S. market -- doctors are legally free to prescribe it off label for any other condition.
One reason: If doctors lacked that option, some valuable treatments might fall through the gaps in the FDA's regulatory scheme.
Once a drug is approved and in widespread use, it may show signs of benefit in treating other ailments. But drugmakers may be loath to spend more money on seeking additional FDA approvals, especially if that new potential market -- say for a rare illness -- would yield little extra revenue.
In pediatrics, there may be little alternative to an off-label medicine. Most drugs submitted for FDA approval were studied only in adults, not in children -- even though kids can react very differently to drugs.
Off-label prescribing also is very common among cancer doctors, who are willing to accept the risks of unapproved treatments when their patients are running out of options.
Beyond that, doctors may have no choice but to stray beyond a drug label's guidelines even in an approved use, said Dr. Ed Colloff, an internist at Kaiser Permanente in Redwood City. The studies submitted to the FDA don't cover every circumstance doctors encounter in the real world with a variety of patients, he said.
"The fact of FDA approval doesn't mean that all risks have been accurately assessed," Colloff said. "What if they're diabetic, and female, and have heart disease?"
Defenders of off-label use see it as a form of "innovative medicine" that may make therapeutic advances available to patients when an FDA review isn't available. Doctors rely on research studies, their own observations and the shared experiences of colleagues.
"Probably the most important thing takes place at meetings, in the hallways," said Dr. Michael Franzblau, a clinical professor of dermatology at UCSF. "Doctors ask each other, 'What do you do for this?' "
The publication of research studies can also start a chain of events by which some drugs come into widespread off-label use, even if the data are never submitted to the FDA. Such studies, whose quality can vary widely, are cited in practice guidelines written by medical experts, and included in drug compendia that health plans consult when deciding what medicines they'll pay for.
Wary observers such as Harvard's Avorn, however, say all these routes from the drug factory to the prescription pad are much too vulnerable to manipulation by pharmaceutical firms. Avorn said doctors are markedly influenced by drug company salespeople who provide free dinners, free samples and questionable information. Doctors sometimes rely on substandard studies that they're ill-prepared to assess, he said.
Physicians at medical meetings may not realize that a fellow practitioner vouching for an off-label use has been hired by the drugmaker to give the presentation. The FDA forbids drug firms to plug off-label uses, but industry watchers say the practice has been rampant at some companies.
The most extreme recent example was the illegal promotion of the epilepsy drug Neurontin for a host of other conditions, including migraine headaches, attention deficit disorder, drug and alcohol withdrawal, and bipolar disorder. Federal prosecutors accused the manufacturer, a unit of Pfizer Inc., of pushing these uses by misleading some doctors and paying others. In May 2004, the Pfizer unit pleaded guilty to two felonies and agreed to pay $430 million to settle the charges.
For reasons like these, Avorn is part of a movement for "evidence-based medicine," advising doctors to rely primarily on the kind of "gold standard" studies the FDA requires -- whether the studies are submitted to the FDA or not.
Such strong published research led Avorn himself to write off-label prescriptions for drugs called beta blockers back in the 1970s because he was convinced they would protect people with hypertension, he said.
On the other hand, he said, some off-label drugs that soared into widespread use were later proved harmful by the kind of large-scale clinical trials the FDA requires for approval. Doctors once prescribed long-term hormone replacement therapy in the belief that it would protect women from stroke, cancer and Alzheimer's disease. Government studies later proved the pills increased the risk of those illnesses.
Dr. Raymond Woosley, a University of Arizona expert in the pharmacology of heart drugs, agrees with Avorn that doctors can prescribe off label responsibly when strong published studies support a new use. High-quality research on the beta blockers showed years ago they could reduce deaths in heart attack victims, he said, although that use was nowhere on the label.
But Woosley also helped abolish the off-label use of two drugs, Enkaid and Tambocor, with a study proving they were dangerous in a new patient population. The drugs, approved to treat life-threatening irregular heartbeats, were widely prescribed in the 1980s for patients with less-serious symptoms. But for the healthier patients, the drugs caused more deaths than they prevented, Woosley's clinical trial proved.
"If that trial hadn't been done, we would still be using those drugs and killing people," Woosley said. "And we'd think we were helping them."