Pandemic Influenza Vaccines: FDA Preparedness Activities

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Pandemic Influenza VaccinesFDA Preparedness
Activities

• Sara Gagneten, Ph.D.CBER/FDA
• April 20, 2005

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Acknowledgement

• Many individuals at CBER/FDA have made
  contributions to pandemic preparedness and have
  contributed to this slide presentation
• Roland Levandowski, M.D., Antonia Geber, M.D.,
  and Karen Goldenthal, M.D.

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Objectives

• Overview of FDA approval process
• Licensing of influenza vaccines
• Pathways for licensing of pandemic vaccines ?
  CBER activities
• Preparedness reagents, surveillance, guidance ?
  CBER activities
• Conclusions

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Stages of Review and Regulation
Clinical Investigational Plan
Phase 4 Inspection Safety Efficacy Lot Release
BLA Data to support approval Inspection
IND
Phase 1 Safety Immuno-genicity
Phase 2 Safety Immuno-genicity Dose Ranging
Phase 3 Safety Efficacy Immuno-genicity
BLA Supplement Post-approval Changes New
Indications Dosing Manufacture Equip./Facilities
IND Investigational New Drug Application
BLABiologics License Application
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Inactivated Influenza Virus Vaccines

• Vaccines are trivalent. Strains (influenza
  A/H1N1, influenza A H3N2, influenza B) are
  selected to match circulating viruses
• Contain at least 15 µg/dose of each HA
  (standardized by SRID)
• Vaccine efficacy
• - Potency of vaccine
• - Match of vaccine HAs with circulating
• viruses

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Routine Licensing Actions for Inactivated
Influenza Vaccines

• Each year, any of the three vaccine strains from
  the previous years vaccine may be replaced with
  a new strain
• Strain changes are based on evaluation of
  circulating wild-type influenza strains and
  recommendations of WHO, CDC and VRBPAC
• A BLA supplement to an existing license is
  submitted for strain changes, and does not
  require clinical data for FDA approval

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Range of Regulation of Pandemic Vaccines

• 1. Vaccine produced using a licensed
  manufacturing process ? immune response (IR) data
• 2. Vaccine produced using a licensed
  manufacturing process but formulated to contain
  less antigen ? immune response data, a novel
  adjuvant or a different delivery method ?
  clinical safety, IR, or efficacy data depending
  on novelty of adjuvant
• 3. Vaccine produced using an unlicensed novel
  manufacturing process ? safety, IR, efficacy data

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1. Licensure of a Pandemic Vaccine Manufactured
Using a Licensed Process

• The new pandemic strain would be reviewed as a
  supplement for strain change
• Either a wild type or a reassortant virus could
  be used to produce the vaccine
• Clinical studies to determine optimal dose and
  schedule for a pandemic vaccine should be
  conducted during interpandemic period

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CBER Activities Clinical Safety and
Immunogenicity Studies

• Review of the design for clinical trials e.g.,
  H5N1 vaccine in healthy adults, children and the
  elderly
• Review and analysis of clinical data

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2. Licensure of a Pandemic Vaccine with Both
Licensed and Novel Components

• Data supporting certain antigen sparing
  strategies (same product, less antigen) would be
  reviewed as a clinical supplement
• Adding a new adjuvant to vaccine formulation
  would likely require more extensive clinical and
  manufacturing data compared to the case above
  (novel adjuvant new product)

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CBER Activities Antigen Sparing Studies

• Review and analysis of clinical data for
• Dose ranging studies in adults and the elderly
• Studies using alternative routes of administration

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3. Licensure of a Novel Investigational Pandemic
Vaccine

• An investigational vaccine made according to a
  new process requires product and pre-clinical
  data, to support the initiation of clinical
  trials
• Clinical studies are required to demonstrate
  safety and efficacy of the new vaccine produced
  with current circulating strains

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CBER Activities Novel Vaccine Studies

• Guidance to sponsors on new cell substrates for
  virus propagation

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Preparation of Reagents

• Generation of wild type or reassortant reference
  viruses
• Preparation of antigen and antisera for potency
  assays

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CBER/FDA Activities Preparation of Reagents

• Development of reagents for laboratory detection
  of novel strains e.g., H5, H7, H9, in
  collaboration with CDC, NIH, and NVPO
• Development of reagents (i.e., anti-HA antisera
  and purified antigen preparations) for
  formulation and evaluation of H5 and H9
  antigen-containing vaccines

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Surveillance Preparedness

• Preparation for collection of clinical data at
  the time of the pandemic
• To assess the incidence of rare adverse events in
  the setting of mass immunization

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CDC/FDA Collaborative activities Surveillance

• Safety monitoring of SAEs for pandemic vaccines
  through VAERS
• Plans developed with recent IND experience

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Regulatory Pathways for Licensure of Pandemic
Vaccines

• Endpoints
• Traditional approval for a new vaccine clinical
  endpoint efficacy data are required as part of
  the data base to support approval
• Accelerated approval for a new vaccine
  licensure is conditionally approved based on
  surrogate endpoints (i.e., IR), with a
  post-marketing commitment to perform a clinical
  endpoint efficacy study to verify and describe
  its clinical benefit

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CBER Activities Guidance to Sponsors and
Manufacturers

• Meet with sponsors of clinical trials to provide
  guidance for the licensure of pandemic influenza
  vaccines
• Provide input in pandemic influenza meetings on
  pathways to licensure and input on the
  identification of product, pre-clinical and
  clinical study priorities for pandemic vaccines

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CBER Activities Preparation of Guidance Documents

• Draft guidance document defining pathways to
  licensure of pandemic or epidemic vaccines (in
  preparation)
• Draft guidance document for the use of an
  unapproved product under an Emergency Use
  Authorization (EUA)
• (attacks, national security)

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Summary

• Supportive studies for licensure range from
  minimal, for the manufacture of pandemic vaccines
  produced using a licensed process, to extensive
  for vaccines produced using novel processes.
• CBER pandemic preparedness activities include
  guidance and oversight of clinical studies,
  regulatory guidance to sponsors, preparation of
  reference reagents for vaccine production and
  evaluation, and surveillance.

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FDA Perspectives

• When the pandemic arrives, there wont be time to
  develop new manufacturing processes and the
  ability to increase the existing capacity will be
  limited.
• Therefore, the main sources of vaccine will be
  manufacturers with processes licensed in the
  interpandemic period.
• Either wild-type virus or high growth
  reassortants may be used to manufacture vaccine.

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FDA Perspectives (cont.)

• Rapid initiation of clinical trials with licensed
  vaccine containing the actual pandemic strain
  could help to evaluate the immunogenicity of the
  vaccine formulation and the need for more than
  one dose of vaccine.
• Epidemiological studies to evaluate the impact of
  the pandemic vaccines on disease burden would be
  of great importance, as would surveillance for
  vaccine-associated adverse events.