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While the Medicare prescription drug benefit provides assistance for many people with their drug costs, the requirements for coverage of the off-label use of a drug are onerous and often result in beneficiaries not being able to get the drug coverage they need.  Unfortunately, the information the law requires beneficiaries to submit to substantiate their claim for an off-label use is not readily available.  As a result, many people cannot access the information and cannot substantiate their claim for drug coverage.  They are left without the means to pay for what may be the only medication available to treat their condition or illness.

The term "off-label usage" applies to any use of a medication in a manner not specifically approved by the FDA and delineated on the label given to the drug during the approval process. Drugs are most commonly used off-label for combating cancer, controlling extreme pain, and treating autoimmune diseases, psychiatric problems, and conditions of the central nervous system such as Multiple Sclerosis.[1]

Studies have shown that one in five prescriptions written in the United States is for an off-label usage, and that as many as 73% of off-label usages have little or no scientific evidence backing up the theory that the drug would prove efficacious in treating the patient's condition.[2] The FDA does not require research into the efficacy of a drug before doctors prescribe it for an off-label usage.

Physician Knowledge of Off-label Use Rules

Many doctors are unaware that the drugs they prescribed have not been approved by the FDA for that use, and they lack up-to-date information on off-label usage. A national survey conducted in 2007-2008 gave physicians and psychiatrists a list of 22 drugs and uses. The doctors were to indicate whether or not these uses of the drugs had FDA-approval. If a doctor identified a drug-use pairing as including an off-label use, the survey instructed the doctor to indicate whether or not scientific evidence supported the usage.  The mean score was 55%,[3] indicating that many prescribers do not know whether the drugs they prescribe have been approved by the FDA for the prescribed use or, if not approved, whether the off-label use is supported by scientific evidence.

Some experts believe that off-label drug usage promotes innovations in medical practice and benefits patients, some of whom may have no other treatment for their condition or diagnosis.  The use of aspirin to reduce the risk of heart attack is a well-known example of how an off-label drug use can become standard medical practice.[4] Other experts raise concerns about off-label prescribing, citing the lack of evidence concerning safety, effectiveness, and potential side effects.[5] 

Getting Coverage for an Off-label Drug Under Medicare Part D

Medicare prescription drug plans impose restrictions on certain formulary drugs in order to limit coverage to what they determine to be medically accepted indications.  For example, a Medicare beneficiary may be required to get prior authorization before a prescription can be filled or may be required to try a different drug before the prescribed drug will be covered.  The drug plan may limit the quantity of a drug to less than the amount prescribed.[6]  In some instances, plans may even make a retroactive determination that a prescription for which they already made payment was not medically indicated.[7] These restrictions are often used to screen for the off-label use of a formulary drug.

Medicare law creates a complicated process through which a beneficiary may seek coverage for a drug when coverage is denied at the pharmacy counter; when a plan requires prior authorization before covering a prescription; or when a plan determines retroactively that a prescription already filled is not medically indicated.  The process involves contacting the drug plan, submitting evidence in support of the prescribed use, seeking support of the doctor or other prescriber, and often appealing through multiple layers of review.  Beneficiaries can request that decisions be expedited if they have not already paid out of pocket to purchase the drug, and if they or their prescriber indicates that adhering to the standard time frames for reviewing claims and appeals could seriously jeopardize their life or health or their ability to regain maximum functioning[8].

Congress limited the proof that beneficiaries must submit to support coverage of off-label drugs under Medicare Part D.  Peer-reviewed medical journals that are identified by Medicare may be used to establish a medically accepted indication for off-label drugs, but only for those used in an anticancer chemotherapeutic regimen covered under Medicare Part D.[9]  Part D rules concerning peer-reviewed medical journals differ from Part B rules, which allow reliance on such peer-reviewed medical journals for all categories and classes of drugs.[10]  The Part D rules also differ from the Medicaid rules, which allow coverage for off-label usage consistent with peer-reviewed medical literature.[11] 

Medicare Part D covers drugs prescribed for off-label use only if the drugs are identified as safe and effective for that use in one of three officially recognized drug compendia. "Compendia" are encyclopedias of drug chemicals, with information on dosage and usage. Congress has given Medicare the authority to revise the list of approved compendia as appropriate.[12]  Unfortunately, the burden of proving if a particular Part D-covered drug has been included in the compendia falls to the Medicare beneficiary, and accessing these compendia can be more complicated than might be imagined.

