Drug study

Internist Caleb Alexander rethinks the way doctors prescribe medicines.

By Lydialyle Gibson
Photography by Dan Dry

Caleb Alexander, SM’03, was halfway through his internal-medicine residency at the University of Pennsylvania when something struck him as odd: “We never seemed to talk with patients about the cost of the tests and treatments we were ordering.” He and other doctors held detailed discussions with patients about the risks and results of those tests, about how much and how often to take the drugs they’d been prescribed, and how those drugs might help them. But money rarely came up.

Drug study
“Doctors face a serious task,” Alexander says, in keeping up with fast-changing prescription-drug research.

There are good reasons why it wouldn’t, Alexander notes. For one, “people are sick.” Treating the acutely ill often leaves little room for financial discretion: patients need what they need. Plus, physicians are largely insulated from the cost of the care they give. “One could make the case that that’s for the better,” Alexander says. “Leading academicians have argued that physicians shouldn’t think about costs as they make clinical decisions.” Still, he wondered, what about less urgent situations, in outpatient clinics or with longer-term treatment? How often do doctors talk—or think—about the price of a pill when they’re writing out a scrip?

So when Alexander’s residency ended in 2001 and he joined the University of Chicago as a Robert Wood Johnson clinical scholar, he arrived with a “burning interest” in the choices doctors make when it comes to prescription drugs. His first study on the topic, in 2003, put some numbers behind his hunch about exam-room conversations: only 35 percent of doctors and 15 percent of patients reported ever having discussed out-of-pocket costs for outpatient care.

“Now, this might not be important,” Alexander says, “if tens of millions of Americans weren’t burdened by their prescription costs, and if 20 to 30 percent of Americans didn’t report that at some point during the previous year, they had skipped or stretched a medicine because of cost. Fifty percent of medicines for chronic conditions are not filled and taken exactly as prescribed.”

Published in the Journal of the American Medical Association, his initial study has spawned half a dozen others, including one in which Alexander, now a Medical Center internist and assistant professor of medicine, examined the barriers to doctor-patient discussions of cost. Physicians feel awkward and pressed for time. They have trouble predicting which patients are financially stressed, and many don’t know how much particular drugs cost. Says Alexander, “Physicians are walking around with averages, and they may not realize that hydrochlorothiazide”—used to treat heart failure and high blood pressure—“is pennies. It’s $3 or $4 a month, whereas some of the expensive, brand-only therapies are hundreds of dollars a month.”

Some patients, meanwhile, assume their doctors can’t help, or that if they mention money they’ll get second-rate care. Not necessarily, says Alexander, who has studied strategies for doctors to assist overburdened patients: choosing generics, eliminating nonessential medicines, prescribing 90-day rather than 30-day supplies, or prescribing twice the dose and having patients split their pills.

But those strategies must begin with a conversation. “And there are obvious cost-quality trade-offs that can’t be navigated unless they’re talked about,” he says. “That is, a treatment may be marginally better, marginally more effective, or marginally safer, but a lot more expensive.” Now Alexander is finishing a study to determine whether “behavioral intervention”—in which researchers call patients and counsel them to raise financial concerns with their doctors—helps lower their prescription costs.

Recently Alexander has turned his attention to another set of choices physicians make about prescription medicines: off-label use. The Food and Drug Administration approves drugs for specific purposes but doesn’t regulate their usage thereafter, and physicians often learn that a treatment approved for one malady also helps remedy another. Most ACE inhibitors, for instance, were initially approved for hypertension and congestive heart failure, but they’re now also widely prescribed off-label to treat diabetes-related kidney damage. Off-label use can be beneficial, as it is with ACE inhibitors, Alexander says, if physicians follow scientific evidence. But the practice, he says, “runs the gamut from evidence-based to completely unsupported by the evidence. And some off-label uses have clearly unacceptable toxicities and safety risks for patients.”

In one study, published in last November’s Pharmacoepidemiology and Drug Safety, Alexander discovered that doctors may not even know when they are prescribing off-label. Physicians correctly identified the FDA approval status of only about half the drugs on a list of 22. Nearly 20 percent who’d prescribed quetiapine for dementia the previous year thought the drug was approved for that purpose, when in fact it carries an FDA “black box” warning that it is dangerous for elderly patients with dementia. (It’s approved for schizophrenia and bipolar disorder.) One in three doctors who prescribed lorazepam for chronic anxiety were similarly mistaken; in 2007 a revised FDA label warned against using lorazepam for chronic anxiety.

Why so much confusion about drugs’ FDA approval status? Many reasons, Alexander says. Often doctors—whose pharmaceutical toolbox is larger and more complex than ever—conflate evidence with FDA approval, or they’re simply overconfident that the data is there. “The evidence base is enormous,” Alexander says. “It’s always changing, and it’s mammoth.” Drug companies promote some off-label uses, creating the impression of FDA backing. And FDA warnings are not always effectively disseminated.

“It’s tough to know how best to regulate off-label prescribing,” Alexander says, “because one doesn’t want to diminish clinical innovation.” Yet “there’s a disincentive for manufacturers to do the safety studies necessary to get a label expansion.” One solution, he says, is making patients’ prescription regimens lean and effective. “As the number of drugs increases, the risk for drug-drug interactions increase, the risk of nonadherence increases, the risk of cost burden increases, and the risk of adverse events increases.”

Next on Alexander’s to-do list is a class of drugs called biologics, increasingly used—on- and off-label—to treat rheumatoid arthritis, cancer, and autoimmune conditions. Single doses can cost $5,000. Because biologics are much more toxic than conventional drugs, off-label use carries greater risks. Finding out how and how often they’re prescribed off-label is his first order of business.


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