Post-Marketing Surveillance: Passive and Active Approaches and Use of Electronic Databases Karen Midthun, MD, Deputy Director Center for Biologics Evaluation and Research, FDA ICDRA Pre-Conference Berne, Switzerland September 15, 2008 - PowerPoint PPT Presentation


PPT – Post-Marketing Surveillance: Passive and Active Approaches and Use of Electronic Databases Karen Midthun, MD, Deputy Director Center for Biologics Evaluation and Research, FDA ICDRA Pre-Conference Berne, Switzerland September 15, 2008 PowerPoint presentation | free to download - id: 1a832f-ZDc1Z


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation

Post-Marketing Surveillance: Passive and Active Approaches and Use of Electronic Databases Karen Midthun, MD, Deputy Director Center for Biologics Evaluation and Research, FDA ICDRA Pre-Conference Berne, Switzerland September 15, 2008


The post-marketing surveillance activities described in the s that follow ... Manufacturer '15 day reports' of serious unexpected events and direct reports of ... – PowerPoint PPT presentation

Number of Views:140
Avg rating:3.0/5.0


Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Post-Marketing Surveillance: Passive and Active Approaches and Use of Electronic Databases Karen Midthun, MD, Deputy Director Center for Biologics Evaluation and Research, FDA ICDRA Pre-Conference Berne, Switzerland September 15, 2008

Post-Marketing Surveillance Passive and Active
Approaches and Use of Electronic Databases
Karen Midthun, MD, Deputy DirectorCenter for
Biologics Evaluation and Research, FDA ICDRA
Pre-Conference Berne, SwitzerlandSeptember 15,
Topics for today
  • Approaches, needs, and opportunities to further
    enhance safety of vaccines and other biological
    products, with focus on post-marketing
    surveillance systems
  • Importance of international collaborations
  • Articulating a vision of an enhanced safety system

Vision for CBER
  • Protect and improve public and individual health
    in the US and, where feasible, globally
  • Facilitate the development, approval and access
    to safe and effective products and promising new
  • Strengthen CBER as a preeminent
  • regulatory organization for biologics

Biological Products Regulated by CBER
  • Vaccines (preventive and therapeutic)
  • Blood, blood components and derivatives
  • Allergenics
  • Cell and Gene Therapies
  • Tissues
  • Xenotransplantation Products
  • Related Devices (including certain IVDs)

Major CBER Initiatives
  • Pandemic influenza and emerging threat
  • Enhancing product safety
  • Integrated safety teams and use of informatics
  • Manufacturing and product quality activities
  • Critical path
  • Global collaboration

Enhancing Product Safety
  • Multi-disciplinary safety teams for vaccines,
    blood, and tissues (epidemiologists,
    clinical/product reviewers, compliance/manufacturi
    ng experts, communications) to improve
    acquisition, analysis, and communication of
    safety information
  • Encompasses entire product life cycle and all
    data relevant to safety, manufacturing, and
  • Uses data to evaluate emerging safety issues
  • Coordinates FDA response to emerging safety
    issues with other HHS agencies (CDC, NVPO, NIH),
  • Enhances collaboration with other govt. agencies,
    WHO, and other entities on safety initiatives
  • Proactive develop research, policy, outreach

Assuring Product Safety
  • Pre-licensure
  • Evaluate clinical, nonclinical, product, and
    manufacturing data, including facility inspection
  • Pharmacovigilance plan evaluated as part of
    biologics license application and informs
    post-marketing surveillance and studies
  • Post-licensure
  • Lot release
  • Biennial inspections
  • Evaluation of post-marketing adverse event
    reports (VAERS for vaccines and AERS for other
    products) and studies

Pharmacovigilance Plan (ICH E2E)
  • Basis for design of Phase 4 studies, passive
    surveillance and other components of
    pharmacovigilance plan is through analysis of
    Safety Specifications
  • Important identified risks
  • Important potential risks
  • Important missing information
  • Manufacturer should consider actions to address
    any such concerns

Pharmacovigilance Plan (cont)
  • Staff member from the Division of Epidemiology is
    assigned to the Biologics License Application
    (BLA) review team
  • Primary responsibility for review of
    pharmacovigilance plan and agreement with
    manufacturer regarding post-marketing safety
    studies is with Division of Epidemiology, working
    together with rest of multi-disciplinary review
  • As appropriate, pharmacovigilance plan is
    presented to FDA Advisory Committee, together
    with efficacy and safety data from BLA prior to

Why do we need post-marketing surveillance?
  • Rare adverse events may not be detected in
    pre-licensure studies
  • Why? Because even very large clinical trials
    have limitations. For example, to detect a
    doubling in an adverse event that occurs at a
    rate of 1/1000 would require a sample size of
    50,000 (two-arm, power80, alpha5)
  • The post-marketing surveillance activities
    described in the slides that follow focus on
    vaccines, but the same principles are applicable
    to other medical products

