Program Brief
The mission of the Centers for
Education & Research on Therapeutics (CERTs) program is to conduct research and provide education that will advance the best use of therapeutics (drugs, medical devices, and biological products). Several CERTs projects are related to child health, and one CERTs center is
devoted solely to studying therapies for children.
The CERTs receive funds from both public and private sources, with
the Agency for Healthcare Research and Quality (AHRQ) providing core support.
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Background
The mission of the Centers for
Education & Research on Therapeutics (CERTs) program is to conduct research
and provide education that will advance the best use of therapeutics (drugs,
medical devices, and biological products).
In addition to conducting research and providing education, the CERTs
program seeks to
increase awareness of the benefits and
risks of new, existing, and combined
uses of therapeutics, thereby improving
the effectiveness and safety of their use.
The program is administered as a
cooperative agreement by AHRQ in consultation with the U.S.
Food and Drug Administration (FDA).
The CERTs receive funds from both
public and private sources, with AHRQ
providing core financial support.
The CERTs comprise seven centers (select for a list of centers), a Coordinating Center, a Steering Committee, and numerous partnerships with public and private organizations. Collectively, the CERTs have more than 40 unique data sources and serve as a national resource of experienced researchers.
CERTs Program Centers
Each center focuses its educational and
research efforts on therapies in a
particular population or therapeutic
area:
- Duke University Medical Center—Therapies for disorders of the heart
and blood vessels.
- HMO Research Network—Drug
use, safety, and effectiveness in
health maintenance organization
populations.
- University of Alabama at
Birmingham—Therapies for
musculoskeletal disorders.
- University of Arizona Health Sciences
Center—Drug interactions that
result in harm to women.
- University of North Carolina at
Chapel Hill—Therapies for children.
- University of Pennsylvania School of
Medicine—Therapies for infection;
antibiotic drug resistance.
- Vanderbilt University Medical
Center—Prescription drug use in a
Medicaid population.
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CERTs and Child Health
Since the inception of the CERTs
program in September 1999, the
centers have developed a portfolio of
more than 200 completed and ongoing
studies with results that have addressed
important issues regarding the best use
of therapies.
Several of these projects are
related to child health and one CERTs
center, the University of North Carolina
at Chapel Hill (UNC) center, is
devoted solely to studying therapies for
children.
The Best Pharmaceuticals for Children
Act was passed by the U.S. Congress in
2001 and provides several avenues to
test drugs in children. Despite this
legislation, an estimated 80 percent of
prescription drugs given to children
have not been tested on this population
and are not labeled for pediatric use.
Children are not "small adults." They
have different metabolic rates, their
bodies change rapidly, and their ability
to understand and express information
varies widely. Research is needed to
describe how children respond to
individual medications and to different
treatment regimens.
The CERTs projects are aimed at:
- Advancing knowledge.
- Informing health
care providers, patients, and
policymakers about that knowledge.
- Improving aspects of the health
care system related to therapeutics.
The following are examples of CERTs
studies that are relevant to children.
Advancing Knowledge
The CERTs study the beneficial and
potentially harmful effects of medical
therapies in children so that parents and
providers can make informed decisions
about treatments.
Evaluating drugs in children with
HIV.1 The "recommended prescribed
dose" of a drug may work very well for
many patients but not for others
because of underlying differences from
patient to patient, including differences
in the way drugs are absorbed and
metabolized. Less is known about these
individual differences in children than
in adults. Children may also metabolize
drugs differently as they grow and
develop. These differences may mean
that the "recommended" dose may not
have the treatment effect a sick child
needs.
HIV provides an important
example. More than 20,000 children
and teenagers in the United States may
be infected with human
immunodeficiency virus (HIV). How
they respond to given doses of anti-HIV drugs such as protease inhibitors
may differ from how adults respond.
Therapeutic drug monitoring (TDM) is
a way of measuring individual patients'
response to drugs and tailoring drug
doses to individual patients' needs. The
UNC center has assessed the
concentrations of protease inhibitors in
the blood of children infected with
HIV. Concentrations that are too high
can be toxic, and concentrations that
are too low can cause the virus to
become resistant to the drug.
The group used a separation technique
(high-pressure liquid chromatography)
to develop a test for measuring four of
the most commonly used protease
inhibitors in blood samples. In a pilot
study, they found that in a group of 15
pediatric patients taking at least one of
the medications, 4 children, or 27
percent, had no detectable protease
inhibitors in their blood plasma. One
child had a suspiciously high
concentration, suggesting that the
patient had taken an incorrect amount
of medication, or that the patient may
have had abnormal metabolism of the
drug.
The UNC center is now engaged in a
larger study to further explore the best
ways to use TDM to tailor the
treatment of HIV-infected children, to
promote ways to get the best effect for
each individual child.
