Off-label use of medical products in radiation therapy: Summary
of the Report of AAPM Task Group No. 121a…
Bruce R. Thomadsenb?
Department of Medical Physics, University of Wisconsin, Madison, Wisconsin 53705
H. Thompson Heaton II
Hagerstown, Maryland 21740
Shirish K. Jani
Department of Radiation Oncology, Sharp Memorial Hospital, San Diego, California 92123
Jeffery P. Masten
Radiation Oncology, Rapid City Regional Hospital, Rapid City, South Dakota 57709
Mary E. Napolitano
Atlanta Research and Development, Elekta, Inc., Norcross, Georgia 30092
Department of Radiation Oncology, Lynn Regional Cancer Center, Delray Beach, Florida 33484
Chester S. Reft
Department of Radiation Oncology, University of Chicago, Chicago, Illinois 60637
Mark J. Rivard
Department of Radiation Oncology, Tufts University School of Medicine, Boston, Massachusetts 02111
T. Tydings Robin
Theragenics Corporation, Buford, Georgia 30518
Department of Research and Development, Best Medical International, Inc., Springfield, Virginia 22153
Orhan H. Suleiman
Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland 20993
?Received 25 July 2009; revised 22 March 2010; accepted for publication 23 March 2010;
published 29 April 2010?
Medical products ?devices, drugs, or biologics? contain information in their labeling regarding the
manner in which the manufacturer has determined that the products can be used in a safe and
effective manner. The Food and Drug Administration ?FDA? approves medical products for use for
these specific indications which are part of the medical product’s labeling. When medical products
are used in a manner not specified in the labeling, it is commonly referred to as off-label use. The
practice of medicine allows for this off-label use to treat individual patients, but the ethical and
legal implications for such unapproved use can be confusing. Although the responsibility and,
ultimately, the liability for off-label use often rests with the prescribing physician, medical physi-
cists and others are also responsible for the safe and proper use of the medical products. When these
products are used for purposes other than which they were approved, it is important for medical
physicists to understand their responsibilities. In the United States, medical products can only be
marketed if officially cleared, approved, or licensed by the FDA; they can be used if they are not
subject to or specifically exempt from FDA regulations, or if they are being used in research with
the appropriate regulatory safeguards. Medical devices are either cleared or approved by FDA’s
Center for Devices and Radiological Health. Drugs are approved by FDA’s Center for Drug Evalu-
ation and Research, and biological products such as vaccines or blood are licensed under a biologics
license agreement by FDA’s Center for Biologics Evaluation and Research. For the purpose of this
report, the process by which the FDA eventually clears, approves, or licenses such products for
marketing in the United States will be referred to as approval. This report summarizes the various
ways medical products, primarily medical devices, can legally be brought to market in the United
States, and includes a discussion of the approval process, along with manufacturers’ responsibili-
ties, labeling, marketing and promotion, and off-label use. This is an educational and descriptive
report and does not contain prescriptive recommendations. This report addresses the role of the
medical physicist in clinical situations involving off-label use. Case studies in radiation therapy are
presented. Any mention of commercial products is for identification only; it does not imply recom-
23002300Med. Phys. 37 „5…, May 20100094-2405/2010/37„5…/2300/12/$30.00© 2010 Am. Assoc. Phys. Med.
mendations or endorsements of any of the authors or the AAPM. The full report, containing
extensive background on off-label use with several appendices, is available on the AAPM website
?http://www.aapm.org/pubs/reports/?. © 2010 American Association of Physicists in Medicine.
Key words: off-label use, FDA, radiotherapy
TABLE OF CONTENTS
I. INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2301
II. REGULATORY AGENCIES. . . . . . . . . . . . . . . . . . . 2302
III. LEGAL ISSUES. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2302
III.A. Liability analysis. . . . . . . . . . . . . . . . . . . . . . . . 2303
III.B. Other legal issues. . . . . . . . . . . . . . . . . . . . . . . 2303
IV. MANUFACTURER RESPONSIBILITIES. . . . . . . 2304
IV.A. Guidance to industry regarding reprint
practices. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2304
IV.B. Knowledge of off-label usage. . . . . . . . . . . . . 2305
V. BILLING AND REIMBURSEMENT ISSUES. . . . 2305
VI. MEDICAL PHYSICIST’S RESPONSIBILITIES
AND DOSIMETRY ISSUES FOR OFF-LABEL
USE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2305
VII. CASE STUDIES. . . . . . . . . . . . . . . . . . . . . . . . . . . 2306
VII.A. Intravascular brachytherapy. . . . . . . . . . . . . . . 2307
VII.A.1. Background. . . . . . . . . . . . . . . . . . . . . . . . . 2307
VII.A.2. Approved labeling for intravascular
brachytherapy devices. . . . . . . . . . . . . . . . . 2307
VII.A.3. Specific IVBT dosimetry issues not
included in original labeling. . . . . . . . . . . . 2307
VII.B. Radiolabeled microsphere brachytherapy.... 2308
VII.B.1. Using one manufacturer’s product to
treat the disease for which the other
manufacturer’s spheres were approved.... 2308
VII.B.2. Using radiolabeled microspheres to treat
a cancer in the liver for which no
microsphere has been approved. . . . . . . . . 2309
VII.B.3. Using radioactive microspheres to treat
disease in other parts of the body........ 2309
VIII. SUMMARY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2309
Medical products, devices, drugs, or biologics must be
cleared, approved, or licensed by the Food and Drug Admin-
istration ?FDA? prior to being legally marketed in the United
States. The terms clearance, approval, and licensing depend
on the type of medical product, and which of the FDA Cen-
ters conducts the review. Medical devices, the main subject
of this report, are either cleared or approved by FDA’s Center
for Devices and Radiological Health ?CDRH?. Drugs are ap-
proved by FDA’s Center for Drug Evaluation and Research,
and biologics are licensed by FDA’s Center for Biologics
Evaluation and Research.
