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A Dangerous Practice: How Drug Companies Bend FDA Rules

If the medication that you use hasn’t been approved by Food and Drug Administration to treat your ailment, you likely are paying extra for a prescription that might do more harm than good. However, drugmakers want even more freedom to market the use of so-called off-label prescriptions.

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Half of all consumers believe that when a doctor prescribes a medication, it has been tested and proven to work for the disease or symptom that a patient has, a survey indicates. Sadly, those consumers are sorely mistaken.

At least 21 percent of all medications that U.S. adults use are prescribed to treat ailments that Food and Drug Administration won’t allow drug companies to list on the medication’s label. These so-called off-label prescriptions are perfectly legal even though three-fourths of the time no independent scientific evidence exists to show that an off-label prescription works for the condition for which it’s used.

Although FDA regulates drug companies, it doesn’t regulate the practice of medicine. As a result, doctors are free to prescribe any treatment, no matter for what FDA originally approved it, says Allen Shaughnessy, who is a professor of medicine at Tufts University School of Medicine. “If a doctor wants to give you a pill and tell you, ‘Put this under your arm and dance on a gravestone at midnight,’ FDA can’t do anything about it,” he says.

Such an environment motivates drug companies to feed new excuses to doctors to get them to prescribe their medications for ever-expanding treatments, which allows the drug companies to boost sales of their medications without having to commit the time and expense of getting FDA approval. As a result, a drugmaker can take the path of least resistance to get FDA approval, then go hog wild on off-label use to rake in big cash even though such an approach frequently works against a patient’s best medical and financial interest, says Dr. Adriane Fugh-Berman, who is the director of PharmedOut, which is a pharmaceutical-industry-watchdog project at Georgetown University.

Off-Label Prescriptions That You Should Avoid

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Without question, circumstances exist where off-label prescriptions deliver benefits for consumers, particularly in the case of cancer medications, where off-label use is considered to be an acceptable practice because of the number of experimental treatments that are used for cancer. Off-label use of medication also is the standard for children’s care, because FDA doesn’t approve any medication for children. (See “Acceptable Off-Label Prescriptions.”)

Acceptable Off-Label Prescriptions

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However, in all too many cases, an off-label prescription is the result of a drug company’s attempt to sell a medication for an unproven and sometimes unsafe use just so the company can fatten its bottom line, independent health-care experts tell Consumers Digest. At the very least, drugmakers appear to be guilty of abusing a prescription-medication system that’s designed to give doctors the flexibility to do what’s best for their patients. The manipulative practices that drug companies employ could become even more widespread in the years ahead if the U.S. Supreme Court is asked to hear a dispute regarding whether FDA restrictions for marketing of medications for off-label use violate the free speech of drug companies. A ruling that favors drugmakers would open the floodgates to more off-label marketing and allow drug companies to push off-label use of medications even more broadly and with less evidence of the medications’ efficacy, experts say.

BEHIND THE SCENES. Here’s how off-label prescriptions commonly materialize, according to the 14 independent experts whom we interviewed: A drug company creates a medication that FDA approves to treat a particular ailment. When a doctor prescribes the medication for that FDA-approved use, it’s called on-label use, because the label that’s on the medication’s container or that’s attached to the prescription that you pick up at the pharmacy says FDA has approved it for that particular ailment.

However, all too frequently drugmakers turn their vast marketing apparatus to push doctors to prescribe FDA-approved medication for other common—and profitable—ailments. Drug companies hire researchers and highly paid ghostwriters to produce quick-hit studies that give the appearance that the medication is better than a placebo is at helping to treat additional health issues. The drug company can’t advertise the medication to consumers for off-label use, but it can start an elaborate word-of-mouth campaign that’s designed to convince health-care providers that the medication should be prescribed for other ailments. The drugmaker hires well-known doctors to speak at fancy dinners, where they tell other doctors about the off-label use of a medication. Drug-company sales representatives give doctors reprints of articles and other research materials that drugmakers help to have published to leverage influence. If the behind-the-scenes marketing campaign is successful, the drug company will take a medication that’s approved for use on a narrow ailment and convert it into a major moneymaker through the use of off-label prescriptions.

Off-label use also applies to medical devices, procedures

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For example, drugmaker Novartis revealed in January 2013 that federal prosecutors launched an investigation into the company’s marketing of FDA-approved blood-pressure medication Tekturna (aliskiren). The investigation was in progress at press time. Although Tekturna never has been shown to reduce the risk of heart attacks, strokes or heart failure, experts tell us that Novartis implies to doctors and patients that the medication will deliver the same benefits as will more-established and less expensive medications, such as water pills, ACE inhibitors and beta-blockers, all of which have excellent data that show that they reduce the risk of dangerous complications of high blood pressure, and they’re labeled as such.

