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A Catch-22: Neurologists Can Prescribe Off-Label, But Risk Health Insurers' Denials for Reimbursement

ARTICLE IN BRIEF

DR. CYNTHIA HARDEN: “I have a sense that the insurance companies are being so selective about how they reimburse that it restricts practice. By their selective reimbursement they're affecting the way patients are treated.”

Neurologists discuss reasons why they prescribe off-label for neurological conditions as well as the challenges they face when insurers deny their claims for reimbursement.

The patient, a 19-year-old male, had “progressive encephalomyelitis with rigidity and myoclonus,” an extremely rare and disabling autoimmune disorder known as PERM.

“It leads to very severe encephalopathies, seizures, status epilepticus, respiratory failure, muscle rigidity, and spasms that can actually break bones,” said Timothy Vollmer, MD, medical director of the Rocky Mountain MS Center at the University of Colorado in Denver.

The only known treatment is rituximab, which shuts down the immune system's attack on the body, but the drug is FDA-approved only for non-Hodgkin's lymphoma. The only evidence supporting off-label use of rituximab against PERM involves anecdotal or single case reports.

“So the insurance company denied reimbursement for the drug, and didn't give me an alternative,” Dr. Vollmer said. “That young man ended up back in the hospital with recurrent seizures as part of his syndrome.”

Although more than 20 percent of prescriptions written in the US — about 150 million — are for indications not officially approved by the FDA, physicians complain that insurance companies routinely deny payment for off-label drugs.

“Every week I'm on the phone with an insurance company trying to defend the use of a therapy,” Dr. Vollmer said. “Typically this occurs with expensive biologics in patients with rare diseases where clinical trials will never be done because the disease is so rare, but we also get denied frequently for Provigil (modafinil) and Nuvigil (armodafinil). We have trials, both open label and randomized, showing their efficacy for fatigue in MS, but we get denied coverage by about half of the insurance plans because that is not part of the indication for the drug. So we have to put patients through other drugs and prove that they fail on them before we can get it approved, and even then we often don't get it approved. We spend a lot of time on appeals.”

WHY PRESCRIBE OFF-LABEL?

Denying reimbursement for off-label drugs affects neurologists in particular since epilepsy, Parkinson disease, dementia, mood disorders, and other neurological conditions respond with notorious variability to medications, making off-label prescribing frequently appropriate and reasonable.

“Because people have such variable responses, prescribing often becomes a matter of trial and error,” said Cynthia Harden, MD, chief of the Division of Epilepsy and Electroencephalography, and professor of neurology at Hofstra North Shore-Long Island Jewish School of Medicine. “For epilepsy, we don't have a lot of targeted drugs. For example, we don't have a drug specifically for seizures that start in the frontal lobe versus the temporal lobe.”

MORE THAN 20 PERCENT of prescriptions written in the US — about 150 million — are for indications not officially approved by the FDA.

Even changing the dose of a drug can result in a denial, she has found. “Prescribing medications at higher-than-approved doses is routinely denied by insurance companies,” Dr. Harden said. “Also, if you prescribe a drug three times per day that is approved for twice per day, it may be denied, although the total daily dose is the same, and within approved prescribed doses. I have a sense that the insurance companies are being so selective about how they reimburse that it restricts practice. By their selective reimbursement they're affecting the way patients are treated.”

Off-label prescribing can be effective, neurologists agree. A recent study in the American Journal of Alzheimer's Disease and Other Dementias, for example, found that “despite lack of evidence for efficacy,” memantine and acetylcholinesterase inhibitors are frequently used to treat behavioral variant frontotemporal dementia. Gabapentin, developed as an anti-seizure medication, is frequently prescribed for chronic pain and restless leg syndrome, and for opsoclonus-myoclonus syndrome in patients with locked-in syndrome. Other drugs are often prescribed off-label to treat non-motor symptoms of Parkinson's disease, such as dementia, fatigue, depression, psychosis, and low blood pressure.

Yet, a recent survey by HealthLeaders-InterStudy, which analyzes health care and managed care markets, found that health plans often don't reimburse for drugs prescribed off-label, or they place restrictions on such prescribing. For example, 21 percent of the 50 health plan pharmacy directors surveyed said that they do not reimburse for off-label prescriptions for pregabalin (Lyrica), which is approved for partial seizures, fibromyalgia, diabetic nerve pain and pain after shingles, but also prescribed off-label for moderate pain and anxiety. Also, 40 percent said they place restrictions on off-label reimbursement for pregabalin.

RESTRICTIONS FROM HEALTH PLANS

“Prior authorization and step therapy are two types of restrictions that health plans formally disclose to the public, and serve to limit patient access to branded therapies,” said Leigh Compton, MD, PhD, an analyst for HealthLeaders-InterStudy, a company that examines reimbursement policies of insurance companies.

