Roberts R, Rodriguez W, Murphy D, Crescenzi T. Pediatric Drug LabelingImproving the Safety and Efficacy of Pediatric Therapies. JAMA. 2003;290(7):905-911. doi:10.1001/jama.290.7.905
Author Affiliations: Office of Counter-Terrorism and Pediatric Drug Development, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Md.
Context Approximately 50% to 75% of drugs used in pediatric medicine have not
been studied adequately to provide appropriate labeling information. In 1997,
Congress passed the Food and Drug Administration Modernization Act (FDAMA),
which encouraged pediatric drug development by providing an incentive in the
form of additional marketing exclusivity.
Objective To identify new drug labeling information from pediatric studies submitted
to the FDA in response to written requests.
Design and Setting Between July 1998 and April 1, 2002, the FDA requested studies on 242
drugs, and 53 drugs were granted exclusivity. As of January 2003, 49 drugs
have new labels. Data from the studies of the first 33 drugs with new pediatric
information on the label as of April 2002 are included. Significant labeling
information was analyzed along with baseline data and types of studies requested.
Main Outcome Measures Safety data and pediatric information for labeled drugs.
Results There were 53 studies for 33 drug products, 12 (23%) were evaluated
for safety only; 23 (43%), safety and efficacy; and 18 (34%), pharmacokinetics
and/or pharmacodynamics. Significant new dosing and/or safety information
was identified for 12 (36%) drugs. New dosing information was determined for
7 of these drugs. Safety information was defined for gabapentin, propofol,
sevoflurane, the combination of ribavirin and interferon alfa-2b, and various
betamethasone-containing dermatologic preparations. There was a higher percentage
of deaths reported with patients who received propofol compared with controls
in the pediatric intensive care unit. Seizures were seen in patients administered
sevoflurane. Patients receiving a combination of ribavirin and interferon
alfa-2b experienced an increased incidence of suicidal ideation when compared
with adults. An unexpectedly high percentage of those receiving betamethasone-containing
dermatologic preparations had documented hypopituitary-adrenal axis suppression.
Conclusion The FDAMA has stimulated pediatric clinical studies resulting in improved
understanding of the pharmacokinetics of drugs prescribed in pediatric medicine,
important dose changes, and improved safety for children taking certain drugs.
The phrase "therapeutic orphan" was used to describe children in 1963
by Harry Shirkey, MD.1 There had been little
stimulus for pharmaceutical companies to study drugs in children because of
the complexity of such trials and the small financial return. Furthermore,
the assumption that children with diseases or conditions similar to adults
respond similarly has perpetuated the use of medications approved in adults
to treat children, frequently without the appropriate studies in the pediatric
population. Forty years later, only one third of drugs used to treat children
have been studied adequately in the population in which they are being used
and have appropriate use information on the product label.2 For
the other two thirds of drugs, information regarding safety and efficacy for
pediatric patients is insufficient or absent. The younger the age group, the
more likely the lack of information.3
As a result, pediatricians and other health care professionals who treat
children have had to use these drugs on a trial and error basis. Furthermore,
information on the drug's efficacy and safety is not methodically collected
and analyzed. Prescribing medications to children that have not been labeled
for their use is termed off-label use —outside of the terms
of the product approval.4 Off-label use may
result in benefit, no therapeutic effect, or harm (adverse reactions). A lack
of efficacy may be the result of underdosing, while adverse effects may result
from a failure to understand the impact of developmental, physiological, or
metabolic influences on a drug's pharmacokinetics.5
Pediatric patients may also be deprived of potentially effective medication
because of the prescriber's reluctance to use a medication for an off-label
use. Off-label use in pediatrics affects both seriously ill hospitalized patients
and the millions of children treated outside the hospital for symptomatic
illness. The problem of off-label use of drugs in pediatrics is international
and affects pediatric patients in the United States, Europe, Asia, Africa,
and South America.4,6- 8 Hence,
initiatives to encourage and promote pediatric labeling for drugs to provide
the needed information to use them safely and efficaciously in the pediatric
population have become a prime concern for legislative and regulatory bodies.
