Off-Label Use of Anticancer Therapies:

Physician Prescribing Trends and the

Impact of Payer Coverage Policy
INTRODUCTION TO EXECUTIVE SUMMARY
Forward by Dr. John E. Feldmann, MD, FACP
Director and Principal Investigator for the Clinical Research Division
Regional Cancer Center in Greensboro, North Carolina

The issues raised in this study of off-label use of cancer medicines and the impact of
coverage policy represent a challenge to all of us who treat patients with cancer. Oncologists
have always recognized the importance of practicing evidence-based medicine in caring for
patients, and the specialty has been at the forefront of research to develop that evidence
since its inception. We live now in exciting times of rapidly advancing technology that
can dramatically improve the length and quality of life for our patients. These rapid
advances often outstrip the traditional ways of disseminating that information through
publications in journals. The question is not the value of evidence-based medicine, but
September what constitutes adequate evidence and who should be the judge of its value. Most oncol-
2005 ogists in practice are aware of new information of value to their patients as soon as it is
disseminated. Yet, many clinicians in private practice feel they cannot offer these innova-
tive new treatments because of the uncertainty of reimbursement. Reimbursement rules
are unclear at best, and there are extremely long delays in payment, even when claims are
successful. Extra office personnel time is needed to fight these battles, and resources are
shrinking as reimbursement for services shrinks. Unfortunately, many oncologists, in the
end, feel it is easier and less risky to avoid offering these new therapies than to jump
through the many hoops required to recover money already spent on the drug in question.
The issues raised in this document are very real. Both providers and policy makers must
collectively address the profound effect the red-tape hassle can have on the practice of
oncology and, more importantly, on patient access to the newest treatments available.
John E. Feldmann, MD, FACP, received his medical degree from Cornell University Medical College and
completed his residency at Cornell Cooperating Hospitals. He was a Medical Oncology Fellow at Memorial
Sloan-Kettering Cancer Center and a Hematology Fellow at University of Virginia School of Medicine.
Dr. Feldmann is currently the Medical Director, Regional Cancer Center for Moses Cone Health System
in Greensboro, NC. In addition to serving on the Board of Directors for the North Carolina Oncology
Association, he is the former President of the Association of Community Cancer Centers (ACCC) and has
held positions on the ACCC Board of Directors and several ACCC committees. Dr. Feldmann was in the
private practice of medical oncology for more than 25 years, during which time he was continuously
involved in clinical research in the office setting.

Co-sponsors
 INTRODUCTION which the therapy is provided; use of the
medicine against a different tumor type based
Effective treatment and management of
on the therapy’s mechanism of action; use of
cancer is complex, and often wrought with
the medicine against a different biological
uncertainty. To determine the most effective
target based on new research; or changes in
course of treatment, physicians must consider
the medicine’s use as part of a multidrug regi-
the type of cancer, the unique presentation
men. Scientific findings that support these
and history and symptoms of each patient,
types of off-label uses often are highlighted in
the stage of cancer, as well as the available
scientific journals, oncology scientific meet-
and accessible therapeutic alternatives.
ings, and the general media before the new
Because cancer can often be life threatening,
indication gains approval by FDA.
advances in clinical management outpace the
drug approval process and reimbursement
In order to foster a wider understanding
policy areas, resulting in the “off-label” use
of the clinical and policy environment in
of drugs and biologicals (a use outside of the
which proposed changes such as these were
labeled indication as approved by the Food
taking place, the Association of Community
and Drug Administration, or FDA). Patients
Cancer Centers, the Biotechnology Industry
who require off-label use of a specific drug
Organization, and the Pharmaceutical
often have advanced stages of cancer, diffi-
Research and Manufacturers of America
cult-to-treat cancer types, or rare cancers. For
commissioned Covance Market Access
these patients, treatment decision making is
Services Inc., a global reimbursement policy
particularly challenging, requiring physicians
and health economics and outcomes research
to draw on clinical expertise and guidance
firm, to examine issues related to off-label use
from a rapidly evolving evidence base, most
of anticancer therapies. Covance interviewed
often from peer-reviewed scientific literature.
28 oncologists and 12 oncology practice
managers (OPMs) to gain insight into
Off-label use of anticancer therapies recently
current trends in off-label use of anticancer
has been the subject of increased attention by
therapies, the types of information that
policy makers. For example, the Centers for
oncologists rely on in making off-label pre-
Medicare and Medicaid Services (CMS),
scribing decisions, and whether Medicare
which runs the Medicare program, earlier this
coverage policy or private insurers’ coverage
year published a national coverage determina-
policies are creating barriers to access to off-
tion (NCD) on certain off-label uses of four
label uses of anticancer therapies.
colorectal cancer drugs. In addition, a CMS
draft guidance document on “coverage with
Though there are inherent limitations due
evidence development” released in April dis-
to a small sample size, there are several indi-
cussed its application to off-label uses of can-
cations that suggest similar findings may be
cer therapies and other medicines under
seen in a broader sample. Findings related
Medicare Part A and Part B. A revised draft
to the evidentiary basis for off-label use of
guidance is expected to be released in the fall
medicines and perceptions of coverage policy
of 2006.
barriers are important and bear further
research. A more detailed description of the
Off-label use varies widely in cancer care, and
study design and limitations is provided
can include: changes in the stage of cancer at
below.

