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.
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.
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%,
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
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.
Other experts raise concerns about off-label prescribing, citing the
lack of evidence concerning safety, effectiveness, and potential
Getting Coverage for
an Off-label Drug Under Medicare Part D
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.
In some instances, plans may even make a retroactive determination
that a prescription for which they already made payment was not
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.
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.
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.
The Part D rules also differ from the Medicaid rules, which allow
coverage for off-label usage consistent with peer-reviewed medical
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
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
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.
Some differences in content exist among the compendia, but only one
compendium need approve an off-label usage for Medicare Part D to
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).
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
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.
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.
Pharmacopeia – National Formulary (USP-NF)
The US Pharmacopeia (USP), a non-profit organization, is
responsible for setting standards for pharmaceutical and medical
Among its responsibilities is the establishment of standards for
categories and classes of drugs to be included in Part D
USP produces USP-NF.
USP-NF contains the USP's decisions regarding acceptable use and
quality standards for drugs.
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.
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.
Unlike AHFS-DI staff, USP-NF staff works in collaboration with
pharmaceutical manufacturers and receives material donations
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.
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.
DRUGDEX is searchable by either drug brand name or the chemical
Internally, employees identify potentially accepted off-label
usages through regular monitoring of primary literature.
In addition, DRUGDEX accepts external suggestions for
consideration of off-label uses to be included in the
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.
Access to the
Cost of the
Access to the
compendia is not free. AHFS-DI is available in print, with free
online updates, for an annual price of $279,
or $259 with ASHP membership.
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
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
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
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
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,
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,
which describes itself on its web page as "the largest medical
library in the world,"
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)
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
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.
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
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.
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
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
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.
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.
prescribers, and advocates should be able to access the
compendia by calling the Medicare information line,
Second, Congress should
revise the appeals process to provide greater protection to
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
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.
provide to Part D plans and others guidance concerning the
publications that may be used for this purpose.
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.
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.
Examples of Part D Off-Label Prescription Drug Cases
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 (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 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.
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
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
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
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.
"Patients, groups eye off-label use of prescription drugs",
(last visited July 8, 2010). See, also, Off-Label Drug Use
is Common and Hurts Nursing Home Residents, (Center for
Medicare Advocacy March 25, 2010),
 Id at Section
 See, 42 C.F.R.
423 Subpart M.
 42 U.S.C.
 42 U.S.C.
§1395x(t)(2)(B)(ii)(II). Legislation has been introduced in
the House of Representatives to apply the same standards for
determining off-label drug use to Part D as are used under
Part B. See, H.R. 5732, Part D Off-Label Prescription Parity
Act, introduced July 15, 2010.
 42 U.S.C. §
 42 U.S.C.
 Some of the
information in this section was collected directly via phone
calls to the organizations that produce the compendia.
 This is the
price when purchasing directly from the publisher. On
Amazon.com, it was available for $251.10 as of July 13,
conversations June-July 2010
 The small
sample consisted of the public library systems in Monroe
County, IN; Washington, DC; Los Angeles, CA; Cambridge, MA;
and Durham, NC and libraries at Indiana University, George
Washington University, UCLA, Harvard University and Duke
University. Schools and public library systems were chosen
on the basis of geographic diversity as well as possession
of a medical school, and include both public and private
 The Library of
Congress referred researchers to NLM, which specializes in
current scientific information.
 As a result of
a settlement in the lawsuit, Erringer v. Thompson No.
CIV01-112TUC-BPV (D. Ariz), filed March 16, 2001, Medicare
agreed to include in Medicare Summary Notices information
that describes any applicable local coverage decision that
Medicare has used as the basis for a denial of a request for
coverage of an item, a service, or a procedure covered under
Medicare Parts A and B.