FDA's Role in Licensing Pandemic

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FDA's Role in Licensing Pandemic Powered By Docstoc
					Regulation of Vaccines: Challenges and

               Norman W. Baylor, Ph.D.
        Office of Vaccines Research and Review
          Presentation Overview
   Introduction to FDA
       Organization Structure
   Regulation of Vaccines
       CMC
       cGMPs
       INDs
   Regulatory Pathways to licensure of pandemic
    influenza vaccines
       New Technologies
   Summary
   Conclusions
Food and Drug Administration
   Office of the Commissioner
   Center for Biologics Evaluation and Research
   Center for Drug Evaluation and Research
   Center for Devices and Radiologic Health
   Center for Veterinary Medicine
   Center for Food Safety and Applied Nutrition
   National Center for Toxicological Research
   Office of Regulatory Affairs
            CBER Structure
   Office of            Office of Cellular,
    Communication,        Tissues and Gene
    Training and
    Manufacturers        Office of Vaccines
                          Research and Review
                         Office of Biostatistics
   Office of             and Epidemiology
    Management           Office of Compliance
   Office of Blood       and Biologic Quality
    Research and
      Product Development and
    Regulation - CBER Philosophy
   Regulation Goal: Balanced, Flexible, Responsive
      Assure  the safety and rights of subjects
      Protect the public health
      Facilitate technological innovation & product
   Influences
      Available  scientific knowledge, pre-clinical, clinical
       knowledge & experience
      Scientific research
      Crises/ tragic events
   Appropriate Risk Management
      Regulation of Vaccines
   Regulated by CBER’s Office of Vaccines Research and
    Review (OVRR)

   Authority resides in Section 351 of the Public Health
    Service Act and the Federal Food, Drug and Cosmetic

   Thorough review of laboratory and clinical data to
    ensure the safety, efficacy, purity and potency of these
Stages of Review and Regulation
                                                            Phase 4
Clinical Investigational Plan                               Inspection
                                              BLA           Safety
                                              Data to       Efficacy
                IND                                         Lot Release
Phase 1      Phase 2           Phase 3        approval;
                                                           BLA Supplement
Safety       Immuno-           Efficacy       Inspection
Immuno-      genicity          Safety                      Changes:
genicity     Safety            Immuno-                     New Indications
             Dose Ranging      genicity                    Dosing

IND = Investigational New Drug Application;
BLA = Biologics License Application
      Vaccine Licensure
 Vaccine development and
  commercialization are complex processes.
 Licensure based upon demonstration of
  safety and effectiveness, and ability to
  manufacture in a consistent manner.
 The FDA is committed to fostering the
  efficient, and rapid development of
  vaccines needed for the public health.
    Facilitating the Development and
      Evaluation of New Vaccines
   Anticipating and Addressing the Regulatory
    Issues for New Products
       General regulatory issues applicable to many
        products or product classes
              substrate issues
          Cell
          Improved test methods (sensitivity, reliability, etc.)

       Product specific issues
          Correlates   of protection necessary for efficacy
          Improved assays (e.g., potency, efficacy)
          Animal models for efficacy evaluation
                     CMC Development
                              DEVELOPMENT ACTIVITIES
Source characterization
                           DS & DP Characterization     Specification Development
Components info.
                           Formulation Development      Stability Studies
DS/DP Characterization
                           Component Characterization/ Manufacturing Process
                         Qualification                 Control & Validation
Clearance of impurities,
contaminants             Assay Development/ Validation
Process control esp. for                                                    BLA
safety processes (e.g.,                 Incremental CMC
sterilization, virus

                                                               Phase 3
  Discovery                                   Phase 2
  Pre-clinical                Phase 1
           CMC Content - Source
   Cells, Viruses, Banking Systems
       Origin/ Method of collection
       History (potential exposure)
       Manipulation, establishment of banks,
       Testing – Source/ source material
         (e.g., Microbiology, endogenous/ adventitious agents, (bovine/
           porcine), identity, purity, activity, replication competent
   Genetic material
       Origin
       Gene modification, construction of vector, purification
       Testing (e.g., sequencing)
          CMC Content - Source
   Evaluation
       Risk assessment of parent cells - history, potential exposure to viral
       Screening donors for risk factors, absence of disease markers
   Testing for viruses
       Endogenous virus testing
       Donors, animals, host cells, cell banks, EPC
       General and Species specific tests
       FDA-approved tests if available
   Control
       Establishing & maintaining cell banks, viral seeds under cGMP’s
       Closed herds & flocks, sentinel animals
       Quarantine until testing and control assures and establishes safety
               What are CGMPs?
   CGMPs cover a broad range of principles,
    methods, and practices that are implemented
    during product development and documented to
    ensure consistent manufacture of quality
   Good Laboratory Practices (GLPs)
       for conducting nonclinical laboratory studies
       purpose is to ensure the quality and integrity of the
        safety data
       support IND and BLA’s
   Recommend that CGMPs be in effect for
    manufacture of products used in clinical IND
    studies - starting with Phase 1 studies

