September 30, 2009

1. Rapid Communication with Clinicians During EmergenciesRapid Communication with Clinicians During Emergencies

2. Rapid Communication with Clinicians During EmergenciesRapid Communication with Clinicians During Emergencies

3. Rapid Communication with Clinicians During EmergenciesRapid Communication with Clinicians During Emergencies

4. Bruce Gellin, MD, MPH Deputy Assistant Secretary for Health Director, National Vaccine Program Office Department of Health and Human Services

5. The Vaccine Safety System

6. Department of Health and Human Services (HHS)Roles and Responsibilities for Vaccine Safety Activities National Vaccine Program Office (NVPO) Coordinates federal vaccine safety activities, reporting to the Assistant Secretary for Health, and bridges federal vaccine safety activities with non-federal partners CDC Makes vaccine recommendation, conducts post-licensure surveillance for adverse events, explores individual variation in vaccine associated adverse events, and conducts risk communication activities to a broad range of groups. FDA Regulatory authority over vaccine licensure, manufacturing and usage and post licensure surveillance HRSA Operates the Vaccine Injury Compensation Program (VICP) with the Department of Justice and the US Court of Federal Claims CMS Vaccine safety studies in >65 year olds AHRQ Background rates of medical conditions NIH Conducts and supports basic research and clinical trials in areas important for vaccine safety

7. Vaccine Safety Activities Outside of HHS Department of Defense Department of Veterans Affairs State public health departments Academic researchers Vaccine manufacturers Healthcare providers Parent groups and advocacy organizations Professional organizations Institute of Medicine Philanthropic organizations

8. Why H1N1 Vaccine Safety Monitoring is Important Strain change: like seasonal influenza vaccine However, the vaccine will be given to millions of people over a short period of time Important to discriminate between causal and coincidental adverse events following immunization Public trust and confidence

9. HHS Vaccine Safety Monitoring Activities Broad Initiatives: Federal Immunization Safety Taskforce (ISTF) National Vaccine Plan National Vaccine Advisory Committee (NVAC) Safety Working Group Public engagement meetings Pediatrics Supplement on vaccine safety

10. Federal Immunization Safety Taskforce Chaired by HHS Assistant Secretary for Health and HHS Assistant Secretary for Preparedness and Response Includes multiple HHS agencies as well as representatives from DoD and VA Enhanced coordination of federal vaccine safety science, practice, public engagement and risk communication Recommendations incorporated into National Vaccine Plan Drafted Federal Plans to Monitor Immunization Safety for a 2009 H1N1 Vaccination Campaign

11. H1N1 Vaccine Safety Monitoring Activities Enhancements to existing vaccine safety systems and development of new monitoring and surveillance systems: Vaccine Adverse Event Reporting System (VAERS), CDC/FDA Vaccine Safety Data Link (VSD), CDC Centers for Medicare & Medicaid Services Databases, CMS Post-Licensure Rapid Immunization Safety Monitoring (PRISM), HHS, FDA & CDC Defense Medical Surveillance System (DMSS), DoD, Department of Veterans Affairs Databases, VA Emerging Infections Program (EIP), CDC Real-Time Immunization Monitoring System (RTIMS), CDC Indian Health Service Resource and Patient Management Database, HIS Clinical Immunization Safety Assessment (CISA), CDC Vaccines and Medications in Pregnancy Surveillance System (VAMPSS), BARDA

12. Development of New Systems – PRISM Post-Licensure Rapid Immunization Safety Monitoring (PRISM) Collaboration between HHS, Harvard Pilgrim Health Center (HPHC), American’s Health Insurance Plans (AHIP), and the Public Health Informatics Institute (PHII) Uses health plan data to actively monitor adverse events following immunization Eight states will supply immunization histories from their registries to supplement health plan immunization records

13. Development of New Systems – PRISM cont. Approximately 15% of the US population under total surveillance Approximately 10-20 million of which will be enhanced by state registry data

