Off-Label Use of Drugs in Children
COMMITTEE ON DRUGS
Pediatrics 2014;133;563; originally published online February 24, 2014;
DOI: 10.1542/peds.2013-4060
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/133/3/563.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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FROM THE AMERICAN ACADEMY OF PEDIATRICS
Organizational Principles to Guide and Define the Child
Health Care System and/or Improve the Health of all Children
POLICY STATEMENT
Off-Label Use of Drugs in Children
COMMITTEE ON DRUGS
abstract
KEY WORDS
off-label drug use, pharmaceuticals, pediatrics, infants, children,
The passage of the Best Pharmaceuticals for Children Act and the Pe-
adolescents, prescribing
diatric Research Equity Act has collectively resulted in an improvement
ABBREVIATIONS
in rational prescribing for children, including more than 500 labeling
BPCA Best Pharmaceuticals for Children Act
changes. However, off-label drug use remains an important public
FDA US Food and Drug Administration
health issue for infants, children, and adolescents, because an over-
PREA Pediatric Research Equity Act
whelming number of drugs still have no information in the labeling for
This document is copyrighted and is property of the American
use in pediatrics. The purpose of off-label use is to benefit the individ-
Academy of Pediatrics and its Board of Directors. All authors
have filed conflict of interest statements with the American
ual patient. Practitioners use their professional judgment to determine
Academy of Pediatrics. Any conflicts have been resolved through
these uses. As such, the term  off-label does not imply an improper,
a process approved by the Board of Directors. The American
illegal, contraindicated, or investigational use. Therapeutic decision-
Academy of Pediatrics has neither solicited nor accepted any
commercial involvement in the development of the content of making must always rely on the best available evidence and the
this publication.
importance of the benefit for the individual patient. Pediatrics
The recommendations in this statement do not indicate an
2014;133:563 567
exclusive course of treatment or serve as a standard of medical
care. Variations, taking into account individual circumstances,
may be appropriate.
All policy statements from the American Academy of Pediatrics INTRODUCTION
automatically expire 5 years after publication unless reaffirmed,
The purpose of this statement is to further define and discuss the
revised, or retired at or before that time.
status of off-label use of medications in children. Since publication of
the 2002 statement from the American Academy of Pediatrics on the
off-label use of drugs,1 the number of drugs approved by the US
Food and Drug Administration (FDA) with pediatric indications or
expanded labeling that informs drug use in pediatric patients
(eg, pharmacokinetic/pharmacodynamic data, safety data) has sub-
stantially increased. The passage of the Best Pharmaceuticals for
Children Act2 (BPCA) and the Pediatric Research Equity Act3 (PREA) has
resulted in more than 500 pediatric labeling changes. However, despite
this success and advances in both basic science and clinical trials in
www.pediatrics.org/cgi/doi/10.1542/peds.2013-4060
pediatrics, off-label drug use remains a common and important issue
doi:10.1542/peds.2013-4060
for children and adolescents. Moreover, off-label use of drugs presents
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
an even larger and more complex issue in preterm and full-term neo-
Copyright © 2014 by the American Academy of Pediatrics
nates, infants and in children younger than 2 years,4 and children
with chronic and/or rare diseases.
DEFINING OFF-LABEL USE
The term  off-label use refers to use of a drug that is not included in
the package insert (approved labeling) for that drug. The purpose of
off-label use is to benefit an individual patient. It is important to note
that the term  off-label does not imply an improper, illegal, contra-
indicated, or investigational use. To approve a drug for sale and
marketing within the United States, the FDA requires substantial
PEDIATRICS Volume 133, Number 3, March 2014 563
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evidence for efficacy and safety, usu- drug s use is improper for that age or before the drug is marketed in in-
ally in the form of 2 well-controlled disorder. Rather, it only means that terstate commerce. For drugs and bi-
trials. Subsequent requests by a spon- the evidence required by law to allow ological agents (eg, vaccines, antibodies),
sor to add a new indication to drug inclusion in the label has not been proof of effectiveness consists of  ade-
labeling must also be accompanied by approved by the FDA. Additionally, in quate and well-controlled studies as
additional evidence in support of that
no way does a lack of labeling signify defined for new drugs in the Code
indication. If the FDA finds that such
that therapy is unsupported by clini- of Federal Regulations.8 Biological
evidence supports approval, the new
cal experience or data in children. agents are approved under the Public
indication is added to the product la- Instead, it specifically means that ev- Health Service Act.9 Given these re-
beling. If the evidence is deemed in- idence for drug efficacy and safety in
quirements as well as the rapid pace of
sufficient or if the sponsor chooses not
the pediatric population has not been
medical discovery, it is not surprising
to submit evidence, the indication is
submitted to FDA for review or has
that labeling does not reflect all possi-
not added.
