Current CDC Vaccine Safety Activities

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Current CDC Vaccine Safety Activities

• Vaccine Safety Evaluation
• Post Marketing Surveillance Conference
• Bethesda, MD
• April 10,2007
• John Iskander MD MPH
• Immunization Safety Office (ISO)
• Office of the Chief Science Officer
• Centers for Disease Control and Prevention

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Outline

• Overview of current CDC post-licensure vaccine
  safety activities
• Immunization Safety Office
• National Center for Immunization and Respiratory
  Diseases (NCIRD)
• New approaches and emerging vaccine safety issues
• Key partnerships and priority setting
• Lessons learned and thoughts on conference theme

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Immunization Safety Office Mission

• Vaccine risk assessment achieved through
• Performance of high-quality research on vaccine
  safety
• Identification of adverse events after
  immunization (AEFI) through public health
  surveillance
• Assessment of causality and preventable risk
  factors for AEFI
• Communication of findings through scientific
  publications and presentations,
  electronic/traditional media, etc.

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• Establishing Causal LinkAdverse Event and
  Vaccine

Illness or Syndrome

No
Yes
Rate in vaccinated a/ab
a
b
Yes
Vaccination
Rate in unvaccinated c/cd
No
c
d
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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, vaccine manufacturers, health
  departments, 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 issues

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Limitations of VAERS

• Reporting biases
• Underreporting, though serious events more likely
  to be reported (Rosenthal and Chen, AJPH, 1996)
• 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 (LLDB) which tracks
• Vaccination (exposure)
• Outpatient, emergency department (ED), hospital
  and laboratory data (health outcomes)
• ICD-9 CM codes used
• Demographic variables (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 accessible
• Availability for urgent studies

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Limitations of VSD Analyses

• Sample size may be inadequate for very rare
  events
• (e.g. Guillain-Barre syndrome with incidence
  rate of
• 1-2/100,000 per year)
• Vaccines administered outside of HMO setting not
  captured
• Lack of demographic and socioeconomic diversity
  in HMO practice
• Variable accuracy of coded data used for studies
• Unvaccinated population may be small

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Self-Controlled Case Series Methodology
Risk Period varies from 6 weeks to 3 months
Zoster Vaccination
Control Period
Control Period
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VSD Database of Pregnancy Outcomes after
Vaccination

• Objective
• To create an analytic database to serve as a
  resource for measuring the risk of adverse
  pregnancy outcomes after inadvertent vaccination
  of pregnant women

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Clinical Immunization Safety Assessment (CISA)
NetworkBackground

• Established in 2001 to investigate the
  pathophysiologic mechanisms and biologic risks
  of AEFI and to provide evidence-based vaccine
  safety assessments
• Network of six academic centers each with vaccine
  subject matter experts

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CISA Mission

• To conduct clinical research of vaccine adverse
  events (VAE) and role of individual variation in
  responses to immunizations
• To provide evidence-based information that
  assists
• Clinicians in the evaluation and management of
  individuals at risk for AEFI
• Individuals in making informed immunization
  choices

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Goals

• To study the pathophysiology of AEFIs
• To identify host risk factors associated with
  developing an AEFI
• To develop evidence-based guidance for use by
  clinicians
• When evaluating AEFIs
• When considering vaccination or re-vaccination
  of
• Individuals with (relative) contraindications
  for vaccination
• Individuals with a history of AEFIs

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CISA Integrating Individual Human Variation into
Studies of Vaccine Safety

• Examples of specific study protocols
• Myocarditis after smallpox vaccination
• Extensive limb swelling (ELS) after 4th/5th doses
  of DTaP
• Possible genetic risk factors for
  post-vaccination GBS

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• THE BRIGHTON COLLABORATION
• Standardizing Vaccine Safety
• http//www.brightoncollaboration.org

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Background

• The Need
• Safety can not be measured directly, only
  inferred from the relative absence of vaccine
  adverse events
• Assessing safety requires standardized
  terminology of VAE across studies
• Lack of a standard vocabulary (i.e., case
  definitions guidelines) for vaccine adverse
  events have hindered comparability of vaccine
  safety data
• The Solution
• A global collaboration to address this missed
  opportunity
• Development of standardized case definitions and
  guidelines
• Case definitions categorized by levels of
  evidence
• Clinical trials vs. postmarketing surveillance
• Developed vs. developing countries

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Network of Participants (N874)
with gt 2 participants
46 countries
25 countries
with 1 participant
www.brightoncollaboration.org
secretariat_at_brightoncollaboration.org
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Working groups
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Outline