In order to introduce a medical device into commerce,
medical device manufacturers must register to notify the
FDA at least 90 days in advance of their intent to market a
medical device. The FDA review process may simply in-
volve filing what is known as a Premarket Notification or
510?k?, named after Section 510?k? of the Food, Drug, and
Cosmetic Act. It allows the FDA to determine whether the
device is equivalent to a predicate device which has already
been placed into one of the three safety classification catego-
ries. If the proposed use of the device is determined to be a
significant risk which may pose a potential for serious risk to
the health, safety, or welfare of a subject, a Premarket Ap-
proval ?PMA? application may be required before the medi-
cal device can be marketed.
Unless the medical product is exempt from FDA regula-
tion, collection of human research data during premarket
clinical trials must be performed under an Investigational
Device Exemption ?IDE? for medical devices, or under an
Investigational New Drug ?IND? application for drugs or
biologics. This is the clinical research phase of medical prod-
uct development and such human research is highly regu-
lated. Human research data collected during this phase are
submitted to the FDA in a separate filing known as a PMA
for a medical device, New Drug Application for a drug, or a
Biologics Licensing Agreement for a biologic.
Institutions conducting clinical trials must have the re-
search approved by an institutional review board ?IRB?. An
IRB is a panel at a facility, comprised of medical and non-
medical persons, to review applications for human investiga-
tional studies. The Board weighs the safety of the study with
the benefit that might come form the study. The protocol,
consent procedure, and evaluation methodology must all be
approved for any research using human subjects. Table I
gives special situations under which treatment devices under
clinical trial may be used for patients not in that trial.
If the medical product is approved by the FDA for mar-
keting, specific conditions of use are specified in the medical
product labeling. Compliance with the specific labeling in-
structions is an assurance that the medical product is consid-
ered by the FDA to be safe and effective for the specific
When medical products are used in a manner that is dif-
ferent than specified in the labeling, or used for medical in-
dications that are not specified in the labeling, this is referred
to as “off-label” use. Such use is not necessarily illegal or
improper. Rather, such use has not been evaluated by the
FDA, and is authorized under a licensed physician’s right to
practice medicine. In order to practice medicine in the U.S.,
one must be licensed in the appropriate state jurisdiction and
properly trained and credentialed. In general, the use of
medical products such as drugs or devices must be per-
practitioners/qualified individuals. The purpose of this report
2301Thomadsen et al.: Off-label use of medical products2301
Medical Physics, Vol. 37, No. 5, May 2010
is to provide for the medical physicist an appreciation of the
responsibility and potential liability when a medical product
is used consistent with its labeling or when it is not.
Section VI discusses recommended actions by the medi-
cal physicist in situations involving off-label use. This is an
educational and descriptive report and does not contain pre-
Appendices referred to in this report can be found in the
version on the website of the American Association of Physi-
cists in Medicine ?http://www.aapm.org/pubs/reports/?.
II. REGULATORY AGENCIES
In order to possess and use radioactive materials, the fa-
cility or user must be licensed either by the Nuclear Regula-
tory Commission ?NRC? or an agreement state. While medi-
cal products may be used by the medical community for
other than the approved indications under the practice of
medicine, radioactive materials which have been licensed for
a specific use cannot be used for other uses. The unautho-
rized use of radioactive material is strictly prohibited and
could result in fines and other penalties. There is an excellent
discussion of this by Glasgow1related to NRC requirements
for intravascular brachytherapy ?IVBT? sources. The NRC
and agreement states have two major responsibilities with
respect to new brachytherapy sources. The first is structural
integrity, ensuring that sealed sources and devices can safely
contain radioactivity under the conditions of their use. The
second is that the users be qualified to safely use these ra-
dioactive materials. This is done by licensing the user and
the site where the radioactive materials are used. The NRC
has no position on off-label use of an approved device. Off-
license use is strictly illegal.
FDA’s regulatory focus is on the manufacturer of the
medical product, namely, on the documentation the manufac-
turer submits to show that the product can be used for its
intended use. If the medical product is approved by the FDA
for marketing, specific conditions of use are specified in the
medical product labeling ?information for use, product in-
serts, advertising material, etc.?. Compliance with the spe-
cific labeling instructions is an assurance that the medical
product is considered by the FDA to be safe and effective for
the specific medical indications. After FDA approval, certain
events must be reported, as given in Table II.
III. LEGAL ISSUES
Stated most simply, the term off-label is a regulatory de-
scription of the use of a medical device or drug. In the words
of one court, it is “a legal status, not a medical fact.”2It can
be safely said that the majority view in the United States is
that off-label use of a drug or device is proper as long as
certain criteria are satisfied.3
Although off-label has a relatively simple meaning from a
legal standpoint, considerable linguistic confusion has been
generated by the attempt to understand what off-label uses in
fact are. Beck et al.4describe the problem succinctly in their
law review article.
Unfortunately, terminology problems persist. It is com-
mon parlance to say that a drug or device is FDA “approved”
TABLE I. FDA mechanisms for expanded access of devices under investigational trials.
Situations in which there is a need to use an
investigational device in a manner inconsistent with the
approved investigational plan or by a physician who is
not part of the clinical study.
Allows access for patients who do not meet the
requirements for inclusion in the clinical investigation
but for whom the treating physician believes the device
may provide a benefit in treating and/or diagnosing their
disease or condition. This provision is typically approved
for individual patients but may be approved to treat a
An approved IDE specifies the maximum number of
clinical sites and the maximum number of human
subjects that may be enrolled in the study. During the
course of the clinical trial, if the data suggests that the
device is effective, then the trial may be expanded to
include additional patients with life-threatening or
FDA may allow continued enrollment of subjects after
the controlled clinical trial under an IDE has been
completed in order to allow access to the investigational
medical device while the marketing application is being
prepared by the sponsor or reviewed by FDA.
• Life-threatening or serious disease or condition;
• No alternative; and
• No time to obtain FDA approval.
