Robert Ball, MD, MPH, ScM

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Evaluation of Safety of Biologic
ProductsThroughout the Lifecycle at CBER

• Robert Ball, MD, MPH, ScM
• Director, Office of Biostatistics and
  Epidemiology
• Center for Biologics Evaluation and Research
• U.S. Food and Drug Administration

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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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Assuring Product Safety

• Evaluate pre-licensure 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
• Lot release may be required prior to distribution
  of licensed products
• Biennial inspections (annual for influenza
  vaccines)
• Evaluation of post-marketing adverse event
  reports (VAERS for vaccines and AERS for other
  products) and studies

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Safety in the Lifecycle of a Licensed Biologic
Pre-clinical Safety

Approval
Phase 1 Safety

Phase 2 Safety Dose- Ranging
Phase 3 Safety Efficacy
Post- Marketing Safety Monitoring
Safety Concern
Risk Management Strategies
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Pre-licensure Safety Evaluation of Vaccines vs.
Other Product Types

• Vaccines are for healthy individuals
• Licensed vaccine may ultimately be used in
  millions of humans
• Goal to ensure that a vaccine is NOT associated
  with any serious adverse events
• How to be sure that something is NOT true?
• Have a reasonable degree of assurance that a
  vaccine is safe before licensure
• Evaluation of Safety is critical

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Clinical TrialsPhase 1 Safety Evaluation

• Usually open-label, uncontrolled
• Small number (20-30) of healthy adults
• Main goal is to describe initial safety profile
  for human use
• No statistical hypotheses for safety

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Clinical TrialsPhase 2 Safety Evaluation

• Vaccine products
• Randomized, double-bind, controlled
• Hundreds of subjects
• Dose selection to minimize AE rate
• Other products
• Not necessarily randomized, double-blind, or
  controlled
• Historical control
• Estimate rates of common adverse reactions and
  laboratory abnormalities

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Clinical TrialsPhase 3 Safety Evaluation

• Vaccine products
• Pivotal trial
• Randomized, controlled
• Sample size may be large
• Evaluation of less common AEs in a randomized
  setting prior to licensure
• Hypothesis testing

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Vaccine Safety Pre-licensure Considerations

• Monitoring in clinical trials for
• Local (e.g., swelling) and systemic reactions
  (e.g., fever) solicited using diary cards (0-14
  days)
• All adverse events (0-30 days)
• e.g., anaphylaxis, seizures, wheezing
• Late onset adverse events through 6 months
  after last dose
• e.g., autoimmune illnesses, SAEs
• Phase III trials, though large, usually well
  powered for detecting common AEs, but less
  suitable for SAEs

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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, 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
• Updates communicated through changes to labeling
  and patient information, Public Health
  Notification, MMWR publication

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Clinical TrialsPhase 3 (continued)

• Other products
• Pivotal trial
• Not necessarily randomized or controlled
• Sample size may be small
• Adaptive design or Bayesian design may be
  considered

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Statistical Analysis Plan(SAP)

• Required for pivotal trials
• Prospective
• Finalize before study begins
• For large vaccine trials, finalize before
  half-way through the trial acceptable
• Objectives (primary, secondary, safety,
  exploratory, etc.)

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Why do we need post-marketing safety monitoring?

• Rare adverse events may not be detected in
  pre-licensure studies
• Limited sample sizes and observation periods
  typically limit reliable detection of side
  effects to the most common ones with relatively
  short latency intervals
• 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)
• Enrollment exclusions more stringent than
  post-licensure use in general population
• Multiple comparisons and post hoc analyses often
  limit inferences about safety

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Post-marketing Safety Monitoring

• Review of Pharmacovigilance Plans submitted with
  Biologics License Applications
• International Conference on Harmonization (ICH)
  Guidance for industry E2E Pharmacovigilance
  Planning
• Review of AE reports (VAERS AERS), case series
  and reporting rate calculation
• Review of pharmacoepidemiology study protocols
  and reports of completed studies

