Transcript IDSA/ISAP/FDA Workshop Dose Selection in Antimicrobial Drug Development INTRODUCTION John A. Lazor, Pharm.D.

IDSA/ISAP/FDA Workshop
Dose Selection in Antimicrobial Drug Development
Incorporation of Pharmacokinetics and Pharmacodynamics
INTRODUCTION
April 16, 2004
John A. Lazor, Pharm.D.
Division of Pharmaceutical Evaluation III
Office of Clinical Pharmacology and Biopharmaceutics
Center for Drug Evaluation and Research
Food and Drug Administration
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
Why Dose Selection as a Topic ?
• Published Literature
– PK-PD for antimicrobial drugs
– Systematic approach for dose selection
• Regulatory Submissions
– Basis for dose selection- not always
transparent
• FDA and CDER initiatives
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
2
FDA Strategic Plan (August 2003)
•
Efficient risk management
–
Number of new drug approvals declining
• Decline in number of new applications
• Multi-cycle reviews
– Efficacy or safety issues (?Dose)
•
Improving Patient and Consumer Safety
•
Protecting America from Terrorist Attacks
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
3
FDA Critical Path Initiative
(March 2004)
• Identifies need to address drug development issues
• Reduce drug product attrition and improve chances for success
• Emphasizes industry – FDA interactions
• Use science to create new tools to get better answers for
demonstrating safety and effectiveness, faster time frames,
more certainty, and lower costs
– Product development toolkit
• New scientific and technical methods
– Animal or computer based predictive models
(quantitative methodology)
– Biomarkers for safety and effectiveness
– New clinical evaluation techniques
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
4
Critical Path Research
•
Basic Research: Directed towards fundamental understanding of biology
and disease processes
•
Translational Research: Concerned with moving basic discoveries from
concept into clinical evaluation
• Critical Path Research: Directed toward improving the
product development process by establishing new
evaluation tools
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
5
Guidance: Exposure-Response Relationships –
Study Design, Data Analysis, and Regulatory
Applications (2003)
• Phase 1 and 2 studies
– Explore relationship of exposure to a response
• Provide guidance in designs for
clinical phase 3 trials
– Choose dose or dose range
– Choose dose interval
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
6
CDER End-of-Phase 2A Meetings
• Create opportunities for sponsors to have
informative discussions with FDA
• Use of Quantitative Methodologies
– Predictive models to forecast clinical outcomes
– Evaluation of exposure-response
– Better informed decision making
• Dose selection and dosing strategies
• Other issues
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
7
OCPB Good Review Practices
• Include but not limited
to:
• Exposure-Response
• Dose regimen
• Dose adjustment
– Subpopulations
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
8
The Right Dose Regimen
• Optimize efficacy
• Minimize risk of adverse events
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
9
A Current Paradigm
Phase III Studies
Outcomes
(Exposure)
Phase II Studies
(Proof of concept)
Knowledge Gained
Human PK
Simulation
PK/PD
(In vitro)
(Animal)
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
10
Meeting Today: Dose Selection
• Overview - use of PK/PD
• In vitro/animal models
– PK/PD development
– Infection models
• Dose regimen selection: Where we are
– PK/PD
– Modeling and Simulation
• Dose selection: What can we do better?
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
11
Factors for Dose Selection
Pathogen
Drug plasma Conc
Infection site
Drug conc at
Infection site
Infection severity
Susceptibility
Protein binding
Drug PK
PAE
PK variability
Patient
PK/PD
Safety
Dose
Dose Interval
Resistance
Duration of Therapy ?
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
12
Focus: Efficacy
Resistance
Safety
Efficacy
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
13
Terminology
• PK/PD Index = PK/PD Parameter
– A measure of drug exposure linked to a
measure of potency relative to the
pathogen
• e.g. AUC/MIC, Cmax/MIC, T>MIC
• PK/PD Target
– Magnitude or value of PK/PD Index
associated with a microbiological effect or
an endpoint
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
14
Meeting Today: Outcome
• Presentations and Discussions
– What works
– What doesn’t work
– Assumptions
– Limitations
QM
PK/PD
– Methodologies or Tools for the
“Toolkit”
• Moving forward
• Evaluate the need to update Guidance
Document: Developing Antimicrobial
Drugs – General Considerations for
Clinical Trials
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
15
Outcome - To Avoid:
Is the dose
right?
Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop April 16, 2004
16