Title: Pandemic Influenza Vaccine Safety and Effectiveness Monitoring and Comments on sanofi pasteur
1Pandemic 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
2General 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
3General Considerations
- Homeland Security Pandemic Influenza Plan
- Track adverse events following vaccine
administration - Define protocols for conducting vaccine-
effectiveness studies during a pandemic
4Factors Affecting Vaccine Safety and
Effectiveness Monitoring
- Stage of pandemic
- Population receiving the vaccine
- Strategy for vaccine distribution
5Key Systems Currently Availableto Study Vaccine
Safety
6The 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
7Advantages 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
8Disadvantages 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
9The 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
10Advantages 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
11Limitations 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
12Other 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
13Supplemental 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
14Additional 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
15Principles 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
16Pharmacovigilance 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
17Notable 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
18Issues 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?
19Issues 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?
20Summary
- 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
21Acknowledgements
- John Iskander MD, MPH
- M. Miles Braun, MD, MPH
- Sukhminder K. Sandhu, PhD, MPH, MS
- Vaccine Safety Branch