Postmarketing Surveillance Conference

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Vaccine Safety Surveillance A Case Study

• Postmarketing Surveillance Conference
• April 11, 2007

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Overview

• Complexities of Vaccine Development
• Overview of Current Surveillance System
• Menactra Case Study
• Enhancing the System
• Conclusions and Recommendations

Menactra Meningococcal (Groups A, C, Y and
W-135) Polysaccharide Diphtheria Toxoid Conjugate
Vaccine
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Vaccine Development and Safety Commitment to
Public Health

• Vaccines work best when most members of a
  community are vaccinated
• Vaccines must be safe for use by as many people
  as possible
• Typically given to healthy people
• Vaccines have been shown to be remarkably safe
  and effective in preventing serious infectious
  diseases and have saved countless lives
• Years of testing are required by law before a
  vaccine is licensed and distributed in the US
• Once in use, vaccines are continually monitored
  for safety and efficacy

As a result, the United States currently has the
safest, most effective vaccine supply in history.
www.cdc.gov/od/science/iso/research_activities/vae
rs
Source www.cdc.gov
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Development of New Vaccines - Current Environment

• In the past 3 decades, more than 2/3 of all new
  vaccines approved worldwide have been developed
  in the US
• 18 new vaccines were approved between 1980 and
  1996, resulting in substantial public health
  benefits
• New vaccine development requires larger pre- and
  post-licensure studies
• Development costs for a new vaccine increased, on
  average, from 231M in 1991 to 802M by 2001
• Escalation of development costs has consequences
  vaccines with small markets are not developed
• Practical limits on the sample size of
  pre-licensure studies
• Pre-licensure trials can never be large enough to
  rule out all rare adverse events
• Accordingly, robust postmarketing surveillance
  (signal detection, hypothesis testing) is
  essential

Source Warren KS. New Scientific Opportunities
and old obstacles in vaccine development,
1986Plotkin, Orenstein. Vaccines, 2004
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Post-Marketing Surveillance

• As with any medical procedure, vaccination has
  some risks, as well as proven benefits
• Social benefits of vaccination increase with
  increasing coverage
• Social compact in return for accepting small
  risk, 2 promises
• Continuous monitoring of vaccine safety
• Fair compensation
• An effective post-marketing surveillance system
  provides assurances that rare adverse events can
  be detected and assessed
• Inactivated measles vaccine, rotavirus vaccine,
  conjugate meningococcal vaccine
• A transparent system can also be used to answer
  questions / concerns of interest to public health
  and the public at large

Effective and transparent surveillance systems
are the pillars for effectively monitoring
immunization safety and maintaining public
confidence
Source Plotkin, Orenstein. Vaccines,
2004www.cdc.gov
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Current US surveillance system has played a key
role in monitoring immunization safety... But
how can we make a good system better?
1st Component (Signal / Hypothesis Generation)
VAERS
Limitations
Strengths

• Incomplete reporting
• Multiple vaccines and other events create
  additional challenges to establish causality
• Data limitations
• Passive reporting
• Undefined denominator

• National in scope
• Able to detect very rare events and previously
  unrecognized events
• Triggers further investigations
• Can detect unusual clusters of adverse events

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Vaccine Safety Datalink Shared MCO databases
linking vaccination records with health outcomes
2nd Component (Hypothesis Testing)
Vaccine Safety Datalink (VSD)
Limitations
Strengths

• Delays in data availability
• It could take up to 18 months to generate a
  cleaned-up data tape compiling information from
  multiple sources
• Lacks complete geographical coverage
• Database currently not large enough to test
  hypotheses for very rare events

• Rigorous safety data
• Relatively time efficient
• Once all the data are collected, analysis can be
  done quickly
• Sample size is big enough to test hypotheses for
  uncommon adverse events

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Menactra Case Study
Menactra Case Study

• VAERS reports of GBS following the administration
  of Menactra vaccine prompted a comprehensive
  review and data collection effort by FDA, CDC,
  and sanofi pasteur
• Frequent communication and information sharing
  among these organizations resulted in rapid
  assessment and public reporting of these events
• Public/private partnerships are key to meet
  vaccine safety surveillance goals and reassure
  the public that the system works
• This case study also identified areas where the
  safety surveillance system could be enhanced