   Follow general approaches and principles that
    are broadly applicable, tailor CGMP
    application to product, process and facility
       Assess risks and take appropriate actions
   Process Validation – Considerations
                    Reasons for Validation
                          Quality cannot be inspected or tested
    “Quality               into the finished product
  By Design”              Quality safety and effectiveness must
                           be designed and built into the
raw material properties    product
                          Each step must be controlled to
                           maximize the probability that the
               process     finished product meets all
               conditions specifications
Design Space
Process Validation – Considerations
    Foundation for validation
        Process and product understanding
           Well   defined and designed product and
              manufacturing process to consistently deliver
              high quality product
        Accurate measure and control of variability
             Consider all sources of variability
      Product lifecycle impact
      Supported by documentation, data
        Toward a Pandemic Influenza
   The regulatory pathway for pandemic
    vaccines is similar to that of annual
    influenza vaccine
       CMC and clinical information (both pre- and
        post licensure) will be required
   FDA’s review process will build on
    existing knowledge of influenza in
    comparison to the annual vaccine
       Will require a composite of data to be filed
     Meeting the Pandemic Vaccine
    Challenge: Overview and Actions
   Developing needed pathways and regulatory
    processes to speed vaccine availability
   Assuring safety and public confidence
   Facilitating vaccine manufacturing and
       scientific and related technical needs
       enabling both current and evolving technologies:
   Considering pathways to prevent a pandemic
   Thinking and working globally
    FDA Role Throughout Pandemic Vaccine Development, Evaluation and Availability

 Development and             Immunogen                     Development of
                            Identification                 manufacturing                      Laboratory
   selection of
                             (e.g. protein,              processes, pilot lots,                   and
candidate vaccines
                         strain) and proof of                   assays                         animal
 and technologies
                                concept                                                         studies


      General         Phase 1                               Phase 3
                      Human               Phase             100s –                                    Phase
         al           Studies               2                1000s                Licensing             4

                                                              •Efficacy                            •Facility
                     •Safety              •Safety
                                                              •Safety                               Inspections
                     •Immunogenicity      •Immunogenicity
                      (surrogate          •Efficacy
                                                                       Manufacturing &              Efficacy
                                                                      Facility Assessment          •Lot release
                     •Dose Ranging

                                Pre                   Possible EUA                          Supplements
                                EUA                                                           (e.g. new
   Development of an investigational
inactivated pandemic influenza vaccine
             for licensure
   Develop candidate pandemic influenza vaccines in
    advance of the pandemic.

   An investigational vaccine made according to a new
    process would require product and pre-clinical data, as
    appropriate, to support the initiation of clinical trials

   Clinical studies demonstrating safety and efficacy
    should be pursued during the interpandemic period
           Influenza Vaccines –
    CBER/FDA Draft Guidance Documents

   Draft Guidance for Industry: Clinical Data
    Needed to Support the Licensure of Trivalent
    Inactivated Influenza Vaccines - March 2006

   Draft Guidance for Industry: Clinical Data
    Needed to Support the Licensure of Pandemic
    Influenza Vaccines – March 2006
 CBER’s Annual Influenza Vaccine
Yearly activities:
 Develop new high growth influenza virus strains
  for vaccines
 Distribute influenza vaccine strains to
 Evaluate manufacturer’s influenza viruses prior
  to vaccine production
 Prepare influenza virus reagents to determine
  purity and strength of influenza vaccines
     CBER’s Pandemic Influenza
        Preparedness Plan
CBER research labs are preparing for a rapid
 response to a new pandemic influenza outbreak

• Developing new vaccine approaches that do not
  require eggs
• Characterizing cell lines that can be used to
  manufacture influenza virus
• Preparing novel influenza virus strains that can
  broadly protect against many types of influenza
    Expediting the Review Process:
        Formal Mechanisms
 BLA Standard Review: 10 month review
 Clinical Efficacy Supplement
       10 month review
   CMC Supplement
       4 month review
   Priority Review
       6 months
 Fast Track
 Accelerated Approval
       http://www.fda.gov/cber/guidelines.htm
                 Fast Track
   Incorporates an end of Phase I meeting
   Allows for more frequent communications with the
   May allow for a “rolling” review of the BLA
   May allow for an accelerated approval of the product
   Designed to facilitate the development and expedite
    the review of new drugs that are intended to treat
    serious or life-threatening conditions and that
    demonstrate the potential to address unmet medical
        Accelerated Approval (AA)
    21 CFR 601.40-46, Subpart E: Accelerated
     Approval of New Biologic Products for Serious
     or Life-Threatening Illnesses*
    “…provide meaningful therapeutic benefit to
     patients over existing treatments (e.g., ability to
     treat patients unresponsive to, or intolerant of,
     available therapy, or improved patient response
     over available therapy).”