14. Coordinated Review of Monitoring Data On July 27, 2009, the National Vaccine Advisory Committee recommended consideration of a committee to perform “a transparent and independent review of vaccine safety data as it accumulates” http://www.hhs.gov/nvpo/nvac/H1N1SubgroupRecommendationsVSMJuly2009.html In response, a vaccine safety risk assessment working group of the National Vaccine Advisory Committee is in the process of being formed All federal H1N1 vaccine monitoring activities are coordinated by the Immunization Safety Task Force

15.  Influenza A (H1N1) 2009 Monovalent Vaccines[H1N1 Vaccines]   Theresa M. Finn, Ph.D Office of Vaccines Research and Review Center for Biologics Evaluation and Research Food and Drug Administration

16. Overview Seasonal Influenza vaccines Yearly formulation change “Strain change” supplement H1N1 vaccine licensure H1N1 vaccines

17. U.S.-licensed Seasonal Influenza Vaccines Inactivated, intramuscular Sanofi pasteur: Fluzone (>6 months) Novartis: Fluvirin (>4 years) CSL: Afluria (>18 years) IDB-GSK: FluLaval (>18 years) GSK: Fluarix (>18 years) Live Attenuated, intranasal MedImmune: FluMist (2-49years)

18. U.S.-licensed Seasonal Influenza Vaccines Trivalent Influenza A (H1N1) Influenza A (H3N2) Influenza B Yearly consideration of optimal strains: WHO/CDC/FDA Advisory Committee Yearly “strain change supplement” to FDA

19. U.S.-licensed Seasonal Influenza Vaccines: Strain change Supplement Each yearly strain change: Same egg based licensed manufacturing process Same in-process controls at multiple stages of manufacture Same lot release requirements No additional clinical data (inactivated vaccines), limited clinical (safety) data (live attenuated)

20. H1N1 Vaccine Licensure U.S.-licensed manufacturers: Strain change supplement to existing license

21. H1N1 Vaccines: Strain Change Supplements Same egg based manufacturing process as licensed seasonal vaccines Same in-process controls as licensed seasonal vaccines Same lot release requirements as licensed seasonal vaccines Same clinical data requirements as licensed seasonal influenza vaccines

22. H1N1 Vaccines September 15, 2009 FDA approved: Inactivated: Influenza A (H1N1) 2009 Monovalent Vaccine Sanofi pasteur, Inc. Novartis Vaccines and Diagnostics, Ltd. CSL Ltd. Live: Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal MedImmune LLC

23. H1N1 Vaccines Licensed for use in the same populations as each manufacturer’s seasonal influenza vaccine: Sanofi pasteur: > 6 months of age Novartis: > 4 years of age CSL: >18 years of age MedImmune: 2-49 years of age Do not contain adjuvants

24. Clinical Studies Manufacturer and NIH sponsored Immunogenicity Safety Optimal dose Optimal number of doses Optimal schedule

25. H1N1 Dosing regimen <9 years of age 2 doses >10 years of age one dose Supported by preliminary data from NIH and manufacturer sponsored studies Adults >18 years: 1 dose Children 10-17 years: 1 dose Children 6m-9 years: 2 doses

26. H1N1 Vaccines Summary licensed monovalent H1N1 vaccines Same populations as licensed seasonal Same manufacturing process and testing as seasonal

27. CDCClinician Outreach and Communication Activity: H1N1 Vaccine Safety Discussion of Clinical Trials to Support Use of the Monovalent H1N1 Vaccine Emphasis on Safety Sept 30, 2009 Richard L. Gorman, MD Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health

28. Outline NIAID Monovalent H1N1 vaccine trials Policy Focus 7 Ongoing protocols 3 adult studies: unadjuvanted 2 pediatric studies: unadjuvanted 1 pregnancy study: unadjuvanted 1 adult study: adjuvanted Safety Oversight

29. NIAID trials “Policy Focus” Help inform policy, “gap” areas accelerate availability of 1 vs. 2 dose data in different populations administration with seasonal influenza vaccine use of different adjuvanted products mixing stockpiled vaccines and adjuvant Data not intended to support licensure Complimentary to company planned trials Safety in General and Special populations young infants pregnant women immunocompromised

