Vaccine Safety: Vision for the Future

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Vaccine Safety Vision for the Future

• Jesse L. Goodman, MD, MPH
• Director, Center for Biologics Evaluation and
  Research, FDA
• April 10, 2007

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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 experiences
• Identify data and research gaps and needs
• Update and articulate a vision of an ideal
  vaccine safety system and help advance that vision

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Perspective Vaccine Accomplishments
As the specter of severe vaccine preventable
diseases becomes seemingly distant in developed
countries, vaccine safety concerns, always
important, gain prominence
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Partnerships in Safety
Public
VRPAC
ACIP
FDA
CDC
Industry
NIH
Healthcare system/providers
Other important governmental partners/contributors
HRSA, DoD, VA, CMS
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Assuring high vaccine safety involves more than
post-licensure surveillance
VACCINE SAFETY
PRODUCTION Manufacturing quality Inspections Tes
ting and Release FDA and industry
POST-APPROVAL CLINICAL SAFETY Planned (PMC)
Studies Surveillance AEs/VAERs/VSD Studies of
problems RISK COMMUNICATION CDC, FDA, industry
PRE-APPROVAL Animal Clinical Product quality
and manufacturing FDA, NIH and industry
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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

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But Can We Do Better?
?
VACCINE SAFETY
POST-APPROVAL Automated and more rapid signal
detection Better studies Better determine
causality of signals and degree of risk Improve
risk communication Profile reduce individual
risk
PRODUCTION Better technologies and process
control New technologies for characterization and
testing
PRE-APPROVAL Better predictive studies, In
vitro, animal and clinical More defined
vaccines and components
FDA Critical Path Initiative
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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.

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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)

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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 term
• 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 lt 1/10,000 (e.g. possible GBS risk
  1/1,000,000)

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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,
  consistency
• New process and product characterization tools
  e.g. NMR, mass spect
• Ability to predict what changes are meaningful

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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

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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
  populations
• More consistent event/disease nomenclature, IT
  architecture, data interchangeability/quality
• Differences between adult and child immunization
• Increase in non-medical data sources e.g.
  pharmacy, supermarket, employer vaccination

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Post-approval Areas of Opportunity

• Data Health systems e.g. VA, DoD, CMS, managed
  care
• More in this meeting
• Global data regulatory, review, inspectional,
  health systems, international surveillance/pharmac
  ovigilance
• Better analytic tools and methods

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Post-marketing Safety- Other Approaches

• 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

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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

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Communications and Transparency

• Respect and autonomy of patients should be a
  guiding principle
• 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
  decision-making
• Initial information and medical/scientific
  opinion and assessments often evolve and can be
  wrong

Not an option!
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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 gt 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

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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

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Transparency and Risk Literacy

• Risk literacy very difficult and non-intuitive
  to understand risk and causal association
  statistically vs. individually
• There are risks in conveying uncertainties,
  including potential decreased use of safe vaccine
• Major behavioral science, educational system and
  risk communication scientific needs

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Conclusion

• While todays 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 expectations.

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Vision

• 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.

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Thanks!

• 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.