Emergency use of an unapproved device
may occur before an IDE is approved
• Serious disease or condition and
• No alternative
Compassionate use can occur during
the clinical trial
• Life-threatening or serious disease;
• No alternative;
• Controlled clinical trial; and
• Sponsor pursuing marketing approval.
Treatment use can occur during
the clinical trial
• Public health need
• Preliminary evidence that the device
will be effective and there
are no significant safety concerns.
Continued use occurs
after the completion
of the clinical trial
2302Thomadsen et al.: Off-label use of medical products2302
Medical Physics, Vol. 37, No. 5, May 2010
for a given use if that use appears on the label. The converse
proposition, however, ?which is decidedly not true? would be
that such products are “unapproved” for all unlabeled uses.
This erroneous concept of approved use takes on derogatory
connotations if divorced from a regulatory context, as would
be the case in an informed consent discussion. To those un-
familiar with FDA regulation, a group that includes most
patients, unapproved suggests “disapproved,” that is, some
affirmative determination by the FDA that an off-label use is
actually too unsafe or too risky to appear on the labeling.
“Off-label drug use by oncologists is quite common” but
people “mistakenly equate … the off-label categorization of
these uses … with lack of evidence of effectiveness.”5A
recent notable example of a court falling into precisely this
error is Proctor v. Davis,6in which the court repeatedly re-
fers to off-label use as “unauthorized” by the FDA, when, as
previously discussed, the agency lacks and has disclaimed
any power to allow or disallow off-label use. FDA ordinarily
looks to a manufacturer’s intended uses when considering
how a drug or device is to be marketed and labeled. Thus,
absent a labeled contraindication, unindicated uses cannot be
considered unapproved; they simply have not been reviewed
at all. ?This appears to be the situation in the Proctor case; no
application was filed with the FDA concerning the off-label
use at issue. 682 N.E.2d at 1209–10. Indeed, FDA refused
the manufacturer’s request to add adverse reactions relating
to that precise off-label use to its labeling shortly before the
incident at suit. Id. at 1210. For unexplained reasons, the
manufacturer’s request and FDA’s refusal of it were excluded
from evidence in Proctor, id., and the court took the position
that the manufacturer was liable for not including in its la-
beling the information that FDA had refused to allow. Id. at
There are other ways of understanding the legal nature of
off-label. One could describe off-label as a silent label. Off-
label has more accurately been termed “extra-label” use. It
simply means that a product is being used for a condition or
in a way not appearing on its FDA-regulated labeling, not
that the agency has judged the use adversely.7
As we pointed out in the beginning of this document, the
FDA has never had authority to regulate the practice of
medicine. This is fundamental to understanding the term off-
label. Physicians may use legally marketed drugs or devices
in any manner that they believe, in their professional judg-
ment, will best serve their patients.8The Legislative History
section of Appendix D of the full report discusses this in
Another area of confusion arises out of the investigational
or experimental use of devices and drugs. An off-label use is
not “investigational” simply because a labeling is silent on
the proposed use. “In the legal context of informed consent
litigation, the potential for confusion is compounded because
this description also misuses FDA terminology with a precise
regulatory meaning.” There are particularized informed con-
sent regulations governing investigational drugs and devices,
but these regulations do not, and should not, apply to off-
label use. The Appendices to this report explore different
aspects of the investigational use issue more fully.
III.A. Liability analysis
The discussion above demonstrates that off-label use of
medical devices is an accepted part of the practice of medi-
cine ?Fig. 1?. In a clinical setting, there are no triggers that
would separate off-label use from the regular use of a medi-
cal device in the context of liability analysis. IDE and IND
trials are excepted here. A full analysis of a potential claim
arising out of the off-label use of a device is beyond the
scope of this report. However, to assist the medical physicist
in appreciating the nature of the legal issues involved in such
a professional liability claim, Appendix D offers an overview
and supporting authorities. For an in depth review of the
parts of a negligence claim written specifically for medical
physicists, see Ref. 86.
III.B. Other legal issues
The above sections focus on the legal issues arising from
harm to a particular patient. The FDA and other regulatory
agencies also focus on the “systematic encouragement” of
off-label use. Systematic encouragement of a practice that is
currently off-label should be preceded by the manufacturer
modifying the labeling to include the off-label use after
proper approval processing through the FDA.
Systematic encouragement of off-label use such as mar-
keting efforts by manufacturers and companies can also be
subject to review by the Department of Justice ?DOJ?. For
TABLE II. Medical device reporting requirements for user facilities and manufacturers.
REPORTEREVENTTO WHOM WHEN
User facilityDeathsFDA and manufacturer
Manufacturer ?FDA only if
manufacturer is unknown?
Within ten working days of death
Reports of serious injuries
30-day reports of deaths, serious injuries,
Baseline report to identify and provide basic data
on each device that is subject of report
Five-day report on events that require immediate
remedial action and other types of events designated
Within ten working days of injury
FDA30 days from becoming aware
Within 30-day report when device is reported
for the first timeFDA
FDA Within five work days of event
2303Thomadsen et al.: Off-label use of medical products 2303
Medical Physics, Vol. 37, No. 5, May 2010
example, Spivak9identifies ongoing DOJ efforts in 2008,
investigating and prosecuting cases of illegal off-label mar-
keting. He indicates that according to published reports,
there are upward of 200 pending qui tam ?i.e., whistleblower
cases? cases involving allegations of off-label promotion by
In some cases, companies have settled the criminal
charges and civil allegations related to their marketing prac-
tices. Remedial actions have included the prohibition of pro-
motion for unapproved or off-label use of drugs or devices,
and compliance training for promotional speakers and sales
representatives. Other remedial actions include prohibiting
company staff from responding to requests for off-label in-
formation unless the request is made in writing. The cases
also signal that the DOJ continues to closely scrutinize those
activities considered nonpromotional, such as support for
medical education and responses to unsolicited requests for
information. Spivak9also indicates that not only distribution
of drugs is of interest to DOJ, but also devices including
In November 2007, the Department of Health and Human
Services and the DOJ published “Fraud and Abuse Control
Program Annual Report for FY 2006.” That document dis-
cussed their accomplishments in investigating and prosecut-
ing health care fraud schemes. Investigations included efforts
in hospital fraud, pharmaceutical fraud, fraud by physicians,
as well as fraud by other practitioners. Off-label issues were
identified only in the pharmaceutical fraud areas and no
cases involving medical physicists were cited in efforts in-
volving fraud by other practitioners. Another example of off-
label activity involving legal issues was reported by The
Wall Street Journal.10The report indicated that the DOJ is
investigating the off-label use of a Medtronic Inc. implant for
promoting bone growth, bringing government scrutiny of
such unapproved uses to the heart of the $189 billion per
year medical device industry.