2

Covance found the following:
• Oncologists place high importance on
off-label use of anticancer medicines in
caring for their patients.
• Some oncologists and OPMs (17 of 40)
report that off-label use of cancer medi-
cines appears to be increasing for a
number of reasons, such as more aggres-
sive treatment of many cancers and, in
some cases, narrower FDA-approved
labeling on new cancer drugs. At the
same time, others (12 of 40) report that
their off-label use is decreasing—nine of
12 cited broadened product labeling on
older medicines and four cited reim-
bursement problems.
• Oncologists draw from a wide range of
evidence—primarily peer-reviewed liter-
ature and drug compendia—in making
off-label treatment decisions.
• Fifteen of 28 oncologists report that
Medicare non-coverage frequently or
very frequently causes them to alter
their treatment decisions; eight out of
28 report that private payer policies
have this effect.
• Similar to 1991 findings by the
Government Accountability Office
(GAO)—formerly the General
Accounting Office—oncologists
reported that Medicare coverage policies
required them to alter treatment deci-
sions more often than private payers’
coverage policies.
• Oncologists generally value the option
of local Medicare coverage of cancer
treatments and would be concerned if
this option was restricted.
BACKGROUND OF
MEDICARE’S COVERAGE
POLICY FOR OFF-LABEL USE
OF ANTICANCER THERAPIES
In 1991, the GAO submitted a report to
Congress on the impact of payer coverage
and reimbursement policies on physician off-
label use of and patient access to anticancer
therapies.1
The GAO study reported that:
• Off-label use of anticancer therapies is wide-
spread.
• Approximately half of all survey respondents
reported reimbursement problems for the
off-label use of anticancer therapies.
“Although respondents reported reimburse-
ment problems with many third-party
payers, the insurer most frequently cited
was Medicare,” the GAO said.
• Restrictive reimbursement policies and the
costs of certain drugs caused providers
(oncologists) to alter their preferred treat-
ment.
Based on these findings, the GAO recommend-
ed that “the Secretary of Health and Human
Services issue a policy for Medicare reimburse-
ment for off-label use,” and that this policy
should “provide a clear basis upon which health
insurers that serve as intermediaries for the
Medicare program can make uniform decisions
regarding reimbursement for off-label use.”
In addition, the GAO report suggested that
Medicare’s coverage policy should be periodical-
ly reviewed to ensure that it remains beneficial
for cancer patients.
In response to the GAO report, Congress
passed Section 1861(t) of the Social Security
Act (SSA) as part of the Omnibus Budget
Reconciliation Act of 1993 to extend uniform
Medicare coverage to off-label uses of drugs or
biologicals, thereby recognizing the importance
3
 of coverage of off-label uses of anticancer drugs.
In particular, section 1861(t)(2)(B) of the SSA
directs Medicare to cover off-label uses of FDA-
approved drugs and biologicals if supported by
drug compendia—currently recognized as the
United States Pharmacopoeia Information
(USP DI) and American Hospital Formulary
Service Drug Information—or recognized
peer-reviewed medical literature.2
On January 28, 2005, CMS published a final
NCD for anticancer therapies for colorectal
cancer. CMS determined that the use of oxali-
platin, irinotecan, cetuximab, or bevacizumab
will be covered for off-label indications in clini-
cal trials identified by CMS and sponsored by
the National Cancer Institute. Medicare
contractors will continue to make reasonable
and necessary coverage determinations under
section 1861(t)(2)(B) of the SSA based on
guidance provided by CMS for medically
accepted uses of off-label indications of the
colorectal chemother-apeutic agents outside
of the identified clinical trials.
CMS’s April 7, 2005 guidance proposed a new
policy of conditioning coverage on further
research (“coverage with evidence develop-
ment”) and cited the NCD on off-label can-
cer medicines as one type of coverage with
evidence development. Comments on the
guidance from patient and provider groups
raised concerns over the potential impact of
the guidance on physician and patient access
to cancer therapies. CMS has since stated that
it will reissue the guidance in revised draft
form.
4
STUDY OBJECTIVES AND
RESEARCH APPROACH
To better understand the impact of off-label
payer policies on oncologists’ selection and
patient access to anticancer therapies, Covance
interviewed geographically diverse oncologists
(N=28) and oncology practice managers
(N=12). The interviews addressed the following
issues about Medicare and private coverage and
reimbursement of off-label use of anticancer
therapies:
• Value and importance placed on off-label
use of anticancer therapies.
• Perceptions of the ease of prescribing and
use of anticancer therapies outside their
FDA-approved indications.
• Types of evidence on which oncologists base
off-label prescribing decisions (abstracts,
unpublished data, published clinical trials
data in peer-reviewed or non-peer-reviewed
journal, other) and how, if at all, these vary
from evidence sources required by CMS for
national and local coverage policies.
• Whether, and to what degree, physicians and
practices/offices feel constrained in their
choice of anticancer therapy due to coverage
policy issues, and alter treatment patterns as
a result.
• How physicians and practices/offices are
affected by local Medicare carrier policies.
• Variation in off-label use by cancer type or
specific patient characteristics.
Covance also researched local Medicare carrier
and private payer coverage and reimbursement
policies for off-label use of anticancer therapies.
Specifically, Covance surveyed policies from 23
Medicare carriers, representing covered lives
from across the United States to determine the
data or evidence required by local Medicare
carriers to support positive coverage decisions
for off-label use.
 STUDY LIMITATIONS
This study was based on in-depth, structured
interviews with a relatively small number of
oncologists and OPMs to identify potential
patterns and issues related to off-label use of
anticancer medicines and payer coverage policy.
Although the findings are not definitive, the
results point to important issues for further
examination in areas such as the basis of
decisions to prescribe an anticancer medicine
off-label and the potential impact of coverage
policy. The results viewed in light of the limita-
tions suggest that off-label coverage policy
continues to present problems for oncologists.
A substantially larger study would be required
to confirm these results.

