current cdc vaccine safety activities

1. Current CDC Vaccine Safety Activities Vaccine Safety Evaluation: Post Marketing Surveillance Conference Bethesda, MD April 10,2007 John Iskander MD MPH Immunization Safety Office (ISO) Office of the Chief Science Officer Centers for Disease Control and Prevention

2. Outline Overview of current CDC post-licensure vaccine safety activities Immunization Safety Office National Center for Immunization and Respiratory Diseases (NCIRD) New approaches and emerging vaccine safety issues Key partnerships and priority setting Lessons learned and thoughts on conference theme

3. Immunization Safety Office Mission Vaccine risk assessment achieved through: Performance of high-quality research on vaccine safety Identification of adverse events after immunization (AEFI) through public health surveillance Assessment of causality and preventable risk factors for AEFI Communication of findings through scientific publications and presentations, electronic/traditional media, etc.

4. Establishing Causal Link:Adverse Event and Vaccine For comprehensive assessment of vaccine safety, what is ultimately needed is capture of all 4 cells of the two by two table, as Dr. Chen presently previously. This is currently obtained through the 3% of the population covered by the vaccine safety datalink, but data may not be available in a timely manner and lacks statistical power to assess rare events or rarely given vaccine combination. Capturing and analyzing this information for a greater proportion of the population will increase CDC’s ability to assure vaccine safety in an increasingly complex vaccination landscape. For comprehensive assessment of vaccine safety, what is ultimately needed is capture of all 4 cells of the two by two table, as Dr. Chen presently previously. This is currently obtained through the 3% of the population covered by the vaccine safety datalink, but data may not be available in a timely manner and lacks statistical power to assess rare events or rarely given vaccine combination. Capturing and analyzing this information for a greater proportion of the population will increase CDC’s ability to assure vaccine safety in an increasingly complex vaccination landscape.

5. The Vaccine Adverse Event Reporting System (VAERS) The “early warning system” of vaccine safety surveillance A national passive surveillance system jointly operated by the CDC and the FDA; established in 1990 Accepts reports from physicians, other health care providers, vaccine manufacturers, health departments, and the public “Hypothesis generating”; seeking signals of potential concern

6. Advantages of VAERS National in scope, covers diverse populations Able to detect rare events in a cost-effective manner Rapid detection of possible signals (hypotheses to be tested ) Can assess lot-specific vaccine safety issues

7. Limitations of VAERS Reporting biases: Underreporting, though serious events more likely to be reported (Rosenthal and Chen, AJPH, 1996) Overreporting, since many reports are not causally related to vaccination Does not provide information on: Number of persons vaccinated Background incidence of conditions in the general population

8. The Vaccine Safety Datalink (VSD) 8 geographically diverse HMO’s that participate in a large linked database (LLDB) which tracks: Vaccination (exposure) Outpatient, emergency department (ED), hospital and laboratory data (health outcomes) ICD-9 CM codes used Demographic variables (confounders) Covers about 3% of U.S. population “Hypothesis testing”

9. Advantages of VSD Analyses All medical encounters are available at most sites Allows calculation of background rates Medical chart review is accessible Availability for urgent studies

10. Limitations of VSD Analyses Sample size may be inadequate for very rare events (e.g. Guillain-Barre syndrome with incidence rate of 1-2/100,000 per year) Vaccines administered outside of HMO setting not captured Lack of demographic and socioeconomic diversity in HMO practice Variable accuracy of coded data used for studies Unvaccinated population may be small

11. So let’s talk about epi studies done in the VSD. The classic method is called a risk interval analysis, in which an individual serves as their own control. Each individual serves as own control High vs. Average Risk controlled for Unknown Confounders controlled for “Clustered” at the individual level Matched analysis required Conditional logistic regression VSD likely good at identifying serious, rare events that require contact with health system Disadvantages: Coding Variation, Not likely to identify mild reactions/fevers, Type I errors will occur, Roll-up variables to lump dx codes together So let’s talk about epi studies done in the VSD. The classic method is called a risk interval analysis, in which an individual serves as their own control. Each individual serves as own control High vs. Average Risk controlled for Unknown Confounders controlled for “Clustered” at the individual level Matched analysis required Conditional logistic regression VSD likely good at identifying serious, rare events that require contact with health system Disadvantages: Coding Variation, Not likely to identify mild reactions/fevers, Type I errors will occur, Roll-up variables to lump dx codes together