Based on the above, medical physicists should carefully
examine their role, if any, in efforts to promote the off-label
use of a drug or device, and should consider obtaining legal
advice if uncomfortable.
IV. MANUFACTURER RESPONSIBILITIES
Manufacturers are allowed to promote a medical product
only for the specific indications for which it was cleared,
approved, or licensed. Manufacturers are prohibited from
promoting off-label use of their products.
Experts in the medical field may report on the off-label
use of a drug or device through publications, conferences,
and other professional forums. Although many medical soci-
eties require the presenters to declare off-label or research
uses ?and any conflicts of interest such as financial interests
with the product being promoted?, the manufacturer has very
little control over enforcement of society requirements or
IV.A. Guidance to industry regarding reprint practices
If a physician or healthcare professional specifically re-
quests a report or publication already available in the peer-
reviewed literature, a manufacturer may be able to provide
unaltered copies of the publication discussing the off-label
use for educational purposes, but not for promotional pur-
poses. Manufacturers are not allowed to distribute unsolic-
ited information for marketing their product for an unap-
FDA guidance and regulations are constantly being re-
vised and good reprint practice is no exception. Section 401
of the FDA Modernization Act, which provided conditions
under which journal articles or reference publication con-
cerning off-label usage could be distributed, ceased to be
effective on September 30, 2006. At the time of printing, the
FDA has published guidance for industry11,12in order to pro-
vide the current views of the agency. This guidance recog-
nizes that truthful and nonmisleading information from jour-
nal articles and reference publications concerning off-label
usage can be of benefit to the public health when appropri-
ately distributed to healthcare professionals.
The agency lists recommendations concerning the types
of reprint/articles/reference publications that would and
would not be considered appropriate, along with the manner
in which the agency considers the distribution appropriate.
For example, an appropriate type of article and dissemination
is a scientific journal article published in accordance with an
FIG. 1. Flowchart of recommended pathway to address off-label uses of
2304Thomadsen et al.: Off-label use of medical products2304
Medical Physics, Vol. 37, No. 5, May 2010
organization’s peer-reviewed procedures being distributed
following a related technical discussion. An inappropriate
type and dissemination would be if a highlighted and
abridged version of the same reference was being distributed
in the exhibit hall. The guidance document lists more infor-
mation for review by the interested reader.
IV.B. Knowledge of off-label usage
Sometimes, a manufacturer may become aware of anec-
dotal results obtained for off-label use of the device. The
manufacturer may decide, based on this new information, to
conduct a formal clinical trial in order to obtain the neces-
sary clinical data to submit to the FDA for approval of a new
indication. Since clinical trials are expensive, the manufac-
turer may also decide that the expanded use through the
practice of medicine is sufficient and may decide not to ap-
ply for a new indication. It may simply be a business deci-
sion to allow the practice of medicine to adopt the new prac-
tice. In this scenario, a medical product may be used legally
for a commonly accepted but unapproved indication.
A debate also exists concerning the responsibility of the
manufacturer with knowledge of prevalent off-label use of
the product when the manufacturer decides not to actively
promote the new indication or conduct a clinical trial for
approval of the new indication. While the physician always
has the prerogative to use an approved device in an off-label
manner, the debate ensues as to the obligation of the manu-
facturer to undergo the expense and manpower required to
conduct the necessary clinical trials and submit the off-label
usage for approval by the FDA. Since the FDA does not
regulate the practice of medicine, the off-label usage without
active promotion by the manufacturer would not fall under
the FDA’s jurisdiction.
Solid medical rationale should support the off-label use of
a drug or device. “Off-label use does not imply an improper
use and certainly does not imply an illegal use or contrain-
dication based on evidence.”13For example, for patients with
“orphan diseases” ?i.e., less than 200 000 patients diagnosed
per year?, drugs are often used off-label because of a lack of
incentives for the manufacturer to develop additional indica-
tions for small markets. The legal and regulatory environ-
ment surrounding off-label use is an area that continues to
evolve. In some areas, in particular, the treatment of cancer,
off-label use is often considered necessary in order to pro-
vide quality patient care. For example, a 1991 study con-
ducted by the General Accounting Office reported that ap-
proximately 60% of cancer patients were treated using at
least one off-label drug.14
Off-label indications may sometimes result in the discov-
ery of new applications for existing drugs. In fact, it has been
stated that well over 50% of drug innovations were devel-
oped as a result of use of drugs in off-label indications by
practicing clinicians rather than by the drug industry.15Al-
though the manufacturer can compile the published off-label
use of a product and provide that to the FDA at periodic
intervals, the healthcare provider is not obligated to provide
the information to the manufacturer or publish the results
unless death or serious injury results. Hence, for practical
and business reasons, it may be difficult for the manufacturer
to monitor all the off-label uses of their products. In a recent
guidance document,11the FDA does specifically encourage
the manufacturer to seek approvals for new uses of approved
V. BILLING AND REIMBURSEMENT ISSUES
Reimbursement can be approved for Medicare and Med-
icaid patients, as well as by third party insurance carriers, for
indications which have not been approved by the FDA, but
this issue sometimes can be confusing. Medical facilities
should consult their local Medicare carrier before using a
device off-label with the expectation of some reimbursement.
