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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

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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

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Vision for CBER
INNOVATIVE TECHNOLOGY ADVANCING
PUBLIC HEALTH
• 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 technologies
• Strengthen CBER as a preeminent
regulatory organization for biologics

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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)

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

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

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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

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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

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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 team
• As appropriate, pharmacovigilance plan is
presented to FDA Advisory Committee, together
with efficacy and safety data from BLA prior to
licensure

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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,
power=80%, alpha=5%)
• The post-marketing surveillance activities
described in the slides that follow focus on
vaccines, but the same principles are applicable to
other medical products

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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

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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

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

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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

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Post-Marketing Surveillance for
Vaccines: Active Approaches
• 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

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Post-Marketing Surveillance for
Vaccines: Active Approaches
• CDC’s 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

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

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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

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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

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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
market

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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, 1:1 vaccine to placebo), no increased
risk of IS
– Post-licensure surveillance: VAERS,
manufacturer’s phase 4 study (44,000 infants)
and CDC’s VSD study (90,000 infants)
– To date, no signal of increased risk of IS after
Rotateq (Pediatrics 2008;121:1206-1212)
– Updates communicated through changes to
labeling and patient information, Public Health
Notification, MMWR publication

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Other Recent Examples of Vaccine Safety
Issues
• Possible increased risk of Guillain-Barre syndrome
after Menactra (quadrivalent meningococcal
conjugate vaccine)
– http://www.fda.gov/cber/safety/gbs102006.htm
• Possible increased risk of febrile seizures after
Proquad (combined Measles, Mumps, Rubella and
Varicella Vaccine)
– http://www.fda.gov/cber/label/proquadLBinfo.htm
• Update on the safety of Gardasil (human
papillomavirus vaccine)
– http://www.fda.gov/cber/safety/gardasil071408.htm

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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 world
– Training: Works with WHO Developing Countries Vaccine
Regulators Network to help build global regulatory capacity of
NRAs with regard to vaccines

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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 immunization
• 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

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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)

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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 risks
• 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

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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 safety
– Not there yet – both major limitations and
opportunities in current health information
systems
– Both problems and solutions to enhance
vaccine safety information and analysis are
applicable to safety initiatives for other
medical products

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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”
populations
– More consistent event/disease nomenclature, IT
architecture, data interchangeability, quality
– Increase in “non-medical” data sources – e.g.,
pharmacy, supermarket, employer vaccination

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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
pharmacovigilance
• Better analytic tools and methods

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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
products

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Summary
• 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

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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 health

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

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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: INNOVATIVE TECHNOLOGY ADVANCING
PUBLIC HEALTH

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CBER Contact Information
http://www.fda.gov/cber
Manufacturers:
matt@fda.hhs.gov
Consumers, health care professionals:
octma@fda.hhs.gov
Phone: 301-827-1800