12. VSD Database of Pregnancy Outcomes after Vaccination Objective: To create an analytic database to serve as a resource for measuring the risk of adverse pregnancy outcomes after inadvertent vaccination of pregnant women Creation of a new analytic database for pregnancy outcomes within the VSD will complement information received by the manufacturer’s pregnancy registry and by VAERS. Creation of a new analytic database for pregnancy outcomes within the VSD will complement information received by the manufacturer’s pregnancy registry and by VAERS.

13. Established in 2001 to investigate the pathophysiologic mechanisms and biologic risks of AEFI and to provide evidence-based vaccine safety assessments Network of six academic centers each with vaccine subject matter experts CISA was created to look more closely at the individual, ie to identify people who have experienced an adverse event, and study the pathophysiology, inflammatory pathways or host risk factors using rigorous scientific methods and therefore ultimately be able to provide the evidence needed to support the management of these individuals or prevent exposure to a vaccine that may result in a negative experience The clinical experts in the CISA network are available to collaborate on research related to aefi’s, and since aefi’s, especially serious aefi’s are rare this national network of clinical sites can develop protocols to study these rare events and obtain a sufficient number of subjects to give the studies power.CISA was created to look more closely at the individual, ie to identify people who have experienced an adverse event, and study the pathophysiology, inflammatory pathways or host risk factors using rigorous scientific methods and therefore ultimately be able to provide the evidence needed to support the management of these individuals or prevent exposure to a vaccine that may result in a negative experience The clinical experts in the CISA network are available to collaborate on research related to aefi’s, and since aefi’s, especially serious aefi’s are rare this national network of clinical sites can develop protocols to study these rare events and obtain a sufficient number of subjects to give the studies power.

14. CISA Mission To conduct clinical research of vaccine adverse events (VAE) and role of individual variation in responses to immunizations To provide evidence-based information that assists: Clinicians in the evaluation and management of individuals at risk for AEFI Individuals in making informed immunization choices VAERS and VSD are great epidemiologic tools to have however they are limited in their ability to evaluate vaccine risks for the individual person. . VAERS and VSD are great epidemiologic tools to have however they are limited in their ability to evaluate vaccine risks for the individual person. .

15. Goals To study the pathophysiology of AEFIs To identify host risk factors associated with developing an AEFI To develop evidence-based guidance for use by clinicians: When evaluating AEFIs When considering vaccination or re-vaccination of: Individuals with (relative) contraindications for vaccination Individuals with a history of AEFIs

16. CISA: Integrating Individual Human Variation into Studies of Vaccine Safety Examples of specific study protocols: Myocarditis after smallpox vaccination Extensive limb swelling (ELS) after 4th/5th doses of DTaP Possible genetic risk factors for post-vaccination GBS

17. THE BRIGHTON COLLABORATION Standardizing Vaccine Safety http://www.brightoncollaboration.org

18. The Need: Safety can not be measured directly, only inferred from the relative absence of vaccine adverse events Assessing safety requires standardized terminology of VAE across studies Lack of a standard “vocabulary” (i.e., case definitions & guidelines) for vaccine adverse events have hindered comparability of vaccine safety data The Solution: A global collaboration to address this “missed opportunity” Development of standardized case definitions and guidelines Case definitions categorized by levels of evidence Clinical trials vs. postmarketing surveillance Developed vs. developing countries

20. Working groups

21. Outline Overview of current CDC post-licensure vaccine safety activities Immunization Safety Office National Center for Immunization and Respiratory Diseases (NCIRD) New approaches and emerging vaccine safety issues Key partnerships and priority setting Lessons learned and thoughts on conference theme

22. Vaccine Analytic Unit (VAU):Objectives Assess unusual, possibly longer-term anthrax vaccine adverse events within Department of Defense (DoD) Conduct investigations to assess whether specific AEFI are associated with: Current anthrax vaccine Future anthrax vaccines Other biodefense vaccines

