46 Current Drug Safety, 2011, 6, 46-48

Off-Label Prescribing of Drugs for Children

Albert Wertheimer*

Temple University School of Pharmacy, Philadelphia, PA, USA

Abstract: Under normal circumstances, children are excluded from clinical trials of new drug candidates. Yet, when the drug
product is approved for marketing by the authorities, it is only a matter of time before physicians use that drug on pediatric
patients. We do know that the practice of prescribing drugs for off-label conditions is found in approximately 50% of all
physician prescribing. We should not look at off-label pediatric drug use as always a bad or negative behavior. It may be that a
manufacturer has conducted a successful clinical trial for a new pediatric condition and has submitted the documentation to the
FDA staff to support that new indication, but the regulatory agency has not completed its review and formally awarded the new
indication to the sponsor. Or it might be the case that over a dozen years of clinician experience informs all clinicians that an off-
label use of a drug works most effectively and yet the manufacturer is reluctant to spend the money required for a supplemental
investigation when it loses patent protection in under a year. As with many other situations where not all of the facts may be
known, it seems that the wisest path is to approach the use of drugs for off-label conditions with great caution and with as much
knowledge as may be gained before the prescribing decision is arrived at.
Keywords: Off-label prescribing, off-label drug use, children, pediatrics.

More than 3.5 billion prescriptions are written in the United possibly pregnant 32-year-old patient who would likely benefit
States each year. Estimates suggest that up to 50% of these from the use of a very successful drug that we are familiar with
prescriptions are for what is called an off-label indication. When and use on a daily basis for our other patients. To use such a
a drug product is approved for marketing by the US Food and drug in one of these patients is an off-label use of a
Drug Administration (FDA), it is given that approval for a pharmaceutical product. In some countries this procedure is a
specific use. There can be two or three or more other uses but violation of the law and in other countries the health insurers of
each one that is approved is gained by the drug product’s sick funds will not pay if they know that the drug is being used
sponsor company presenting clinical trial data to prove the in an off-label manner.
drug’s value against a specific medical condition.
Let us first look at the extent of this practice and then we
The manufacturer is legally able to only promote the drug will explore the reasons for it. In one study [1] Radley and his
for use in those approved conditions. Yet, in the course of colleagues determined that in the United States in 2001 there
widespread use, it becomes known by the clinician community was a 21% overall use of off label medications and this number
that certain drugs also possess effectiveness against other reached 46% when dealing with cardiac medications and with
medical conditions for which there is no clinical data anticonvulsants. In a British study conducted in 1998, it was
submission to the FDA to produce the evidence needed to found that 36% of children in hospitals received drugs
enable approval of that indication and advertising of the drug for prescribed in either an unlicensed or off label manner. The
use against the additional indications. authors conclude that the use of drugs in an off label or
unlicensed manner to treat children is widespread [2]. These
In some categories, off-label use can even exceed 50% of
results have been replicated in other studies in Germany, in The
total prescriptions for that condition. Several groups of patients
Netherlands and in the United States [3]. A report in the British
are somewhat disadvantaged by clinical trial evaluations of new
Medical Journal tells of 28.9% of prescriptions prescribed for
product candidates. Pregnant women are nearly always
excluded from drug clinical trials, as are young children. This children as being either not licensed for use in children or off
label [4]. In one of the largest and most extensive studies
report will focus on the issues, problems, opportunities and
Conroy and her colleagues examined drug use in pediatric
regulations surrounding such drug products in pediatric drug
wards of hospitals in five countries (United Kingdom, Sweden,
use.
Germany, Italy, The Netherlands). Findings were that nearly
For a typical clinical trial, a drug is tested in several half of all drug prescriptions were either unlicensed or off label
thousand ill patients who are between the ages of 18 or 21 and and that over half of the patients (67%) received at least one
60 years. Women in their childbearing years are often also unlicensed or off label prescription [5].
discriminated against by being excluded by the investigators.
There is no need to report on the numerous additional
Therefore, when a product is eventually approved, it will be
studies that are available with very similar results to the ones
legal to promote the drug product for only those patients who
just portrayed above. It is a fair statement to indicate that off-
are between the ages of 18 or 21 to 60 years as well as males.
So, what is to be done? We have a 16-year-old patient or a label prescribing is an international, widespread and growing
practice.
Why then does this practice exist? The answer to this
*Address correspondence to this author at the Temple University of School of question lies in the nature of the process by which a company
Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140, USA; Tel: 215- receives marketing approval for an additional medical
707-1291; Fax: 215-707-8188; E-mail: [email protected]
indication. Usually, a manufacturer will conduct an additional

1574-8863/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

Off-Label Prescribing of Drugs for Children Current Drug Safety, 2011, Vol. 6, No. 1 47