The ongoing initiatives in the United States have been perceived as beneficial
and a sign of leadership in public health by caregivers in other areas of
Well-controlled studies involving children have been encouraged for
many years.9 The Food and Drug Administration
(FDA) in 1994 spelled out scenarios that would allow establishing pediatric
claims. These included extrapolating efficacy data from adequate and well-controlled
studies in adults in which the course of the disease or condition and the
drug's effects are sufficiently similar between adults and children. To support
such a claim, pharmacokinetic studies to allow determination of an appropriate
pediatric dose and safety studies are necessary; it may not be necessary to
repeat the efficacy studies for certain drugs.10
The Food and Drug Administration Modernization Act (FDAMA) was signed
into law on November 21, 1997. The FDAMA encourages studies of certain therapies
being used in pediatrics by providing an exclusivity incentive provision.
This provision provides an additional 6 months of marketing exclusivity (ie,
no generics can be approved), if the sponsor voluntarily conducts the studies
requested by FDA in the written request, submits them in the specified time
frame, and the studies fairly respond to the written request. Under FDAMA,
the FDA was mandated to develop, prioritize, and publish a list of approved
drugs used off label and for which information on how to use the drugs in
the pediatric population was needed. The initial working list comprised recommendations
from the American Academy of Pediatrics, the Pharmaceutical Research Manufacturers
Association, the National Institutes of Health, the Pediatric Pharmacology
Research Units Network, the National Pharmaceutical Alliance, the Generic
Pharmaceutical Industry Association, the National Association of Pharmaceutical
Manufacturers, and the United States Pharmacopeia. Most written requests issued
by the FDA have been for drugs on this list.
This incentive has been a driving force stimulating the conduct of pediatric
studies. The pediatric labeling process in the United States progressed from
encouraging the pharmaceutical industry to conduct pediatric studies in the
1980s and 1990s to a combined approach of the FDAMA's voluntary incentives
(1997) and mandatory regulation (1998; Pediatric Rule).11 The
FDAMA exclusivity legislation should not be confused with the Pediatric Rule.
The latter required pediatric studies for those conditions being studied in
adults and in which significant use or benefit in pediatrics was expected.
As of October 17, 2002, the US District Court for the District of Columbia
enjoined the FDA from enforcing the Pediatric Rule.
Marketing exclusivity has been a driving force stimulating the conduct
of pediatric studies. To examine the health benefits that were derived from
the pediatric studies linked to the exclusivity incentives, we analyzed the
resulting new labeling changes between July 1998 and April 2002. The Best
Pharmaceuticals for Children Act,12 enacted
January 4, 2002, renews the pediatric exclusivity provision. Our aim is to
provide information supported by evidence available to and reviewed by the
FDA that has been submitted in response to written requests and has resulted
in new pediatric information on the label.
We identified new labeling information from all drugs in the referenced
time frame that received approved pediatric labeling under the FDAMA exclusivity
program. The pediatric studies asked for by the FDA were outlined in written
requests issued by the FDA to the pharmaceutical companies. The results of
the studies were submitted by the pharmaceutical companies with a request
for an exclusivity determination. The responsible regulatory division(s) reviewed
the data and negotiated the new labeling information with the pharmaceutical
company. We examined the types of studies and the data submitted that resulted
in new labeling information. For the purpose of this article, we have defined off-label use as use outside of the FDA-approved label.
Pediatric studies are defined as representing at least 1 clinical investigation,
which could include pharmacokinetic studies, in the pediatric age groups in
which the drug was anticipated to be used.13 We
divided the new labeling information into 2 groups: those active moieties
with new adverse events or dosing information defined as significant (Table 1);
and those active moieties for which information led to approval of their use
in pediatric subpopulations (Table 2).
We also examined non-FDA source data for pediatric information on safety and
dosing recommendations available to prescribers for these products from 2
Between July 1998 and April 2002, 53 drugs were granted pediatric exclusivity
and 33 drug products have new labels with pediatric information. This information
was derived from the 53 studies conducted in response to written requests.
The spectrum of use of these products indicates a wide array of pediatric
conditions such as fever and pain, sedation and anxiety, gastroesophageal
reflux, allergic conditions (rhinitis, conjunctivitis, urticaria), diabetes,
xerosis/ichthyosis, juvenile rheumatoid arthritis, human immunodeficiency
virus infection, obsessive-compulsive disorder, hypertension, cholesterol
management, anesthesia, and seizures. The 33 drugs and the new pediatric information
about each drug are listed in Table 1 and Table 2.
