Vaccine Safety Vision for the Future

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					Vaccine Safety: Vision for the

            Jesse L. Goodman, MD, MPH
     Director, Center for Biologics Evaluation and
                   Research, FDA
                    April 10, 2007
      Purpose of Our Meeting
• Discuss approaches, methodologies and
  opportunities to further enhance vaccine
  safety, using both current and developing
  tools – focus is on post-licensure systems
• Share international perspectives and
• Identify data and research gaps and needs
• Update and articulate a vision of an ideal
  vaccine safety system and help advance
  that vision
                   Perspective: Vaccine

As the specter of severe vaccine preventable diseases becomes seemingly distant in
developed countries, vaccine safety concerns, always important, gain prominence
       Partnerships in Safety
                         Problem detection, reporting
                         and personal decision-making
    Approval, quality and
  inspections, surveillance        Public    Immunization services, safety
     and post-marketing                      and effectiveness and related
studies, regulatory decisions, VRPAC    ACIP            research
       safety research     FDA                CDC

Innovation, production/quality,                  NIH
  pre and post license studies
                              Healthcare       Research and development
                            Surveillance, reporting,    Other important
                                   education            governmental
                                                        HRSA, DoD, VA, CMS
Assuring high vaccine safety involves more
     than post-licensure surveillance

                       VACCINE SAFETY

    PRE-APPROVAL:           Manufacturing
                                                  CLINICAL SAFETY:
    Animal                  quality
                                                  Planned (PMC) Studies
    Clinical                Inspections
                                                  Surveillance: AEs/VAERs/VSD
    Product quality and     Testing and Release
                                                  Studies of “problems”
    manufacturing           FDA and industry
                                                  RISK COMMUNICATION
    FDA, NIH and industry                         CDC, FDA, industry
         Result – High Safety
• Vaccines are carefully evaluated pre-licensure,
  manufactured and released under tight process
  controls and with FDA oversight, typically
  studied further post-approval and monitored
  carefully. Information communicated and, where
  needed, actions taken promptly.

  – Total: ~ 235 million vaccine doses distributed
    annually in US, ~ 2400 potential SAEs reported
           But Can We Do Better?

                             VACCINE SAFETY

                                                    POST-APPROVAL :
PRE-APPROVAL:                                       Automated and more rapid
                             Better technologies
Better predictive studies,                          signal detection
                             and process control
In vitro, animal and                                Better studies
                             New technologies for
clinical                                            Better determine causality of
More defined vaccines                               signals and degree of risk
                             and testing
and components                                      Improve risk communication
           FDA Critical Path Initiative             Profile & reduce individual risk
        Pre-approval: Vision
• Vision: Scientific advances predict safety
  risks and efficacy based on molecular,
  cellular, animal and human systemic and
  immune responses. Vaccine technologies
  use fully molecularly defined antigen(s)
  and other components that predict the
  clinical response.
Pre-approval: Needs & Opportunities
• “Purer” or molecularly defined vaccines
  – Acellular pertussis
  – Recombinant proteins, chemically
    synthesized peptides/nucleic acids/conjugates
     • Currently often less immunogenic
• Better predictive models and markers
  – Animal/cell models to identify rare events
    (e.g., gene expression responses, genetically
    prone transgenic mice, cytokine responses)
  – Live vaccine virulence measures/models – or
    substitutes (e.g. OPV-IPV)
           Pre-approval: cont.
• Enhanced information from clinical trials
  – Non-clinical human trial markers from clinical
    trials (e.g. PBMC, proteome, cytokines etc.)
  – Larger/simpler safety trials welcome where
    appropriate (e.g. Rota ~ 35K)
     • Focused follow up, major endpoints, short and long
     • Trade off should allow smaller intensely monitored
       studies (could embed within LST)
     • More diverse populations (genetic perspectives
       may help define future needs)
     • Still will never reliably detect/predict rarest AEs <=
       1/10,000 (e.g. possible GBS risk ~ 1/1,000,000)
Manufacturing and Quality: Vision,
   Needs and Opportunities
• Vision: A completely defined product
  produced consistently, with continuous
  process and product monitoring that
  detects potential risks.
• Needs and opportunities:
  – Further enhanced biologic process controls,
  – New process and product characterization
    tools e.g. NMR, mass spect
  – Ability to predict what changes are meaningful
     Post-approval: Vision
– All patients’ vaccinations and health
  experiences are immediately and
  continuously accessible in automated
  database(s) allowing optimal detection and
  analysis of potential problems in vaccine
  safety (and effectiveness).
  • Not there yet - both major limits and opportunities
    in current health information systems
  • Both problems and solutions to enhance vaccine
    safety information/analysis should link to safety
    initiatives for all medical products and procedures
Post-approval: Needs - surveillance
 – Access to more patients and better data (vs.
   proprietary issues, costs)
    • Given diversity of sources, innovative more
      “Google” - like approaches to retrieval of key data
      may have great potential vs. single unified systems
 – Better background rates, comparable “control”
 – More consistent event/disease nomenclature,
   IT architecture, data interchangeability/quality
 – Differences between adult and child
 – Increase in “non-medical” data sources – e.g.
   pharmacy, supermarket, employer vaccination
      Post-approval: Areas of

