For patients with rare diseases — or who have simply tried every FDA-approved treatment to no avail — going off-label may be the only hope. But what happens when health insurance providers say no? (Photo: Getty Images/Fanatic Studio/Yahoo Health)
Imagine you’re diagnosed with a disease so rare that there’s no established treatment for it. Hope seems lost until your doctor’s dogged pursuit yields a more-than-promising therapy. But then your health insurance provider refuses to cover it, leaving you with no medical lifeline.
What sounds like an impossible nightmare is the reality for Manny Alvarez, a 23-year-old Florida International University student diagnosed with alveolar soft part sarcoma (ASPS), a type of cancer that occurs in only 15 to 80 people nationwide each year. Your odds of being struck by lightning are greater.
ASPS, which is often characterized by a painless lump in the leg or buttocks, doesn’t tend to respond to standard chemotherapy. That means treatments involving new chemotherapy drugs are a “reasonable” option, according to the National Organization for Rare Disorders.
When the chemotherapy Alvarez received as part of a National Institutes of Health clinical trial failed, his oncologist, Breelyn Wilky, MD, set out to find a combination of drugs that would effectively combat his cancer, which had begun eroding the bones of his leg. After subjecting a sample of malignant cells from Alvarez’s tumor to a battery of chemotherapy drugs, Wilky found that a treatment typically used for leukemia effectively wiped out the rogue cells. The next step seemed straightforward enough: submitting a request for coverage of the roughly $300,000 treatment to Alvarez’s insurance provider, Blue Cross Blue Shield of Florida.
Manny Alvarez is only 23 years old, but his family is already facing the prospect of bankruptcy in order to pay for his chemotherapy. (Photo: Crowdrise/Manny Alvarez)
Although that sum may sound astronomical, it’s actually not unreasonable. “A typical cancer drug will cost a patient a quarter of a million dollars,” Randy Vogenberg, PhD, an adjunct professor at the University of Rhode Island College of Pharmacy and co-founder of Access Market Intelligence, a health systems consulting firm, tells Yahoo Health. “That’s just for one drug, and usually these patients are on multiple drugs.”
But this juncture is where Alvarez’s journey turns tragic: His insurer refused to pay for the treatment, since it’s not standard care for his cancer. But the irony is that there is no standard care for ASPS, says David Katz, MD, who wrote a recent editorial about Alvarez’s case for the Hartford Courant. Even after Alvarez appealed this decision, coverage was still denied, again because the proposed chemotherapy, which is FDA-approved for another type of cancer, is considered “off-label” (a term that can be used to describe a number of prescribing practices).
In a statement provided to Yahoo Health, Blue Cross Blue Shield of Florida said:
We recognize there may be cases in which coverage for a specific treatment is requested, where that treatment is not clinically proven or not U.S. Food and Drug Administration (FDA) approved for that particular use. In these cases, as a health solutions leader, we collaborate with our members and their physicians to explore proven, safe and effective covered alternatives.
If coverage of a non-clinically proven treatment is denied, members have the right to appeal. This process includes an internal review of the case by Florida Blue medical professionals, as well as an independent external review by physicians who are experts in the particular medical field.
It is important to note that Florida Blue regularly monitors and evaluates new advances in medical and pharmaceutical treatments. We are continually updating our coverage policies based upon ongoing medical research and evidence-based conclusions.
Using a Drug ‘Off-Label’
“Although we often think about off-label as using a drug for a different disease [than what it’s approved to treat], products can also be used off-label when they’re used at a higher or lower dose than approved, when they’re used in an unapproved population, or when used with a different route of delivery,” for example, when given rectally instead of through an IV, says Caleb Alexander, MD, co-director of the Center for Drug Safety and Effectiveness at Johns Hopkins University.
Despite the potential hurdle of insurance reimbursements, off-label prescribing is far from a fringe practice. “Virtually all drugs are used off-label, and some are commonly used off-label,” Alexander tells Yahoo Health. As Katz puts it, “medicine would fall apart if we didn’t do off-label prescribing. We do it all the time — every day. It’s not like the concept is controversial or radical.” The practice is especially common for drugs used to treat cardiovascular diseases, seizure medications, antipsychotics, antidepressants, and asthma medications, and among pediatric, geriatric, or pregnant patients, who are often excluded from clinical trials.
