Introduction to the Meeting Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee November 17-18, 2003 Lawrence J. Lesko, Ph.D., FCP Office of Clinical Pharmacology and Biopharmaceutics, CDER, FDA - PowerPoint PPT Presentation

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Introduction to the Meeting Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee November 17-18, 2003 Lawrence J. Lesko, Ph.D., FCP Office of Clinical Pharmacology and Biopharmaceutics, CDER, FDA

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Title: Introduction to the Meeting Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee November 17-18, 2003 Lawrence J. Lesko, Ph.D., FCP Office of Clinical Pharmacology and Biopharmaceutics, CDER, FDA


1
Introduction to the MeetingAdvisory Committee
for Pharmaceutical SciencesClinical Pharmacology
Subcommittee November 17-18, 2003 Lawrence J.
Lesko, Ph.D., FCPOffice of Clinical Pharmacology
and Biopharmaceutics, CDER, FDA
2
Review of Meetings to Date
1st October 22-23, 2002 2nd April 22-23,
2003 3rd November 17-18, 2003
Input of the CPSC has had a significant impact on
the progress made in each of the topic areas
discussed at both of these meetings
3
Main Focus Has Been on Risk
  • Risk assessment
  • science-based estimates of a risk faced by a
    special population under- and over-exposed to a
    drug treatment
  • Risk management
  • taking action to reduce the risk through dosing
    adjustment or appropriate label language

4
New FDA Strategic Plan
a key element of FDAs new strategic plan is
efficient risk managementto use the best
biomedical science to achieve our health policy
goalsto make new treatments and technology
less risky, with greater predictability and less
time from concept to bedside
http//www.fda.gov/oc/mcclellan/strategic.html
5
Scope of Topics
  • Quantitative Risk Analysis Using
    Exposure-Response Relationships
  • Pediatric PK and Analysis of FDA Pediatric
    Database
  • Pharmacogenetics Improvement in Existing
    Therapies
  • Metabolism- and Transport-Based Drug Interactions

6
Quantitative Risk Analysis Using
Exposure-Response Relationships
  • Basically finalized a systematic pharmacometric
    methodology to apply to dose adjustments
  • apply to efficacy and/or safety biomarkers and/or
    clinical endpoints, often taken together, to
    assess risk/benefit
  • integrating into routine NDA reviews and, in the
    future, early meetings with sponsors
  • Evaluation of utility function is a work in
    progress
  • approaches discussed at prior meetings have
    raised awareness and issues
  • need future dialogue with physicians and
    statisticians

7
Todays Meeting-Topic 1
Introduce a new proposal for an end-of-phase 2A
(EOP2A) meeting between FDA and industryDiscuss
topics for this meeting revolving around
evaluation of E-R and prospective dose
selectionShow case studies of E-R analysis from
NDA reviews as models for EOP2A meetings
8
Todays Meeting-Topic 2
Methodology for evaluating QT1.
Points-to-consider for PK-PD (QT) study
design2. Use of clinical trial simulation to
optimize study design for PK-PD (QT)
evaluation3. Case study illustrating
pharmacometric considerations arising from NDA
review of QT data
9
Pediatric PK and Analysis of FDA Pediatric
Database
  • PPK study design template
  • basically complete and utilized as alternative to
    determining PK in pediatrics
  • further work on simulation to optimize number of
    samples, sampling times and number of patients
  • Pediatric database analysis
  • retrospective evaluation has been challenging and
    not very successful
  • incomplete datasets, non-optimal study designs
    etc
  • likely undertake more selective, case-by-case
    analysis of pediatric vs adult data

10
Todays Meeting-Topic 3
Re-visit the clinical pharmacology principles of
the pediatric decision tree with case
studiesPresent a quantitative method to
determine similarity in E-R relationshipsFDA
perspective and an academic perspective on
experience using the pediatric decision tree
11
Pharmacogenetics Improvement in Existing
Therapies
  • Polymorphism in metabolizing enzymes that
    determine variability in drug exposure
  • focus CYP 2D6, 2C19, 2C9 and TPMT
  • Additional discussion of TPMT and modification of
    thiopurine labels
  • pediatric subcommittee of ODAC in July 2003
  • many issues raised (need, cost, predictive value
    etc)
  • recommended including PG information in label
  • test should not be required before receiving drug

12
Todays Meeting-Topic 4
Shift discussion to the question what should be
done in new drug development for substrates
metabolized by polymorphic enzymes?Three expert
perspectives academic, industry and
clinician Discussion will influence
recommendations in a general pharmacogenetic
guidance under development
13
Metabolism- and Transport-Based Drug Interactions
  • Introduced topic as foundation for subsequent
    discussion
  • increased awareness of emerging mechanisms of
    drug interactions and what to do about them
  • revision of drug interaction guidance in progress

14
Todays Meeting-Topic 5
Get more specific what should be done to in
consideration of new drug interactions of
emerging clinical importanceExpert opinion on
evaluation of CYP 2B6- and CYP 2C8-based
metabolic drug interactionsDiscussion will
impact future regulatory advice on these issues
15
Summary
We are asking for CPSC input and advice on 5
separate topicsSpecific questions to focus
discussion will accompany each topicWe are
confident that your input will help us improve
and refine our thinking about these topics
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