1. (Slide 1 of 22) Response to the National Vaccine Advisory Committee Recommendations on the Immunization Safety Office Scientific Agenda Frank DeStefano, MD, MPH Immunization Safety Office "The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention”

2. (Slide 2 of 22) Overview Background on ISO Scientific Agenda Update on ISO Response to NVAC Recommendations

3. (Slide 3 of 22) Background on ISO Scientific Agenda *Vaccine Safety Research, Data Access, and Public Trust, available at http://www.nap.edu/catalog/11234.html,http://www.nap.edu/catalog/11234.html In February 2005, IOM recommended “a subcommittee of NVAC [National Vaccine Advisory Committee] that includes representatives of a wide variety of stakeholders… review and provide advice on the VSD research plan… the group should meet publicly and allow interested persons to observe the process and provide input through established mechanisms.”

4. (Slide 4 of 22) Background on ISO Scientific Agenda  ISO/CDC developed a draft Scientific Agenda (Jan 07 -Jan 08): 3 meetings with input from external consultants, federal scientists, vaccine manufacturers, partners, scientific literature and other sources  CDC/ISO requested NVAC undertake and coordinate a scientific review of ISO’s draft Scientific Agenda (July 9, 2007) and advise on: –Content of draft ISO Scientific Agenda; –Prioritization of scientific topics; and –Identify possible scientific barriers to implementing the Scientific Agenda  NVAC formed the Vaccine Safety Working Group to review ISO’s draft Scientific Agenda (April 2008 - May 2009). This group made 32 recommendations in 3 categories: General, Capacity, and Research recommendations  On July 29, 2009, the HHS Assistant Secretary for Health sent the NVAC recommendations to CDC.

5. (Slide 5 of 22) Overview of ISO Response to NVAC Recommendations  ISO has or will implement many of the NVAC recommendations  Also working with NVPO to consider best way to address those that are beyond the scope of ISO/CDC.  Today ISO will present draft responses to selected recommendations, focusing on the ISO/CDC role.  Considerations in developing response include: resources feasibility change in circumstances (events on the ground) and alignment with CDC and ISO mission  Harmonize ISO Scientific Agenda with the National Vaccine Plan (Chapter 2)

6. (Slide 6 of 22) Current ISO Efforts Related to the Recommendations ISO had activities underway prior to the development of the Scientific Agenda that addressed some recommendations ISO has begun implementing activities to address the majority of the 17 general and capacity building recommendations ISO has begun or implemented some of the15 specific recommendations including: –Metabolic/mitochondrial studies –3 research questions prioritized by NVAC

7. (Slide 7 of 22) Recommendation #1 NVAC recommends ISO develop the research topic sections of Vaccines and Vaccination Practices, Special Populations, and Clinical Outcomes to consist of testable research questions that can be prioritized. ISO supports implementing this Recommendation Other agencies also may have a role in this area

8. (Slide 8 of 22) Response to Recommendation #1  ISO will generate a list of testable hypothesis that could be prioritized according to the following considerations: –New vaccines –Vaccines with expanded recommendations –Potential signals for risks after vaccines identified in pre-licensure studies, VAERS or by other bodies such as IOM that have not been adequately studied –Vaccines for special populations (those who may have different risks for adverse events than the general population, e.g., pregnant women) – Questions from the current IOM safety review sponsored by HRSA and CDC to update 8 vaccines in the Vaccine Injury Table –Priorities in the updated National Vaccine Plan (i.e., Chapter 2 on immunization safety) –Specific “high priority” hypotheses identified in the NVAC Recommendations on ISO’s draft Scientific Agenda

9. (Slide 9 of 22) Recommendation #2  NVAC recommends periodic external review of VSD and CISA research and the ISO Scientific Agenda more broadly.  ISO supports implementation of this recommendation

10. (Slide 10 of 22) Recommendation #5  To prepare for mass vaccination use of vaccines not traditionally given to the civilian population, the NVAC recommends ISO research in advance approaches to safety monitoring, including the extent to which they would be used off-label or in new populations.  This recommendation has been partially implemented

11. (Slide 11 of 22) Recommendation #6  In order to better understand the biological mechanisms of action responsible for adverse events following immunization, the NVAC recommends that ISO should coordinate with other agencies to support basic research into such mechanisms and that CISA should conduct clinical research on the pathophysiologic basis of adverse events.  ISO supports the need for research in this area

12. (Slide 12 of 22) Recommendation #7  NVAC endorses the Writing Group’s recommendation for an external expert committee, such as the Institute of Medicine, with broad methodological, design, and ethical expertise to consider “strengths and weaknesses, ethical issues and feasibility including timelines and cost of various study designs to examine outcomes in unvaccinated, vaccine delayed and vaccinated children and report back to the NVAC.”  ISO/CDC and NVPO are working on implementing this recommendation