What Are the Three Compendia?[13]

The three compendia identified in the Medicare statute are the American Hospital Formulary Service – Drug Information (AHFS-DI), the United States Pharmacopeia – National Formulary (or its successor publication), and DRUGDEX Information System.[14]  Some differences in content exist among the compendia, but only one compendium need approve an off-label usage for Medicare Part D to cover it.[15]

American Hospital Formulary Service – Drug Information (AHFS-DI)

American Society of Health-System Pharmacists (ASHP), a non-profit organization, produces AHFS – Drug Information. AHFS-DI consists of monographs that discuss safety and efficacy of drug uses, and that are indexed by brand and generic names.  The monographs assess previously published material about the drug in question and, according the ASHP web site, are researched, written and edited by its staff. Volunteer medical experts then review these monographs for quality and accuracy. Among these are practicing doctors, researchers, and professional groups such as the American Medical Association (AMA), as well as governmental bodies such as the National Institutes of Health (NIH) and Center for Disease Control (CDC).[16] ASHP contends that its policy of separation from the private sector minimizes any potential for undue influences from pharmaceutical companies in discussing off-label usage of a particular drug.[17]

 

According to information on its website, ASHP, before reviewing an off-label use of a particular drug, considers factors including the availability of published reports of studies and support for the use in literature, as well as the reliability of both the studies and the literary support. In addition, the staff evaluates possible dangers associated with use of the drug and the drug's effectiveness, as well as the availability of alternative methods of treatment and the severity and frequency of the condition.[18] AHFS-DI claims its reviewing process to be comprehensive in its description of effects (positive or negative), suggested dosages, recommended audience, and inclusion of any inconclusive data that may have emerged.

 

United States Pharmacopeia – National Formulary (USP-NF)

The US Pharmacopeia (USP), a non-profit organization, is responsible for setting standards for pharmaceutical and medical products.[19] Among its responsibilities is the establishment of standards for categories and classes of drugs to be included in Part D formularies.

 

USP produces USP-NF. USP-NF contains the USP's decisions regarding acceptable use and quality standards for drugs.[20] After reviewing information, including standards, monographs, and data, provided by the pharmaceutical companies, USP's staff investigates the findings through scientific tests if necessary and opens the findings up to public revision.[21] A committee of volunteer scientific experts ultimately decides what to include in the published edition.

 

USP-NF is a resource available in print, CD, and digital forms and made up of two compendia, the United States Pharmacopeia and the National Formulary, published in one volume.[22]  Unlike AHFS-DI staff, USP-NF staff works in collaboration with pharmaceutical manufacturers and receives material donations from them.[23] Also, unlike AHFS-DI, USP-NF, staff does not necessarily produce the monographs published within the compendium, and while the monographs are titled by the chemical name, they are not indexed by the brand name of the drug.

 

DRUGDEX, Micromedex Healthcare System

DRUGDEX Information System is the only compendium of the three produced by a publicly traded corporation. Thomson Reuters Healthcare produces DRUGDEX as part of the Micromedex Healthcare System. The system is only available digitally, which limits access to those who have a computer or compatible mobile device available for them to use, as well as the technological skills necessary to use these devices.[24] DRUGDEX is searchable by either drug brand name or the chemical drug name.

Internally, employees identify potentially accepted off-label usages through regular monitoring of primary literature.[25] In addition, DRUGDEX accepts external suggestions for consideration of off-label uses to be included in the compendium.[26] DRUGDEX claims that, during this process, staff pays particular attention to issues of safety and any new methods of treatment.  According to its web site, DRUGDEX may seek review by an external Editorial Board when questions arise about documentation in support of a particular usage. The editorial staff makes the final decisions, whether for or against inclusion in the compendium.[27]

Access to the Compendia

Cost of the Compendia

Access to the compendia is not free. AHFS-DI is available in print, with free online updates, for an annual price of $279[28], or $259 with ASHP membership.[29] It is the least expensive of the three compendia. The 2010 edition of USP-NF, which is the most up-to-date, along with supplementary issues US Pharmacopeia produces over the course of the year in which a subscription is purchased, is available for $820.[30] The starting cost of DRUDGEX is $6000 for an individual user.

 

Both AHFS-DI and USP-NF can be purchased by anyone directly from the websites of their publishers. Because DRUGDEX is not available for purchase by members of the public, Thomson Reuters Healthcare has a procedure in place for those permitted to purchase a subscription. Subscribers generally consist of hospitals, medical libraries, and doctor's offices. According to DRUGDEX, subscriptions are priced according to a tiered system based on the number of users. The greater the number of users, the lower the cost per individual user, but smaller organizations will pay less overall than large organizations. There are discounts available for non-profit entities, and each subscription seems to be priced individually, taking into account the specific situation of the potential subscriber. In telephone conversations, sales representatives at Thomson Reuters Healthcare were unwilling or unable to provide specifics of discount breakdowns.[31]

 

While the cost of the three compendia varies significantly, none is inexpensive.  And, a beneficiary would need to purchase all three compendia to ensure thorough research, as the prescribed off-label use in question might be included in one but not in the others. It is therefore unlikely that a Medicare beneficiary would buy any of the compendia in order to support Part D coverage of one prescription.  Similarly, the cost is substantial enough to prohibit public interest advocates who assist Medicare beneficiaries with Part D and other claims from purchasing the compendia. 