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Post-marketing Safety Monitoring (cont)

• Conduct pharmacoepidemiology studies of CBER
  regulated products
• Participate in CBER Tissue, Blood and Vaccine
  Safety Teams
• Collaborate and coordinate with other government
  agencies on post-marketing biologic product
  safety monitoring

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Pharmacovigilance Plan

• Basis for design of Phase 4 studies, including
  passive surveillance and thorough analysis of
• Important identified risks
• Important potential risks
• Important missing information
• Manufacturer should consider actions designed to
  address any of these concerns.

ICH Guidance for Industry. E2E Pharmacovigilance
Planning, April 2005 http//www.fda.gov/cber/gdln
s/ichpvp.htm
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Safety Teams - 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
  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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CBER Collaborations with Centers for Disease
Control and Prevention on Safety Monitoring

• Vaccines
• VAERS (co-managed with FDA)
• Vaccine Safety Datalink (VSD)
• Clinical Immunization Safety Assessment Centers
  (CISA)
• Brighton Collaboration for standardized case
  definitions of adverse events following
  immunization
• Blood
• National Healthcare Safety Network
• Tissues
• Transplantation Transmission Sentinel Network

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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
  Network to help build global regulatory capacity
  of NRAs with regard to vaccines

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Global Collaboration

• International Conference on Harmonisation
• Pharmaceutical Inspection Cooperation/Scheme
• Information sharing arrangements with various
  regulatory authorities and WHO and engagement in
  priority areas
• 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/capacity building

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• FDAs Safety Surveillance forVaccine Products

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Vaccine Adverse Events Law and Regulations on
Reporting

• Law National Childhood Vaccine Injury Act
• Vaccine Adverse Events Reporting System (VAERS)
• Mandates reporting of Adverse events on vaccine
  injury table
• Regulations For Human Biological Products
• 21CFR 600.80 Post marketing reporting of adverse
  experiences

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Types of Reports Reviewed

• Manufacturer reports
• 15-Day Reports of Serious Unexpected Events
• Periodic Reports/Periodic Safety Update Reports
  (PSUR), quarterly for first 3 years after US
  approval and then annually
• Follow-up Reports
• Lot distribution reports
• Direct reports
• Public health clinics
• Health professionals
• Vaccinees, parents, others

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VAERS Report Follow-Up

• Acknowledgement letters to all reporters
• Automatically generated
• Missing key information solicited
• VAERS contractor nurse follows up on serious
  direct reports for additional details, medical
  records, and autopsy
• Selected cases receive special FDA/CDC follow-up
• 60 day and 1 year follow up of direct reports for
  non-fatal events without notation of recovery

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Vaccine Safety Monitoring Resources

• VAERS (co-managed with FDA)
• Vaccine Safety Datalink (VSD)
• Clinical Immunization Safety Assessment Centers
  (CISA)
• Brighton Collaboration for standardized case
  definitions of adverse events following
  immunization
• Supplementary external data systems

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• FDAs Safety Surveillance forBlood and Blood
  Products

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Blood Safety Assurance and Surveillance

• Encompasses protection of blood (including
  components and products), donors, and recipients
• Multiple interconnected and overlapping safety
  domains and reporting systems
• Deaths donors, recipients
• Product failures (errors and accidents)
• Device malfunctions
• Adverse events (AEs) in product recipients
• Medical errors

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How are Donors Protected?

