Exposure Response Application to Antimicrobial Drug Development IDSA PhRma FDA Working Group Meeting

							Exposure-Response: Application to
 Antimicrobial Drug Development

                    IDSA/PhRMA/FDA Workshop
                        November 19, 2002


           Philip Colangelo, Pharm.D., Ph.D.
         Division of Pharmaceutical Evaluation III
 Office of Clinical Pharmacology and Biopharmaceutics
              Food and Drug Administration


 Office of Clinical Pharmacology and Biopharmaceutics
 IDSA/PhRMA/FDA Workshop 11/19/02
Guidances: Exposure-Response (E-R)
 • Draft Guidance (2002): Exposure-Response
   Relationships: Study Design, Data Analysis, and
   Regulatory Applications

 • Guidance (1998): Providing Clinical Evidence of
   Effectiveness for Human Drugs and Biological
   Products

 • Draft Guidance (1998) Developing Antimicrobial
   Drugs - Considerations for Clinical Trials

 • ICH E4 (1994): Dose-Response Information to
   Support Drug Registration
     Office of Clinical Pharmacology and Biopharmaceutics
     IDSA/PhRMA/FDA Workshop 11/19/02                       2
                            Definitions

• Exposure
  – Drug input (e.g., dose, dose rate)
  – Plasma conc (e.g., Cmax, AUC)

• Response
  – Desired drug effect (e.g., clinical cure, micro
    cure)
  – Undesired drug effect (adverse events)




   Office of Clinical Pharmacology and Biopharmaceutics
   IDSA/PhRMA/FDA Workshop 11/19/02                       3
       Antimicrobial Drugs
Exposure-Response Working Group

• Formed June 2002

• Multidisciplinary
    Charles Bonapace                                  John Powers
    Phil Colangelo                                    George Rochester
    Sue-Chih Lee                                      Albert Sheldon
    Marilyn Martinez                                  Robert Walker
    Frank Pelsor (Chair)                              Steve Yan
    Janice Pohlman                                    Jenny Zheng

    Office of Clinical Pharmacology and Biopharmaceutics
    IDSA/PhRMA/FDA Workshop 11/19/02                                     4
       Antimicrobial Drugs
    Working Group - Objectives
• Critically evaluate antimicrobial exposure-
  response information and develop an
  internal consensus
• Determine applicability of exposure-
  response data in antimicrobial drug
  development
• Determine where exposure-response data
  can be used to support regulatory
  decisions
    Office of Clinical Pharmacology and Biopharmaceutics
    IDSA/PhRMA/FDA Workshop 11/19/02                       5
   Antimicrobial Working Group -
          Potential Goals
• Develop an exposure-response
  knowledge base
  – by antibiotic class
  – by indication and/or organism (including
    resistant strains)
  – by outcome (clinical and micro)

• Correlate human exposure-response
  outcome data with in vitro/animal data

    Office of Clinical Pharmacology and Biopharmaceutics
    IDSA/PhRMA/FDA Workshop 11/19/02                       6
 Integration of Exposure-Response
Knowledge Within Drug Development

 Pre-Clinical                                Clinical Development

  In-Vitro/
  Animal                    Phase 1                        Phase 2   Phase 3
  Studies                   Studies                        Studies   Studies




    Office of Clinical Pharmacology and Biopharmaceutics
    IDSA/PhRMA/FDA Workshop 11/19/02                                      7
          In vitro/Animal Studies
• Well designed studies can provide
  important information for clinical trials
  (hypothesis generating)

• Some design issues
  – dose fractionation to establish E-R index/indices
  – correction for protein binding
  – neutropenic vs. non-neutropenic animals
  – inoculum size; timing of drug administration;
    duration of experiments; micro endpoint(s)
  – applicability to clinical setting
      Office of Clinical Pharmacology and Biopharmaceutics
      IDSA/PhRMA/FDA Workshop 11/19/02                       8
                   Phase 2 Studies
• Proof of concept (hypothesis testing)
  – critical component of development
  – opportunity to explore exposure-response
    in the targeted patient population
  – facilitate selection of right dosage
    regimen

• Some limitations of current design
  – limited indications
  – limited dose range
  – plasma samples usually not obtained
    Office of Clinical Pharmacology and Biopharmaceutics
    IDSA/PhRMA/FDA Workshop 11/19/02                       9
                     Phase 2 Studies




Phase 1                Phase 2                    Phase 3   Approval

    Office of Clinical Pharmacology and Biopharmaceutics
    IDSA/PhRMA/FDA Workshop 11/19/02                               10
                    Phase 3 Studies
• Confirmatory
  – right dose(s) and duration of therapy
  – relationship between exposure-response
    index/indices and outcome in patients

• Some limitations of current design
  – sparse PK sampling usually not
    performed, or often not adequate to allow
    reliable estimation of PK parameters

     Office of Clinical Pharmacology and Biopharmaceutics
     IDSA/PhRMA/FDA Workshop 11/19/02                       11
Antimicrobial Exposure-Response Issues
 • May not be an absolute/ideal value associated with
   a given PK/PD index
    – may be specific to drug, organism, site of infection
    – may be other PK/PD indices
 • Plasma concentrations  Infected tissue
   concentrations
    – can PK/PD index derived from plasma predict outcome in
      all sites of infection?
    – if yes, then is the magnitude of this index also the same at
      site of infection vs. plasma?
 • Predictability of indices to outcome
    –   clinical vs. microbiological endpoint
    –   timing of endpoint measurement (EOT vs. TOC)
    –   drug effect vs. spontaneous resolution
    –   true micro eradication vs. presumed eradication
        Office of Clinical Pharmacology and Biopharmaceutics
        IDSA/PhRMA/FDA Workshop 11/19/02                        12
Exposure-Response for Susceptible
    and Resistant Pathogens
• Where we would like to be
  – optimize exposure-response indices to
    ensure adequate dosage regimen for all
    pathogens, balanced with acceptable
    safety

• Where we are now
  – evaluate exposure-response indices to
    support clinical trial outcome data for all
    pathogens
   Office of Clinical Pharmacology and Biopharmaceutics
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