• Overview of current CDC post-licensure vaccine
  safety activities
• Immunization Safety Office
• National Center for Immunization and Respiratory
  Diseases (NCIRD)
• New approaches and emerging vaccine safety issues
• Key partnerships and priority setting
• Lessons learned and thoughts on conference theme

22
Vaccine Analytic Unit (VAU)Objectives

• Assess unusual, possibly longer-term anthrax
  vaccine adverse events within Department of
  Defense (DoD)
• Conduct investigations to assess whether specific
  AEFI are associated with
• Current anthrax vaccine
• Future anthrax vaccines
• Other biodefense vaccines

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Data Defense Medical Surveillance System (DMSS)

• Active surveillance system of U.S. military
  personnel (1.4 million person years each year
  from 1998-present)
• Relational database containing numerous variable
  types
• Demographic
• Inpatient Outpatient (ICD-9 coded diagnoses)
• Vaccination
• Deployment

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VAU Research Agenda

• Partnership with DoD and FDA (NVAC workgroup)
• Establish research agenda to study long-term
  AEFIs (2004)
• Hypothesis testing studies
• Hypothesis generation studies

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VAU Key Benefits

• Unique infrastructure for conducting immunization
  safety postmarketing surveillance studies
• Increased understanding of safety profiles of
  anthrax and other (biodefense) vaccines given in
  military
• Complements VAERS and VSD to inform immunization
  policy makers about important vaccine safety
  questions

26
Outline

• Overview of current CDC post-licensure vaccine
  safety activities
• Immunization Safety Office
• National Center for Immunization and Respiratory
  Diseases
• New approaches and emerging vaccine safety issues
• Key partnerships and priority setting
• Lessons learned and thoughts on conference theme

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General Approaches for Safety Monitoring of New
Vaccines

• Summary of pre-licensure safety data
• Identified or uncertain risks from phase III
  trials
• Review of any available post-marketing data
• VAERS monitoring plan
• VSD plan key outcomes for Rapid Cycle Analysis
  (RCA), other planned studies
• Identification/creation of key case definitions
• Identification of candidate CISA protocols
• Identification of need for special studies

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ISO Milestones since 1st NVPO meeting (11/2000)

• 2001 VSD expands from 4 to 8 sites
• 2001 Internet-based VAERS public access dataset
  established
• 2001 Clinical Immunization Safety Assessment
  (CISA) Network
• 2002 Secure web-based VAERS reporting
  implemented
• 2003 VAERS support of U.S. smallpox vaccination
  program
• Casey et al, JAMA 2005
• 2004 1st Immunization Safety Office led field
  vaccine safety investigation (Rue et al,
  submitted for publication)
• 2005 VSD Rapid cycle analysis
• Davis et al, Epidemiology 2005
• 2005 ISO transferred to Office of Chief Science
  Officer, Office of the Director, CDC
• 2006 VAERS Data mining activities reviewed
• Iskander et al, Drug Safety 2006

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Emerging Issues

• Enhanced surveillance for newly licensed products
  and existing vaccines with new indications
• New target populations adolescence, pregnancy
• Combined vaccines and simultaneous vaccination
  with resulting increased complexity of databases
  used to study vaccine adverse events
• Increasing overlap of vaccine safety with
  patient safety issues new scientific
  approaches needed
• Examples vaccine administration errors, syncope
  challenging to study in LLDB
• Preparing vaccine safety infrastructure for a
  pandemic or other emergency responses

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Increase in Number of Licensed Vaccines

• 1990 16 vaccines under surveillance for safety
• Source CDC Monitoring System for Adverse Events
  Following Immunization (MSAEFI)
• 2004 49 U.S. licensed vaccine products
• Source Immunization Action Coalition,
  www.immunize.org

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VAE Reports after Infant (lt 1 y.o.)
Vaccinationby Vaccine Combination Received,
VAERS 1991-2002
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Outline

• Overview of current CDC post-licensure vaccine
  safety activities
• Immunization Safety Office
• National Center for Immunization and Respiratory
  Diseases
• New approaches and emerging vaccine safety issues
• Key partnerships and priority setting
• Lessons learned and thoughts on conference theme