See Appendix E of the full report for more details on
VI. MEDICAL PHYSICIST’S RESPONSIBILITIES
AND DOSIMETRY ISSUES FOR OFF-LABEL USE
Many radiation-producing devices or radiopharmaceuti-
cals that have labeling restrictions also have some form of
dosimetry associated with the standard uses. Very often, the
dosimetry for the approved uses fails to reflect true dose
information, but rather provides simple standardization for
consistent applications between patients. The standard treat-
ments may deliver a mostly consistent dose, such as in the
case of the Cordis IVBT system, which originally required
ultrasound measurements of the treatment geometry and pa-
tient anatomy for calculation of dose to a defined location in
the vessel wall. On the other extreme are treatments such as
89SrCl2injections for metastatic bone pain that specified a
fixed activity for all patients. In each case, the approval pro-
cess established that the procedure was safe as tested during
the formal clinical trials. However, the meaning of safety
varies, especially for patients with refractory disease where
the approved indication may be palliation.
Off-label use puts the user outside the officially approved
bounds of safety and effectiveness, and also where the dose
to the patient may be unknown, unknowable, or unexpected.
Consider the problem using the Novoste BetaCath source to
treat vessel diameters larger than those specified in the label-
ing. Several problems could be encountered. First could be
the lack of data for longer treatment distances. Since the
vendor only specifies treatments for a range of vessel diam-
eters, dose information beyond that range may not be in-
cluded. Extrapolating doses beyond existing data for beta
sources can introduce considerable errors because of the
rapid gradient in the dose with distance. Even in cases where
the dosimetry factors may be known and the treatment time
calculated at some greater distance, there could be unex-
pected consequences. For example, the treatment time could
become very large because the fraction of the radiation pen-
etrating to the greater distance may be small. If the catheter
is not centered in the vessel, the dose to the closest point in
the vessel wall could be several times that normally deliv-
ered, while the dose on the farthest point might fall beyond
the range of the beta particles and be severely underdosed.
2305Thomadsen et al.: Off-label use of medical products2305
Medical Physics, Vol. 37, No. 5, May 2010
The treatment could fail either by injuring the proximal side
or failure to deliver an adequate dose distally.
Some off-label uses of devices pose no dosimetric issues
for a medical physicist, for example, using a linear accelera-
tor to treat mitral valve replacements. Assuming successful
addressing of motion problems, the dose distribution can be
known as well as when treating cancer. Not withstanding the
absence of a dosimetric question, the FDA may consider
such irradiation as significant risk, such as in this case.
Most treatment modalities that can be used off-label are
outside of the normally encountered situations. For new de-
vices and drug-based therapies, the manufacturers are usually
required to provide training to the critical staff, including
medical physicists. During this training, the medical physi-
cist learns the indications and limitations for use, which
leaves anything else as off-label use. Medical physicists
should become familiar with the approved uses so as to rec-
ognize when an application would be off-label. The physi-
cians involved should recognize off-label situations and call
that fact to the physicist’s attention early in discussions about
the patient. Anything unusual about the patient’s treatment
should initiate a check by the medical physicist as to whether
the treatment would be off-label. This can be verified by
simply seeking written answers from the manufacturer for
clarifications. Linear accelerators, as a product, have general
approval to treat cancers and certain benign diseases, al-
though some have not included benign diseases in their la-
beling. For units that include treatment of benign diseases in
their labeling, benign diseases for which there is not infor-
mation in standard textbooks raises flags about the therapy
Judgments on the usage of a device for a proposed off-
label situation must be made for each particular case ?Fig. 1?.
Examples of some items that could be considered include the
• Will the changes from usual treatment produce changes
in the dose distribution?
• If the dose distribution will change, can the new dose
distribution be calculated or otherwise determined?
• Might any new dose distribution affect the patient’s
• Could a new dose distribution produce unintended
Very likely, the answers to at least some of these questions
will not be available and cannot be found in time to address
the given treatment. Calculation of doses in unusual situa-
tions or from new devices often proves challenging to re-
search institutions with specialized resources, and is not
something that most clinics could perform. Those difficulties
notwithstanding, expected changes in dosimetry and possible
results must be considered before performing the off-label
treatments. It is prudent to contact someone who was in-
volved with the original dosimetry to solicit an opinion re-
garding these issues.
The off-label use of a device can have both desirable and
nondesirable results. When desirable results are achieved, it
usually occurs when the usage of the device has been con-
sidered thoroughly for the off-label situation by all members
of the treatment team. Using a device off-label will also re-
quire a plan of action, understood by the whole team, to be
executed in the event of a nondesirable situation. Issues can
range from discomfort to a serious consequence, since no
clinical trials were performed under the same clinical situa-
tion. As an example, consider the Novoste BetaCath system
being used for a long lesion. These kinds of lesions usually
require a “stepping method” to cover the whole length. The
Novoste catheter is placed in the vessel and left in place until
both segments are treated. This will amount to having the
catheter in place for a longer period of time, approximately
twice the time of a short lesion. The presence of the catheter
might create a serious discomfort for some patients and, if
not taken seriously by the cardiologist, could potentially lead
to serious consequences. The stepping method might require
an overlap or gap of the sources between the two segments.
The clinical consequences are not well understood because
of the lack of clinical data and might be more critical when
there is curvature of the vessel within the area to be treated.
This uncertainty could lead to serious overdose or underdose
in the overlap or gap region. The clinical results of these
unusual situations can only be evaluated with time. From the
regulatory side, the concern would be that the stepping
method could lead to a possible medical event ?e.g., an over-
dose or underdose at the match line?.
One has to be aware that while the purpose of the off-
label use is well intentioned, sometimes the results can cause
serious problems for the patient. Since off-label use deviates
from the formal labeling instructions, it may shift liability of
the product from the manufacturer elsewhere, eventually to
the institution. One will have to be prepared and act on non-
Some examples of steps the medical physicist should take
in proposed off-label treatments include
• Ensuring that, if possible, appropriate dosimetry calcu-
lations are in place at the time of treatment for each
case to avoid “on-the-fly” dosimetry calculations.
