PEDIATRIC AND OBSTETRIC
PHARMACOLOGY AT THE EUNICE
KENNEDY SHRIVER NATIONAL INSTITUTE
OF CHILD HEALTH AND HUMAN
DEVELOPMENT
Anne Zajicek, MD, PharmD
Chief, Obstetric and Pediatric Pharmacology Branch
Center for Research for Mothers and Children
OUTLINE
The Obstetric and Pediatric Pharmacology
Branch Research Initiatives
 The Best Pharmaceuticals for Children Act
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Clinical trials
 Formulations platform
 Infrastructure and Training
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What’s New at the NIH
OBSTETRIC AND PEDIATRIC
PHARMACOLOGY BRANCH MISSION
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The OPP Branch promotes research to improve
the safety and efficacy of pharmaceuticals and to
ensure centralization and coordination of
research, clinical trials, and drug development
activities for obstetric and pediatric populations.
OBSTETRIC AND PEDIATRIC
PHARMACOLOGY RESEARCH INITIATIVES
TRANSLATIONAL RESEARCH IN PEDIATRIC
AND OBSTETRIC PHARMACOLOGY
PAR 09-154/155/156
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Application Submission/Receipt Date(s):
September 16, 2009, January 19, 2010, May 19,
2010, September 16, 2010, January 19, 2011,
May 19, 2011
TRANSLATIONAL RESEARCH IN PED AND
OB PHARMACOLOGY PAR
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To support pharmacology research in
obstetrics and pediatrics, including:
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New drug targets
Biomarkers
Pharmacogenomics,
Modeling and simulation
Pre-clinical models of drug disposition and effect
Placental transport
Drug delivery devices
DEVELOPMENTAL PHARMACOLOGY
PAR 08-215/216
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Purpose. To encourage multidisciplinary,
investigator-initiated basic and translational
research in developmental pharmacology with
particular emphasis on the role of ontogeny on
drug metabolizing enzymes, transporters,
receptors and signaling pathways activity across
developmental periods from fetal life to
adolescence.
MECHANISMS OF ADVERSE DRUG EFFECTS
IN CHILDREN
PAR 08-248/249
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Purpose. This FOA encourages projects that
enhance the state-of-the-science on the molecular
and cellular, genetic and epigenetic mechanisms
involved in the production of adverse drug
reactions in children.
RFA 10-010: MOLECULAR MECHANISMS
OF ADVERSE METABOLIC DRUG EFFECTS
IN CHILDREN AND ADOLESCENTS (R01)
The purpose of this initiative is to encourage
investigator-initiated research to characterize the
molecular mechanisms of adverse metabolic
effects of drugs used in children and adolescents.
 Expiration Date: December 01, 2010
 Application Submission/Receipt Date(s):
November 30, 2010
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PEDIATRIC PHARMACOLOGY RESEARCH
UNITS NETWORK 1994-2009
Mission
 The PPRU Network facilitates and promotes
pediatric labeling of new drugs or drugs already
on the market. In this process, the Network
strives to foster cooperative research efforts
among academia, industry, and health
professionals.
RFA 10-026: RESEARCH IN PEDIATRIC
DEVELOPMENTAL PHARMACOLOGY (U54)
These Centers will provide an arena for
multidisciplinary interactions among basic and
clinical scientists interested in establishing high
quality translational research programs which
will investigate the fundamental mechanisms of
changes in drug disposition and response over
the course of human development from birth
through adolescence.
 Due date: March 22, 2011
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RFA 10-026: RESEARCH IN PEDIATRIC
DEVELOPMENTAL PHARMACOLOGY (U54)
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Establish predictive non-clinical models including animal studies,
cell, tissue and organ based systems, computational and systems
modeling, and integration of signals and information from multiple
systems to evaluate response- and age-specific toxicity, particularly
neurologic and behavioral effects.
Establish interdisciplinary approaches that utilize non-clinical
approaches integrated with clinical approaches to
understand developmentally specific responses and toxicities.
An example may include non-clinical studies used to understand
observations from a clinical study that would not be feasible or ethical
to perform in clinical settings.
Perform non-clinical and clinical research to understand
mechanisms of age- and developmentally- related changes in
metabolism and response to medicinal products.
Develop outcome measures that are age-appropriate to determine
response or toxicity.
Incorporate the use of medicinal products as tools to
understand developmental metabolism and pharmacology.
Develop, calibrate and validate PD assessments to evaluate
response and toxicity for different pediatric populations.