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A Comprehensive Effort
Menactra Case Study

• CDC, FDA and sanofi pasteur held weekly meetings
  to share data, discuss case findings, review
  Menactra distribution data, and coordinate
  investigations
• CDC utilized numerous resources and partners to
  collect data
• Safety Branch and VSD partners
• CISA centers
• State surveillance
• The Brighton Collaboration
• Sanofi pasteur clinical, regulatory, and medical
  affairs teams worked closely with FDA to provide
  updated labeling and rapid communications to
  healthcare professionals
• Comprehensive communications designed to prompt
  immediate reporting of potential cases

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Menactra Case Study
Active Surveillance for GBS cases

• CDC led the States team responsible for active
  identification of GBS cases
• Council of State and Territorial Epidemiologists
  (CSTE) participated in active GBS surveillance
• State epidemiologists and Emerging Infectious
  Disease specialists in 7 states (New Jersey, New
  York, Pennsylvania, Ohio, California, Illinois,
  Texas), as well as other states where GBS is a
  reportable disease, participated in active GBS
  case surveillance and identification
• American Society of Plasmapheresis (50-60 of GBS
  cases receive Plasmapheresis) participated in
  case detection efforts
• Working with AHIP, CDC, FDA, Sanofi pasteur led
  efforts to expand the population under active
  surveillance (VSD-like)

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What has sanofi pasteur, along with CDC and FDA,
done to ensure HCPs were informed and proactively
looking for GBS cases
Menactra Case Study
Label changes in Menactra US Package Insert and
Companys Core Data Sheet
Scientific Information (MMWR Fact Sheet
Revised VIS)
FDA / CDC / sanofi pasteur Coordination of Press
Releases
Dear Health Care Professional Letter
GBS Surveillance Form
Sept 05
Dec 05
Stakeholders Involved
FDA, CDC, Medical Affairs, Regulatory Affairs
CDC
FDA / CDC
FDA, Pharmacovigilance, Medical and Regulatory
Affairs
Medical and Regulatory Affairs
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Effective Public/Private Partnership
Menactra Case Study
Action Plan
Cooperation

• GBS surveillance form
• Active surveillance
• Label changes
• Data sharing (VAERS, CISA,

Communication

• Active Media Statement
• Updated MMWR and Fact Sheet
• Updated VIS
• HCP letters

Coordination

• Weekly conference calls
• Coordinated press releases, statements
• Coordination regarding ongoing and planned
  investigations

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Menactra Case Study
GBS Reports in Menactra vaccine recipientsACIP
Meeting of February 21-22, 2007

• Update through the end of January 2007
• Total of 19 cases of GBS after Menactra vaccine
  with onset interval of 2-33 days
• 17 cases were in the 11-19 years old age group
• VSD Rapid Cycle Analysis project
• 156,542 doses administered
• Zero cases observed among vaccine recipients
  11-19 years old within 6 weeks of vaccination
• Projection 0-1 cases were expected
• Does the number of reported GBS cases exceed the
  expected rate?
• Observed compared to expected rate calculations
• Confounders/uncertainties age, season,
  background rates

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Menactra Case Study
GBS Reports in Menactra vaccine recipientsACIP
MEETING (February 21-22)
ACIP meeting
MMWR update communication on October 20, 2006
(data through the end of September 2006)
versus 1.73 (95 CI 1.04-2.88)
versus 1.72 (95 CI 0.83-3.55)

• Calculation using sale data through end of
  November 2006 - 6.93 million doses distributed to
  11-19 y/o.

Source www.cdc.gov
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Menactra Case Study
GBS Reports in Menactra vaccine recipients with
Age Stratification ACIP MEETING (February 21-22)
Source www.cdc.gov
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Enhancing the surveillance system will provide
additional data
Menactra Case Study
Source www.cdc.gov
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Enhanced surveillance needed to further assess
potential relationship between Menactra and GBS

• Complications
• Rare outcome (if associated, attributable risk is
  on the order of 1 per million)
• Uncertainty regarding background rates
• Confounding with age and seasonality
• Expanded cohort surveillance needed
• VSD, even in current expanded form, too small
• The potential exists to establish a much-expanded
  VSD-like capability
• There are lt 10 very large MCOs
• Taken together, they could contribute 100-150 M
  covered lives
• No economic incentive for MCOs to participate
• MCO participation would rest on public health
  importance, assurance of non-intrusiveness