 

Availability of Compendia

 

Because of the cost of the compendia, beneficiaries must rely on other means of accessing the information they need. The logical way to gain access to print materials without paying for them is through a library, but accessing the compendia through a library can be difficult.

 

The chief difficulty may lie in gaining admittance to places where the compendia are likely to be available.  Based on a small sample of medical school libraries, for example, it was learned that public medical school libraries are more open to the public than those of private schools,[32] and therefore more accessible to Medicare beneficiaries who wish to conduct their research in person.  It is important to note, however, that although public university libraries might be open for general use, patrons unaffiliated with the university might not be permitted to use all the libraries' services, including programs like Inter-Library Loan, and might not be permitted to check out library holdings.

 

Few of the libraries contacted possessed all three compendia; some had lapsed subscriptions and some no longer possessed up-to-date compendia. Even the National Library of Medicine (NLM) at the National Institute of Health in Bethesda, Maryland,[33] which describes itself on its web page as "the largest medical library in the world,"[34] does not have all three compendia. 

 

Given the likelihood that a Medicare beneficiary may not have access to a library in his or her community that has the most recent compendia in its holdings, the beneficiary will need to investigate other options. Beneficiaries may request an inter-library loan (ILL)[35] through their local library for AHFS-DI and USP-NF.  Since DRUGDEX is proprietary and available only through subscription, its materials are not available through ILL requests. Many, if not all, libraries participate in an ILL program, which allows materials contained in one library's holdings to be sent to another library at a patron's request. The procedure for making an ILL request depends on the library, with some allowing online requests and others requiring in-person requests with a fee paid up-front. The ILL request forms are often available on library websites, as well as at the libraries themselves.

 

Attempting to access the compendia through a library creates multiple hurdles.  The first hurdle involves library access.  A beneficiary may have to invest considerable time and effort to get to the library.  Beneficiaries without access to computers would need to make sure they could receive printed rather than digital copies of the requested materials. The second hurdle involves currency of materials.  A beneficiary who utilizes a library system cannot always be assured that the compendia are the most current or that the monographs provided are the only ones that discuss a particular drug.  The third hurdle involves timing. The information may not be available quickly enough for a beneficiary who needs a monograph to support an expedited request or appeal in order to receive prescribed medication.  The last hurdle involves comprehension.  The beneficiary may not have enough knowledge or understanding about the compendia to frame an ILL request that will produce the information needed.  If a monograph is obtained through ILL or through other sources, the beneficiary may not be able to understand the information provided.

 

Public Comprehension of the Compendia

 

Even if a beneficiary is able to access the compendia through a library system or through other means, he or she may not know what to look for or may not understand whether a pertinent monograph supports the prescribed use.  In addition, the beneficiary would have to know the chemical name, not just the brand name, of the drug. Micromedex classifies drugs in DRUGDEX according to its own proprietary rating system. Medicare beneficiaries who are somehow able to access DRUGDEX would likely need to request a copy of the DRUGDEX rating system table as well, or the classifications will make little sense.

 

Once beneficiaries have obtained the pertinent monographs from each of the three compendia, issues of literacy become relevant.  The compendia monographs are intended to be resources for medical practitioners rather than for laypeople. They are written using highly technical language. Most beneficiaries will be unfamiliar with the layout of the compendia which vary somewhat from compendium to compendium.  Beneficiaries may be unfamiliar with the terms used in the compendia. It may be difficult for beneficiaries to locate an approval notation for their specific off-label use.

 

A Medicare beneficiary needs the support of the prescriber in order to get coverage of an off-label prescription.  If the beneficiary can obtain the monograph, the prescriber's office may be a resource for examining the monograph to see whether the off-label usage has been approved.  However, for some beneficiaries who have difficulty getting out of the house or for whom transportation is an issue, getting the information to the prescriber's office may create an additional burden and delay.