OBSTETRIC PHARMACOLOGY RESEARCH
UNITS NETWORK (U10)
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Funds basic, translational and clinical research
in pregnant women to determine changes and
mechanisms in drug disposition and response
Small clinical trials with basic science component
 Opportunistic studies
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Requirement of clinician and basic
pharmacologist at all sites
 Projects:
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Gestational diabetes mellitus
 RCT glyburide vs metformin
 17-α-hydroxyprogesterone caproate PK/ mechanism
of action
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BEST PHARMACEUTICALS
ACT
FOR
CHILDREN
Goal: to improve pediatric labeling
 Implementation by NIH
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Prioritization
 Sponsorship of pediatric clinical trials
 Submission of clinical trials data to FDA
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2002: Master List of all Off-Patent Drugs
which lack adequate pediatric labeling
Consultation with
experts in pediatric
practice and research
Consider for prioritizing:
Availability of S/E data
Are additional data needed?
Will new studies produce
health benefits?
Reformulation?
Develop, prioritize, publish an
Annual List of Drugs
2007: Therapeutic Areas
Consider for prioritizing:
•Therapeutic gaps
•Potential health benefits
of research
•Adequacy of necessary
infrastructure
Consultation with
experts in pediatric
practice and research
Develop, prioritize, publish an
Annual List of Therapeutic Areas
and Specific Needs
BENCHMARKS
Prioritization
Written Request/ PPSR
Clinical Trial
Data Submission to FDA
Label Change
STUDIES UNDER BPCA
TYPES OF STUDIES
Pharmacoepidemiology Research
o Frequency of condition
o Frequency of use
Preclinical Drug Studies (extrapolation)
o Ketamine
o Methylphenidate
PEDIATRIC CLINICAL TRIALS
Lorazepam: Clinical studies of sedation of
children on ventilators in an intensive care unit
 Lorazepam: Clinical studies for treatment of
status epilepticus
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Exception from informed consent
Nitroprusside to reduce blood pressure during
surgery
 Lithium to treat mania in children with bipolar
disorder
 Dopamine- co-fund with Neonatal Research
Network to determine feasibility
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PEDIATRIC CLINICAL TRIALS
Baclofen (oral)for spasticity
 Meropenem for neonate infections
 Hydroxyurea for sickle cell disease (NHLBI)
 Azithromycin for prevention of BPD in neonates
(grant)
 Morphine for treatment of pain in neonates
(grant)
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ONCOLOGY STUDIES
 Vincristine:
Studies to evaluate
neurotoxicity, PK in children (NCI-COG)
 Actinomycin-D: Studies to evaluate
hepatotoxicity/ VOD, PK in children (NCICOG)
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Study 1: data extraction of National Wilms’
Tumor Study database for toxicity
Study 2: catheter-clearing experiments
Study 3: PK modeling of published VCR, Act-D
data to design prospective PK study
Study 4: Prospective PK study
ONCOLOGY STUDIES
 Methotrexate:
Clinical studies to evaluate
neurocognitive outcomes of pediatric
patients with high risk acute
lymphoblastic leukemia (NCI-COG)
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Relationship of neurocognitive testing to DTIMRI
Longitudinal and cross-sectional
 Daunomycin:
Pharmacokinetics, safety,
efficacy of daunomycin to treat childhood
cancers and relationship to body weight
(NCI-COG)- COMPLETED
ISOTRETINOIN
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Isotretinoin
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Discussion at Pediatric Subcommittee of the
Oncologic Drug Advisory Committee
Labeling- for neuroblastoma (new indication)
 Data received from the Children’s Oncology Group for
new indication
 Formulation: Clinical Trials Agreement in process
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OUTCOME MEASURES
Clinical and Translational Science Awards
(CTSA) co-fund with National Center for
Research Resources (NCRR)
 Areas
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Neurology
 Cardiovascular medicine
 Neonatology
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Snapshot of BPCA Projects
(18 recommended for funding)
Topic Areas:
8-neonatology, 5-neurology, 4-hypertension/hypotension, 3-“other”; >1 topic area possible
1
Duke
Development of a PK algorithm to improve neonatal outcomes
2
UTHSC
Advanced MRI to assess neonatal care and outcome
3
Columbia
Targets and Barriers for Hydroxyurea use in Sickle Hemoglobinopathies
4
Utah
Improving Management of the Neonatal Abstinence Syndrome
5
U Pitt
Cardiac Outcome Measures for Pediatric Muscular Dystrophy
6
UNC
Outcome Measures for chronic lung disease of prematurity
7
U-CO
Small volume fentanyl PK/PD & PG in neonates
8
UC-Davis
Outcome Measures for Trials in Children with Autism
9
Vanderbilt
Wireless Home-Based Tools for studying sleep in Autism
10
U-MI
Pediatric Cardiac Intensive Care Data Standards Repository
11
Stanford
Methadone vs. Morphine PD/PD in infants after cardiac surgery
12
Indiana
Predictors of Vincristine-induced peripheral neuropathy
13
UAB
Nasal Potential Difference Studies Utilizing CFTR Modulators
14
CWRU
