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Current Status of Dose Selection in Antimicrobial Drug Development Programs: FDA Perspective

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.

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Current Status of Dose Selection in Antimicrobial Drug Development Programs: FDA Perspective

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  1. 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

  2. Objectives • 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. Why is Dose Selection Important? • Antimicrobial Therapy: • Efficacy • Patient Status • Microorganisms • Drug • Complimentary Effect, e.g. anti-inflammatory • Antibacterial Effect • Delivery of free drug to site of action • Dependent on magnitude and timing of inputs • Domain of acceptable toxicity

  4. Why is Dose Selection Important? • Antimicrobial Drug Therapy Concepts: • Shift in relationship between Dose-Efficacy Profile and Dose-Toxicity Profile

  5. Why is Dose Selection Important? • Antimicrobial Drug Toxicity Management: • Dose Adjustment • Special Populations • Pediatric, Geriatric, Renal Impaired, and Hepatic Impaired Patients • Interpretation of PK/PD Relationships

  6. OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications • 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 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?

  7. OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications • Optimal Process: Learn/Confirm Knowledge Gained

  8. OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications • Regulatory Submission: • Sponsor Rationale for Dose Selection – highly variable • PK/PD-Based • Preclinical In vitro/Animal Models • Phase 1/2 PK/PD • Market-Driven • Compliance/Convenience Rationale is not always transparent to the Agency

  9. OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications • Regulatory Submission: • Rationale for Dose Selection wisdom connectedness understanding principles knowledge understanding patterns information understanding relations understanding data

  10. OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications • Regulatory Submission: • Rationale for Dose Selection. – Information (no data) T>MIC = 40%

  11. OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications • Regulatory Submission: • Dose Selection for Phase 3 Clinical Trials • 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 • will not meet therapeutic objective • results of Phase 3 trial • inferior to the control

  12. OCPB Review Experience with Dose Selection in Antimicrobial Drug Applications • Regulatory Submission: • Dose Selection based on detailed development program using PK/PD relationships • Protocols and Data • Microbiological data • In vitro & animal model data • Phase 1 pharmacokinetics data • Phase 2 study design • Analyses Information Knowledge • Understanding

  13. Summary • 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. Summary • 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

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