Not only does Tekturna cost as much as 10 times more than do the more beneficial medications, but when Novartis performed studies to gather evidence that the medication helps to decrease the risk of a heart attack and renal complications, it found that the medication actually increased the number of nonfatal strokes and renal failure, says Jim Carlson, who is the director of Pharmacy Clinical & Health Plan Services at Group Health, which is a nonprofit health-care provider for people who reside in Idaho and Washington.

“So not only was it not beneficial, it was harmful, and we still have no evidence that it will be beneficial in any way other than reducing blood pressure, which in and of itself isn’t helpful,” Carlson says.

In July 2012, GlaxoSmithKline agreed to pay $3 billion as part of a settlement with Department of Justice over allegations that the drugmaker prepared, published and distributed to health-care providers a medical-journal article that made misleading claims about antidepressant medication Paxil (paroxetine hydrochloride). The article indicated that Paxil is effective for children and teenagers who have depression. However, FDA found that the medication could be dangerous for children, and it now requires Paxil to have a warning label that states that the use of the medication can increase the risk of suicidal thoughts and behavior for patients who are under 18.

OUT OF CONTROL. As Consumers Digest reported (“Under the Influence: How Doctors Are Courted by Drugmakers” at ConsumersDigest.com), drug companies employ a wide range of behind-the-scenes practices to persuade doctors to prescribe their products, particularly for off-label purposes.

For example, GlaxoSmithKline invited doctors to dinners, lunches and health-spa getaways that were designed to help to promote the off-label use of Paxil, according to the DOJ settlement. In another case, Abbott Laboratories paid $1.5 billion in May 2012 to resolve allegations by the federal government that the company illegally pushed its anti-seizure medication Depakote (divalproex sodium) for inappropriate off-label uses, such as the treatment of autism. The case included accusations that Abbott paid illegal kickbacks to prominent doctors who agreed to talk up the benefits of off-label use of Depakote.

Even if a drug company gets hit with lawsuits and huge settlement fees for illegal off-label marketing, the damage is diffucult to undo, experts say. Patients continue to use the medication for years after drug companies are punished, because the off-label use of the medication has been established as acceptable, experts say. After a medication has been prescribed commonly for off-label use, it’s difficult to get doctors to stop prescribing that particular medication in such a way, Fugh-Berman says.

For example, menopausal hormones that originally were approved by FDA to treat the hot flashes and vaginal dryness that are associated with menopause still are prescribed as a treatment for cardiovascular disease and even dementia in post-menopausal women. This comes despite a 2002 study that showed that the medication could increase the risk of heart disease, stroke, blood clots and breast cancer. Every clinical trial since 2002 that studied the off-label use of menopausal hormones showed that such prescriptions “do harm and don’t work,” Fugh-Berman says.

Of the three aforementioned drug companies that we requested to interview, only two responded, and only one—GlaxoSmithKline—answered specific questions. Yet we believe that the responses that we received from GlaxoSmithKline reveal a disturbing truth about the business of off-label prescriptions. For instance, GlaxoSmithKline tells Consumers Digest that it “denies and vigorously disputes” the allegations that were made by FDA in the aforementioned case that GlaxoSmithKline agreed to settle. So why did GlaxoSmithKline agree to pay $3 billion to settle charges that it says aren’t true? Independent experts tell us that drug companies see such settlements as a cost of doing business. If a drugmaker can make, say, $200 million by selling an off-label prescription that relies on misleading or illegal marketing, the drug company sees no harm in having to pay, say, $20 million to FDA to settle a lawsuit, because drugmakers would come out $180 million ahead.

Furthermore, Pharmaceutical Research and Manufacturers of America (PhRMA), which is a trade group for drugmakers, tells Consumers Digest that drug companies would have to spend significantly more time and money than they do now to conduct tests that would justify the off-label use of a particular medication.

“The process is one that can take more than 2 years and costs hundreds of millions of dollars in certain circumstances,” PhRMA’s James Spears says. “Full-scale, double-blind placebo-controlled [medication] trials are extremely expensive.”

Spears says it’s better for consumers to let doctors decide whether patients should use an off-label prescription rather than to have drug companies use more resources to meet a higher test-result threshold, because doctors have the freedom and expertise to determine what treatments work best for their patients. We can’t help but wonder whether Spears merely wants to allow drugmakers to make more money while they dodge responsibility.