– Data: Health systems: e.g. VA, DoD, CMS,
  managed care
   • More in this meeting
– Global data: regulatory, review, inspectional,
  health systems, international
– Better analytic tools and methods
    Post-marketing Safety- Other
• “Roll-out” – e.g. slower/initial uptake in
  high disease burden population(s)
  – but n to detect and analyze is still the same n
• Large(r) simpler studies (as for premarket)
  – More pts. for same/less $$: focus on key data
  – Major endpoints (medical care,
    hospitalization, death)
  – Enhanced VSD type studies
• New reporting strategies:
  cell phone, internet
    Post-marketing Safety- Other
       Approaches continued
• “Personalized Vaccination”: Identifying
  patients “at risk” for rare AEs and either
  not vaccinating, changing dose, or using
  alternate vaccine strategy
  – Population defined risk factors
  – Genetic risk factors
     • Whole genome, someday
     • Risk loci/signatures/SNPs/Immune
       response genes
Communications and Transparency
 – Respect and autonomy of patients should be
   a guiding principle              Not an option!
 – Early, open and continuing
   communication of possible
   safety signals is expected and
   beneficial to consumers/HCPs/science
    • Critical to confidence in integrity of the vaccine
      safety system, government and industry, and the
      safety of vaccines
    • Enhances reporting and informs consumer/HCP
    • Initial information and medical/scientific opinion
      and assessments often evolve and can be wrong
 Modern Vaccine Safety: Meeting
Challenges to Detect, Analyze and
       Communicate Early
  • Rotavirus- earlier vaccine approved in 1998
     – Though no excess pre-licensure, intussusception (IS)
       noted as possible AE: term specifically added to VAERs
     – Post-license: likely excess IS noted through VAERs and
       ACIP recommendation withdrawn in 98 (likely 1 in 5-11k)
  • Next generation vaccine, licensed 2006
     – Larger pre-licensure studies: > 70,000, no excess IS
     – Larger post-licensure studies: sponsor 44k+ VSD 90k
     – Careful VAERS monitoring/analysis in place – in first
       year 17 cases reported w/in 21 days vs. 52 “expected”
     – Transparency: though below expected, label and patient
       info updated 1/07, FDA provided early Public Health
       notification 2/12 & FDA/CDC publish MMWR 3/16
 Meeting Challenges to Detect,
Analyze and Communicate cont:
• Meningococcal conjugate vaccine - licensed 1/05 -
  prevents life threatening disease
   – No GBS seen pre-licensure in ~ 7k recipients but 5 cases
     reported to VAERS by 9/05 triggering concern re:
     potential safety signal
   – Rapid investigation, communication, with
     cooperation/info sharing among FDA, CDC,
     manufacturer and public transparency
       » FDA statement 9/05 – MMWR & label update 10/05
       » Current information: uncertain but possible GBS risk
         ~1.25 cases/million doses (CI = 0.058--5.99)
       » Challenges: uncertainties in background rate, VAERs
         reporting - studies continuing, no cases seen in VSD
       » Continued joint FDA/CDC monitoring/analyses and
         updates x 3 in MMWR, last 10/06, label update 9/06
  Transparency and “Risk Literacy”
– Risk literacy – very
  difficult and non-intuitive
  to understand risk and
  causal association
  statistically vs.
– There are risks in
  conveying uncertainties,
  including potential
  decreased use of safe
– Major behavioral science,
  educational system and
  risk communication
  scientific needs
• While today’s vaccines are very safe and
  safety systems and activities are stronger
  and more transparent than ever, there are
  opportunities to apply advances in
  laboratory, manufacturing, clinical and
  population sciences, and in health
  informatics, to meet our highest
Completely defined vaccines are found
safe in sensitive, predictive pre-clinical and
clinical studies, are manufactured to the
highest possible quality using new
technologies, and given to individuals with
a low likelihood of serious adverse events.
Populations are actively monitored for
vaccine adverse event signals which are
analyzed accurately allowing potential
risks (and benefits) to be communicated
rapidly and effectively.
We look forward
to sharing information
and insights
concerning tools for
vaccine safety - and
to working together to
achieve our shared
vision – both during
 this workshop and in
the future.

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