23. Data: Defense Medical Surveillance System (DMSS) Active surveillance system of U.S. military personnel (~1.4 million person years each year from 1998-present) Relational database containing numerous variable types: Demographic Inpatient & Outpatient (ICD-9 coded diagnoses) Vaccination Deployment Data: DMSS The DMSS is a relational database and for this study data will come from several of the tables. The study period of interest is 1998-2003 which includes the DoD’s anthrax vaccination program that began in 1998 and the smallpox vaccination program that began in 2003. Over 30 Oracle tables and approaching 1 billion records Our present study uses data from: Demographics Personnel Vaccinations DeploymentData: DMSS The DMSS is a relational database and for this study data will come from several of the tables. The study period of interest is 1998-2003 which includes the DoD’s anthrax vaccination program that began in 1998 and the smallpox vaccination program that began in 2003. Over 30 Oracle tables and approaching 1 billion records Our present study uses data from: Demographics Personnel Vaccinations Deployment

24. VAU Research Agenda Partnership with DoD and FDA (NVAC workgroup) Establish research agenda to study long-term AEFIs (2004) Hypothesis testing studies Hypothesis generation studies

25. VAU: Key Benefits Unique infrastructure for conducting immunization safety postmarketing surveillance studies Increased understanding of safety profiles of anthrax and other (biodefense) vaccines given in military Complements VAERS and VSD to inform immunization policy makers about important vaccine safety questions

26. Outline Overview of current CDC post-licensure vaccine safety activities Immunization Safety Office National Center for Immunization and Respiratory Diseases New approaches and emerging vaccine safety issues Key partnerships and priority setting Lessons learned and thoughts on conference theme

27. General Approaches for Safety Monitoring of New Vaccines Summary of pre-licensure safety data Identified or uncertain risks from phase III trials Review of any available post-marketing data VAERS monitoring plan VSD plan: key outcomes for Rapid Cycle Analysis (RCA), other planned studies Identification/creation of key case definitions Identification of candidate CISA protocols Identification of need for special studies This slide presents the general scientific framework used by the CDC Immunization Safety Office for newly licensed vaccine surveillance. In conducting these activities, ISO partners with the FDA, managed care organizations and other parts of the private sector, academic medical centers, and internationally based collaborators. This slide presents the general scientific framework used by the CDC Immunization Safety Office for newly licensed vaccine surveillance. In conducting these activities, ISO partners with the FDA, managed care organizations and other parts of the private sector, academic medical centers, and internationally based collaborators.

28. ISO Milestones since 1st NVPO meeting (11/2000) 2001: VSD expands from 4 to 8 sites 2001: Internet-based VAERS public access dataset established 2001: Clinical Immunization Safety Assessment (CISA) Network 2002: Secure web-based VAERS reporting implemented 2003: VAERS support of U.S. smallpox vaccination program Casey et al, JAMA 2005 2004: 1st Immunization Safety Office led field vaccine safety investigation (Rue et al, submitted for publication) 2005: VSD “Rapid cycle” analysis Davis et al, Epidemiology 2005 2005: ISO transferred to Office of Chief Science Officer, Office of the Director, CDC 2006: VAERS “Data mining” activities reviewed Iskander et al, Drug Safety 2006

29. Emerging Issues Enhanced surveillance for newly licensed products and existing vaccines with new indications New target populations: adolescence, pregnancy Combined vaccines and simultaneous vaccination with resulting increased complexity of databases used to study vaccine adverse events Increasing overlap of vaccine safety with “patient safety” issues; new scientific approaches needed Examples: vaccine administration errors, syncope challenging to study in LLDB Preparing vaccine safety infrastructure for a pandemic or other emergency responses Future challenges for vaccine safety activities at CDC include the need for enhanced surveillance of newly licensed products and those with expanded indications, the expectation to provide safety data on potentially unavoidable “off label” use of licensed vaccines, and systems solutions needed to deal with increasingly complex vaccine safety databases. Future challenges for vaccine safety activities at CDC include the need for enhanced surveillance of newly licensed products and those with expanded indications, the expectation to provide safety data on potentially unavoidable “off label” use of licensed vaccines, and systems solutions needed to deal with increasingly complex vaccine safety databases.

