WASHINGTON - May 8, 2006 - Doctors wrote more than 100 million prescriptions in the United States in 2001 for reasons that had "little or no scientific support," according to a just-published study on the prevalence of so-called "off-label" drug use.
The authors of the study, printed in the prestigious Archives of Internal Medicine, said that the widespread use of off-label therapies needs to be examined further to see if it "compromises patient safety or represents wasteful medication use."
In all, the study estimated that one in seven prescriptions was written without good medical evidence that it would work. The estimate was derived from prescriptions written by doctors in office-based medical practices.
Senior author Randall Stafford said the study has implications for all drug consumers.
"We want to avoid the situation where a drug clearly has some risks associated with it but we are uncertain about its benefits," said Stafford, an associate professor of medicine at the Stanford Prevention Research Center.
Asked about the study's conclusions, Dr. Edward Langston, a member of the board of trustees of the American Medical Association, said that the nation's primary physician organization "certainly supports off-label use, but based on sound scientific data. Otherwise, we have to be very cautious."
The Food and Drug Administration approves drugs after extensive studies have found them safe and effective in treating specific ailments in specific populations.
Once the drugs are on the market, however, doctors can prescribe them as they see fit, even for unapproved, or off-label, uses. Physicians say they need that flexibility to practice the art of medicine.
While some off-label uses are beneficial and based on good science, others have little proof of effectiveness behind them. The issue becomes one of risk: Because virtually every drug has side effects -- some merely annoying, some deadly -- an off-label prescription can mean that a patient is assuming the risk of harm with no assurance of benefit.
Stafford said that the risks of some off-label prescriptions could be higher than they are for on-label uses. "Just because the risk has been studied in one population doesn't mean that same level of risk will occur in other populations," he said. "It could be lower, it could be higher."
The recent study examined one of the nation's main drug-prescription databases for 160 drugs, determining whether each specific drug prescription met FDA or scientific standards. It was funded by a federal grant and was conducted by researchers from Stanford, Dartmouth Medical School and the Massachusetts Institute of Technology.
It found that 79 percent of the prescriptions were for FDA-approved uses, 6 percent were for off-label uses with "strong scientific support," and 15 percent were for off-label uses with "little or no scientific support."
Here is a different version of the same basic story.
August 28 2006 - In choosing which drugs to prescribe, doctors often select medications for patients despite a lack of conclusive medical evidence of their effects and safety, according to a new study led by researchers at Dartmouth Medical School and the Stanford University School of Medicine. This practice of "off-label prescribing" offers doctors flexibility and innovation in treating patients but also carries unknown risks. Of a wide sampling of prescriptions dispensed to patients in 2001, 21 percent were intended to treat medical conditions for which the drugs lacked specific approval from the U.S. Food and Drug Administration (FDA), though other published research suggested possible benefits. About three of every four of those prescriptions were for conditions for which there were little or no evidence of the drugs' effectiveness.
The findings, which will be published May 8 in the Archives of Internal Medicine, are believed to be the first estimate based on a sizeable data base of the actual number of off-label prescriptions among the 100 most-used drugs and 60 other randomly-selected, commonly used medications.
"Our results suggest that prescription drugs are frequently prescribed outside of their evidence base," said David Radley, lead author of the study and a graduate student in the Center for Evaluative Clinical Sciences at Dartmouth Medical School. "The use of unproven therapies could be risky for patients and may represent economically wasteful medication use."
Dr. Randall Stafford, associate professor of medicine at the Stanford Prevention Research Center and senior author of the study, added that many doctors may be unaware if a drug has been FDA-approved for a specific use or how much research supports its use. "Many doctors prescribed drugs when there is little or no evidence supporting its efficacy and safety," Stafford said. "The study can't tell us why doctors prescribe drugs off label. Some uses are more reasonable than others, but, by definition, off-label uses receive less scrutiny than FDA-approved indications."
It is unclear how off-label uses become established within the medical community in cases where limited or no scientific evidence backs up its use. Informal communication between physicians, promising or preliminary scientific studies, and marketing by the pharmaceutical industry could play roles, Stafford said.
Of course, just because a drug is unapproved by the FDA doesn't mean it's ineffective. The FDA approves drugs for treating specific conditions only, and there are many reasons that may explain why a drug has not been approved for treating a particular condition. Since the studies required for FDA approval are often time-consuming and costly, there is little incentive for pharmaceutical companies to seek approval for additional indications, said Radley.
For patients with severe medical conditions, the potential benefits of treatment might outweigh the increased risk associated with off-label use. A physician might choose to prescribe a drug off-label to adjust for a patient's sensitivities, to avoid interactions with other drugs or to try a different approach if FDA-approved drugs haven't worked. While nothing prevents a doctor prescribing a drug off-label, pharmaceutical companies are prohibited from directly promoting such uses.
With collaborator Stan N. Finkelstein, MD, of the Massachusetts Institute of Technology, Radley and Stafford compiled data taken from the 2001National Disease Therapeutic Index, a continuing survey of U.S. physicians conducted by IMS Health, a pharmaceutical and health-care marketing company based in Plymouth Meeting, Pa. The survey compiles data from 3,500 physicians who report information about patient care during two randomly selected, consecutive workdays every quarter. The data represents 403,957 encounters between doctors and patients.