Recommendations 

Off-label drug use, while a common medical practice, is not without controversy.  Because of the controversy, Medicare may have legitimate medical reasons for ensuring that a prescribed off-label drug usage is safe and efficacious before paying for the drug under Medicare Part D.  Nevertheless, in establishing standards for proving that a prescription meets the definition of a medically accepted indication, Medicare cannot create such substantial barriers that the standard will almost never be met.  The current standard interferes with a beneficiary's right to receive Medicare Part D coverage for a drug prescribed by his or her authorized prescriber

The following recommended changes could protect the right of beneficiaries to receive Medicare Part D coverage for a drug prescribed to them that meets current standards for a medically accepted indication, including off-label uses.

First, Medicare should establish a process whereby all beneficiaries, their providers and their advocates, have access to the three compendia, AHFS-DI, USP-NF, and DRUGDEX.  Under this process:

• Part D drug plans should be required to inform beneficiaries, when seeking prior authorization or coverage of a prescription, that the requested use is an off-label use which must be supported by the compendia.

• Part D notices should be modified to state that the denial of coverage is based on an off-label use, that support for the usage must be found in one of the compendia, and that describes the process for requesting access to the compendia.[36]

• Part D drugs plans should be required to provide beneficiaries, prescribers and their advocates with copies of all relevant compendia monographs.  Where no such monographs exist, drug plans should be required to provide certified statements that they have reviewed the compendia and the requested off-label drug usage is not included.  Drug plans that fail to comply with these requirements or that are found to misrepresent the content of the compendia should be subject to sanctions.

• Where the prescribed off-label usage is not supported by the compendia, Part D drug plans should be required to provide beneficiaries with information about alternative drug therapies that are available on their formularies.

• Beneficiaries, prescribers, and advocates should be able to access the compendia by calling the Medicare information line, 1-800-MEDICARE.

Second, Congress should revise the appeals process to provide greater protection to beneficiaries. 

• The burden of proof should be changed so that a drug plan is required to substantiate that a prescribed usage is not approved by the FDA or included in the compendia.,

• Drug plans should be required to certify that they have reviewed the compendia and the requested off-label drug usage is not included. 

• Non-compliance by a drug plan should result in the plan being sanctioned by Medicare.

Third, Congress should also extend to Medicare Part D the standards for determining off-label drug usage under Medicare Part B.

• A beneficiary who wants a Part D drug plan to cover an off-label prescription should be allowed to submit supportive clinical evidence from peer reviewed medical literature.

• Medicare should provide to Part D plans and others guidance concerning the publications that may be used for this purpose.

Conclusion

Medicare Part D promised Medicare beneficiaries that they would have health insurance coverage for necessary prescribed medications.  Yet for those beneficiaries who rely on an off-label drug to treat an illness or condition, including many for which no other treatment is available, obtaining drug coverage under Part D is difficult at best. Unless Medicare or Congress improves access to the drug compendia upon which Medicare coverage is based, the promise of Part D is not being kept for beneficiaries who require off-label medications.

The Center for Medicare Advocacy thanks Center Healthcare Intern Nicole Berne for all her work on this report.  Questions or comments regarding the report can be addressed to attorney Vicki Gottlich (vgottlich @ medicareadvocacy.org) in the Center for Medicare Advocacy's Washington, DC office at (202) 293-5760.
 

APPENDIX A

Examples of Part D Off-Label Prescription Drug Cases

Provigil

Provigil is approved by the FDA for treatment of excessive daytime sleepiness due to narcolepsy; obstructive sleep apnea and shift work sleep disorder.

a.  Provigil was prescribed for a 53-year-old man, with history of brain tumor and stroke who resides in a nursing home in Maine. While in the hospital, in 2006, a neurologist started him on Provigil for hyper somnolence secondary to stroke. Coverage was denied as an off-label use.  His doctor sought expedited approval for Provigil, noting "He has done well on this medication over the past two years. I tried to stop the medication over the past week; however, he became much more somnolent, falling asleep frequently during the day. The preferred medications such as Ritalin are not indicated in this patient because of his seizure disorder."

b.  Provigil was prescribed for a 72 year -old woman who lives in an assisted living facility in Maine to treat Chemo brain, which causes, among other things, narcolepsy- like symptoms. She has breast cancer, anemia, and metastases of bone marrow and Hepatic lesions.  She made major improvements when she was on Provigil, which was paid for by her for a short time.  Her condition declined when her daughter could no longer afford to purchase the drug.