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Menactra Case Study
The need for additional data on GBS rates
triggered the creation of a Health Plan Consortium

• Purpose
• To create an expanded, rapid and sensitive,
  active post-marketing safety surveillance system
  to inform public health and regulatory
  decision-makers
• Consortium Concept
• An activity of the Centers for Evaluation and
  Research on Therapeutics (CERTs) - a national
  program with a congressional mandate administered
  by the Agency for Healthcare Research and Quality
  (AHRQ) and FDA
• Dr. Richard Platt leads the Harvard CERT
• AHIP is a key partner in organizing and
  administering consortium
• Health plans are members and contribute with data
• Advisory Committee with diverse stakeholders,
  including industry
• Funding from a variety of sources

The Health Plan Consortium could only be
developed through a multi-party public-private
collaborative effort
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Menactra Case Study
Health Plan Consortium - Managed Care
Organizations (MCO) database study

• The currently active study is a multi-site
  retrospective cohort study of the relationship
  between immunization with tetravalent
  meningococcal conjugate vaccine (MCV4) and
  Guillain-Barré syndrome (GBS) in adolescents over
  the 42-month period of March 1, 2005 to August
  31, 2008.
• Data currently being collected
• Funded by sanofi pasteur
• The study will use a cohort assembled from health
  plan members enrolled at selected health plans
  throughout the United States.
• Initial effort encompasses data from 4 major US
  health plans
• Total of 40 million covered lives

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Menactra Case Study
Health Plan Consortium - Managed Care
Organizations (MCO) database study

• The consortium plan is to add other health plans
  incrementally, reaching approximately 100 million
  covered lives
• Cases will be identified using administrative
  data, and case validation and collection of
  information on risk factors and other covariates
  will be performed by medical record review.
• Quarterly data extracts and cumulative analyses
• First quarterly report Q3 or Q4 2007
• A Cox proportional hazards model will be used,
  with age and days since vaccination as
  time-dependent covariates.

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This effort exemplifies sanofi pasteur's and
industrys commitment to public health and to
maintaining public confidence in vaccines

• Strong orientation to public health
• Unique responsibility
• Immunizations are strongly recommended, widely
  used, and targeted towards healthy individuals
• Accordingly, lower risk tolerance
• Transparency
• Direct communication and cooperation
• Long-term public health commitment

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Moving forward
Conclusions and Recommendations

• Vaccination is one of the greatest public health
  achievements over the last century
• Incidence of many vaccine-preventable diseases
  has been reduced by more than 97 in the US
  compared with pre-immunization era
• Pre-licensure studies for new vaccines cannot be
  made large enough to rule out important but rare
  AEs
• Diminishing returns
• Public health consequences
• Therefore, robust postmarketing surveillance is
  mandatory
• Postmarketing commitment trials (manufacturer)
• Population surveillance (public or
  public-private partnership)

Source CDC MMWR 46(12), April 1999
CDC MMWR 47(53), Dec 1999
Plotkin, Orenstein. Vaccines, 2004
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Moving forward
Conclusions and Recommendations

• Existing US vaccine safety surveillance system
  has proved effective but can be enhanced
• Improved vaccination databases (registries)
• Enlarged populations under surveillance for
  outcomes
• Improved coordination between manufacturer, FDA,
  CDC, other public health agencies
• All patients' vaccinations and health
  experiences are immediately and continuously
  accessible in automated databases allowing
  optimal detection and analysis of potential
  problems in vaccine safety (and effectiveness).
  - Jesse Goodman, 4/10/07

Source CDC MMWR 46(12), April 1999
CDC MMWR 47(53), Dec 1999
Plotkin, Orenstein. Vaccines, 2004
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Moving forward
Conclusions and Recommendations

• Public/private cooperation is key to meet new
  goals and challenges in vaccine safety
  surveillance.
• Advances in postmarketing surveillance will
  require national-scale resources
• Vaccine registries very-large-population
  outcome databases
• Further extend public/private partnerships to
  secure appropriate funding to institutionalize
  additional data collection and evaluation
  capabilities
• The Health Plan Consortium, which was put
  together to address a specific acute need, can
  play an important role in a longer-term solution