Developing Drugs for the Treatment of Infections due to Resistant Pathogens IDSA PhRma FDA Working Group Meeting by FDADocs

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									    Developing Drugs for the
  Treatment of Infections due to
      Resistant Pathogens
              IDSA/PhRMA/FDA Workshop
                  November 19, 2002

                Edward Cox, M.D., M.P.H.
Division of Special Pathogen and Immunologic Drug Products
        Center for Drug Evaluation and Research
          U.S. Food and Drug Administration

                                                      1
      Identifying RP of PH
          Importance
• Which resistant pathogens (RPs) rise to
  the level of posing a significant public
  health (PH) problem in a specific
  indication(s)?
• Antimicrobial resistance is a dynamic
  problem evolving over time
• How do we identify these RPs?


                                         2
Identifying RPs of PH Importance -
 A Characteristic-based Approach

• Characteristics to identify resistant
  pathogens that pose a significant
  public health problem within an
  indication(s)
• The RP should meet some, but not
  necessarily all of the characteristics



                                           3
Identifying RPs of PH Importance -
          Characteristics
–   Organism of sufficient prevalence
–   Organism of sufficient virulence
–   Data to show resistance affects outcomes
–   Is the drug commonly used to treat infections
    due to the organism?
–   Insufficient therapeutic alternatives
–   Is the organism resistant to multiple drug
    classes?
–   Resistance affects therapeutic decision making
–   Drug is an essential treatment to prevent
    spread of a disease in the population (e.g. TB,
    STDs)                                         4
Identifying RPs of PH Importance

• RPs for which we have previously
  awarded claims
• Other RPs - Sponsors submit data
  addressing the characteristics of a
  RP of PH importance
• Other proposals



                                        5
    Prior FDA Meetings on
          Resistance
General
• July, 1998
• October, 1998
• October, 1999
• February, 2002
Product-specific
   – Synercid      February, 1998
   – Levaquin      October, 1999
   – Zyvox         April, 2000
   – AugmentinES   January, 2001
                                    6
   Types of Data - 1

           Clinical Data
     -Clinical outcomes
     -Microbiological outcomes
     -Within target indication


In Vitro     Animal        PK/PD
             Model

                                   7
        Types of Data - 2
• Quality of the agent in treating
  – the indication, e.g. CAP
  – the pathogen of interest including
    susceptibles
  – serious infections due to the
    pathogen of interest
  – the resistant pathogen of interest

                                         8
          Types of Data - 3
• To what degree can we rely on data other
  than clinical outcomes data (e.g. PK/PD, in
  vitro, animal model data) for the subject
  resistant pathogen in the target indication
  to provide support for a resistant pathogen
  claim?
• What level of evidence should these data
  provide?
   – For out-of-class claims?
   – For in-class claims?
                                           9
Data from Other Indications - 1
    What role can efficacy data from other
    indications for the same resistant
    organism play in supporting efficacy?
•   Can HAP support CAP?
•   Can meningitis data support CAP?
•   Can CAP support meningitis?
•   Can cSSSI data support HAP?
•   Can uUTI data support HAP?
•   Can OM data support ABS & vice versa?
                                            10
Data from Other Indications - 2
  Factors to consider when weighing
  data from other indications?
  – Similarity of disease process across
    disease sites
     • Organs/tissues involved
     • Drug levels achieved
     • Spectrum of disease severity
     • Host differences
  – Certainty of diagnosis across sites
                                           11
Points for Discussion




                        12
          Points for Discussion - 1
What are the characteristics that would deem a resistant
organism to be “of public health importance”? Please include
in your discussion such points as:
      The prevalence of the organism in the disease under
       study
      The virulence of the organism in question
      How commonly is the drug used to treat infections
       caused by the organism
      The availability of alternative therapies for the disease
       under study
      Organisms resistant to multiple drug classes
      Drug is an essential treatment to prevent spread of the
       disease in the population (e.g. sexually transmitted
       diseases) where vaccines are not available
      Data demonstrating the correlation of in vitro
                                                             13
       resistance with clinical outcomes
        Points for Discussion - 2a
Please discuss the nature of the clinical data needed to
demonstrate efficacy for a drug against resistant
pathogens. Please include in your discussion such
points as:
  Demonstration of efficacy in the disease in which the
   resistant pathogen is most likely to be present (e.g.
   efficacy in hospital-acquired pneumonia when
   studying MRSA, complicated intra-abdominal
   infections for VRE).
  The utility of demonstration of efficacy in susceptible
   isolates of the pathogen as it relates to efficacy
   against resistant pathogens. How does this equation
   differ for “in-class” resistance (e.g. a glycopeptide for
   VRE) as opposed to “out-of-class” resistance (e.g. a
   quinolone for PRSP)?                                14
        Points for Discussion - 2b
Please discuss the nature of the clinical data needed to
demonstrate efficacy for a drug against resistant
pathogens. Please include in your discussion such
points as:
 – Can one use efficacy in one disease to support
   efficacy in another disease? Please discuss such
   points as:
    • The severity of the disease in question (e.g. can
      microbiologically proven ABS support CAP?)
    • Relevance of the site of infection (e.g. can UTI
      studies support efficacy in pneumonia?)
    • Certainty of the diagnosis in question (can AECB
      support other respiratory tract infections?)
                                                     15
         Points for Discussion - 2c
Please discuss the nature of the clinical data needed to
demonstrate efficacy for a drug against resistant pathogens.
Please include in your discussion such points as:
 – In an effort to obtain quality data, what would help to
   define a “well-characterized” case of a given infection
   caused by a resistant pathogen? Please discuss such
   points as:
     • The certainty of diagnosis (e.g. bacteremia vs. other
       forms of disease)
     • The severity of disease (e.g. VRE UTI vs. intra-
       abdominal infections)
     • Certainty of poor outcome in absence of effective
       antimicrobial therapy (e.g. endocarditis or meningitis)
     • How comorbid conditions impact on assessment of
       outcome                                             16
        Points for Discussion - 3

 Please discuss the strengths and limitations of data
other than that obtained from Phase 3 clinical trials
in supporting the demonstration of efficacy of drugs
for resistant pathogens? Please include in your
discussion such points as:
 – In vitro measurement of MICs/ MBCs
 – Animal models of infection
 – Pharmacokinetic and pharmacodynamic studies



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