Pandemic Influenza Vaccine Safety and Effectiveness Monitoring and Comments on sanofi pasteur

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Pandemic Influenza Vaccine Safety and
Effectiveness Monitoring and Comments on sanofi
pasteurs H5N1 Vaccine Pharmacovigilance Plan

• Robert Ball, MD, MPH, ScM
• Vaccine Safety Branch
• Division of Epidemiology, CBER, FDA
• VRBPAC
• February 27, 2007

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General Considerations

• Limited safety and effectiveness data available
  for pandemic influenza vaccines prior to use
• Robust safety and effectiveness monitoring after
  licensure is essential
• Morbidity due to adverse events may be severe
  (e.g. Guillain Barré Syndrome after 1976-77 swine
  influenza pandemic)
• Alleviate unwarranted fears to strengthen
  confidence in vaccine
• Facilitate benefit-risk analysis

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General Considerations

• Homeland Security Pandemic Influenza Plan
• Track adverse events following vaccine
  administration
• Define protocols for conducting vaccine-
  effectiveness studies during a pandemic

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Factors Affecting Vaccine Safety and
Effectiveness Monitoring

• Stage of pandemic
• Population receiving the vaccine
• Strategy for vaccine distribution

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Key Systems Currently Availableto Study Vaccine
Safety
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The Vaccine Adverse Event Reporting System (VAERS)

• The early warning system of vaccine safety
  surveillance
• A national passive surveillance system jointly
  operated by the CDC and the FDA
• Established in 1990
• Accepts reports from physicians, other health
  care providers, and the public
• Hypothesis generating seeking signals of
  potential concern

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Advantages of VAERS

• National in scope, covers diverse populations
• Able to detect rare events in a cost-effective
  manner
• Rapid detection of possible signals (hypotheses
  to be tested )
• Can assess lot-specific vaccine safety

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Disadvantages of VAERS

• Reporting biases
• Underreporting, though serious events more likely
  to be reported
• Overreporting, since many reports are not
  causally related to vaccination
• Does not provide information on
• Number of persons vaccinated
• Background incidence of conditions in the general
  population

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The Vaccine Safety Datalink (VSD)

• 8 geographically diverse HMOs that participate
  in a Large Linked Database which tracks
• Vaccination (exposure)
• Outpatient, emergency department, hospital and
  lab data (health outcomes)
• Demographic variables (can be confounders)
• Covers about 3 of U.S. population
• Hypothesis testing

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Advantages of VSD Analyses

• All medical encounters are available at most
  sites
• Allows calculation of background rates
• Medical chart review is possible
• Availability for urgent studies

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Limitations of VSD Analyses

• Sample size may be inadequate for very rare
  events (e.g. GBS with incidence rate of
  1-2/100,000 per year)
• Vaccines administered outside of HMO setting not
  captured by database
• Limited demographic and socioeconomic diversity
  in HMO practice
• Unvaccinated population may be small

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Other Resources Used in Study of Vaccine Safety

• Standardized case definitions of adverse events
  following immunization for use in clinical trials
  or epidemiologic studies
• Brighton Collaboration
• Clinical Immunization Safety Assessment Centers
  (CISA)
• Standardized patient evaluations
• Clinical guidelines for providers

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Supplemental Vaccine Safety Data Sources

• Biologics Surveillance
• Vaccine dose distribution
• (not doses administered)
• Nationally Representative Vaccine Coverage
  Surveys
• National Health Interview Survey, National
  Immunization Survey, Behavioral Risk Factor
  Surveillance System
• State/local Immunization Registries
• Hospital Discharge/Mortality Datasets

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Additional FDA and CDC Pandemic Influenza Vaccine
Safety Activities

• Pilot projects to assess use during a pandemic
• Evaluation of VAERS using 2006-7 influenza season
  reports
• In collaboration with Harvard, planned expansion
  of VSD to another site and evaluation of other
  large automated databases of encounter and/or
  claims data
• Rapid access to data on influenza vaccine and
  treatment claims from Centers for Medicare and
  Medicaid Services
• Discussions with DOD and VA on their plans for
  pandemic influenza vaccine safety and
  effectiveness monitoring

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Principles for Expanding Safety and
Effectiveness Monitoring

• Complementarity, coordination, and
  minimized-overlap between government agencies and
  vaccine manufacturers to ensure that each is
  contributing valuable information for safety
  monitoring

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Pharmacovigilance Planning and Post-licensure
Commitments

• Since 2005 FDA has requested that vaccine
  manufacturers submit a Pharmacovigilance Plan
  (PvP) with their Biologics License Application
  (BLA)
• PvP should follow FDA and International
  Conference on Harmonization E2E guidelines
• In addition to reporting of adverse events to
  VAERS as required by regulation, enhanced safety
  surveillance and/or observational studies are
  often required
• Highly recommended for sponsors to work closely
  with FDA and CDC to develop and conduct studies
  to monitor safety post-licensure

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Notable Aspects of sanofi pasteur
Pharmacovigilance Plan

• Sanofi has proposed changes to adverse event
  reporting during a pandemic that are not
  consistent with current regulations including
• Less frequent or simplified submission of
  Periodic Safety Update and other reports
• Use of simplified reporting forms
• Sanofi does not propose to conduct
  additional safety or effectiveness studies of
  the H5N1 vaccine

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Issues Requiring Clarification for Safety
Monitoring

• Should specific adverse event reporting
  requirements be increased or decreased?
• Do we need to monitor for particular adverse
  events of interest, and if so, what are they?
• Who (FDA, CDC, sanofi pasteur, other) should be
  responsible for what aspects of safety monitoring
  of the H5N1 vaccine?
• How might the above vary according to pandemic
  stage?

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Issues Requiring Clarification for Effectiveness
Monitoring

• What outcomes should be assessed to evaluate
  effectiveness (i.e. how should influenza be
  defined)?
• What study designs should be used to evaluate
  effectiveness?
• Who (FDA, CDC, sanofi pasteur, other) should be
  responsible for what aspects of effectiveness
  monitoring of the H5N1 vaccine?
• How might above vary according to pandemic stage?

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Summary

• Robust and flexible safety and effectiveness
  monitoring system needed to address range of
  possibilities during an influenza pandemic
• Epidemiological studies will likely be important
  and close coordination between government
  agencies and sanofi pasteur would be beneficial
• Desirable for sanofi pasteur to commit to working
  with FDA CDC to fill gaps in collection and
  analysis of safety and effectiveness data if the
  H5N1 vaccine is used

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Acknowledgements

• John Iskander MD, MPH
• M. Miles Braun, MD, MPH
• Sukhminder K. Sandhu, PhD, MPH, MS
• Vaccine Safety Branch