Post-Marketing Surveillance for Vaccines
Passive Approach
  • Vaccine Adverse Event Reporting System (VAERS)
  • National system for passive surveillance of
    adverse events after vaccination established in
    1990 in response to the National Childhood
    Vaccine Injury Act of 1986
  • Jointly managed by FDA and CDC
  • VAERS contractor receives reports, manages report
    database, and conducts routine report follow-up
  • Reports received from health professionals,
    vaccine manufacturers, and the public

Adverse Event Report Review
  • Manufacturer 15 day reports of serious
    unexpected events and direct reports of death and
    serious adverse events are forwarded by VAERS
    contractor to assigned CBER staff within 1
    business day
  • Reviewed daily for unexpected events
  • Follow-up with reporters as necessary
  • Periodic reports/periodic safety update reports
    reviewed when submitted
  • Weekly vaccine safety surveillance meeting

VAERS Advantages
  • National in scope, covers diverse populations
  • Able to detect rare adverse events
  • Rapid detection of possible signals (hypothesis
  • Can assess adverse events by lot

VAERS Limitations
  • Reported diagnoses not verified
  • Lack of consistent diagnostic criteria
  • Wide range of data quality
  • Underreporting
  • Inadequate denominator data (i.e., number of
    persons vaccinated)
  • No unvaccinated control group
  • No information on background rates of conditions
    in general population
  • Usually not possible to assess whether vaccine
    caused the reported adverse event

Post-Marketing Surveillance for Vaccines Active
  • Manufacturers phase 4 studies
  • FDA sentinel initiative
  • Activities ongoing or under development with
    Centers for Medicare and Medicaid Services,
    Department of Veterans Affairs, Department of
    Defense large medical encounter and claims
    databases for controlled observational studies of
    specific safety issues
  • Other public-private partnerships being sought
  • FDA Amendments Act of 2007 prescribes an active
    post-market risk identification and analysis
    system intended to link and analyze safety data
    from multiple sources, with goal of including 25M
    patients by 2010 and 100M patients by 2012

Post-Marketing Surveillance for Vaccines Active
  • CDCs Vaccine Safety Datalink (VSD)
  • 8 geographically diverse health maintenance
    organizations that participate in large linked
    database that tracks
  • Vaccination (exposure)
  • Outpatient, emergency department, hospital and
    laboratory data (health outcomes)
  • Demographic variables (confounders)
  • Includes approximately 3 of U.S. population
  • Hypothesis testing studies can be conducted

VSD Analyses Advantages
  • All medical encounters are available at most
  • Allows calculation of background rates of various
    conditions of interest
  • Medical chart review is accessible
  • Available for urgent studies

VSD Analyses Limitations
  • Sample size may be inadequate for very rare
    adverse events (e.g., Guillain-Barre syndrome
    with incidence rate of 1-2/100,000 per year)
  • Lack of demographic and socioeconomic diversity
    in HMO practices
  • Variable accuracy of coded data used for studies
  • Unvaccinated population may be small

FDA and CDC Interactions on Vaccine Safety
  • FDA and CDC, in conjunction with HHS and other
    agencies, work closely together on vaccine safety
    surveillance activities (e.g., VAERS, VSD and
    other active surveillance activities) and the
    analysis and communication of safety concerns

A Case Study Rotavirus Vaccine and
Intussusception (IS)
  • First rotavirus vaccine (Rotashield) licensed by
    FDA in August 1998
  • Pre-licensure IS noted as possible AE,
    difference in rate between vaccine and placebo
    groups not statistically significant
  • Post-licensure likely excess of IS noted in
    VAERS, CDC-conducted epidemiological studies show
    elevated risk, and in October 1999, ACIP
    withdraws recommendation for vaccine and
    manufacturer voluntarily withdraws vaccine from

How did this impact next rotavirus vaccine?
  • Second rotavirus vaccine (Rotateq) licensed by
    FDA in February 2006
  • Pre-licensure very large safety study (70,000
    infants, 11 vaccine to placebo), no increased
    risk of IS
  • Post-licensure surveillance VAERS,
    manufacturers phase 4 study (44,000 infants) and
    CDCs VSD study (90,000 infants)
  • To date, no signal of increased risk of IS after
    Rotateq (Pediatrics 20081211206-1212)
  • Updates communicated through changes to labeling
    and patient information, Public Health
    Notification, MMWR publication

Other Recent Examples of Vaccine Safety Issues
  • Possible increased risk of Guillain-Barre
    syndrome after Menactra (quadrivalent
    meningococcal conjugate vaccine)
  • http//
  • Possible increased risk of febrile seizures after
    Proquad (combined Measles, Mumps, Rubella and
    Varicella Vaccine)
  • http//
  • Update on the safety of Gardasil (human
    papillomavirus vaccine)
  • http//