“Step therapy means the plan requires the beneficiary to fail one or more therapies before they will reimburse that drug,” she explained. “Prior authorization means the health plan must approve the drug before reimbursement. That might mean they want to make sure the patient has the correct diagnosis, or that appropriate tests were performed, or that they require specialists to prescribe the drug. They may also want to know particular information about the severity of the disease, and if the drug prescribed (off-label) is appropriate.”

Researchers at the Center for the Study of Drug Development at Tufts University found that about 25 percent of health plans in the US do not reimburse for off-label drugs. Those that do reimburse often impose conditions including step therapy, prior authorization, quantity limits, and other restrictions.

“With off-label use I don't see a trend toward more restrictions, but I do see a trend toward higher cost sharing,” said Joshua P. Cohen, PhD, Senior Research Fellow at the Center. “For example, insurance companies may require coinsurance, a percentage of the drug cost. With some cancer drugs, which may cost $2,000 or $3,000 per unit, they may levy 20-35 percent of the cost on the patient. That is not specific to off-label use.”

One trend that has actually increased reimbursement for off-label drugs, according to Cohen, is the acceptance of four drug compendia that contain evidence for off-label indications.

“The problem until four or five years ago had been that it wasn't clear which compendium Medicare would authorize,” he said. Now, however, Medicare, and therefore most insurance plans, refer to four major drug compendia: American Hospital Formulary Service Drug Information, National Comprehensive Cancer Network Drugs and Biologics Compendium, Drugdex (published by Thomson Micromedex), and Clinical Pharmacology.

“These will cover a very large number of off-label uses,” Cohen said. “Some off-label uses have proven useful and beneficial, but it's important that the evidence be codified. Over the last few years insurance companies have relied on this evidence-based movement to ensure that everything they pay for has an evidential basis. Third-party payers are reluctant to pay for off-label uses that do not appear in compendia, but that's not new, and it makes sense — they want an evidence base before making a reimbursement decision. “

Inclusion in an accepted compendium is a key criterion for approval of a drug prescribed off-label, according to Susan Pisano, vice president of communications for America's Health Insurance Plans (AHIP), a national association representing nearly 1,300 health insurance providers.

“The prescribed drug has to be supported by an established standard reference compendium, and/or published studies,” she said. “There has to be some evidence that it's safe and effective for use in a particular indication. In other words, you don't want to be providing coverage or prescribing when there isn't an evidence base for that approach. I think it would not be the case that that coverage would be provided in all instances, but certainly there is considerable coverage for off-label use when those points are met.”

DR. TIMOTHY VOLLMER: “Every week I'm on the phone with an insurance company trying to defend the use of a therapy…. We have trials, both open label and randomized, showing their efficacy for fatigue in MS, but we get denied coverage by about half of the insurance plans because that is not part of the indication for the drug. So we have to put patients through other drugs and prove that they fail on them before we can get it approved, and even then we often don't get it approved. We spend a lot of time on appeals.”

Pharmaceutical companies may not promote a drug for off-label use, and several have paid large fines in recent years for doing so. Most recently, Elan Pharmaceutials, Inc., a subsidiary of Irish drugmaker Elan Corporation, PLC, agreed to pay $203.5 million for marketing the epilepsy drug zonisamide (Zonegran), approved only for the treatment of partial seizures in adults. Elan, aware that 50 percent of prescriptions written for the drug were for off-label uses such as migraine, chronic headache, mood stabilization for mania and bipolar disorder, eating disorders, obesity, movement disorders in Parkinson's disease, and seizures in children, began promoting it for such uses in violation of the Federal Food, Drug, and Cosmetic Act.

Prescribing off-label also raises ethical questions for physicians. In a 2009 commentary in the Archives of Internal Medicine, the authors asserted that “new drugs, novel off-label uses, drugs with known serious adverse effects, and high-cost drugs,” should all signal a need for a higher level of scrutiny before they are prescribed. They also suggested classifying off-label uses as “supported, suppositional, or investigational” — a system that would identify “the strength of the evidence for net health benefit.”

But such concerns remain largely philosophical if insurance companies constrain off-label prescribing by restricting reimbursement, since such resistance discourages physicians from attempting novel uses for approved drugs.

“I've had pretty long fights with insurance companies,” said Dr. Harden. “I've won some of the fights, but it's painful, and sometimes you don't win. You just give up.”

REFERENCES:

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Bogan RK, Cramer Bornemann MA, Kushida CA, Barrett RW,et al, for the XP060 Study Group. Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study. Mayo Clin Proc 2010;85(6):512–521.
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Food and Drug Administration press release, “Elan Pharmaceuticals Pleads Guilty, Sentenced for Off-Label Marketing of Zonegran,” Feb. 28, 2011 http://www.fda.gov/ICECI/CriminalInvestigations/ucm245523.htm
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