KEY FINDINGS

Oncologists interviewed indicate that off-label use of anticancer therapies plays an

important role in the treatment of their cancer patients. Nineteen oncologists inter-
viewed place high importance on their ability to use anticancer therapies for off-label diag-
noses. An additional six oncologists interviewed rate it of medium importance.

Almost all oncologists interviewed (26 of 28) report that off-label use of anticancer
therapies is more commonly reserved for advanced stages of cancer. However, some
oncologists note that for some cancer types, such as pancreatic cancer, off-label use of anti-
cancer therapies is necessary independent of cancer stage.

“We are using more drugs off-label for advanced stages of

cancer. However, there are certain cancer types for which
off-label drug use is important even in the early stages of
cancer. For example, for [hepatocellular carcinoma] there
are no good indicated therapies, and we see a fair amount
of it.”
— Oncologist 19

Over the past five years, the frequency of off-label use has changed in most practices
surveyed. Some oncologists and OPMs (17 of 40) report that off-label use of cancer medi-
cines appears to be increasing for a number of reasons, such as more aggressive treatment of
many cancers and, in some cases, narrower FDA-approved labeling on new cancer drugs.
Oncologists and OPMs attribute increased off-label use to greater availability of and access
to new drugs. At the same time, others (12 of 40) report that their off-label use is decreas-
ing—nine of 12 cited broadened product labeling on older medicines; four cited reim-
bursement problems.

5
 KEY FINDINGS Continued

Overall, oncologists and OPMs identified more than 50 physician-administered

anticancer therapies used for a variety of off-label diagnoses. The top five physician-
administered anticancer therapies used off-label by oncology practices surveyed represent
nearly 50 percent of the total number of mentions of physician-administered drugs used
off-label. Oncologists and OPMs identified 87 distinct oral anticancer therapies used off-
label. The top two oral drugs represent 31 percent and 16 percent, respectively, of the oral
anticancer drugs mentioned. As with off-label use of physician-administered anticancer
drugs, oncologists and OPMs cite use of oral anticancer therapies for a variety of off-label
diagnoses.

Oncologists rely on a wide range of evidence sources for clinical decision making. The
type of evidence most often cited (by 25 of 28 oncologists) was peer-reviewed literature,
followed by drug compendia (17 oncologists), manufacturer hotlines (seven), and case
reports (seven). Phase II and Phase III clinical trial data and unpublished trial data were
mentioned a combined total of 13 times.