not met the regulatory standards of
ble uses of an agent. Off-label use of
 substantial evidence for FDA ap- drugs in children is not overseen by the
According to the Code of Federal Reg-
proval. In contrast to the absence of
ulations,5 a sponsor is the entity that FDA, because the FDA does not regulate
pediatric-specific information on some
holds an investigational new drug the prescription practices of individual
medications, other drug labels contain
application and that both takes re- practitioners.
statements such as  the safety and ef-
sponsibility for and initiates a clinical
The FDA maintains a system for post-
ficacy in pediatric patients have not been
investigation. The sponsor may be an
marketing drug surveillance, compil-
established, and explicit evidence-based
individual or pharmaceutical company,
ing and analyzing information about
warnings and contraindications are in-
governmental agency, academic in-
the incidence and severity of adverse
cluded on the label where indicated.
stitution, private organization, or other
events reported by practitioners,
Understanding the distinction between
organization. A sponsor does not ac-
sponsors, hospitals, and other health
the lack of FDA approval for a particular
tually conduct the investigation unless
care facilities. It is important to note
use or dosing regimen in the former
the sponsor is a sponsor-investigator.
that this postmarket surveillance
case versus explicit warnings or con-
A person other than an individual who
system is passive and that the total
traindications against use in the latter is
uses 1 or more of his or her own em-
number of adverse event reports in
essential for the pediatric practitioner. In
ployees to conduct an investigation that
pediatrics relative to adults is small. To
addition, when considering best prac-
he or she has initiated is considered to
address this issue, the BPCA provides
tices for therapeutic decision-making, it
be a sponsor, not a sponsor-investigator.
for a systematized review of adverse
is essential to understand that the FDA
In this case, the employees are inves-
event reports in pediatric patients
does not regulate the use of drugs as
tigators. Sponsor-investigators both
through the FDA Pediatric Advisory
they pertain to the practice of medicine.6
initiate and conduct an investigation
Committee. When the FDA notes an
and direct the administration or dis-
apparent association between use of
THE ROLE OF THE FDA
pensing of the investigational drug. The
a drug and an adverse event, the FDA
requirements applicable to a sponsor-
may choose from several actions: to
The FDA is the federal government
investigator include both those applica-
agency charged with oversight re- request further focused study of the
ble to an investigator and a sponsor. It is
drug, to add a contraindication or
sponsibility for the manufacturing,
important to note that sponsors are not
warning to the drug labeling, to issue
labeling, advertisement, and safety of
allowed to promote or even speak to off-
therapeutic drugs and biological prod- a warning about use of the drug, or to
label use. If a physician speaks on behalf
seek voluntary or compulsory removal
ucts. The Food, Drug, and Cosmetic Act7
of a sponsor, the same rule applies. It is
of the drug from the market. There-
requires that  substantial evidence,
acceptable to use drugs off label and to
resulting from  adequate and well- fore, although the FDA does not reg-
publish results related to off-label use,
controlled investigations demonstrat- ulate the practice of medicine,
but it is not acceptable to receive re-
ing that a new drug  will have the effect practitioners should be aware of new
muneration from the sponsor for these
it purports or is represented to have information brought forward by the
uses.
under the conditions of use prescribed, FDA, because it can serve as a valuable
The absence of labeling for a specific recommended, or suggested in the resource for information regarding
age group or for a specific disorder proposed labeling, be submitted to and the potential or proven adverse effects
does not necessarily mean that the reviewed and approved by the FDA of drugs (see www.fda.gov).
