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

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


1
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

2
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

3
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.

4
Obstetric and Pediatric Pharmacology Research
Initiatives
5
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

6
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

7
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.

8
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.

9
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

10
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.

11
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

12
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.

13
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

14
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15
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

16
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
17
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
18
Benchmarks
19
Studies under BPCA
20
Types of Studies
  • Pharmacoepidemiology Research
  • Frequency of condition
  • Frequency of use
  •  
  • Preclinical Drug Studies (extrapolation)
  • Ketamine
  • Methylphenidate

21
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

22
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)

23
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

24
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

25
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

26
Outcome Measures
  • Clinical and Translational Science Awards (CTSA)
    co-fund with National Center for Research
    Resources (NCRR)
  • Areas
  • Neurology
  • Cardiovascular medicine
  • Neonatology

27
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

28
Building a National CTSA Consortium
WA
ME
MT
ND
VT
MN
OR
NH
ID
WI
NY
SD
MA
MI
WY
RI
CT
IA
PA
NJ
NE
NV
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)
29
Infrastructure
  • Training in translational/clinical pharmacology
  • Infrastructure to perform pediatric clinical
    trials

30
Infrastructure
  • Clinical Pharmacology Training Program
  • T32 co-fund with NIGMS
  • Mayo Clinic
  • UCLA
  • UCSF
  • Jefferson University
  • University of Pennsylvania
  • Vanderbilt University
  • University of Chicago

31
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

32
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

33
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34
Loan Repayment
  • http//www.lrp.nih.gov/about_the_programs/pediatri
    c.aspx

35
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36
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)

37
Pediatric Trials Network
  • Potential Therapeutic Areas
  • -Cardiovascular diseases
  • -Infectious diseases
  • -Respiratory diseases
  • -Gastroenterology
  • -Pediatric oncology
  • -Neonatology

38
Formulations NIH-FDA Partnership
39
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

40
NICHD Visioning Process
  • 9 Areas
  • Behavior
  • Cognition
  • Development
  • Developmental Origins of Adult Disease
  • Diagnostics and Therapeutics
  • Environment
  • Plasticity
  • Reproduction
  • Pregnancy
  • Cross-cutting topics

41
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

42
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/

43
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48
Translational Medicine and Therapeutics Proposal
  • http//smrb.od.nih.gov/meetings/nov_meeting/ATTACH
    MENT7_TMATPresentationNov102010.pdf

49
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

50
Contact Information
  • Anne Zajicek, MD, PharmD
  • 301-435-6865
  • zajiceka_at_mail.nih.gov
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