Pediatric and Obstetric Pharmacology at the Eunice Kennedy Shriver National Institute of Child Health and Human Development

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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

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Outline

• The Obstetric and Pediatric Pharmacology Branch
  Research Initiatives
• The Best Pharmaceuticals for Children Act
• Clinical trials
• Formulations platform
• Infrastructure and Training
• Whats New at the NIH

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Obstetric and Pediatric Pharmacology Branch
Mission

• 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.

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Obstetric and Pediatric Pharmacology Research
Initiatives
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Translational Research in Pediatric and Obstetric
Pharmacology PAR 09-154/155/156

• Application Submission/Receipt Date(s) September
  16, 2009, January 19, 2010, May 19, 2010,
  September 16, 2010, January 19, 2011, May 19,
  2011

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Translational research in ped and OB pharmacology
PAR

• To support pharmacology research in obstetrics
  and pediatrics, including
• New drug targets
• Biomarkers
• Pharmacogenomics,
• Modeling and simulation
• Pre-clinical models of drug disposition and
  effect
• Placental transport
• Drug delivery devices

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Developmental Pharmacology PAR 08-215/216

• 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.

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Mechanisms of Adverse Drug Effects in Children
PAR 08-248/249

• 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.

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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.

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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)

• 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.

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Obstetric Pharmacology Research Units Network
(U10)

• 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
• Requirement of clinician and basic pharmacologist
  at all sites
• Projects
• Gestational diabetes mellitus
• RCT glyburide vs metformin
• 17-a-hydroxyprogesterone caproate PK/ mechanism
  of action

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Best Pharmaceuticals for Children Act

• Goal to improve pediatric labeling
• Implementation by NIH
• 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

• Consider for prioritizing
• Availability of S/E data
• Are additional data needed?
• Will new studies produce
• health benefits?
• Reformulation?

Consultation with experts in pediatric practice
and research
Develop, prioritize, publish an Annual List of
Drugs
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2007 Therapeutic Areas
Consultation with experts in pediatric practice
and research

• Consider for prioritizing
• Therapeutic gaps
• Potential health benefits
• of research
• Adequacy of necessary
• infrastructure

Develop, prioritize, publish an Annual List of
Therapeutic Areas and Specific Needs
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Benchmarks
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Studies under BPCA
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Types of Studies

• Pharmacoepidemiology Research
• Frequency of condition
• Frequency of use
•  
• Preclinical Drug Studies (extrapolation)
• Ketamine
• Methylphenidate

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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
• 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 (NCI-COG)
• 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

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Oncology Studies

• Methotrexate Clinical studies to evaluate
  neurocognitive outcomes of pediatric patients
  with high risk acute lymphoblastic leukemia
  (NCI-COG)
• Relationship of neurocognitive testing to DTI-MRI
• Longitudinal and cross-sectional
• Daunomycin Pharmacokinetics, safety, efficacy of
  daunomycin to treat childhood cancers and
  relationship to body weight (NCI-COG)- COMPLETED

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Isotretinoin

• Isotretinoin
• Discussion at Pediatric Subcommittee of the
  Oncologic Drug Advisory Committee
• Labeling- for neuroblastoma (new indication)
• Data received from the Childrens 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
• 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 gt1 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
• UNC Outcome Measures for chronic lung disease
  of prematurity
• 7 U-CO Small volume fentanyl PK/PD PG in
  neonates
• UC-Davis Outcome Measures for Trials in
  Children with Autism
• 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

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Building a National CTSA Consortium
WA
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MT
ND
VT
MN
OR
NH
ID
WI
NY
SD
MA
MI
WY
RI
CT
IA
PA
NJ
NE
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OH
IN
DE
IL
UT
MD
WV
CO
VA
KS
MO
CA
KY
NC
TN
AR
AZ
OK
SC
NM
GA
AL
MS
TX
LA
AK
FL
HI
Participating Institutions
BPCA awardees CTSAs (Sept 2009)
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Infrastructure

• Training in translational/clinical pharmacology
• Infrastructure to perform pediatric clinical
  trials

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Infrastructure

• Clinical Pharmacology Training Program
• 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

• http//www.lrp.nih.gov/about_the_programs/pediatri
  c.aspx

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Infrastructure

• Pediatric Trials Network
• Awarded September 28, 2010
• Duke University
• https//www.fbo.gov/index?sopportunitymodeform
  idcf49c1b60b546914941b266295b24c84tabcore_cvie
  w1
• 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

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Formulations NIH-FDA Partnership
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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,
  taste-masked, with good oral absorption, in
  suitable dosage increments, with minimal
  excipients

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NICHD Visioning Process

• 9 Areas
• Behavior
• Cognition
• Development
• Developmental Origins of Adult Disease
• Diagnostics and Therapeutics
• Environment
• Plasticity
• Reproduction
• Pregnancy
• Cross-cutting topics

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Visioning Cross-cutting topics

• 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

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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)
• https//rarediseases.info.nih.gov/TRND/
• Rapid Access to Interventional Development (RAID)
• http//nihroadmap.nih.gov/raid/

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Translational Medicine and Therapeutics Proposal

• http//smrb.od.nih.gov/meetings/nov_meeting/ATTACH
  MENT7_TMATPresentationNov102010.pdf

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Conclusion

• 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
• New focus of translational medicine, therapeutics
  and clinical pharmacology at NIH

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Contact Information

• Anne Zajicek, MD, PharmD
• 301-435-6865
• zajiceka_at_mail.nih.gov