• Confidential interview
• Health status evaluations
• Rapid access to emergency care
• Notification of donors with medical referrals
  upon deferral for abnormal findings, including
  infectious disease test results

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Six Layers of Blood Safety

• Selection of suitable donors
• Donor education
• Extensive risk factor screens (include malaria
  and vCJD)
• Limited physical examination
• Deferral registries to identify unsuitable donors
  
• Infectious disease testing (HIV-1, HIV-2, HCV,
  HBV, HTLV-I HTLV-II, syphilis, CMV)
• Blood quarantine pending tests and suitability
  assessments
• Monitoring, investigating, and corrective actions
  for errors, accidents, and adverse reactions
• Pathogen reduction, well established for plasma
  derivatives under investigation for blood
  components

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cGMPs and Product Standards apply in all areas

• Staff training and certification
• SOPs
• Use of approved methods
• Pathogen reduction for plasma derivatives
• Bacterial contamination monitoring

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How are Recipients Protected ?

• Safe blood (including components and products)
  assured through six blood safety layers and
  cGMPs
• Automated processes reduce human errors
• Recently implemented bar codes
• Radio Frequency Identification (RFID) tags on
  horizon
• Blood and components are grouped, typed, and
  crossmatched for compatibility with recipient
• Other safety systems include
• Recipient, sample, and unit identifiers
• Hospital practice standards
• Event investigation and reporting
• Corrective actions

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Blood Safety Reporting

• Mandatory reporting by manufacturers
• Fatalities (donors and product recipients)
• Product failures (errors and accidents)
• Biological Product Deviation Reports
• Medical Device Reports
• Other adverse events
• Voluntary spontaneous reporting to FDAs
  Adverse Event Reporting System (AERS, MedWatch)
  from any source
• Medical errors primarily reported through the
  hospital system, rather than to FDA
• Currently excludes manufacturers of blood and
  blood components

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Blood Fatality Reporting

• 21 CFR 606.170(b)) ...current good
  manufacturing practice (CGMP) regulations for
  blood and blood components require that you
  report fatalities related to blood collection or
  transfusion to CBER
• 21 CFR 640.73 in Subpart G Source Plasma
• Must report if a donor has a fatal reaction
  which, in any way, may be associated with
  plasmapheresis

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• FDAs Safety Surveillance forHuman Tissue and
  Cell Products

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Tissue and Cell Safety Surveillance

• Products not licensed
• Regulatory framework differs from that for drugs
  and most biologicals
• Based on FDA authority to control transmission of
  infectious disease
• Hence primary current focus on allograft-attributa
  ble infections from
• contaminated donor (cadaveric or living) cells
  and tissue or
• contamination through processing
• CBER frequently collaborates with CDC

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• FDA Amendments Act and CBER Safety Activities

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FDA Amendments Act of 2007

• New authorities to
• Require postmarketing studies and clinical trials
• Require sponsors to make safety related labeling
  changes
• Require sponsors to develop and comply with risk
  evaluation and mitigation strategies (REMS)

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FDA Amendments Act of 2007

• FDA must develop a postmarket risk identification
  and analysis system to link and analyze safety
  data from multiple sources, with at least
  25,000,000 patients by 2010 and 100,000,000 by
  2012.

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Vision for Post-Market Safety Monitoring

• All patients biologic product exposures 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

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Post-Market Safety Monitoring 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 Safety Monitoring 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
• FDA Sentinel Network

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Analytic Epidemiology Branch and Genomics for
Safety Assessment

• Analytic Epidemiology Branch is a new unit within
  CBER in 2008
• Devoted to expansion of capabilities for
  biological product safety hypothesis testing and
  surveillance within defined population databases
• Builds on 18 years of collaborative experience
  with CDCs Vaccine Safety Datalink
• New Genomics initiative to focus on identifying
  possible human genetic contributions to adverse
  reactions
• Goal improve biologic product safety

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Communications and Transparency

• Respect and autonomy of patients should be a
  guiding principle
• Early and continuing communication of possible
  safety signals is expected and beneficial to
  consumers, health care providers, science
• Critical to confidence in integrity of biologic
  product 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
• Biologic products have real 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

• Jesse Goodman, MD, MPH
• Karen Midthun, MD
• Robert Wise, MD, MPH
• Jingyee Kou, PhD