IDSA/ISAP/FDA Workshop Dose Selection in Antimicrobial Drug Development Incorporation of Pharmacokinetics and Pharmacod

1. IDSA/ISAP/FDA WorkshopDose Selection in Antimicrobial Drug Development Incorporation of Pharmacokinetics and PharmacodynamicsINTRODUCTIONApril 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. OCPB Good Review Practices • Include but not limited to: • Exposure-Response • Dose regimen • Dose adjustment • Subpopulations

9. The Right Dose Regimen • Optimize efficacy • Minimize risk of adverse events

10. A Current Paradigm Phase III Studies Outcomes (Exposure) Phase II Studies (Proof of concept) Knowledge Gained Human PK Simulation PK/PD (In vitro) (Animal)

11. 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?

12. 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 ?

13. Focus: Efficacy Resistance Safety Efficacy

14. 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

15. Meeting Today: Outcome • Presentations and Discussions • What works • What doesn’t work • Assumptions • Limitations • Methodologies or Tools for the “Toolkit” • Moving forward • Evaluate the need to update Guidance Document: Developing Antimicrobial Drugs – General Considerations for Clinical Trials QM PK/PD

16. Outcome - To Avoid: Is the dose right?