1. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 Current Status of Dose Selection in Antimicrobial Drug Development Programs: FDA Perspective IDSA/ISAP/FDA Workshop April 16, 2004 Francis R. Pelsor, Pharm.D., M.S. Division of Pharmaceutical Evaluation III Office of Clinical Pharmacology and Biopharmaceutics Food and Drug Administration IDSA/ISAP/FDA Workshop April 16, 2004 Francis R. Pelsor, Pharm.D., M.S. Division of Pharmaceutical Evaluation III Office of Clinical Pharmacology and Biopharmaceutics Food and Drug Administration

2. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 2 ObjectivesObjectives Why is dose selection important? Discuss some Office of Clinical Pharmacology and Biopharmaceutics (OCPB) review experience with dose selection in antimicrobial drug product applications Why is dose selection important? Discuss some Office of Clinical Pharmacology and Biopharmaceutics (OCPB) review experience with dose selection in antimicrobial drug product applications

3. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 3 Why is Dose Selection Important? Antimicrobial Therapy:Antimicrobial Therapy: –Efficacy Patient StatusPatient Status MicroorganismsMicroorganisms DrugDrug –Complimentary Effect, e.g. anti-inflammatory –Antibacterial Effect Delivery of free drug to site of actionDelivery of free drug to site of action – Dependent on magnitude and timing of inputs –Domain of acceptable toxicity Antimicrobial Therapy:Antimicrobial Therapy: –Efficacy Patient StatusPatient Status MicroorganismsMicroorganisms DrugDrug –Complimentary Effect, e.g. anti-inflammatory –Antibacterial Effect Delivery of free drug to site of actionDelivery of free drug to site of action – Dependent on magnitude and timing of inputs –Domain of acceptable toxicity

4. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 4 Why is Dose Selection Important? Antimicrobial Drug Therapy Concepts:Antimicrobial Drug Therapy Concepts: –Shift in relationship between Dose-Efficacy Profile and Dose-Toxicity Profile Antimicrobial Drug Therapy Concepts:Antimicrobial Drug Therapy Concepts: –Shift in relationship between Dose-Efficacy Profile and Dose-Toxicity Profile

5. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 5 Why is Dose Selection Important? Antimicrobial Drug Toxicity Management:Antimicrobial Drug Toxicity Management: –Dose Adjustment Special PopulationsSpecial Populations –Pediatric, Geriatric, Renal Impaired, and Hepatic Impaired Patients Interpretation of PK/PD RelationshipsInterpretation of PK/PD Relationships Antimicrobial Drug Toxicity Management:Antimicrobial Drug Toxicity Management: –Dose Adjustment Special PopulationsSpecial Populations –Pediatric, Geriatric, Renal Impaired, and Hepatic Impaired Patients Interpretation of PK/PD RelationshipsInterpretation of PK/PD Relationships

6. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 6 OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications Key Components of an OCPB Review:Key Components of an OCPB Review: –What are the characteristics of the exposure response relationship for efficacy and safety? Are the dose and dosing regimen consistent with the known relationship between dose (~concentration) and response?Are the dose and dosing regimen consistent with the known relationship between dose (~concentration) and response? Are there significant risks related to Clinical Pharmacology issues?Are there significant risks related to Clinical Pharmacology issues? –e.g., any changes in exposure related to intrinsic or extrinsic factors? –how should these risks be managed? dosage adjustment?dosage adjustment? Key Components of an OCPB Review:Key Components of an OCPB Review: –What are the characteristics of the exposure response relationship for efficacy and safety? Are the dose and dosing regimen consistent with the known relationship between dose (~concentration) and response?Are the dose and dosing regimen consistent with the known relationship between dose (~concentration) and response? Are there significant risks related to Clinical Pharmacology issues?Are there significant risks related to Clinical Pharmacology issues? –e.g., any changes in exposure related to intrinsic or extrinsic factors? –how should these risks be managed? dosage adjustment?dosage adjustment?

7. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 7 OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications Optimal Process: Learn/Confirm Optimal Process: Learn/Confirm Phase 3 Studies (Outcomes Exposure) In vitro / Animal PK/PD Studies Phase 1 (PK) & Phase 2 (Proof of Concept) Knowledge Gained

8. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 8 OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications Regulatory Submission:Regulatory Submission: –Sponsor Rationale for Dose Selection – highly variable PK/PD-BasedPK/PD-Based –Preclinical In vitro/Animal Models –Phase 1/2 PK/PD Market-DrivenMarket-Driven Compliance/ConvenienceCompliance/Convenience Rationale is not always transparent to the Agency Regulatory Submission:Regulatory Submission: –Sponsor Rationale for Dose Selection – highly variable PK/PD-BasedPK/PD-Based –Preclinical In vitro/Animal Models –Phase 1/2 PK/PD Market-DrivenMarket-Driven Compliance/ConvenienceCompliance/Convenience Rationale is not always transparent to the Agency

9. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 9 OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications Regulatory Submission:Regulatory Submission: –Rationale for Dose Selection Regulatory Submission:Regulatory Submission: –Rationale for Dose Selection datadata connectedness connectedness understanding understanding informationinformation knowledgeknowledge wisdomwisdom understanding relations understanding patterns understanding principles

10. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 10 OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications Regulatory Submission:Regulatory Submission: –Rationale for Dose Selection. – Information (no data) Regulatory Submission:Regulatory Submission: –Rationale for Dose Selection. – Information (no data) T>MIC = 40%

11. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 11 OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications Regulatory Submission:Regulatory Submission: –Dose Selection for Phase 3 Clinical Trials based on data presented, including:based on data presented, including: –MICs for pertinent organisms, –drug concentration-time profiles from Phase 1, and –insufficient assessment of free drug concentrations proposed dosage regimen proposed dosage regimen –will not meet therapeutic objective results of Phase 3 trialresults of Phase 3 trial –inferior to the control Regulatory Submission:Regulatory Submission: –Dose Selection for Phase 3 Clinical Trials based on data presented, including:based on data presented, including: –MICs for pertinent organisms, –drug concentration-time profiles from Phase 1, and –insufficient assessment of free drug concentrations proposed dosage regimen proposed dosage regimen –will not meet therapeutic objective results of Phase 3 trialresults of Phase 3 trial –inferior to the control

12. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 12 OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications Regulatory Submission:Regulatory Submission: –Dose Selection based on detailed development program using PK/PD relationships Protocols and DataProtocols and Data –Microbiological data –In vitro & animal model data –Phase 1 pharmacokinetics data –Phase 2 study design AnalysesInformation KnowledgeAnalysesInformation Knowledge –Understanding Regulatory Submission:Regulatory Submission: –Dose Selection based on detailed development program using PK/PD relationships Protocols and DataProtocols and Data –Microbiological data –In vitro & animal model data –Phase 1 pharmacokinetics data –Phase 2 study design AnalysesInformation KnowledgeAnalysesInformation Knowledge –Understanding

13. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 13 SummarySummary The basis for dose selection is critical to understanding how to manage changes in patient drug exposure while maintaining acceptable safety. –unclear where we are on the exposure/response curve Is the aim of dose selection to find the dose with the highest probability of efficacy? –unclear how PK/PD target is related to clinical outcome The basis for dose selection is critical to understanding how to manage changes in patient drug exposure while maintaining acceptable safety. –unclear where we are on the exposure/response curve Is the aim of dose selection to find the dose with the highest probability of efficacy? –unclear how PK/PD target is related to clinical outcome ??

14. Office of Clinical Pharmacology and Biopharmaceutics IDSA/ISAP/FDA Workshop 4/16/04 14 SummarySummary Large differences in the level of detail included in rationale to support dose selection –data – information – knowledge continuum seldom presented –mean data often submitted variation? –rationale for dose selection is not always apparent –dose adjustment based on PK/PD targets is often difficult Large differences in the level of detail included in rationale to support dose selection –data – information – knowledge continuum seldom presented –mean data often submitted variation? –rationale for dose selection is not always apparent –dose adjustment based on PK/PD targets is often difficult