Blood glucose monitoring of children
with type 1 diabetes. Controlling
blood glucose levels closely can prevent
or delay the serious complications of
diabetes due to low insulin production,
yet controlling glucose too closely can
lead to episodes of hypoglycemia severe
enough to cause unconsciousness.
Children are more susceptible to
hypoglycemia than adults, but they are
less able than adults to recognize and
respond to early symptoms of
hypoglycemia.
The UNC center is conducting a study
among children and adolescents with
type 1 diabetes to determine whether
continuous glucose monitoring devices
can help reduce hypoglycemia while
maintaining good blood glucose
control. The devices have a small sensor
that is inserted under a patient's skin
and connected to a pager-sized
monitor. They measure glucose every
few minutes. While continuous glucose
monitors have been used in adults for
nearly two decades, experience in
children is very limited. This study
should assist physicians in deciding
whether continuous glucose monitoring
is feasible, well tolerated, and beneficial
in children and adolescents with type 1
diabetes.
Prenatal and early erythromycin
exposure and pyloric stenosis.2,3
Pyloric stenosis is a narrowing of the
lower part of the stomach caused by
enlarged muscles in the pylorus. This
prevents food from emptying out of the
stomach and can cause forceful
vomiting or lead to dehydration.
Approximately 3 in 1,000 infants in the
United States have the condition.
The cause of pyloric stenosis is unclear,
but evidence indicates that it may result
from exposure to the commonly
prescribed antibiotic, erythromycin.
The Vanderbilt center conducted two
studies to determine whether infants
who had been exposed to erythromycin
prenatally or in the first 90 days of life
were more likely to develop pyloric
stenosis. Patients in the study included
mothers and infants in Tennessee's
Medicaid program, TennCare.
The researchers found that exposure to
erythromycin in infants 3 to 13 days
old was associated with an increased
risk of stenosis, but exposure either
prenatally or after 13 days was not.
This evidence provides practitioners
with useful information to weigh the
risks and benefits of prescribing
erythromycin for infants and expectant
mothers.
Effect of tetracycline on bacterial
resistance.4 It is believed that long-term
use of antibiotics by patients plays
a role in the development of organisms
that are resistant to multiple antibiotics.
Individuals with acne are a natural
population for studying the effects of
long-term antibiotic use since they are
generally young, healthy patients who
are sometimes exposed to antibiotics for
prolonged periods.
The University of Pennsylvania center
explored whether long-term use of
tetracycline, a commonly prescribed
acne medicine, affected bacterial
populations in the throats of
adolescents and young adults with acne.
Researchers found that patients taking
tetracycline were more likely to have
the bacteria Streptococcus pyogenes in
their throats than those not taking the
drug. Further, the S. pyogenes in the
tetracycline-treated patients were more
likely to be resistant to at least one
antibiotic than those in patients not
taking tetracycline.
These results suggest that long-term use
of an antibiotic for treating acne could
lead to antibiotic resistance in regions
of the body, such as the throat, known
to be a potential site of more serious
systemic infections.
Increased antibiotic-resistant
pathogens in Hispanic children. To
further explore antibiotic resistance in
children, the UNC center led a project
that addressed whether antibiotic
resistance can vary according to
ethnicity. They started by reviewing
clinical laboratory and medical records
of children with urinary tract infections
at the UNC clinics from 1996 to 2003.
The types and frequency of urinary
tract infection pathogens, their patterns
of susceptibility to different antibiotics,
and patient clinical and demographic
data were tracked.
Of the Escherichia coli bacteria for
which there were antibiotic sensitivity
data, only 54 percent were pan-susceptible,
meaning treatable with
several different antibiotics. Among
white children with an E. coli infection,
47 percent could be treated with several
antibiotics, and for African-American
children, the rate was 60 percent. But
among Hispanic children, the rate of
infection with pan-susceptible bacteria
was only 20 percent.
The next phase of the project includes
testing children in community pediatric
clinics, especially those serving Hispanic
children. Results should help to assess
whether resistance rates at UNC clinics
are similar to those in the community
and should also lead to a better
understanding of risk factors.
Informing Patients and Providers
Understanding the risks and benefits of
medical therapies is critical to
improving the safety and effectiveness
of their use. It is also critical to ensure
that practitioners, patients, and their
guardians have the knowledge needed
to use medical therapies appropriately.
Asthma improvement strategies.
From 1982 to 1996, the prevalence of
asthma increased 38 percent in children
under the age of 18. The UNC center
has made it a goal to give local
physicians and their patients the tools
they need for the best management of
asthma.