• If dosimetry for the proposed off-label use raises new
safety and effectiveness issues for treating patients, in-
forming the rest of the clinical team, preferably in
• Ensuring that any new safety and effectiveness con-
cerns raised by the dosimetry calculations or other
physics-related issues are communicated to the treating
physician to be included in the Informed Consent Form
for the patient ?see the discussion in Appendix D?.
VII. CASE STUDIES
The material in the following case studies is not intended
to be guidance on how to treat patients in an off-label man-
ner. Rather, it is intended to provide guidance on the types of
concerns the medical physicist should consider when told by
the physician how the device will be used off-label for the
treatment of an individual patient. These case studies provide
only some of the details of the type of information the medi-
cal physicist should consider and they are not intended to be
2306Thomadsen et al.: Off-label use of medical products2306
Medical Physics, Vol. 37, No. 5, May 2010
an all inclusive discussion. In these case studies, it is as-
sumed that a medical decision has been made to treat an
individual patient using a medical device in a specific off-
label manner. Any physics concerns of the proposed treat-
ment should clearly be conveyed to other members of the
clinical team in writing. As with all off-label uses of a de-
vice, it is a medical decision that the use of the device for
that individual patient is in the best interests of treating that
patient. In all of the case studies, just as for conventional
treatments or human-use research trials, it is assumed the
physician has provided an informed consent form, including
specifics of the treatment, for the patient to consider.
VII.A. Intravascular brachytherapy
To treat individual patients, IVBT devices were frequently
used off-label ?see Sec. VII A 2 for more information on
their labeling?. The first medical products to show significant
results in a clinical trial for the reduction in in-stent resteno-
sis following balloon angioplasty were intravascular brachy-
therapy sources, although they were eventually superseded to
a great extent by drug-eluting stents. During the development
stages of IVBT, the radiation sources used in the coronary
vessel clinical trials included seed trains ?with16,17and
stents,38–40radioactive liquid filled balloons,41–43radioactive
gas filled balloons,44
and balloons impregnated with
radioactivity.45,46In addition there were peripheral vascular
trials47using a HDR
external beam therapy for patients with A-V shunts.48Most
of the device sources were delivered to the intended treat-
ment site by first inserting a catheter through the femoral
artery and using this catheter to move the source for treat-
ment of predetermined dwell times to deliver the prescription
dose at the prescription point. The intended use for all ap-
proved coronary IVBT devices is to treat coronary in-stent
restenosis with a prescribed dose of radiation ?which may
depend on vessel diameter? at a prescribed point.
There is a different regulatory paradigm for brachytherapy
sources used in the vascular system for treating disease from
that for conventional brachytherapy sources used to treat
cancer. Since brachytherapy sources were used before 1976
to treat cancer, they were grandfathered in when the Medical
Device Amendments were passed. When new interstitial
brachytherapy sources or auxiliary devices were developed,
the normal regulatory route to market was to claim they were
substantially equivalent to, and had the same intended use as,
a legally marketed preamendment predicate device. Addi-
tionally, the manufacturers had to state that any technological
changes to the device did not raise any new safety and ef-
fectiveness issues for its intended use. This allowed manu-
facturers to file premarket notification under Section 510?k?
of the Act as discussed in 21 CFR 807.81–807.100. This also
meant that the typical operations the physicist performed,
such as quality assurance, source calibration, treatment plan-
ning, etc., did not violate labeling.
192Ir remote afterloading system and
The situation with IVBT sources was quite different. First,
the FDA determined that the use of radiation to treat disease
in the vascular system was a new intended use of radiation.
Second, the FDA determined that the use of radiation to treat
disease in the vascular system was a significant risk, i.e., a
FDA-approved IDE was needed to gather clinical data. Thus,
for IVBT devices, a PMA was needed before the product
could be legally marketed.
VII.A.2. Approved labeling for intravascular
In gathering the clinical data for IVBT devices, the device
is investigated under a very specific set of conditions includ-
ing prescription dose, prescription point, range of source ac-
tivities, etc. Hence, the only information FDA can evaluate
for the safety and effectiveness of the device is the clinical
and nonclinical data gathered during the IDE study and sub-
mitted in the PMA.
The instructions for use ?IFUs? for the three FDA-
approved IVBT systems for treating in-stent restenosis ?units
by Cordis, Novoste, and Guidant? summarize the information
obtained during the clinical trial. Most of the information in
these IFUs pertains to the clinical trial and typically most of
the dosimetry is in an appendix. All three systems are only
approved for treating in-stent restenosis of specified lesion
lengths, specified vessel diameters, and use a specific pre-
scription dose at a specific prescription point. Only one sys-
tem is approved for stepping or source pull-back. Any other
use of these systems for treating vascular disease is off-label
use of the system. The dosimetry parameters of the three
approved IVBT systems for treating in-stent restenosis are
found in their IFUs.49–51
VII.A.3. Specific IVBT dosimetry issues not
included in original labeling
One of the important considerations if an IVBT source is
to be used off-label is to be able to calculate the dose rate
from the source at any clinically relevant point. In particular,
the dose rate at the prescription point is needed to calculate
the dwell time. Further, one needs the dose rate distribution
if the dose at the vessel wall for a noncentered source is
desired, the dose along a curved vessel, the dose in the mar-
gins of the treatment volume, effects of stent attenuation,
effect of contrast media, and the dose maximums and mini-
mums created by pull-back. In addition to the references
cited above, dosimetry from IVBT sources is discussed in the
Some examples of conditions when it may be desirable to
use an IVBT source off-label or for physical conditions not
considered in the dosimetry for the original labeling include:
dose at bifurcations,64effect of plaque on dose rate,65,66ef-
fect of contrast media on dose rate,67,68effect of vessel cur-
vature or source movement,69treating peripheral vessels,70
treating SVG,71,72dosimetry based on IVUS,73source pull-
back during treatment,74–77use of radiation treatment plan-
sources,79,80and quality management for IVBT.81
2307Thomadsen et al.: Off-label use of medical products2307
Medical Physics, Vol. 37, No. 5, May 2010
VII.B. Radiolabeled microsphere brachytherapy
Microspheres labeled with
treatment of cancer in the liver. The microspheres are in-
jected intra-arterially into the hepatic artery. The micro-
spheres flow with the blood until they reach the capillaries,
where, being too large to fit, they lodge in the capillary
mouths. This therapy selectively delivers dose to the tumors
because they receive almost all their blood supply from the
hepatic artery, while the liver proper receives 80% of its
blood supply from the portal vein. The products of two
manufacturers were approved for this use.