30. Increase in Number of Licensed Vaccines 1990: 16 vaccines under surveillance for safety Source: CDC Monitoring System for Adverse Events Following Immunization (MSAEFI) 2004: 49 U.S. licensed vaccine products Source: Immunization Action Coalition, www.immunize.org Since the beginning of the modern era of vaccine safety, there has been a three fold increase in the number of licensed vaccine products. Since the beginning of the modern era of vaccine safety, there has been a three fold increase in the number of licensed vaccine products.

31. VAE Reports after Infant (< 1 y.o.) Vaccinationby Vaccine Combination Received, VAERS 1991-2002 The increasing number of potential vaccine combinations is reflected in reports to VAERS, which can be thought of as a national sample of vaccination activity, albeit an inherently non-representative one. This series of slides shows the increasing number of individual vaccines and vaccine combinations involved in adverse event reports received for infants from 1985 through 2003. Between 1991 and 2004, the total number of vaccines and vaccine combinations seen in reports to VAERS for both children and adults increased from 101 to 951The increasing number of potential vaccine combinations is reflected in reports to VAERS, which can be thought of as a national sample of vaccination activity, albeit an inherently non-representative one. This series of slides shows the increasing number of individual vaccines and vaccine combinations involved in adverse event reports received for infants from 1985 through 2003. Between 1991 and 2004, the total number of vaccines and vaccine combinations seen in reports to VAERS for both children and adults increased from 101 to 951

32. Outline Overview of current CDC post-licensure vaccine safety activities Immunization Safety Office National Center for Immunization and Respiratory Diseases New approaches and emerging vaccine safety issues Key partnerships and priority setting Lessons learned and thoughts on conference theme

33. Key Partners for CDC Vaccine Safety Activities NCIRD; primarily responsible for vaccine risk management (i.e. policy setting related to vaccine safety issues) Other CDC centers Occupational Health, Birth Defects, HIV/STD/TB, etc. Governmental (non-CDC): FDA Center for Biologics, HRSA, NVAC, DoD, National Library of Medicine State and local health departments Academic centers (CISA network) Private sector: managed care organizations, manufacturers, others in vaccine related industries Professional organizations (e.g. AAP) Immunization advisory bodies U.S. ACIP, WHO Global Advisory committee

34. Partnerships Provide Additional Data Sources Biologics Surveillance (NCIRD, FDA) Vaccine dose distribution (not doses administered) Vaccine Coverage Surveys (NCIRD) National Health Interview Survey, National Immunization Survey, Behavioral Risk Factor Surveillance System State/local immunization registries (NCIRD) Hospital Discharge/Mortality Datasets

35. Priority Setting:Research Agenda Development Scope limited to ISO activities but extends beyond Institute of Medicine (IOM) recommended VSD research agenda (RA) Coordinated 3-step development process with extensive internal and external input ISO/CDC develops draft research agenda National Vaccine Advisory Committee (NVAC) provides a policy perspective on RA ISO/CDC finalizes agenda and responds to feedback from NVAC process Evaluate process after developning first research agenda

36. Outline Overview of current CDC post-licensure vaccine safety activities Immunization Safety Office National Center for Immunization and Respiratory Diseases New approaches and emerging vaccine safety issues Key partnerships and priority setting Lessons learned and thoughts on conference theme

37. Lessons Learned: VAERS Despite underreporting, VAERS is sensitive (at times overly sensitive) with regard to detection of rare events Example: doubling of influenza vaccine associated GBS reports translated to 1/1 million doses attributable risk (Lasky et al, NEJM 1998) Menactra® associated GBS a similar recent example Public use data (required by law) has both advantages and disadvantages A “systematic approach” cannot be done efficiently on a report by report basis, hence the need for use of advanced signal detection techniques More operational research is needed (e.g. to quantify underreporting and provider awareness of system)