    * Federal Register 57;58942-60, 1992.
    See 21 CFR 314.500-560, Subpart H for AA of new drugs
        Accelerated Approval (AA)
   FDA interprets 21 CFR 601.40, as allowing AA of an
    influenza vaccine during a shortage because influenza is a
    serious and sometimes life-threatening illness
       Providing vaccine to those who would not otherwise be immunized
        during a shortage provides a meaningful benefit over the then-
        existing treatments, in short supply

   Estimated annual US target population of 185 M
    recommended by to receive influenza vaccine

   First time AA used for a vaccine – Fluarix (Influenza
    Virus Vaccine) approved 8/31/05
  Pathways to Speed Availability:
Accelerated Approval for Inactivated
         Influenza Vaccines
   FDA considers influenza vaccines in short supply
   CBER will consider HI anti-HA antibody levels as a
    likely surrogate marker for efficacy
   Accelerated approval can be sought based on
    immunogenicity provided:
       validated assays
       post-approval studies of clinical efficacy
       complete manufacturing data, controls & inspections
       satisfactory safety data; clinical trials and data from
        experience with same vaccine under foreign licensure can
Pathways to Speed Availability:
Annual US Influenza Vaccines
   Each year, any of the previous three vaccine
    strains may be replaced with a new strain
   Strain changes based on evaluation of
    circulating wild-type strains
   Submission of a prior approval manufacturing
    supplement to an existing license is required
    for annual influenza strain changes
   FDA does not require clinical data for approval
    of these annual supplements for licensed
    manufacturers of inactivated flu vaccine
    Pathways to Speed Availability:
    Licensure of Pandemic Influenza
   FDA views a pandemic influenza strain used in a
    licensed manufacturing process as a strain
       Biologically, a new HA antigen is just that, another
        HA antigen, such as used in routine strain changes
       For licensed manufacturers using licensed processes,
        would not be treated as a new vaccine but as a
        supplement with some clinical data important
    Pathways to Speed Availability:
    Licensure of Pandemic Influenza
   Either a wild type or a reassortant virus
    (including virus derived by reverse genetics) can
    be used.
       FDA has no special requirements for use of
        recombinant or cell culture based technologies in
        strain production so long as adequate controls and
    Enabling New Approaches and

 Addition of adjuvants
 Different route of administration
 Cell culture and recombinant vaccines
 Cross protective antigens
 Live attenuated vaccines
         New Technologies: Adjuvants
   Addition of adjuvant to vaccine formulation.
       Conflicting results (published and unpublished) in past
            adequate studies are needed
       Requires submission of a new BLA
       Safety and efficacy (immunogenicity) data required
            aluminum (extensive experience in licensed vaccines)
            early studies should demonstrate rationale (e.g., significant
             increases in immunogenicity with acceptable safety profile) and
             determine dose
            Novel adjuvants or those would require more safety data
            Supporting manufacturing and product information required
       If proof-of-concept and other studies favorable, Phase 3
        studies should be pursued in interpandemic period
New Technologies: Antigen Sparing
   Changing route of vaccine delivery
       Intradermal administration
            Safety and efficacy (immunogenicity) data required
       Other delivery methods promising, e.g., mucosal
            More data needed
   Use of immune stimulators, (e.g. use of patch
    with heat-labile toxin).
       Safety and efficacy data required
       Such strategies are in relatively early development;
        lack of experience will require safety testing
      New Technologies: Cell Culture &
          Recombinant Vaccines
   Potential advantages in flexibility afforded by non-egg based
      Egg-based manufacturing has been successful & cost effective
      Other technologies have not been marketed or widely used
   Cell culture derived and recombinant based vaccines previously
    licensed by FDA
      No extraordinary regulatory concerns with these technologies
        for influenza vaccines
   Scientific/technical challenges include:
      Cell based: usual safety issues (i.e. tumorigenicity,
        adventitious agents), sufficient yield, manufacturing scale &
      Recombinant: Antigenicity and protective immune response
        Other New Technologies

 Cross-protective antigens
 Live attenuated vaccines
     Provide multiple immunogens, some may be
     May enhance more rapid development of
     May raise potential containment issues for
      public health and agriculture
                   Conclusion -
               Vaccine Development
   Influenza vaccines present unique considerations for
    clinical trial design & clinical development
   Overall planning and coordination:
      Product characterization & manufacturing plans
      Anticipate needs of future trials (e.g., critical assays to
        support endpoints)
      Accumulate sufficient safety, immunogenicity & efficacy
        data during development
      Importance of critical communications, e.g.,
           End-of-Phase 2 meeting
      Clinical bridging studies: Population; Product Scale-up
   Utilize available FDA documents & resources
CBER Available Information
 Internet www.fda.gov/cber
 Fax Information System
      InUS toll-free: 1-888-CBER-FAX (1-888-223-7329)
      Outside US: 301-827-3844
   Manufacturers assistance: MATT@CBER.FDA.GOV
   CBER Voice Information System at:
      1-800-835-4709   or 301-827-1800

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