clinical trial using perhaps 2000 patients to demonstrate efficacy Yet, in spite of these actions, the off-label use of drugs in the
against a new medical condition (indication). If the results of the pediatric population is increasing rather than declining. Much of
clinical trial are positive and the FDA is convinced that the this has to do with the enormously expanded use of
benefits from using this drug product for the new condition psychotropic drugs in psychiatric and behavioral practices [8].
outweigh the risks, then the product is approved for this The reaction to off-label drug use in various countries differs
additional indication. In practical terms, this approval enables
greatly. In much of northern Europe and in Scandinavia, the
only that manufacturer to promote and market the drug product
practice is not permitted or it may be permitted with informed
for the new indication. Another brand of the same product or
consent of the patient. Another very different approach is that
any of the other analogs, no matter how closely related to this
used in Germany and some other Western European countries
product are prohibited from making that claim until such time as
where the practice is considered unacceptable and should the
they provide the same clinical evidence for that other molecule. health insurer or sick fund determine that a prescribed drug was
Needless to say, a clinical trial involving 2000 patients is used in an off-label manner, they will refuse to pay for it and
costly and will not be undertaken under several conditions: expect that the cost of the medication will come from the pocket
of the prescriber.
• If the patent period is nearing an end, the manufacturer
will not deem it a wise investment to conduct the trial for Perhaps the most progressive stance is that now taken by the
the benefit of the generic producers and other US FDA which is leaning toward allowing drug companies to
brands/sources that are soon surely to follow give physicians journal articles that discuss off-label uses of
products not yet approved by the FDA. This approach would
• If the patent has already expired and there is generic
then replace the FDA 1997 Modernization Act (FDAMA)
competition, the same decision as above will be made
which expired in 2006. The new guidelines include a provision
• If the product has not been particularly profitable or allowing dissemination of information if a drug company meets
successful, the same decision will be made. certain criteria. In this way the FDA makes it easier for
Then there are other circumstances where the manufacturer pharmaceutical companies to distribute truthful and non-
has conducted the trial and his submitted the supplemental NDA misleading information than had been possible in the past.
and is waiting for the regulatory authority to grant approval for It is assumed and hoped that this will benefit patients who
the new indication. Until such time as the actual approval if might now have access to beneficial products which their
formally granted, any use of that product for unapproved physicians were previously unaware [9].
indications or unapproved patient populations is off-label. One
Even with these protections and the additional latitude
hears stories of how such supplemental applications take two or
provided to drug companies and prescribing physicians, there
more years for regulatory authority action in some countries.
are some who object, claiming that there are insufficient
Since children are excluded from most clinical trials, the protections for the patient. For example, a recent article argues
result is that a great deal of pediatric prescribing becomes, by that the ethics related to informed consent and shared decision-
definition, off-label. This is not a new phenomenon and making provide an imperative for doctors to inform patients
clinicians as well as the regulatory authorities in the United about the risks of a medical treatment when its use has not been
States and abroad have been aware and concerned about it for formally approved. They argue that the public often assumes
quite a while. The US FDA deserves credit for attempting to that all common uses of prescription drugs have been approved
deal with this problem. In 1994 it promulgated regulations by the FDA, which of course, is not always the case. These
requiring a manufacturer to determine whether there was data in authors acknowledge that off-label prescribing is sometimes
existence that would permit modification of labeling of necessary, especially in pediatrics but that off-label use may
approved drugs to include children. By taking advantage of the pose potentially serious risks, especially since no governmental
existing body of published literature, the FDA was legally body has conducted a review of the effectiveness or safety of
permitted to consider a manufacturer’s submission and the drug for the off-label indications. Therefore, they argue that
consequently modify the approved labeling to include children. there should be a strict requirement compelling doctors to obtain
While this process exists, it has almost never been used to informed consent from patients who are to be prescribed drugs
modify labeling. for an off-label use just as they would before enrolling patients
The FDA along with the American Academy of Pediatrics in a clinical research study [10].
championed the 1997 FDA Modernization Act which permitted Others support the stance. One clinician determined that the
manufacturers of drugs under patent to have an additional six information found in current compendia did not include the
months of patent extension in return for performing studies most updated information on research findings and that there
leading to labeling for children. Some manufacturers waited were significant and confusing differences between the way that
until the patent was nearly expired to claim the additional six common compendia presented and updated information.
months, and but the result was a sufficient incentive for an Therefore it is argued that the practicing physician does not
increased number of drugs to undergo pediatric clinical trials have the opportunity to individually make decisions about the
and be approved for children’s use [6]. appropriateness of some off-label drug uses [11].
A further revision was achieved in 1999 which permitted the The matter of off-label drug use remains controversial and
FDA to mandate pediatric patients when a product was contentious and it does not appear that any universal solution
considered to be likely used in a substantial number of children may be expected in the near future. There are few arguments
[7]. against off-label use of drugs for terminal and end-stage
conditions. When the conventional therapeutics prove to be
incapable of arresting tumor growth or some other life-
48 Current Drug Safety, 2011, Vol. 6, No. 1 Albert Wertheimer

threatening condition, there seems to be very little risk or and officially approved use of a drug. It is becoming possible
downside potential in attempting to obtain therapeutic benefit for the practitioner to gain some legitimate and not
from other pharmacologically active agents where the physician commercially biased information. The reference work FACTS
thinks that there might be some, albeit small, possibility of AND COMPARISONS includes information about known off-
achieving a position outcome or therapeutic success. In fact, a label uses of many of the drugs listed in that valuable reference
1991 study by the US General Accounting Office found that book. In addition the USP-DI reference compendium lists at the
one third of all drugs administered to cancer patients were off- end of a monograph, information about any known off-label use
label and that more than one half of cancer patients received at of that drug. These are conveniently listed as probably effective,
least one drug for an off-label indication [12]. or without substantial scientific support or where there is little
reason to believe that the drug has effectiveness for a stated
The special case of pediatric drug use: There is usually very
little harm caused by the use of an approved drug in condition. And of course, every day on the World Wide Web,
new sites and other information sources become available to
approximately the same dosage for an unapproved indication in
help with dilemmas such as this.
an adult patient. However, when an approved drug is used for a
child it can be an entirely different matter. While many drugs As with many other situations where not all of the facts may
have the same effect in adults and children, this is not always be known it seems that the wisest path is to approach the use of
the case. We know for example that tetracycline and related drugs for off-label conditions with great caution and as much
antibiotics cause the mottling of teeth in children, while it does knowledge as may be gained before the prescribing decision is
not have this effect in adult patients. Similarly, the drugs that are arrived at.
used as antidepressants in adults, such as the selective serotonin
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way and today in off-label use may lead to tomorrow’s effective

Received: July 9, 2009 Revised: December 23, 2009 Accepted: October 25, 2010