13. (Slide 13 of 22) Recommendation #9  NVAC recommends ISO have an active role in risk communications research.  This is an agency-wide priority in which CDC and ISO are actively engaged

14. (Slide 14 of 22) Recommendation #10  NVAC recommends ISO identify and evaluate ways to (1) increase the number of serious events reported to VAERS; and (2) improve the quality and completeness of reports received.  This recommendation has been partially implemented during the H1N1 response

15. (Slide 15 of 22) Recommendation #11  NVAC recommends ISO evaluate approaches to follow up individuals reported to VAERS with rare or unusual adverse events for further study, including the collection of biological specimens, when appropriate  Activities regarding this recommendation are ongoing

16. (Slide 16 of 22) Recommendation #17  NVAC recommends ISO include the vaccination of children with mitochondrial disease, mitochondrial dysfunction, and other metabolic diseases as a priority scientific area for research to develop clinical guidance  Activities regarding this recommendation are ongoing

17. (Slide 17 of 22) Next Steps  ISO will finalize the Scientific Agenda taking into consideration the NVAC recommendations  ISO/CDC will provide a written response to NVAC and the HHS Assistant Secretary for Health specifying changes to the agenda and responses to the NVAC recommendations

18. (Slide 18 of 22) Additional Slides

19. (Slide 19 of 22) Summary of Recommendations General Recommendations & Capacity Recommendations 1.The NVAC recommends ISO develop the research topic sections of Vaccines and Vaccination Practices, Special Populations, and Clinical Outcomes to consist of testable research questions that can be prioritized. 2. The NVAC recommends periodic external review of VSD and CISA research and the ISO Scientific Agenda more broadly. 3.The NVAC recommends ISO regularly engage the public and stakeholders as ISO conducts research, interprets the findings from their studies, and revises their research agenda. 4. the NVAC recommends CDC perform case studies of past decision making processes related to vaccine safety issues to identify lessons learned regarding the use of scientific data in decision making. 5. To prepare for mass vaccination use of vaccines not traditionally given to the civilian population, the NVAC recommends ISO research in advance approaches to safety monitoring, including the extent to which they would be used off-label or in new populations. 6. In order to better understand the biological mechanisms of action responsible for adverse events following immunization, the NVAC recommends that ISO should coordinate with other agencies to support basic research into such mechanisms and that CISA should conduct clinical research on the pathophysiologic basis of adverse events.

20. (Slide 20 of 22) Summary of Recommendations General Recommendations & Capacity Recommendations 7.The NVAC endorses the Writing Group’s recommendation for an external expert committee, such as the 7.The NVAC endorses the Writing Group’s recommendation for an external expert committee, such as the Institute of Medicine, with broad methodological, design, and ethical expertise to consider “strengths and weaknesses, ethical issues and feasibility including timelines and cost of various study designs to examine outcomes in unvaccinated, vaccine delayed and vaccinated children and report back to the NVAC.” 8. The NVAC recommends that ISO studies are designed and adequately powered to assess the role of differences in race/ethnicity and gender when appropriate. 9. The NVAC recommends ISO have an active role in risk communications research. 10. The NVAC recommends ISO identify and evaluate ways to (1) increase the number of serious events that are reported to VAERS; and (2) improve the quality and completeness of the reports received. 11. The NVAC recommends ISO evaluate approaches to follow up individuals reported to VAERS with rare or unusual adverse events for further study, including the collection of biological specimens, when appropriate. 12. The NVAC recommends that the ISO Scientific Agenda specify the laboratory capacity needed for vaccine safety research and identify potential collaborations with other Federal agencies or private entities for those areas where CDC/ISO lacks capacity. For the laboratory capacity that CDC/ISO currently possesses, ISO should request input from external experts to advise on the ongoing work and development of new laboratory methodologies.

21. (Slide 21 of 22) Summary of Recommendations Continued General Recommendations & Capacity Recommendations 13. The NVAC recommends ISO study molecular immune responses to vaccinations, including common adverse events such as fever or rash, as subclinical correlates that might predict severe adverse events. 14. he NVAC recommends ISO create an expert advisory group on genomics and vaccine safety to assist with developing a focused genomics research agenda and protocol development. 15. The NVAC recommends ISO focus Brighton Collaboration research efforts on the adequacy of the case definitions and their usefulness in ongoing safety research conducted by VSD and other groups. 16. The NVAC recommends ISO create a single written guide dedicated to comprehensive clinical guidance, including identification, reporting, and treatment, for vaccine adverse events. 17.The NVAC recommends ISO include the vaccination of children with mitochondrial disease, mitochondrial dysfunction, and other metabolic diseases as a priority scientific area for research to develop clinical guidance.

22. (Slide 22 of 22) Recap of Summary of Recommendations Research Needs Recommendations 18-32 focus on specific research questions or editorial comments Three priority questions have been addressed