It’s also a fairly standard part of cancer treatment, since many cancers have few approved therapies and desperation may drive both patients and oncologists to take an experimental route, according to the American Cancer Society. “If you use chemotherapy to kill cells, the ones left behind are most resistant to the drugs,” adds Katz. “Those cells start to divide, and then you have a whole new population of cells — and they’re all the progeny of the cells that were most resistant to the drugs that you used the first time.” As a result, cancer patients are often forced to branch out beyond the chemotherapy drugs approved for their particular type of tumor.
In fact, a recent University of Chicago analysis of 10 commonly used chemotherapies found that they’re administered off-label 30 percent of the time, which accounts for $4.5 billion of the approximately $12 billion spent on these drugs annually in the U.S. The potentially tricky part: More than half of these off-label chemotherapies aren’t in accordance with National Comprehensive Care Network Compendium recommendations, a basis for insurance coverage policies. Similarly, in a 2006 study of outpatient prescribing, researchers found that 21 percent of drugs prescribed are off-label, and 73 percent of these unapproved applications have little or no scientific support.
Deciding What Insurance Companies Cover
Compendia — a series of reference manuals that summarize information on both on-label and off-label drug uses — are one of the primary tools health insurance providers use to determine whether or not to cover an off-label treatment. “Being listed in a compendium can favorably influence coverage and reimbursement determinations by insurers,” says Alexander.
In other words, if a drug isn’t yet FDA-approved for treatment of a specific disease, but a compendium presents evidence in favor of such use of the medication, an insurance provider may cover patients who seek the off-label treatment. Medicare and Medicaid, for example, will cover off-label drug uses if they’re included in certain major compendia, according to a journal article in Pharmacy and Therapeutics.
What sounds like a reasonable solution to a gray area of insurance coverage is actually somewhat controversial, since compendia aren’t comprehensive and are sometimes produced by for-profit companies. “Although they serve a valuable purpose in synthesizing enormous amounts of scientific information, they’re far from perfect in their ability to do so,” says Alexander.
In fact, when Alexander and his co-researchers analyzed compendia entries for two classes of antipsychotics, “it was difficult to determine why compendia made the decisions they did about listing products as having certain levels of evidence, and there were inconsistencies in the ways that evidence was evaluated,” Alexander says. “We also found evidence suggesting a potential commercial bias — that is, products that were branded were generally treated more favorably than [generic drugs].” Although his study was limited to psychotropic medications, he believes he’d uncover a similar lack of transparency for other classes of drugs.
Equally concerning is the general lack of evidence to support treatment of rare diseases. “If there’s virtually nothing to summarize, there will be no compendia,” Katz says. Read: If a disease is extremely rare, compendia have little or no research to draw from, which means conditions like alveolar soft part sarcoma are unlikely to be covered in compendia, leaving patients with no way to petition insurance providers for coverage. Compounding the problem is the fact that many previously recognized compendia are no longer even being published.
Yet, in most cases, patients have little difficulty gaining approval for off-label drug uses, since so many are well established in the medical community. “Off-label prescribing is routine and usually questions aren’t asked,” says Katz. He cites the example of the antidepressant Prozac being used for migraine prevention. “I’ve prescribed it that way many times over the years,” without any trouble from insurance providers, he says. Why? It’s a relatively inexpensive drug. By contrast, the off-label treatment Alvarez seeks comes with a six-figure price tag, which Katz speculates is the reason he was denied coverage. “To be honest, I think it’s cost more than anything,” he says.
As Vogenberg explains, there are two domains that insurers consider when deciding whether to cover an off-label use: “One has to do with the clinical evidence — FDA approval, the clinical studies, or cases published in the medical literature that demonstrate safety and effectiveness of a product. And then there’s the economic domain — the cost of this drug — where you get the controversy.”
