Docstoc

Exposure-Response Application to Anti-Infective Drug Development

Document Sample
Exposure-Response Application to Anti-Infective Drug Development Powered By Docstoc
					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



Office of Clinical Pharmacology and Biopharmaceutics
IDSA/ISAP/FDA Workshop 4/16/04
                              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




    Office of Clinical Pharmacology and Biopharmaceutics
    IDSA/ISAP/FDA Workshop 4/16/04                         2
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

    Office of Clinical Pharmacology and Biopharmaceutics
    IDSA/ISAP/FDA Workshop 4/16/04                                 3
  Why is Dose Selection Important?

• Antimicrobial Drug Therapy Concepts:
  – Shift in relationship between Dose-Efficacy
    Profile and Dose-Toxicity Profile




   Office of Clinical Pharmacology and Biopharmaceutics
   IDSA/ISAP/FDA Workshop 4/16/04                         4
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




    Office of Clinical Pharmacology and Biopharmaceutics
    IDSA/ISAP/FDA Workshop 4/16/04                                 5
    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?


   Office of Clinical Pharmacology and Biopharmaceutics
   IDSA/ISAP/FDA Workshop 4/16/04                                               6
    OCPB Review Experience with Dose
Selection in Antimicrobial Drug Applications
• Optimal Process: Learn/Confirm

                   Phase 1
                                                 Phase 3
                   (PK) &
                                                 Studies
                   Phase 2
                                                 (Outcomes
                  (Proof of
                                                 Exposure)
                  Concept)




                                   In vitro /
                                   Animal                    Knowledge Gained
                                    PK/PD
                                    Studies
    Office of Clinical Pharmacology and Biopharmaceutics
    IDSA/ISAP/FDA Workshop 4/16/04                                              7
    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


    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:
   – Rationale for Dose Selection
          connectedness
          connectedness                               wisdom
                                                      wisdom
                                                           understanding principles
                                                           understanding principles
                                        knowledge
                                        knowledge
                                            understanding patterns
                                            understanding patterns
                          information
                           information
                               understanding relations
                               understanding relations
                  data
                  data                                     understanding
                                                           understanding

    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:
  – Rationale for Dose Selection. – Information (no data)




                             T>MIC = 40%




   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:
  – 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
    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:
  – 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


    Office of Clinical Pharmacology and Biopharmaceutics
    IDSA/ISAP/FDA Workshop 4/16/04                                12
                                  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


      Office of Clinical Pharmacology and Biopharmaceutics
      IDSA/ISAP/FDA Workshop 4/16/04                             13
                                  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




      Office of Clinical Pharmacology and Biopharmaceutics
      IDSA/ISAP/FDA Workshop 4/16/04                             14

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:0
posted:7/24/2013
language:English
pages:14