Her neurologist wrote: "With the many types of chemotherapy treatments she has needed, she has developed a condition called Chemo Brain Syndrome. This condition causes symptoms that are similar to narcolepsy and she falls to sleep at a moments notice. This causes a lot of concern to the patient, effects her quality of life and is a safety issues. Because of other medical conditions, such as Cardiac concerns, she is unable to take medications like amantadadine. She has had very good effects with the use of the Provigil doses she had been taking. It is very important that this patient be able to continue taking this medication..."A study by the University of Rochester Medical Center found that Provigil helped a small group of breast cancer survivors deal with the side-effect of their chemotherapy that resulting in "chemo-brain." 

Zofran

Zofran (Ondansetron) is approved by the FDA for nausea and vomiting caused by cancer chemotherapy, radiation therapy and surgery.

A 35 year old woman in New York has a combination of medical problems, including severe abdominal pain and intractable nausea and vomiting attributed to suspected chronic pancreatitis that began acting up after she experienced liver failure due to kidney disease. 

Her doctor has tried her on several medications, including Compazine and Phenergan, to quell her nausea and vomiting, but they were not effective and caused unwanted side effects like acathisia.  Zofran (ondansetron) ODT seems to be the only medication which helps.  Because Medicare won't cover the drug under Part D, she has been forced to go without it. 

Because Medicare won't cover Zofran, she goes without the drug. This results in her nausea and vomiting getting worse so that she can't keep any of her medications down, and she eventually winds up in the emergency room when the pain, nausea and vomiting become unmanageable.  When she is in the hospital she is given Zofran and that manages to get her nausea and vomiting under control.  She's then discharged home and the cycle begins again.

The client is extremely discouraged and her health has declined considerably.  She is afraid to leave her house because of the constant nausea and vomiting, which sometimes wakes her out of her sleep.  As she has stated:  "I don't think I should have to watch the quality of my life fade before my eyes … especially when there is a medication which works for me and which my doctor has deemed medically necessary."

ACTIQ

Actiq is approved for breakthrough pain in cancer patients who have developed a tolerance to other opioid drugs. Actiq is a "lollipop" form of fentanyl.  The patient sucks on the lollipop to obtain pain relief.  This mode of administration is critical for patients who suffer nausea and cannot swallow or keep anything down.

A 62 year old Connecticut woman has had seven surgeries over the past 10 years for resection of multiple brain aneurisms, i.e., balloon-like swellings in the arteries of the brain.  Aneurisms are usually discovered when they rupture, causing stroke, brain damage and even death.  She is being carefully watched as two more aneurisms appear to be developing.

It is not usual for patients with aneurisms to experience migraine headaches.  This patient has almost daily and extreme migraines that cause excruciating pain, nausea and vomiting, double vision and sensitivity to light.  She cannot eat or perform normal function of daily living during these attacks.

Her physician has tried many other drugs, including other forms of fentanyl, but Actiq is the only drug that relieves her pain and that she is able to tolerate during periods of nausea.  Her Part D plan had been covering her Actiq for several years, but cut her off in 2010.  She has been paying about $700 per month out-of-pocket, which she cannot afford, and is putting on charge cards.  To make matters worse, there is no PAP (manufacturer's patient assistance program) for this drug.  She and her doctor have contemplated other drug options but none can be found that will be effective and that she can tolerate.

IVIG

Intravenous immune gamma globulin (IVIG) is a blood product derived from the plasma of donors and administered intravenously to balance and strengthen the body's immune system.  It is one of a group of drugs that may be covered by Medicare Part B or Part D, depending on the diagnosis and/or method of administration.  Part B covers if the diagnosis is primary immune deficiency.  Part D covers if the diagnosis is one of 8 other indications approved by the FDA (such as chronic lymphocytic leukemia, allogenic bone marrow transplant, kidney transplant and pediatric HIV).

IVIG is sometimes prescribed off label for other conditions, including a form of Muscular Dystrophy called "inclusion body myositis" (IBM).  IBM causes chronic and progressive muscle inflammation and weakness throughout the body, affecting muscles that control fine movement, ambulation and swallowing.  There is no known cure or standard treatment.

A 48 year old well educated and articulate Connecticut man with IBM lost his private insurance coverage when his wife was laid off from her corporate job in early 2010.  His private insurance had always covered his home-administered IVIG.

Although he was able to secure a Medigap policy and a Part D plan shortly after losing his insurance, he was devastated to learn that neither Part B nor Part D would cover his IVIG because his diagnosis did not meet B or D criteria.  Without IVIG, he feared his condition would continue to deteriorate, affecting his ability to walk, write, eat and participate in most aspects of daily living.

Fortunately, he was able to qualify for the manufacturer's pharmacy assistance program (PAP), which provided the necessary drug.  Not all beneficiaries are so fortunate.  PAPs do not cover all drugs, and some have income or residency limits that preclude eligibility.