The center developed an educational
effort to share knowledge about
strategies for improving care of children
with asthma that includes a 3-hour
continuing medical education session
for physicians and a learning
collaborative within a North Carolina
Area Health Education Center region.
The educational program has been
adopted as a statewide Medicaid
demonstration project.
Tools for diagnosing and managing
ADHD. The UNC center is
committed to providing physicians,
children, and parents with resources to
better diagnose and manage attention
deficit hyperactivity disorder (ADHD).
It is estimated that between 3 percent
and 5 percent of children have ADHD.
The UNC center has helped create a
Web site (http://www.nichq.org/resources/toolkit/) that provides an
online toolkit for parents, teachers, and
health care providers of children who
have ADHD. The toolkit provides the
best evidence on the diagnosis,
treatment, and management of ADHD
in an easy-to-use format.
Online resource to prevent
arrhythmia. Long QT syndrome is a
hereditary disorder of the heart's
electrical rhythm that can occur in
otherwise-healthy people. The
incidence of children with congenital
long QT syndrome is approximately 1
in 5,000, and those with the condition
are at very high risk of sudden death
due to arrhythmia. Since there are more
than 50 drugs that can precipitate an
arrhythmia in children, the Arizona
center developed a Web site
(www.torsades.org) to use as a reference
to routinely review children's
medications for possible risk.
Antibiotic use among children.5
CERTs research frequently uncovers
therapeutic areas where antibiotics are
prescribed more often than needed,
which increases the risk for antibiotic-resistant
bacteria. But in a recent study,
the HMO Research Network center
found that antibiotic use dropped in
one area. Between 1996 and 2000,
there was a significant drop in the
number of antibiotics prescribed to
children ages 3 months to 17 years. In
previous years, from 1977 through the
early 1990s, antibiotic use in children
had increased.
In 1998, the Centers for Disease
Control and Prevention, working with
other national and State organizations,
began to actively promote more
judicious prescribing for children. They
based their efforts on results from a
group of studies that tested the impact
of education programs on parents and
providers.
The CERTs conducted one
study of 16 towns in Massachusetts
(REACH Mass), testing the
effectiveness of certain education
programs on parental knowledge, actual
antibiotic use, and incidence of
resistant organisms. The results were
encouraging: there was a drop in
antibiotic prescriptions for children,
which suggests that it is possible to
effectively educate both health care
providers and patients about the
dangers of overusing antibiotics.
Improving the System
The CERTs' broadest reaching and
potentially most beneficial efforts are
those that improve aspects of the health
care system. A number of projects are
aimed at increasing the efficiency of
health care, making pediatric therapies
safer, and giving health care providers
better access to current treatment
information.
Prevalence and prevention of rickets.6
Rickets was a common disease in the
United States during the Industrial
Revolution. Recognizing that vitamin
D helped to prevent rickets led to a
drop in the number of cases, and by the
1960s, physicians rarely saw patients
with the disease.
In the 1990s, however, the prevalence
of rickets increased, and UNC
researchers wanted to better understand
the reason why. Examining data about
children in the North Carolina Women,
Infants, and Children Program (WIC),
the researchers found that all the rickets
cases among pediatric patients were in
dark-skinned children who were breast
fed and who did not receive vitamin D
supplementation. The darker an infant's
skin, the more sun exposure the infant
needs to synthesize vitamin D.
The study's findings caused an
immediate change in North Carolina
public health practice. The North
Carolina Pediatric Society requested
that the State of North Carolina
distribute a multivitamin supplement
free of charge to any exclusively
breastfed infant or child older than 6
weeks. Funding for the
supplementation was provided through
a Maternal and Child Health Block
Grant and distributed through the
Supplemental Nutrition Program for
Women, Infants, and Children.
During a 16-month period, more than 1,500
children received this supplementation
at a cost of about $1.50 per month per
child. Fact sheets were also developed to
help educate parents and health
professionals about the need for vitamin
D supplementation for breastfed infants
and children.
Recommendations for safe
prescribing for children. The UNC
center worked with the United States
Pharmacopeia (USP) to develop
recommendations for safe prescribing
for children. The USP publishes legally
recognized standards of strength,
quality, and purity for drugs and other
therapeutic products. Together, UNC
and the USP studied more than 5,600
medication errors reported by more
than 500 hospitals to the USP's
anonymous Web-based reporting
system, MEDMARXSM. They
considered the error reports and the
best published evidence on the causes of
and solutions for pediatric medication
errors.
Based on this information, five sets of
recommendations about all phases of
medication use were made. The topics
ranged from packaging and storing, to
prescribing and administering
medications to pediatric patients. In
April 2003, the USP published the
recommendations on its Web site:
http://www.usp.org/patientSafety/tools/pedRecommnds2003-01-22.html. The
recommendations can be used by all
health care providers who treat children.
