Why doctors prescribe drugs off-label.

Health and medicine explained.
Dec. 27 2007 12:05 PM

Help, My Prescription Pen Is Running Out of Ink

Why doctors need to keep the power to give drugs off-label.

Albuterol inhaler
Doctors often prescribe off-label drugs for children

When a child with asthma comes to my office wheezing, he or she often needs help fast. The coughing, gasping, and hunger for air of an asthma attack call for an immediate dose of albuterol, an inhaled medication that reopens the bronchioles, or air pipes. And yet this is a prescription that the Food and Drug Administration, guardian of all things medical and pharmaceutical in this country, has not sanctioned. Amazingly, though albuterol is the drug most commonly used to treat asthma in children, it isn't FDA-approved for them. The drug's label reads: "Safety and effective dosing of albuterol … have not been established in children below the age of 12 years."

Nevertheless, I prescribe this drug to kids, off-label, without reservation. I can do this because while the FDA has the authority to approve and label drugs, it cannot interfere with how doctors practice medicine. This is the right legal balance. Off-label prescriptions allow doctors to take calculated risks to help their patients. We need more of this experimentation. But drug companies and insurers are threatening to leave us with less.

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I can't imagine practicing medicine without the independence to write a prescription as I see fit. The evidence shows my colleagues agree with me: A 2006 study published in the Archives of Internal Medicine showed that in the course of a year, roughly one-fifth of prescriptions for the 169 most common drugs were for off-label uses. That comes out to a 150 million prescriptions per year.

Kids probably reap the greatest benefit from off-label prescriptions. Three-quarters of all drugs aren't approved for them, forcing pediatricians to regularly improvise. This despite the FDA's "pediatric rule," which rewards drug makers with a six-month patent extension if they do studies on kids. This sounds pretty good, but since it takes a lot more than six months of money and time to complete such research, the pediatric rule is little more than a token incentive, and most companies don't bother to take advantage of it.

Cancer patients are another big group who benefit from off-label drug use: Cancer drugs are prescribed off-label 60 percent of the time. This is essential, as Stanford oncolgist Richard Miller wrote in a recent op-ed for the Wall Street Journal: "The off label use of cancer drugs … is vital to patient care and makes important new drugs available to more patients … with different types of cancer more quickly than could occur by requiring formal clinical testing in each kind of cancer."

Miller describes off-label uses to treat types of cancer that vary from those for which the drug has been approved, but doctors often go off-label to venture further afield, because they find that a drug has benefits in treating an entirely different condition. Such is the case with Avastin, a drug approved for colon cancer in 2004. * Soon after its approval, some clever ophthalmologists found that Avastin could help patients who were losing their eyesight because of  macular degeneration. This led to widespread off-label use for that condition.

But Avastin also exemplifies the clash between a doctor's good intentions and a drug company's profit motive. For a patient with macular degeneration to be given Avastin, pharmacies have to compound, or specially prepare, it. Because of volume and dosing differences, that process dramatically cuts the price. Avastin costs $40 a month to treat macular degeneration instead of the $4,000 per month that the drug's maker, Genentech, charges for colon cancer. Realizing this, Genentech submitted a compound similar to Avastin to the FDA for separate approval as a treatment for macular degeneration, calling the new drug Lucentis, which it priced at $2,000 for a month's dose for macular degeneration. * After pretty simple comparison shopping between a $40 drug and a $2,000 drug, most ophthalmologists simply stuck with off-label Avastin. In response, Genentech recently decided to stop supplying Avastin to pharmacies that compound it.

Genentech's typical—and tired—argument is that Avastin's reduced off-label price cuts into profits that the company needs to develop new drugs and preserve America's edge in health-care innovation. But even as it was cracking down on the pharmacies that were dispensing the drug more cheaply, Genentech reported a 21 percent rise in profits for the third quarter of this year—a gain it credited to strong sales of Avastin. Meanwhile, patients prescribed Lucentis have co-payments as high as $400, which makes the drug unaffordable to many of them.

The government has also started making off-label prescription more difficult, through Medicare's effort to control drug costs. Medicare has traditionally supported off-label uses by deferring to doctors when it comes to covering the cost of prescriptions. But in recent years, Medicare started to demand the justification of an off-label prescription with formal evidence, including head-to-head trials against other drugs. The government has specifically refused to cover prescriptions for Actiq, which is FDA-approved to treat pain in cancer patients, when it's being used to treat patients with pain with other causes. In support of this position, Medicare cites the lack of evidence that Actiq is any better than other, perhaps cheaper, pain medications.

That may make financial sense given the ever-increasing cost of prescription drugs, but Medicare risks hindering innovation. A 2006 study by MIT researchers published in the journal Pharmacotherapy showed that almost two-thirds of off-label uses resulted from "field discovery." A doctor thinks of a new way to use a drug, trusts her intuition, tries it, and then publishes the results to alert her peers. That's how the off-label benefits of Avastin and albuterol were discovered. How does one put a price tag on this? Medicare ought to think hard about that question before abandoning off-label coverage.

The conflict over off-label prescribing is really just another chapter in the continuing conflict between two schools of doctoring: The cottage industry of the past and the industrial-government-insurance complex of medicine's last quarter-century. I have no illusions about who is winning here. But given the benefits, can't we preserve a thing or two from the old days, like my authority to follow my instincts when I write a prescription?

Correction s, Jan. 7, 2008: This article originally stated, incorrectly, that Genentech submitted Avastin to the FDA for separate approval as a treatment for macular degeneration, as opposed to a compound similar to Avastin. (Return to the corrected sentence.) The article also incorrectly stated that Avastin was approved for colon cancer in 2003. (Return to the corrected sentence.)

Rahul K. Parikh is a physician in the San Francisco Bay Area who writes about medicine and society.

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