Efficacy Outcomes Measures in Antihypertensive Trials in Children
15
CWRU
Effect of BMI on Exposure-Response Relationships to Lisinopril in Children
16
U-Wash
Advancing Patient Reported Outcomes (PROs) in children with Cystic Fibrosis
17
AECOM
Pediatric hypertension outcome measures
18
Tufts
Improving BPD predictors and outcomes for clinical trials
29 September 2009
CC-CHOC update
27
BUILDING
NATIONAL CTSA CONSORTIUM
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NH
WI
SD
WY
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NE
NV
NY
MI
IN
PA
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WV
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KY
NC
AZ
OK
TN
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NM
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GA
TX
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FL
HI
Participating Institutions
BPCA awardees
CTSAs (Sept 2009)
NJ
DE
IL
UT
RI
CT
MD
MA
INFRASTRUCTURE
Training in translational/clinical pharmacology
 Infrastructure to perform pediatric clinical trials
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INFRASTRUCTURE
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Clinical Pharmacology Training Program:
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T32 co-fund with NIGMS
Mayo Clinic
 UCLA
 UCSF
 Jefferson University
 University of Pennsylvania
 Vanderbilt University
 University of Chicago
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RFA-HD-10-005: POST-DOCTORAL RESEARCH
TRAINING IN PEDIATRIC CLINICAL AND
DEVELOPMENTAL PHARMACOLOGY
NICHD RFA for pediatric clinical pharmacology
training
 For secondary review at NICHD Council January
20, 2011
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F31 NIGMS CO-FUND (PA 10-178)
Ruth L. Kirschstein National Research
Service Awards (NRSA) for Individual
Predoctoral Fellows in PharmD/PhD
Programs (F31)
 Expiration Date: May 08, 2013
 Application Submission/Receipt Date(s):
Standard dates apply
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LOAN REPAYMENT
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http://www.lrp.nih.gov/about_the_programs/pedia
tric.aspx
INFRASTRUCTURE
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Pediatric Trials Network
Awarded September 28, 2010
 Duke University
 https://www.fbo.gov/index?s=opportunity&mode=for
m&id=cf49c1b60b546914941b266295b24c84&tab=cor
e&_cview=1
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Cores:
Management
 Clinical trials performance
 Formulations development for clinical trials
 Clinical pharmacology study design and analysis
 Device development (validation)
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PEDIATRIC TRIALS NETWORK
Potential Therapeutic Areas
-Cardiovascular diseases
-Infectious diseases
-Respiratory diseases
-Gastroenterology
-Pediatric oncology
-Neonatology
FORMULATIONS: NIH-FDA PARTNERSHIP
NIH-FDA FORMULATIONS PLATFORM
Inter-Agency Agreement with FDA 2010-2012
 Develop an open-source, technically feasible
platform based on chemical structure, to produce
orally dissolvable solid dosage forms that are
stable at high temperatures/humidity, tastemasked, with good oral absorption, in suitable
dosage increments, with minimal excipients
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NICHD VISIONING PROCESS
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9 Areas
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Behavior
Cognition
Development
Developmental Origins of Adult Disease
Diagnostics and Therapeutics
Environment
Plasticity
Reproduction
Pregnancy
Cross-cutting topics
VISIONING: CROSS-CUTTING TOPICS
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Analytical and measurement tools and methods
Animal and computational models
Bioethics
Bioinformatics
Biotechnologies/bioengineering, including high throughput, assistive,
and other related technologies
Developmental trajectory
Differences/disparities across populations
Epigenetics /meta-genomics
Functional status
Global health
Implementation science, including health economics
Nutrition
Prevention/personalized medicine
Stem cells
Systems biology
Training and mentoring
NEW AT NIH
Consideration of a proposed new Center at the
NIH: National Center for Advancing
Translational Sciences (NCATS)
 Therapeutics for Rare and Neglected Diseases
(TRND) Program at National Human Genome
Research Institute (NHGRI)
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https://rarediseases.info.nih.gov/TRND/
Rapid Access to Interventional Development
(RAID)
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http://nihroadmap.nih.gov/raid/
TRANSLATIONAL MEDICINE AND
THERAPEUTICS PROPOSAL
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http://smrb.od.nih.gov/meetings/nov_meetin
g/ATTACHMENT7_TMATPresentationNov10
2010.pdf
CONCLUSION
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Multifaceted work to improve pediatric and
obstetric pharmacology by
Training
 Basic, translational and clinical research
 Performance of clinical trials under BPCA
 Creating an open-source formulations technology
platform to improve drug delivery to children and the
elderly
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New focus of translational medicine, therapeutics
and clinical pharmacology at NIH
CONTACT INFORMATION
Anne Zajicek, MD, PharmD
 301-435-6865
 zajiceka@mail.nih.gov