IN YOUR HANDS. The unfortunate truth is that off-label use of medication can leave consumers—and sometimes even doctors—in the dark. The problem is that few methods exist for patients to know whether they’re being prescribed a medication for off-label use unless they carefully read the medication’s package insert or grill their doctor or pharmacist about the prescription.

Even most doctors aren’t aware that the medications that they prescribe are for on-label or off-label use, says Dr. Eric Larson, who studies the cost-effectiveness of health care at Group Health’s Research Institute. “If you asked me about the drugs I prescribe, ‘Which are off-label and on-label?’ I might have to look it up to be sure that I knew the answer,” Larson says.

What are your options as a patient? First, you have to ask your doctor whether the medication is being prescribed for on-label or off-label use; the doctors who do know typically won’t volunteer such information, because it’s so common in medical practice to prescribe medications for off-label use, Fugh-Berman says. If a doctor says he/she is prescribing a medication for off-label use, ask him/her why. A good reason might exist, and doctors should be able to tell you what it is.

For instance, a legitimate reason could be that the medication no longer is under patent, which means that it’s so inexpensive that no economic incentive exists for a drug company to conduct the tests that prove that the medication works for a particular off-label use. Only when medications are under patent do companies want to spend the money to do such tests, because they know that they—and only they—will benefit. Nonetheless, experts tell us that by the time a medication has been around long enough to come off patent, medical experts typically have a good sense of whether the medication is safe and effective for off-label use.

If the doctor can’t give you a legitimate reason for the off-label use, you should request that he/she give you an on-label prescription.

If your doctor becomes defensive when you ask about off-label use, it might be a sign that you should find another doctor, says William Soller, who is a professor in the school of pharmacy at University of California-San Francisco. Soller says it isn’t necessarily a bad sign if a doctor excuses himself/herself when you ask about off-label uses, because it typically means that he/she is going to his/her computer to find more information for you. “I want someone who will admit they don’t know something and go find out,” Soller says.

Ultimately, you want to see evidence from independent sources that supports the use of an off-label prescription. For example, if the research that supports the off-label use of a particular medication was paid for by the medication’s manufacturer, that’s a major red flag that indicates that the results are biased in favor of the drugmaker. Consequently, you should request a different prescription.

When you have doubts about a prescription, you should speak with your pharmacist. Independent experts tell us that a pharmacist often is the most qualified person to determine whether your prescription is for on-label or unnecessary off-label use, because pharmacists often are more knowledgeable about FDA approval of a medication than are the doctors who prescribe it. If the pharmacist says a prescription is for off-label use, you should ask him/her to recommend an on-label alternative, so you can have the option to request that your doctor write a new prescription.

You also can get help online. Experts say the most reliable source is dailymed.nlm.nih.gov, which is run by National Institutes of Health and has up-to-date information about all medications, including full FDA labels. If you determine that the prescription that you have is an unwanted medication that’s designed for off-label use, Fugh-Berman says you should take the prescription back to your doctor and tell him/her: “Thank you, but I prefer a time-tested drug.”

Finding out whether a low-cost and FDA-approved alternative exists is almost as difficult as finding out whether a medication is for off-label use. Although the Patient Protection and Affordable Care Act created Patient-Centered Outcomes Research Institute (PCORI), which is supposed to be a source of information about the comparative effects of different medications and treatments, it leaves out price comparisons, because lawmakers caved to lobbying by the pharmaceutical industry, experts tell us. As a result, PCORI isn’t allowed to tell people what medications cost, says Randall Stafford, who is a professor of medicine at Stanford University who specializes in evidence-based medicine and prescribing.

Unfortunately, the missed opportunity by lawmakers isn’t the only example of how the federal government could do more to protect consumers when it comes to unnecessary off-label prescriptions. Experts insist that FDA should expand its role. For example, Stafford says, FDA could do a better job of enforcing restrictions that are designed to reduce unnecessary use of off-label prescriptions. He says FDA can better anticipate which medications would be prescribed for off-label use and should monitor more aggressively the patterns of use for all medications. For instance, FDA could implement a threshold for the amount of off-label use and more heavily scrutinize that medication when it exceeds that threshold.

When we asked FDA whether it would take such additional steps to monitor and scrutinize off-label use and drugmakers, FDA spokesperson Sarah Clark-Lynn responded with a statement that didn’t address our question. She says FDA will continue to enforce existing provisions that restrict how drugmakers market off-label use of medications. We take her comments to mean that FDA won’t apply more scrutiny.