A total of 50 482 patients participated in the 53 studies that
provided the information for new labeling. This includes the 41 356 patients
(aged 6 months to 2 years) who participated in 2 large safety (actual use)
studies of ibuprofen over-the-counter products. The remaining 31 products
involved 9126 patients. The types of studies conducted were as follows: safety
only, 12 (23%); safety and efficacy, 23 (43%); and pharmacokinetic and pharmacodynamic,
18 (34%). Safety data were collected in all studies. New data for the 33 drug
products were provided for the following specified ages: neonates, 7 (21%);
1 month to 3 years, 11 (33%); older than 3 years to 6 years, 20 (61%); and
older than 6 years to 12 years, 24 (73%). Studies in 21 (64%) of 33 drug products
included adolescent patients older than 12 years and younger than 17 years.
Thirty-two labels lowered the age in the pediatric population for which there
was information on how to use the product.
For 12 (36%) of these products, the data obtained resulted in knowledge
that has improved understanding of the specific drug based on pharmacokinetics
or safety information (adverse events). Of the 12 labels with highly important
new information, 7 (58%) were relevant to dosing and had new safety information.
For 2 (sotalol hydrochloride and the combination of ribavirin and interferon
alfa-2b) of the 12 drugs, significant safety information was obtained, although
efficacy was not demonstrated. For buspirone hydrochloride, there was a failure
to demonstrate efficacy (Table 1).
The important dosing information defined for 7 (21%) of 33 drug products
demonstrates the value of conducting pharmacokinetic or pharmacodynamic studies
in the pediatric population (Box). The benefits and information provided through labeling in the 20
other drugs are shown in Table 2.
Generally speaking, the benefits included enhancement of the understanding
of the safety and the pharmacokinetic profile of the drugs down to the age
specified. Of note, there is no need to increase the dose of loratadine in
children aged 2 to 5 years. Instead, the pharmacokinetic profile shows that
these patients should receive half the dose compared with children aged 6
to 12 years.
Midazolam hydrochloride (Versed): Information
demonstrated a need to modify the approach to dosing for a vulnerable group
of children (ie, patients with congenital heart disease and pulmonary hypertension).
Fluvoxamine maleate (Luvox): Dose adjustments
for pediatric patients were necessary to obtain a therapeutic effect and to
minimize adverse events. The previous label reported a prominent treatment
effect in patients aged 8 to 11 years and essentially no effect in patients
aged 12 to 17 years.14
Gabapentin (Neurontin): Dosing for patients
aged 3 to 12 years was defined based on the pharmacokinetic parameters measured.
A higher oral clearance was noted when normalized by body weight in patients
5 years or younger. Neuropsychiatric adverse events were noted as a significant
adverse effect more often in those treated than in the controls.
Etodolac (Lodine): Now indicated for
treatment of the signs and symptoms of juvenile rheumatoid arthritis in patients
aged 6 to 16 years. The pharmacokinetic information demonstrated that the
volume of distribution for pediatric patients was different from adults. A
higher dose is recommended for younger children.
Sotalol hydrochloride (Betapace): Individualized
dosing should be on a milligram per meter squared basis particularly for patients
with a body surface area of less than 0.33 m2 in which increased
corrected QT interval effects were seen.
Buspirone hydrochloride (Buspar): Despite
pharmacokinetic parameters (area under the curve and maximum concentration
of drug) of buspirone and its active metabolite, which were equal to or exceeded
the adult levels, safety and effectiveness were not established for generalized
Atovaquone and proguanil hydrochloride (Malarone):
New pediatric information on the safety and efficacy in prophylaxis and treatment
of malaria were shown, as well as pharmacokinetic differences between the
pediatric and adult populations.
Ribavirin and interferon alfa-2b (Rebetron):
Neuropsychiatric and generally reversible growth adverse events were identified
for pediatric patients receiving the combination of ribavirin and interferon
Pimecrolimus (Elidel): Labeling with
the original approval identified safety concerns (eg, increase in infections,
pyrexia, and diarrhea in patients younger than 2 years).
Betamethasone (Diprolene, Diprosone,
Lotrisone): Topical betamethasone-containing dermatologic products were associated
with a suppression of the hypopituitary-adrenal axis in 28% to 75% of the
pediatric patients depending on the age of the patient and product used.
Propofol (Diprivan): Studies allowed
the indication for maintenance of anesthesia to be lowered to patients aged
2 months or older, but raised concerns about its use for sedation in the pediatric
intensive care unit. Serious adverse events were identified when drug was
administered with fentanyl.