Prescription drug use in pregnant
women.7,8 Using medications during
pregnancy poses a potential risk to both
the mother and fetus. To alert
physicians and pharmacists about the
possible risks of prescribing medications
during pregnancy, the FDA uses a risk
classification system for drugs taken
while pregnant. The risks of drugs in
category C are unknown, drugs in
category D have known risks that may
be outweighed by their benefits, and
those in X have definite risks that
outweigh benefits. Using the FDA's
classification system as a guide, the
CERTs have conducted several studies to
learn more about the frequency of such
prescriptions.
To assess how often unborn babies are
exposed to drugs that may cause them
harm, the HMO Research Network
center recorded drug use before and
during pregnancy for 152,531 women in
eight different health systems and
geographic regions. Of these women,
71,913—or almost half—were prescribed
drugs that fall within categories C, D,
and X of the FDA's risk classification
system. The HMO Research Network
center study suggests that a significant
number of pregnant women are
prescribed drugs that present unknown
or harmful risks.
The Vanderbilt center has also looked at
the use of prescription drugs during
pregnancy, focusing on drugs in the
FDA's category X. The group looked at
how many of 95,284 pregnant women
in TennCare filled prescriptions for
category X medications. Within the
group, 391 filled such prescriptions,
meaning that about 4 in 1,000 fetuses
were exposed to potentially harmful
medication. Women over the age of 35
and women enrolled in TennCare
because of disabilities were more likely to
fill category X prescriptions during
pregnancy than other categories of
pregnant women. Study results
underscore the need to inform both
physicians and women so they can
consider the risks in taking these
medications during pregnancy.
Looking to the Future
The CERTs continue to conduct
research and develop educational
projects that study and report the
efficacy, safety, and use of various
medical therapies in children. Because so
little is known in this area, the CERTs
face great challenges but great
opportunities as well.
For More Information
More information on the CERTs program is available from:
Anne Trontell, M.D., M.P.H.
Program Director, Centers for Education and Research in Therapeutics
Center for Outcomes and Effectiveness Research, AHRQ
Phone: (301) 427-1607
Fax: (301) 427-1640
E-mail: Anne.Trontell@ahrq.hhs.gov
Carmen Kelly, Pharm.D.
Project Officer, CERTs Coordinating Center
Center for Outcomes and Effectiveness Research, AHRQ
Phone: (301) 427-1513
E-mail: Carmen.Kelly@ahrq.hhs.gov
In addition, the CERTs program welcomes input about the types of research and education that Medicaid programs need to better address costs, effectiveness, and safety issues related to the use of therapeutics. Comments may be sent to CERTs program staff at AHRQ, or to:
Judy Donald
Project Manager
CERTs Coordinating Center
Kaiser Foundation Center for Health Research
E-mail: Judy.L.Donald@kpchr.org
References
- Walson PD, Cox S, Utkin I, et al.
Clinical use of a simultaneous HPLC
assay for indinavir, saquinavir,
ritonavir and nelfinavir in children
and adults. Ther Drug Monit
2003;25:588-92.
- Cooper WO, Ray WA, Griffin MR.
Prenatal prescription of macrolide
antibiotics and infantile hypertrophic
pyloric stenosis. Obstet Gynecol
2002;100:101-6.
- Cooper WO, Griffin MR, Arbogast
PA, et al. Very early exposure to
erythromycin and infantile
hypertrophic pyloric stenosis. Arch
Pediatr Adolesc Med 2002;156:647-50.
- Levy RM, Huang EY, Roling D, et
al. Effect of antibiotics on the
oropharyngeal flora in patients with
acne. Arch Dermatol 2003;139:467-71.
- Finkelstein JA, Stille C, Nordin J, et
al. Reduction in antibiotic use
among US children, 1996-2000.
Pediatrics 2003;112:620-7.
- Kreiter SR, Schwartz RP, Kirkman
HN, et al. Nutritional rickets in
African American breast-fed infants. J
Pediatr 2000;137:153-7.
- Andrade SE, Gurwitz JH, Davis RL,
et al. Prescription drug use in
pregnancy. Am J Obstet Gynecol
2004;191(2):398-407.
- Cooper WO, Hickson GB, Ray WA.
Prescriptions for contraindicated
category X drugs in pregnancy
among women enrolled in TennCare.
Paediatr Perinat Epidemiol
2004;18:106-11.
AHRQ Publication No. 05-P005
Current as of January 2005
Internet Citation:
CERTs Research: Child Health. Program Brief. AHRQ Publication No. 05-P005. January 2005. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/research/certschil.htm
540 Gaither Road Rockville, MD 20850