Ironically, it’s the enormous expense of the drug approval process that necessitates off-label prescribing in the first place. Since it costs about a billion dollars to gain FDA approval, there’s small motivation to pursue permission to market a drug in a new way, especially if it’s nearing the end of its patent life. “If the product is for an extremely small population” — for example, if a drug manufacturer determines that an existing medication may treat a rare cancer — “or if the evidence to support the product’s efficacy is flimsy, the manufacturer has very little incentive to seek a label extension,” says Alexander. Why? Because there’s little promise of profit.
Although the FDA regulates the approval and marketing of medications, doctors are free to prescribe drugs as they see fit — that is, they’re not legally obligated to use, say, antidepressants exclusively to treat depression, although it’s generally considered preferable to prescribe an “on-label” drug when one is available for a patient’s condition. Though drug companies are prohibited from marketing drugs for unapproved uses, sales reps can provide peer-reviewed journal articles demonstrating the efficacy of a new drug use to physicians, the article in Pharmacy and Therapeutics reports.
This further reduces the odds of drug companies conducting clinical trials, which, as you’d expect, has its inevitable downsides. Take, for example, the now-infamous drug combination known as “fen-phen,” of fenfluramine, an appetite suppressant approved for short-term use, and phenteramine. Doctors began prescribing this drug duo for long-term weight loss — and consequently, “thousands of people developed heart valve damage from this off-label use before the adverse effect was identified and fenfluramine was removed from the market,” according to the Pharmacy and Therapeutics article. “This incident is often cited as an example of undesirable consequences when drugs are used in an unapproved dosage regimen, for an unapproved purpose, and without evidence of safety.”
Crowdsourcing: The Last Hope?
Sometimes, as in Manny’s case, an off-label treatment is the patient’s only option. According to the EveryLife Foundation for Rare Diseases, 95 percent of rare diseases (those that affect fewer than 200,000 people in the U.S.) have no FDA-approved treatment.
“Manny Alvarez’s family is just the poster child for a bigger issue,” says Katz. A quick perusal of GoFundMe, the crowdfunding website, reveals a litany of desperate patients seeking monetary aid for off-label treatments — in some cases, for rare diseases; in others, for unapproved treatments after FDA-approved options have failed — that aren’t covered by their insurance.
In one case, the children of Minh Tran, a woman diagnosed with stage 4 kidney cancer, sought funding for a drug that was FDA-approved for melanoma but not any other type of cancer; although they raised nearly $30,000 of the necessary $65,000, Tran died in February of this year. The husband of a woman with an aggressive form of brain cancer has successfully raised more than $20,000 — the cost of one month of treatment, he says — for an off-label therapy for his wife.
As new technology permits more in-depth analyses of potential treatments, “I think this is going to be more and more of a common problem,” Vogenberg says. “Then it becomes a societal question: How are we going to handle this? We haven’t really dealt with this.”
For cancer drugs in particular, there’s hope in the pipeline, as the National Cancer Institute conducts “bucket trials” that aim to designate cancer treatments according to their genomic pathway, rather than by the part of the body they target. “Any particular biologic drug may work in a whole variety of different kinds of cancers, based on that genomic mechanism,” explains Vogenberg. “Now, the FDA would likely be compelled to say, ‘Well, if this cancer has this pathway, then it’s an approved indication for use [of this drug].’ This is a big paradigm shift.” Eventually, this could eliminate — or at least reduce — the instances where a particular type of cancer has no approved treatment.
Still, “it’s enormously expensive to get FDA approval,” says Katz. And right now, “that’s a public safety issue.” After becoming a champion for Alvarez, who is a friend of Katz’s daughter, he’s also become an advocate for regulatory revisions surrounding insurance coverage of off-label drug usage. “I wasn’t looking for this per se, but it found me — and I can’t let it go,” he says.
To join Katz’s fight for Manny’s coverage, sign this petition, which urges Blue Cross Blue Shield of Florida to reverse its decision. You can also make donations to help pay for Manny’s care on Crowdrise.
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