COURTING DANGER. Some experts worry that the Supreme Court could undermine the little power that FDA already exercises if the Supreme Court is asked to settle federal appeals court cases that question whether FDA’s marketing-claim restrictions for off-label prescription use violate the free speech of drug companies.

We likely won’t know until at least summer 2013 whether the issue will reach the Supreme Court. If the Supreme Court agrees to rule on the issue and then rules in favor of drugmakers, the decision would make it more difficult for FDA to rein in drugmakers who exploit off-label use of their medications, experts say.

The dispute stems from two conflicting federal appeals court rulings. In March 2013, the Ninth Circuit Court of Appeals in San Francisco upheld the 2009 conviction of Scott Harkonen, who is the former CEO of drug company InterMune. Harkonen was convicted of wire fraud for writing and distributing a press release that touted the off-label use of a medication that FDA approved only for treatment of severe osteoporosis. The press release was based on Harkonen’s manipulation of study data, and Harkonen actually said he would “cut that data and slice it until [he] got the kind of results [he was] looking for,” the court’s ruling said.

His lawyer argued that Harkonen’s statements were protected by the First Amendment and that the statements were part of “genuine scientific debate.” The appeals court disagreed, saying it was clear that Harkonen’s aim was to defraud and that he had a financial incentive to do so. Harkonen’s lawyer says he plans to appeal, although no appeal had been filed at press time.

Alternately, in December 2012, the Second Circuit Court of Appeals overturned the conviction of drug-company sales representative Alfred Caronia. Caronia was charged with promoting the off-label use of a central-nervous-system depressant medication that’s approved to treat narcolepsy. The off-label uses that Caronia promoted included treatment of insomnia and fibromyalgia. The federal appeals court ruled that the conviction restricted Caronia’s right to “commercial speech,” as long as his statements were truthful, saying the government can’t prosecute companies “for speech promoting the lawful, off-label use of an FDA-approved drug.”

FDA decided not to appeal the Caronia decision, because it doesn’t believe that the decision “will significantly affect the agency’s enforcement” of medication-misbranding laws, Clark-Lynn tells Consumers Digest. Nonetheless, the Second Circuit Court effectively ruled that FDA marketing restrictions for off-label use of medication violates free speech as long as the communication is truthful, whereas the Ninth Circuit ruled that FDA may restrict off-label marketing to some degree. As a result, FDA marketing restrictions for off-label use of medications is an issue that the Supreme Court eventually will have to resolve, says Marcia Boumil, who is a lawyer and professor at Tufts.

Some medical experts whom we interviewed worry that a Supreme Court decision that sides with drugmakers could be the first step toward dismantling FDA’s 75-year-old system that’s designed to protect consumers against unscrupulous medication sales. The Second Circuit Court ruling indicates that it isn’t the responsibility of the government to help doctors and consumers to sort through marketing claims—no matter how misleading they might be—and to make good decisions about medications, says Aaron Kesselheim, who is a professor of medicine at Harvard Medical School. Kesselheim was among the authors of a February 2013 article in Journal of the American Medical Association that called the Second Circuit Court’s position “disturbing.” We agree.

If the Supreme Court’s 2010 ruling on corporate-campaign contributions is any indication, consumers have every right to fear the worst. In that case, the Supreme Court ruled that campaign contributions by corporations and unions are protected by the First Amendment, which has been interpreted by consumer advocates to mean that the Supreme Court supports broader free-speech rights for corporations. As a result, doctors are bracing for the possibility that the Supreme Court will rule that FDA doesn’t have the right to regulate how drugmakers market their medications for off-label use, which would take away even the limited protection that FDA can provide to consumers.

How worried that consumers should be depends on whom you ask. For instance, Boumil insists that “we are still a long way from a situation where drug companies can promote snake oil without oversight.” However, Soller says consumers face “a perfect storm” when it comes to off-label drug use. He predicts that the Supreme Court will allow off-label marketing as an element of free speech, as long as the claims that drugmakers publish aren’t false. Of course, the studies on which drugmakers rely to market the off-label use of their medications often are based on evidence that’s as thin as the paper on which the studies are printed, independent experts tell us.

If the Supreme Court gives drug companies the freedom to promote off-label prescriptions for anything for which they can gin up a study, the scope for which many medications are prescribed for off-label use will widen broadly, experts warn. “Harm will happen” under such a scenario, Soller says, because consumers will be even more in the dark about what medication they take and why the medications are prescribed. We’d call that a tough pill to swallow.

Elizabeth Weise has written about health and science for USA Today since 2002. She also investigated food fraud in the May/June 2012 issue of Consumers Digest.

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