One of the manufacturers, MDS Nordion ?Kanata, On-
tario? makes TheraSpheres, glass spheres 10–30 ?m in di-
ameter with an average90Y labeling of 2.5 kBq per sphere.
TheraSpheres were approved via a Humanitarian Device Ex-
ception H980006.82The indicated use for these spheres is
“… for radiation treatment or as a neoadjuvant to surgery or
transplantation in patients with unresectable hepatocelluar
carcinoma ?HCC? who can have placement of appropriately
positioned hepatic arterial catheters.”82The other manufac-
turer, SIRTex, markets resin spheres called SIRSpheres. SIR-
Spheres are a little larger, ranging from 20 to 40 ?m in
diameter, but carry less activity per sphere, averaging about
50 Bq per sphere. These were approved via Premarket Ap-
proval Application P99065 ?and supplements S001 and
S004?.83The indication for use for these spheres is “… for
the treatment of unresectable metastatic liver tumors from
primary colorectal cancer with adjuvant intrahepatic artery
chemotherapy ?IHAC? of FUDR ?Floxuridine?.”
Because the microspheres block the capillaries, one con-
cern in the delivery of the treatment is that the spheres may
block so much of the blood flow that the material injected no
longer flows into the arteries leading to the tumors ?ante-
grade flow? but shunts backward ?retrograde flow? and into
arteries feeding other locations ?of particular concern is the
gastric artery supplying the stomach?. The probability of fill-
ing the capillary bed depends on the number of microspheres
Off-label use mostly centers around three situations: ?1?
Using one manufacturer’s product to treat the disease for
which the other manufacturer’s spheres were approved; ?2?
using radiolabeled microspheres to treat a cancer in the liver
for which microspheres have not been approved; and ?3? us-
ing radioactive microspheres to treat diseases in other parts
of the body. Each of these situations involves different is-
sues. An additional “dosimetry” issue is that the prescription
is normally in terms of activity to be injected into the liver
rather than dose to the liver. Note, however, that in a recent
guidance document84on microspheres, the NRC specifies
“For Y-90 microspheres, ‘prescribed dose’ means the total
dose ?rad or Gy?. Alternatively, prescribed activity ?mCi or
GBq? may be used in lieu of prescribed dose.” Additionally,
it specifies that the written directive should include: ?1?
“Preadministration: The date; the signature of the AU; the
treatment site; the radionuclide ?including the physical form
?Y-90 microspheres??; the prescribed dose/activity; and, if
appropriate for the type of microsphere used, identify the
90Y have been approved for
manufacturer and include the statement ‘or dose/activity de-
livered at stasis’;” and ?2? “after administration but before
the patient or human research subject leaves the postproce-
dural recovery area: The date; the signature of the AU; and
the total dose/activity delivered to the treatment site. If the
administration was terminated because of stasis, then the to-
tal dose/activity to the treatment site is the value of the total
dose/activity administered when stasis occurred and the ad-
ministration was terminated. Note: The postadministration
entries into the written directive are not an amendment to the
written directive; rather, these entries complete the written
VII.B.1. Using one manufacturer’s product to treat
the disease for which the other manufacturer’s
spheres were approved
FDA approval for the microspheres being limited to a
specific disease resulted from the clinical trials sponsored by
the manufacturers to prove the safety and efficacy of their
products. Because of the costs of running a clinical trial, the
vendors picked a specific disease. The choices may seem
arbitrary, but some reasons support the differentiation. While
hepatocellular cancer often presents with disease widely dis-
seminated through the liver, sometimes only a few, discrete
foci are involved. These may be best treated with a small
number of microspheres with a relatively high specific activ-
ity. Microspheres with less activity per sphere would have a
difficult time getting enough products in place to deliver the
dose without filling the capillary bed prematurely. On the
other hand, while metastases to the liver may appear as few
nodules, very likely many smaller sites exist below the res-
olution of the imaging systems. In these cases, the radioac-
tive material should cover a wide volume of the liver, sug-
gesting a large number of lower-activity spheres. While the
foregoing discussion finds basis in reasoning, no clinical data
supports the arguments.
A treatment facility may have been licensed for one of the
two products, and be faced with a patient having the disease
specific to the other type of microspheres but without the
time needed for authorization, training, and logistical setup
to use appropriate microsphere product. Using the product
they already have authorization for qualifies as off-label use.
Before proceeding, questions to be addressed include:
a.Will the injection likely cover the target region ad-
equately without filling the capillary bed prematurely?
How does the dose as calculated by one system com-
pare to that of the other system. Neither product calcu-
lates the dose to the tumor nor do they make a realistic
calculation of the dose to the liver. The clinical results
in the trials were tied to the calculation method used,
through simple, empirical designs. Because of the dif-
ference in the distribution of the microspheres between
the manufacturers’ products, the empirical calculations
from one manufacturer may not result in the same bio-
logical effect when used with the other product.