Sevoflurane (Ultane): Studies have established
the safe and effective use as an anesthetic to age 1 month, as well as a new
precaution about rare cases of seizures noted in children and young adults.
Within a year of FDA label approval, data for 11 (33%) of the drug products
had already been incorporated in sources available to those who prescribe
medications for pediatric patients. Of the 33 drug products, 6 (18%) were
new molecular entities for which pediatric labeling became available at the
time of the original new drug application approval. The information provided
herein is now available to pediatricians and may be different from the information
currently available from readily accessible sources.14,15 An
important benefit of this initiative has been the development of new commercially
available formulations in 5 (15%) products to facilitate pediatric use (abacavir
sulfate, midazolam hydrochloride, gabapentin, ibuprofen/pseudoephedrine hydrochloride,
and atovaquone and proguanil hydrochloride). Additionally, a recipe for an
extemporaneous formulation was evaluated and included on the label for 2 of
the drugs (enalapril maleate and sotalol hydrochloride).
In 1996, a committee of the American Academy of Pediatrics reported
17 drugs with widespread use in children and lack of appropriate drug labeling
information.2 One of these products is no longer
marketed. Of the 16 remaining drugs, 3 (19%) have had the requested studies
conducted and the results have been submitted to the FDA. These 3 drugs now
have new pediatric labeling (gabapentin, fluoxetine hydrochloride, and midazolam
hydrochloride). These labels include information critical to understanding
the safety and efficacy of these drugs.
Of the first 33 labeled drug products, observations for 7 (21%) led
to major adjustments in the dosing instructions. With the information obtained
from the pharmacokinetic and/or pharmacodynamic studies, the labels now contain
appropriate dosage information for the pediatric population. For other drugs,
the labels contain special precautions about use in a specific setting (eg,
propofol and the risk for severe adverse events in the pediatric intensive
care unit, rare cases of seizures associated with sevoflurane, suicidal ideation
noted in some patients receiving a combination of ribavirin and interferon
alfa-2b, and hypopituitary-adrenal axis suppression with betamethasone-containing
Studies continue to be submitted and the number of drugs with pediatric
use information on the labels continues to increase. As of January 2003, 16
more drugs have been labeled with pediatric use information, which brings
the total to 49 new labels.
These pediatric initiatives are expected to have worldwide effects and
benefit all children. A report by ‘t Jong et al4 on
off-label use of drugs in the Children's Hospital in the Netherlands found
that of 238 children and adolescents from birth to age 17 years, only 725
(34%) of the 2139 prescriptions they received were for uses approved on the
label. Of the remaining 66%, 1024 (48%) were unapproved and 390 (18%) were
for off-label use. McIntyre et al16 examined
3347 prescriptions for 1175 children in the English midlands and 160 different
drugs. Approximately 11% of the prescriptions deviated from licensed use.
The same investigators found that of 455 prescriptions for 70 neonates, only
161 (35%) of the prescriptions "were licensed drugs used in a licensed way."17
The off-label ("outside the terms of their license") or unlicensed ("not
specifically licensed for use in children") use of medications is also reported
by Gravilov et al7 from an ambulatory hospital
unit in Israel. The authors reported approximately 42% of drug prescriptions
to children were for off-label and/or unlicensed use. A survey of off-label
drug use was also performed in 5 European countries.18 Of
624 pediatric patients in 5 hospitals who received 2262 prescriptions, 1036
(46%) prescriptions were for unlicensed or off-label use; 421 (67%) patients
received drugs for an unlicensed or off-label use. The problem is more acute
in neonatal units. Avenel et al8 reported an
experience in which 62% of drug use was for off-label indications for premature
infants and 64% for off-label indications for newborns. Unfortunately, there
were no therapeutic alternatives among the few available licensed drugs.
The recent policy changes in the United States, which have resulted
in increased numbers of studies of the drugs being prescribed to children,
have been called for internationally by others.4,19 Drugs
used in children should be studied in accordance with sound ethical and scientific
principles to define differences in efficacy, age-dependent changes in pharmacokinetics
and/or pharmacodynamics, and to identify unique pediatric adverse events,
as well as verify the adverse events that are similar to those experienced
by adults.20 Steinbrook's21 recent
report including some of the benefits derived from the exclusivity incentive
supports our observation. The beneficial effects of studying drugs that are
being prescribed to children include important dose changes, as well as improved
safety information on how to more appropriately prescribe these drugs for
the pediatric population.