Oncologists view “compendia-accepted” 3 listings as a guide to reimbursement, but

rely on a broader range of evidence sources for clinical decision making. Recognized
compendia represent only one of many sources of evidence that support off-label uses of
anticancer medicines: the source most widely cited by oncologists and OPMs is peer-
reviewed literature.

Extent to Which Medicare and Private Payer Policies for Off-Label Use of
Anticancer Medicines Interfere With Oncologists’ Clinical Decision Making
N=28 Oncologists

0
Very Frequently
4

8
Frequently
11

9
Occasionally Private Payers
3
Medicare
7
Infrequently
6

4
Never
4

0 2 4 6 8 10 12

Fifteen of the 28 oncologists surveyed reported that concerns about Medicare non-
coverage frequently or very frequently cause them to alter their treatment decisions.
Eight report that private payer policies have this effect. While the survey sample size
was small, this finding is important and bears further examination in future research.

6
 KEY FINDINGS Continued

Medicare coverage and reimbursement policy exerts a strong influence on treatment

decisions for Medicare beneficiaries. Nine of 28 oncologists report that they will only
prescribe an anticancer therapy to Medicare beneficiaries for an off-label use if they
know it will be covered (i.e., either accepted by drug compendia or listed in a local
Medicare carrier policy as covered). The majority of oncologists anticipate that anticancer
therapies that are not listed in drug compendia or in a drug-specific coverage policy will
result in payment denials and increased administrative and financial burden on their prac-
tice. Therefore, to avoid potential payment denials, some oncologists avoid other off-label
therapies that may be eligible for coverage but lack an affirmative policy (e.g., an off-label
use supported by peer-reviewed medical literature but not listed in recognized compendia).4

“I find it hard, because Medicare will deny every off-label

indication that is not listed in one of the two compendia.
So, at this point, I am only using those products off-label
for those indications that are listed in the compendia.”
— Oncologist 9

CONCLUSIONS AND POLICY patient access to off-label uses, and reduce

IMPLICATIONS
• Policy makers should recognize the wide range
of medically appropriate off-label uses, and the
wide range of evidence sources oncologists rely
on to support such uses. In particular, policy
makers should accept peer-reviewed medical
literature and other clinical sources in addition
to the specified drug compendia as bases for
coverage of off-label use, particularly for new
cancer therapies, advanced stages of cancer,
and rare cancer types. Compendia listings
represent an important but incomplete subset
of medically appropriate off-label uses. Listings
in recognized compendia are outdated, incom-
plete, and may not include references to poten-
tial off-label uses of new drugs that may be
supported by other published clinical evidence.
• Future coverage policies should seek to
improve, rather than constrain, provider and
administrative burden on providers seeking to
verify patient eligibility for therapies routinely
deemed medically necessary by oncology spe-
cialists.
• In order to provide more certainty that
medically appropriate off-label uses of cancer
medicines will be covered, Medicare carriers
should provide clear guidance on the data or
evidence required to support positive coverage
decisions for individual off-label uses, or per-
haps minimize documentation requirements—
and thus provider administrative burden—for
those anticancer therapies used regularly for
rare cancer types.
• Further research—perhaps with a large sam-
ple size of oncology practices—should be
undertaken to examine further the extent of
coverage/reimbursement policy impact on
patients’ ability to receive cancer therapy for
off-label uses.

7
Endnotes
1.
“Off-Label Drugs: Reimbursement Policies Constrain Physicians in Their Choice of Cancer Therapies,” Sept.
1991. Report to the Chairman, Senate Committee on Labor and Human Resources (GAO/PEMD-91-14).
2
Section 1861(t)(2)(B) of the Social Security Act.
3.
We refer to diagnoses supported by drug compendia as “compendia-accepted diagnoses” (instead of compendia-
listed diagnoses), as the USP DI, for example, includes a list of diagnoses as “acceptance not established.” Many
uses that are not “compendia-accepted” might still be considered “medically-accepted” by physicians based on
existing peer-reviewed literature.
4.
In instances where coverage for an off-label use of a medicine is denied by Medicare, the patient has the opportu-
nity to appeal the denial to the carrier and higher levels if necessary. Examination of coverage appeals was outside
the scope of this study.

Tom Goss
Covance Market Access Services Inc.
9801 Washingtonian Boulevard, Ninth Floor
Gaithersburg, MD 20878-5355