38. Lessons Learned: VSD Utility not limited to classical hypothesis testing studies Natural history/burden of disease Hypothesis generating Vaccine usage and uptake Active surveillance data is useful prospectively as well as retrospectively Timeliness of studies to address important public health concerns must be balanced with maintaining high study quality

39. Lessons Learned: The Way Forward There is a predictable relationship between vaccine-preventable disease levels, coverage, and degree of concern about vaccine safety/VAE Well conducted epidemiologic studies will continue to be a cornerstone of vaccine safety; nevertheless they must be supplemented by studies conducted in other settings (laboratory, genomics, patient level) as we move towards an era of “personalized medicine” National and global public health benefits of vaccines require high coverage levels; these cannot be achieved if concerns about vaccine safety are not comprehensively addressed The needs of the many must outweigh the needs of the few, or the one, is too simplistic an approach. The needs of the many must outweigh the needs of the few, or the one, is too simplistic an approach.

40. Conference Theme What would an ideal post licensure vaccine safety system be? Have more specific information than is currently available about actual vaccine usage More integration and linkages b/w systems (e.g. automated use of case definitions within surveillance databases) More readily available and usable operational research-quantification of underreporting, scientifically designed provider outreach/education strategies, etc. More integrated into “mainstream” public health activities

41. CDC Commitment to Vaccine Safety Objectively assess risks from vaccines Contribute to national preparedness Serve as a partner and resource for global vaccine safety activities Communicate findings to all involved parties in a clear and transparent manner

42. Vaccinate. Safely.

43. Acknowledgments Jane Gidudu Claudia Vellozzi Michael McNeil Karen Broder Kenneth Bart Robert Davis Susan Duderstadt Tanja Popovic James Stephens Julianne Gee Robert T. Chen Nancy Levine Paul Gargiullo

44. Timeline of Selected “Emergency Responses” 1999-2004: Rotavirus vaccine and intussusception 1999-present: Thimerosal and childhood vaccines 2001-present: yellow fever vaccine and viscerotropic/neurotropic disease 2001-2: Use of smallpox and anthrax vaccines under IND protocols 2002-4: Smallpox vaccination program 2004: Recall of selected lots of rabies vaccine Detection of vaccine safety “signals” from VAERS and other sources and the need to support DHHS wide bioterrorism preparedness activities have resulted in a series of vaccine safety related emergency response efforts over the past 5 years. Activities have included formation and ongoing support of working groups, field deployment of staff, and increasing technological and high level administrative support for VAERS. Detection of vaccine safety “signals” from VAERS and other sources and the need to support DHHS wide bioterrorism preparedness activities have resulted in a series of vaccine safety related emergency response efforts over the past 5 years. Activities have included formation and ongoing support of working groups, field deployment of staff, and increasing technological and high level administrative support for VAERS.

45. Emergency Response: Anticipating Future Needs New VAERS contract contains an “emergency response” module Requirement to be able to process up to 40,000 additional adverse event reports over a three month period Surge capacity would be needed in settings such as an influenza pandemic or in response to a confirmed smallpox case Contractor will also be required to establish or link with additional safety systems such as active surveillance The VAERS contractor, which receives and processes safety reports, plays an important role in the ability to rapidly identify potential vaccine safety concerns. The VAERS contract has recently been rewritten to stress the importance of supporting vaccine safety emergency response and surge capacity. Specifically, the contractor will need t to be able to process up to 40,000 additional reports represents an approximately ten fold increase of the systems current capacity. The contract specifies that this ramp up will be achieved within 10 days. Though funding for the VAERS contractor to develop emergency response procedures and systems has been secured, funding for implementation cannot be secured in advance of a demonstrated need. The VAERS contractor, which receives and processes safety reports, plays an important role in the ability to rapidly identify potential vaccine safety concerns. The VAERS contract has recently been rewritten to stress the importance of supporting vaccine safety emergency response and surge capacity. Specifically, the contractor will need t to be able to process up to 40,000 additional reports represents an approximately ten fold increase of the systems current capacity. The contract specifies that this ramp up will be achieved within 10 days. Though funding for the VAERS contractor to develop emergency response procedures and systems has been secured, funding for implementation cannot be secured in advance of a demonstrated need.