While the physicist and physician in a clinic may be able
2308Thomadsen et al.: Off-label use of medical products2308
Medical Physics, Vol. 37, No. 5, May 2010
to estimate the probability of the adequate coverage, the
question of dose equivalency between the products and be-
tween the calculational approaches remains a research topic
of considerable difficulty. The estimation of the classic radia-
tion absorbed dose is problematic with any radiopharmaceu-
tical, and especially so in this case. The exact tumor volume
treated is unknown or extremely difficult to determine and
the administered radioactivity will distribute according to the
circulation. The inhomogeneity of the tumor and the micro-
sphere distribution leads to such an extremely high uncer-
tainty in dose estimation that it is fair to say that, at the
present time, it is unknown.
VII.B.2. Using radiolabeled microspheres to treat a
cancer in the liver for which no microsphere
has been approved
Many cancers metastasize to the liver and often fail to
respond to conventional treatments. Clinicians may be
tempted to use the radiolabeled microsphere for therapy
since they have proven effective for hepatocelluar primaries
and colorectal metastases. One major issue with other types
of metastases concerns their vascularity. On arteriograms, the
approved tumors demonstrate a marked vascularity, which is
part of their biology. Other tumors often do not have this
property. Infusing such tumors would likely result in little
uptake of the radionuclide in the cancer and a concomitantly
high dose to the liver parenchyma, potentially injuring the
VII.B.3. Using radioactive microspheres to treat
disease in other parts of the body
The unique anatomy of the liver, the dual arterial supply
and the partition between tumor and normal cells, provides
the liver with the ideal situation for treatment with radiola-
beled microspheres. However, tumors in many locations fail
to respond to other therapies. Attempting to use radiolabeled
microspheres in such situations takes the practitioner far
afield from the clinical trials. All the issues in the two situa-
tions discussed above apply as does the question of shunting.
Many tumors exhibit bizarre vascular patterns and flow
anomalies that could result in major, unexpected exposure to
sensitive, normal tissues. These questions raise serious issues
that need to be addressed before proceeding. While solid
answers to almost any of the questions remain unavailable,
the considerations must support that serious injury to the
patient would be unlikely before such off-label use is under-
It is important to understand the concept of off-label use
of a FDA-approved medical product ?device or drug?, espe-
cially for the medical physicist. To have a better understand-
ing of the implications of using a medical product off-label,
it is helpful to review the role of labeling in the FDA ap-
proval process of a medical device or drug. Hence, the first
part of this report and Appendix C in the full report review
the various processes that a device manufacturer can use to
obtain premarket approval before the device can be legally
Sometimes, device labeling is quite specific in what its
intended use?s? encompasses. However, once a medical prod-
uct is approved, even for a limited indication, as part of the
practice of medicine, a licensed physician can decide to treat
an individual patient in a manner not included in the label-
ing, and hence treat in an off-label manner. As part of the
clinical team treating the patient, if the medical physicist
determines that the proposed use of the medical product
raises new safety and effectiveness issues, these should be
communicated in writing to other team members before
treating that patient. A medical physicist usually learns about
what the labeling uses are for a treatment modality during
the training provided by the manufacturer. During this train-
ing the medical physicist should ask for clarification about
specific FDA-approved labeling indications. Any other use is
considered off-label and the manufacturer is not permitted by
the FDA to promote such use. There are, however, situations
where off-label use has been described in the published lit-
erature; in such cases, the manufacturer may reference such
studies when FDA requirements and guidelines have been
followed. To make the medical physicist more aware of the
relevant legal issues of treating an individual patient off-
label, a summary of the legal issues is included.
Finally, two case studies of off-label use are presented.
These raise some of the issues that the medical physicist
should consider as a clinical team member concerned with
the role of radiation and clinical implications of the proposed
product for that patient, as discussed in Sec. VI. The case
studies do not represent any type of official FDA policy on
the off-label use of the devices in the case studies, but are
simply examples of the type of issues the medical physicist
should consider when a medical product device is to be used
off-label in treating an individual patient. The appropriate
Center within the FDA should be contacted directly if there
are questions on the FDA approval process for medical de-
vices or drugs since the information in 21 CFR will change
with new Congressional legislation. Information on the indi-
cations for use of approved medical products can be found
through the links on the CDRH database website.85
a?The opinions expressed herein are those of the authors and are not to be
construed as conveying either policies of or an official endorsement or
criticism by the U.S. Department of Health and Human Services, the
Public Health Service, or the U.S. Food and Drug Administration.
b?Electronic mail: firstname.lastname@example.org; Telephone: 608-263-
4183; Fax: 608-262-2413.
1G. P. Glasgow, “Nuclear Regulatory Commission regulatory status of
approved intravascular brachytherapy systems,” Cardiovasc. Radiat. Med.
3, 60–66 ?2002?.
2See, for example, Klein v. Biscup, 673 N.E.2d 225, 231 ?Ohio Ct. App.?,
appeal denied, 667 N.E.2d 987 ?Ohio 1996?.
3See, e.g., Rhone-Poulenc Rorer Pharm., Inc, v. Marion Merrell Dow, Inc.,
93 F.3d 511, 514 n.3 ?8th Cir., 1996?, Bristol Myers Squibb Co. v.
Shalala, 91 F.3d 1493 ?D.C. Cir. 1996?; Weaver v. Reagen, 886 F.2d 194,
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2309Thomadsen et al.: Off-label use of medical products2309
Medical Physics, Vol. 37, No. 5, May 2010
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7See, e.g., Washington Legal Foundation v. Kessler, 880 F. Supp. 26, 28 n.
1?D.D.C. 1995?. Off-label can mean many things. “?U?sing an approved
drug to treat a disease that is not indicated on its label, but is closely
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and treating the indicated disease but varying from the indicated dosage,
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1996?; In re Orthopedic Bone Screw Products Liability Litigation, MDL
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medical judgment, not of regulatory approval”? ?citation and quotation
marks omitted?. The FDCA was “not intended as a medical practices act
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74th Cong., 1st Sess. 3 ?1935?.
9P. S. Spivak, “Off-label promotion under scrutiny by DOJ, The Depart-
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