33
Key Partners for CDC Vaccine Safety Activities

• NCIRD primarily responsible for vaccine risk
  management
• (i.e. policy setting related to vaccine safety
  issues)
• Other CDC centers
• Occupational Health, Birth Defects, HIV/STD/TB,
  etc.
• Governmental (non-CDC) FDA Center for Biologics,
  HRSA, NVAC, DoD, National Library of Medicine
• State and local health departments
• Academic centers (CISA network)
• Private sector managed care organizations,
  manufacturers, others in vaccine related
  industries
• Professional organizations (e.g. AAP)
• Immunization advisory bodies
• U.S. ACIP, WHO Global Advisory committee

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Partnerships Provide Additional Data Sources

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

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Priority SettingResearch Agenda Development

• Scope limited to ISO activities but extends
  beyond Institute of Medicine (IOM) recommended
  VSD research agenda (RA)
• Coordinated 3-step development process with
  extensive internal and external input
• ISO/CDC develops draft research agenda
• National Vaccine Advisory Committee (NVAC)
  provides a policy perspective on RA
• ISO/CDC finalizes agenda and responds to feedback
  from NVAC process
• Evaluate process after developning first research
  agenda

36
Outline

• Overview of current CDC post-licensure vaccine
  safety activities
• Immunization Safety Office
• National Center for Immunization and Respiratory
  Diseases
• New approaches and emerging vaccine safety issues
• Key partnerships and priority setting
• Lessons learned and thoughts on conference theme

37
Lessons Learned VAERS

• Despite underreporting, VAERS is sensitive (at
  times overly sensitive) with regard to detection
  of rare events
• Example doubling of influenza vaccine associated
  GBS reports translated to 1/1 million doses
  attributable risk
• (Lasky et al, NEJM 1998)
• Menactra associated GBS a similar recent example
• Public use data (required by law) has both
  advantages and disadvantages
• A systematic approach cannot be done
  efficiently on a report by report basis, hence
  the need for use of advanced signal detection
  techniques
• More operational research is needed (e.g. to
  quantify underreporting and provider awareness of
  system)

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Lessons Learned VSD

• Utility not limited to classical hypothesis
  testing studies
• Natural history/burden of disease
• Hypothesis generating
• Vaccine usage and uptake
• Active surveillance data is useful prospectively
  as well as retrospectively
• Timeliness of studies to address important public
  health concerns must be balanced with maintaining
  high study quality

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Lessons Learned The Way Forward

• There is a predictable relationship between
  vaccine-preventable disease levels, coverage, and
  degree of concern about vaccine safety/VAE
• Well conducted epidemiologic studies will
  continue to be a cornerstone of vaccine safety
  nevertheless they must be supplemented by studies
  conducted in other settings (laboratory,
  genomics, patient level) as we move towards an
  era of personalized medicine
• National and global public health benefits of
  vaccines require high coverage levels these
  cannot be achieved if concerns about vaccine
  safety are not comprehensively addressed

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Conference Theme

• What would an ideal post licensure vaccine safety
  system be?
• Have more specific information than is currently
  available about actual vaccine usage
• More integration and linkages b/w systems (e.g.
  automated use of case definitions within
  surveillance databases)
• More readily available and usable operational
  research-quantification of underreporting,
  scientifically designed provider
  outreach/education strategies, etc.
• More integrated into mainstream public health
  activities

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CDC Commitment to Vaccine Safety

• Objectively assess risks from vaccines
• Contribute to national preparedness
• Serve as a partner and resource for global
  vaccine safety activities
• Communicate findings to all involved parties in a
  clear and transparent manner

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Vaccinate. Safely.
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Acknowledgments

• Jane Gidudu
• Claudia Vellozzi
• Michael McNeil
• Karen Broder
• Kenneth Bart
• Robert Davis
• Susan Duderstadt

• Tanja Popovic
• James Stephens
• Julianne Gee
• Robert T. Chen
• Nancy Levine
• Paul Gargiullo

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Timeline of Selected Emergency Responses

• 1999-2004 Rotavirus vaccine and intussusception
• 1999-present Thimerosal and childhood vaccines
• 2001-present yellow fever vaccine and
  viscerotropic/neurotropic disease
• 2001-2 Use of smallpox and anthrax vaccines
  under IND protocols
• 2002-4 Smallpox vaccination program
• 2004 Recall of selected lots of rabies vaccine

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Emergency Response Anticipating Future Needs

• New VAERS contract contains an emergency
  response module
• Requirement to be able to process up to 40,000
  additional adverse event reports over a three
  month period
• Surge capacity would be needed in settings such
  as an influenza pandemic or in response to a
  confirmed smallpox case
• Contractor will also be required to establish or
  link with additional safety systems such as
  active surveillance