564 FROM THE AMERICAN ACADEMY OF PEDIATRICS
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FROM THE AMERICAN ACADEMY OF PEDIATRICS
THERAPEUTIC DECISION-MAKING In general, if existing evidence sup- may be accountable for the negligent
ports the use of a drug for a specific use of any drug in a civil action, re-
Therapeutic decision-making should
indication in a particular patient, the gardless of whether the FDA has ap-
always be guided by the best available
usual informed-consent conversations proved the use of that drug. Labeling
evidence and the importance of the
should be conducted, including antic- is not intended to preclude the prac-
benefit for the individual patient. Prac-
ipated risks, benefits, and alternatives. titioner from using his or her best
titioners are in agreement regarding
If the off-label use is based on sound medical judgment in the interest of
the importance of practicing evidence-
medical evidence, no additional in- patients or to impose liability for
based medicine. However, for the pedi-
off-label use. Indeed, the practice of
formed consent beyond that routinely
atric population, gold standard clinical
medicine will more than likely require
used in therapeutic decision-making is
trials are often not available, so prac-
a practitioner to use drugs off label to
needed.10 However, if the off-label use
titioners must rely on either less de-
provide the most appropriate treatment
is experimental, then the patient (or
finitive information, such as expert
parent) should be informed of its ex- of a patient. However, because the use of
opinion for the age group that they are
drugs in an off-label capacity can in-
perimental status.11 It would be pru-
treating, or use evidence from a differ-
crease the liability risk for a practitioner
dent for pediatricians to know and
ent population to guide practice. There
should an adverse event or poor out-
abide by the appropriate informed
are now many resources available to
come ensue, it is essential that practi-
consent laws in their respective states.
help assess the quality of evidence-
tioners document the decision-making
In addition, particular risk-benefit ra-
based medicine, including but not re-
process to use a drug off label in the
tios presented by the unproven thera-
stricted to articles in peer-reviewed
patient s medical record.
pies must be carefully considered and
journals, American Academy of Pediat-
disclosed, and standard of care prac-
rics practice guidelines and policy
tices should be reviewed. When use of FEDERAL LEGISLATION TO
statements, consensus statements, and
INCREASE DRUG TESTING IN
a drug is truly investigational, drug
handbooks and databases (ie, Cochrane,
use should be performed in conjunc- CHILDREN
Lexicomp, and Harriet Lane). At times,
tion with a well-designed clinical trial
there may be little or no published in-
The BPCA and the PREA are 2 com-
whenever possible. This is especially
formation to guide therapy. This situa-
plementary federal laws that have
true when the physician proposes to
tion is especially true when treating rare
substantially increased clinical evalu-
treat a group of patients rather than
diseases or sparse populations such as
ation and labeling of drugs in children
neonates. In such situations, the prac- a single individual. Patients and/or their
both by the pharmaceutical industry
legal guardians should be specifically
ticing physician can play an important
and through government-sponsored
informed that the proposed therapy
role in adding to therapeutic information
trials.8 The PREA mandates that al-
is investigational, and their consent to
by publishing his or her experience with
most all new drugs and certain ap-
proceed despite the risks of inves-
off-label uses of drugs. These reports
proved drugs must be studied in
can serve as the basis of more formal tigational therapy should be carefully
children for approved uses of the
efficacy and safety studies and can serve documented. Whether institutional re-
product if there is potential for use of
as a therapeutic decision-making re- view, consultation, or written consent
that drug in children and that the
source for other physicians. The prac- are required for a given intervention
application for new drug approval in-
ticing physician also has a responsibility depends on the degree of risk or
clude the results of adequate pediat-
to report adverse events to the FDA departure from standard practices
ric studies unless the studies are
through the Medwatch program (www. and the extent to which research,
deferred or waived by the FDA. The
fda.gov/Safety/MedWatch).
rather than individual patient care, is
BPCA allows sponsors to qualify for an
involved.
In most situations, off-label use of additional 6 months of market exclu-
sivity if the sponsor completes and
medications is neither experimenta- Practitioners may be concerned that
tion nor research. The administration submits pediatric studies to the FDA,
the off-label use of an approved drug
as outlined in an FDA-issued written
of an approved drug for a use that is may invite a variety of legal actions.
request. A written request may in-
not approved by the FDA is not con- To conform to accepted professional
sidered research and does not war- standards, the off-label use of a drug clude off-label as well as approved
rant special consent or review if it is should be done in good faith, in the uses of a drug. In addition, the BPCA
deemed to be in the individual patient s best interest of the patient, and with- authorizes the National Institutes of
best interest.6 out fraudulent intent. A practitioner Health, in conjunction with the FDA
PEDIATRICS Volume 133, Number 3, March 2014 565
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and physicians from clinical dis- when making therapeutic decisions 4. Journals should be encouraged to
ciplines, to work together to assign for their patients. The PREA and BPCA publish the results of all well-
priority for testing of specific drugs have been extremely successful and designed investigations, including
in children. The National Institutes of represent an essential first step in negative studies.