Global Collaboration
  • CBER is a WHO Collaborating Center
  • Expert Committee on Biologic Standards
  • Strategic Advisory Group of Experts
  • Global Advisory Committee on Vaccine Safety
  • Global Collaboration on Blood Safety and Blood
    Regulators Network
  • Expert consultation in specific product areas
  • Participates in WHO prequalified vaccines program
  • Participates in WHO teams to assess competency of
    national regulatory authorities (NRA) around the
  • Training Works with WHO Developing Countries
    Vaccine Regulators Network to help build global
    regulatory capacity of NRAs with regard to

Global Collaboration
  • Information sharing arrangements and engagement
    in priority areas with various regulatory
    authorities and WHO
  • Brighton collaboration for standardized case
    definitions of adverse events following
  • CIOMS vaccine safety working group
  • Partnering with WHO and NGOs to explore
    additional means of providing global regulatory
    assistance and capacity building
  • International Conference on Harmonisation
  • Pharmaceutical Inspection Cooperation/Scheme

FDA Amendments Act (2007) Some Highlights
  • Pediatric Research Equity Act Pediatric studies
    required with application or supplement for new
    active ingredient, indication, dosage form,
    dosing regimen, or route of administration,
    unless deferral or waiver granted
  • Safety FDA to require post-marketing studies or
    clinical trials at time of approval, or after
    approval, based on certain safety concerns (e.g.,
    to assess known serious risk or signal of serious
    risk, or to identify expected serious risk if
    data indicate such potential)

FDA Amendments Act (cont)
  • Safety Labeling Changes FDA to require if new
    safety information needs to be included, specific
    timelines noted
  • Risk Evaluation and Mitigation Strategies FDA
    can require at time of or after approval, if
    deemed necessary to ensure that benefits outweigh
  • Active Post-market Risk Identification and
    Analysis System to link and analyze safety data
    from multiple sources, with goal of including
  • at least 25M patients by 2010,
  • at least 100M patients by 2012

Vision for Post-Market Surveillance
  • All patients vaccinations and health outcomes
    are immediately and continuously accessible in
    automated database(s) allowing optimal detection
    and analysis of potential problems in vaccine
  • Not there yet both major limitations and
    opportunities in current health information
  • Both problems and solutions to enhance vaccine
    safety information and analysis are applicable to
    safety initiatives for other medical products

Post-Market Surveillance Needs
  • Access to more patients and better data
  • Given diversity of data sources, innovative
    approaches to retrieval of key data may have
    great potential vs. single unified system
  • Better background rates, comparable control
  • More consistent event/disease nomenclature, IT
    architecture, data interchangeability, quality
  • Increase in non-medical data sources e.g.,
    pharmacy, supermarket, employer vaccination

Post-Market Surveillance Opportunities
  • Access to additional health systems data CMS,
    VA, DoD, managed care organizations
  • Access to global data regulatory, inspectional,
    health systems, international surveillance and
  • Better analytic tools and methods

Communications and Transparency
  • Early and continuing communication of possible
    safety signals is expected and beneficial to
    consumers, health care providers, science
  • Critical to confidence in integrity of vaccine
    safety system, government and industry
  • Enhances reporting and informs decision-making of
    consumers and health care providers
  • Initial information and medical/scientific
    opinion and assessments often evolve
  • Conveying uncertainty of risk difficult, includes
    potential for decreased use of safe and effective

  • Pre-licensure clinical, product, and
    manufacturing data are critical foundations for
    evaluating the safety and effectiveness
  • However, post-licensure surveillance is essential
    to assure product safety
  • Vaccines and other medical products have risks
    that may include rare serious adverse events not
    detected in pre-licensure studies
  • Government agencies play an important role in
    monitoring, analyzing, and communicating re
    safety of vaccines and other medical products

Summary (cont)
  • Passive and active surveillance, including
    observational studies, after licensure are needed
    to detect and evaluate vaccine safety concerns
  • Need for robust, continuously operating and
    technologically advanced safety monitoring
    systems that include epidemiological, clinical,
    and laboratory assessments of causality
  • Public communication and engagement regarding
    vaccine safety concerns is critical to
    maintaining confidence in the vaccine safety
    system, optimal vaccine coverage, and the public

  • Robert Ball, MD, MPH, ScM
  • Jesse Goodman, MD, MPH
  • John Iskander, MD, MPH
  • Douglas Pratt, MD, MPH
  • Joan Blair, MA

Thank you!
  • We are actively engaged in assuring the safety,
    effectiveness, and availability of products that
    touch so many lives and are critical for public
    health and preparedness
  • Emerging threats, technologies, and opportunities
    demand constant renewal of scientific expertise
    and capacity
  • The challenges and opportunities for leadership
    and public health are truly global and
    collaboration is key!

CBER Contact Informationhttp//
  • Manufacturers
  • Consumers, health care professionals
  • Phone 301-827-1800