According to the IMS Health data, the 160 commonly prescribed drugs represented an estimated 725 million annual prescriptions. About 575 million, or 79 percent of the total, were prescribed for a condition approved by the FDA. Off-label prescriptions accounted for 150 million, or 21 percent of the total number. Of those, 27 percent were for indications supported by scientific evidence, while the remaining 73 percent, or 109 million prescriptions, had little or no evidence.
The team considered a drug's use scientifically supported if the indication appeared with a listing of at least good evidence in DRUGEX, a nationally recognized pharmaceutical compendium. To be listed in this way, controlled trials or rigorous observations in clinical settings must show evidence of a drug's efficacy.
The medication gabapentin was prescribed off-label most frequently—about 83 percent of the total prescriptions for that drug. In 66 percent of these instances, the drug had little or no scientific evidence for its efficacy in treating the indication. As of 2001, the FDA had approved gabapentin as an anticonvulsant and as a pain-reliever for patients with shingles. Scientific evidence supported its use for social anxiety, migraine prevention and certain diabetic conditions. But doctors commonly prescribed it to treat bipolar disorder and chronic pain, uses not supported by adequate scientific evidence.
"Although this study could not measure the costs associated with off-label medication use, it should remind us that ineffective therapies may not represent the best use of healthcare resources," said Radley. "At a time when healthcare spending is so great, physicians, patients, and policy makers should all be concerned about overuse of unproven therapies."
May 8, 2006 (HealthDay News) -- The "off-label" use of prescription medications -- for conditions other than those approved by the U.S. Food and Drug Administration -- occurs in about one in every five prescriptions filled in the United States, a new study finds.
Unfortunately, the practice is potentially risky, since three-quarters of these off-label uses lack solid scientific support, experts say.
"The science for off-use can range from very carefully done rigorous trials that are available in peer-reviewed literature but not submitted to the FDA, to anecdotal evidence with no real scientific basis," said Dr. Mark Fendrick, professor of internal medicine at the University of Michigan School of Medicine in Ann Arbor.
"Before we say off-label use is positive or negative, we need to understand the amount of evidence for [a] particular use," said Fendrick, who was not involved in the study.
"The FDA approves for specific indications. It doesn't vouch for the safety and efficacy of all uses," added Dr. Randall Stafford, senior author of the study and associate professor of medicine at the Stanford Prevention Research Center. "That means there are drugs that are used for things other than FDA indications. We don't necessarily know if this is a good thing or a bad thing, but we do know that drugs used for those off-label indications have clearly received less scrutiny."
One possible remedy might be better monitoring of off-label use after drugs make it to the marketplace.
This type of surveillance, Stafford said, "would be particularly important for off-label uses which haven't gone through that initial step of being reviewed by the FDA."
"Difficulties have arisen over the last decade with drugs being approved and then removed from the market. Those situations have largely involved using the drugs exactly as they're approved. Off-label is, in a sense, where we are going out on a limb," he said.
As it now stands, once a medicine is approved by the FDA and makes it to the marketplace, it can be prescribed for any condition. But while the practice is legal, it may not always be safe.
For example, the blood-clotting drug NovoSeven, approved in the United States to treat hemophilia, has been linked to strokes, heart attacks and deaths when used off-label to treat cerebral hemorrhages and other types of serious bleeding.
And the drug letrozole (brand name Femara) is often prescribed as a fertility aid, even though it is only approved to treat breast cancer in postmenopausal women. When prescribed off-label, it may cause birth defects and miscarriages.
But Fendrick noted that getting any additional FDA approval for a drug costs pharmaceutical companies lots of money.
"To get a claim in the FDA in the U.S., you need two randomized, controlled trials," Fendrick explained. "It's expensive to get a claim."
To determine how frequently and for what reasons off-label use occurs, the authors of this study analyzed data from a national survey of office-based physicians. The survey, conducted in 2001, looked at prescribing patterns for 160 commonly prescribed drugs.
That year, 725 million total prescriptions were written for this sample of drugs.
According to the survey results, there were an estimated 150 million off-label prescriptions written, representing 21 percent of total use.
Of those, 27 percent were for indications supported by scientific evidence, while the remaining 73 percent, or 109 million prescriptions, had little or no evidence supporting the use in question.
The most common off-label uses were for heart medications (46 percent), anticonvulsants (46 percent) and asthma medications (42 percent).
The highest proportion of off-label use among specific medications was for gabapentin (brand name Neurontin, an anti-seizure drug), for which 83 percent of prescriptions were off-label, and amitriptyline hydrochloride (brand name Elavil, an antidepressant), for which 81 percent of prescriptions were off-label.
Eighty percent of the off-label prescriptions for gabapentin had little or no scientific evidence to back them up, the study found. Gabapentin drew controversy when its manufacturer, Pfizer, was accused and convicted of inappropriate marketing of off-label uses. It is illegal for pharmaceutical companies to promote off-label usage of their products.
Psychiatry and allergy medications were most likely to be prescribed off-label with limited or no scientific basis (96 percent and 89 percent, respectively).
Among the drugs that did have support for off-label use were certain antibiotics and Albuterol, approved for asthma but used also for chronic obstructive pulmonary disease.
The bottom line, the authors stated, is that off-label usage needs to be more rigorously scrutinized. Physicians, too, need to be alert to the potential pros and cons.
"Since all medical interventions, including all drugs, come with a risk, it's important to inquire about the potential benefit before exposing an individual to potential adverse consequences and costs," Fendrick said.
More information:
For more on off-label use of drugs, head to the U.S. FDA (www.fda.gov ).