Health, acting through the Eunice expanding this evidence as a means of
5. Institutions and payers should not
Kennedy Shriver National Institute of achieving the ultimate goal that any
use labeling status as the sole
Child Health and Human Development, and all drugs used to treat children
criterion that determines the
then solicits proposals for pediatric will have age-appropriate evidence
availability on formulary or re-
drug testing concordant with the drug sufficient to provide information for
imbursement status for medica-
prioritization recommendations and labeling. However, labeling with pedi-
tions in children. Similarly, less
funds clinical studies that are judged atric information still exists in less
expensive therapeutic alterna-
meritorious by external review. The than 50% of products,15 such that
tives considered appropriate
ratification of these 2 laws has been much work remains to be done to
for adults should not automati-
considered a significant success, be- ensure the best possible practice
cally be considered appropriate
cause there have been more than for therapeutic decision-making in
first-line treatment in children.
500 pediatric labeling changes. Also pediatrics.
Finally, off-label uses of drugs
as a result of these laws, increased
should be considered when ad-
prospective pediatric drug testing
RECOMMENDATIONS
dressing various drug-related
has occurred via industry-sponsored
concerns, such as drug short-
1. The practitioner who prescribes
studies, investigator-initiated studies,
ages.
a drug is responsible for deciding
and consortia, such as the National
which drug and dosing regimen
Institute of Child Health and Human
LEAD AUTHOR
the patient will receive and for
Development funded Pediatric Trials
Kathleen A. Neville, MD, MS
what purpose.
Network. The net result has been
a. This decision should be made on
an expansion of both pediatric labeling
COMMITTEE ON DRUGS, 2012 2013
the basis of the information con-
Daniel A. C. Frattarelli, MD, Chairperson
information and the knowledge base
tained in the drug s labeling (when Jeffrey L. Galinkin, MD, MS
from which practitioners can draw to
Thomas P. Green, MD
available) or other data available
make informed therapeutic decisions.12,13
Timothy D. Johnson, DO, MMM
to the prescriber.
Kathleen A. Neville, MD
In 2012, Congress passed the Food and
b. The use of a drug, whether off
Ian M. Paul, MD
Drug Administration Safety and In-
or on label, should be based John N. Van Den Anker, MD, PhD
novation Act,14 reauthorizing and
on sound scientific evidence,
strengthening the BPCA and PREA. The
FORMER COMMITTEE ON DRUGS
expert medical judgment, or
legislation aims to ensure that pedi-
MEMBER
published literature whenever
atric evaluations under PREA are
Matthew Knight, MD
possible.
conducted earlier in the drug de-
c. Off-label use is neither incorrect
LIAISONS
velopment process to improve the
nor investigational if based on
John J. Alexander, MD  Food and Drug
quality of and accountability for com-
sound scientific evidence, expert
Administration
pletion of such studies and to advance
Sarah J. Kilpatrick, MD  American College of
medical judgment, or published
the neonatal drug studies under the
Obstetricians and Gynecologists
literature.
BPCA and PREA. The legislation also Janet D. Cragan, MD, MPH  Centers for Disease
2. Pediatricians should continue to
Control and Prevention
makes both the BPCA and PREA per-
advocate for necessary incentives
Michael J. Rieder, MD  Canadian Pediatric
manent law.
Society
and requirements to promote the
Adelaide S. Robb, MD  American Academy of
study of drugs in children.
Child and Adolescent Psychiatry
CONCLUSIONS
3. Physician researchers are encour- Hari Sachs, MD  Food and Drug Administration
Anne Zajicek, MD, PharmD  National Institutes
Off-label drug use remains an impor- aged to continue the rational and
of Health
tant public health issue, especially for critical study of drugs in children
infants, young children, and children through conducting and/or collab-
STAFF
with rare diseases. Evidence, not label orating in well-designed pediatric
Tamar Haro
indication, remains the gold standard drug studies, including national
Raymond K. Koteras, MHA
from which practitioners should draw consortium studies. Mark Del Monte, JD
566 FROM THE AMERICAN ACADEMY OF PEDIATRICS
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FROM THE AMERICAN ACADEMY OF PEDIATRICS
REFERENCES
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diatrics. 2002;110(1 pt 1):181 183 formation sheet. Available at: http://www. 1998)
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12. Roberts R, Rodriguez W, Murphy D, Crescenzi
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a new drug. Adequate and well-controlled
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1915
PEDIATRICS Volume 133, Number 3, March 2014 567
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Off-Label Use of Drugs in Children
COMMITTEE ON DRUGS
Pediatrics 2014;133;563; originally published online February 24, 2014;
DOI: 10.1542/peds.2013-4060
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/133/3/563.full.ht
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org by guest on May 29, 2014