30. NIAID H1N1 Vaccine Trials First 3 protocols: 1 vs. 2 doses of unadjuvanted CSL vaccine in healthy adults: enrollment complete ~ 400 1 vs. 2 doses of unadjuvanted SP vaccine in healthy adults: enrollment complete ~ 400 co- vs. sequential administration of TIV and H1N1 vaccine in adults: enrollment complete ~ 800 Next 2 protocols 1 vs. 2 doses of unadjuvanted SP vaccine in healthy children: enrollment complete ~ 600 co- vs. sequential administration of TIV and H1N1 vaccine in children: enrollment complete ~ 600

31. NIAID H1N1 Vaccine Trials 2 protocols presently enrolling Mixing and Matching Adjuvant and Antigen from different companies: vaccines: CSL and sanofi pasteur H1N1 vaccine adjuvant: GSK’s AS03 mixed prior to administration protocol: 3.75µg +AS03, 7.5µg and 15µg +/- AS03 2 doses, 21 days apart status: Sanofi pasteur/AS03: started 24 Sept 2009 Target enrollment ~ 750, presently enrolling CSL/AS03 IND to follow

32. NIAID H1N1 Vaccine Trials 2 protocols presently enrolling Monovalent H1N1 in Pregnant Women Sanofi Pasteur, unadjuvanted, 1 dose, 2 dose 21 days apart 2nd and 3rd trimester women Status: trial initiated 9 Sept 2009 Target Enrollment: ~120, presently enrolling

33. Monovalent H1N1 Vaccine Safety Oversight Safety Monitoring Committee 5 Members All with infectious disease expertise Additional Expertise: HIV, OB-GYN, Internal Medicine, Pediatrics, Biostatistics 2 Special Safety Consultants Expertise: Large Clinical Trial Phamacovigilence, Adjuvant 10 to 30 Independent Safety Monitors: local, independent, medical evaluator

34. Monovalent H1N1 Vaccine Safety Oversight Safety Monitoring Committee Reviews all protocols prior to implementation for safety considerations Reviews all adverse events, serious adverse events, subject withdrawals, subject terminations, protocols deviations After analysis of safety, determines if a study should proceed, be modified or be stopped.

35. Monovalent H1N1 Vaccine Safety Oversight Conclusion and Take Home Message At this time, the Safety Monitoring Committee has not recommended a modification or halting of any trial The observed pattern of reactogenicity and adverse events is comparable with seasonal influenza vaccination

36. Acknowledgements DHHS H1N1 vaccines for NIH trials under BARDA contract FDA CDC Manufacturers VTEU investigators EMMES Corporation SRI Birmingham Fisher Bioservices PPD Independent Safety Committee members NIAID and DMID colleagues

37. Monitoring the Safety of Influenza A (H1N1) 2009 Monovalent Vaccine Claudia Vellozzi, MD, MPH Deputy Director Immunization Safety Office Division of Healthcare Quality Promotion Centers for Disease Control and PreventionAtlanta, GA

38. Objectives To provide an overview of the CDC influenza A (H1N1) 2009 monovalent vaccine safety monitoring activities To review the Vaccine Adverse Event Reporting System (VAERS) To provide key resources for 2009 H1N1 vaccine safety for clinicians and public health officials

39. Overview of the CDC influenza A (H1N1) 2009 monovalent vaccine safety monitoring activities

40. Background When seasonal influenza vaccines are used according to licensed indication and usage information they are considered to be safe. It is anticipated that the safety profile of licensed influenza A (H1N1) 2009 monovalent vaccine (2009 H1N1 vaccine) will be similar to seasonal influenza vaccines. Serious adverse events after vaccination are uncommon. Vaccine safety monitoring is an important component of the 2009 H1N1 response.

41. Background Review of adverse events following TIV among adults reported to VAERS from 1990-2005 (15 years)* Approx 750 million doses distributed Overall adverse event reporting rate of 24 per million TIV vaccinations 3.4 serious adverse events/million TIV vaccinations** reporting rates have been fairly constant over time and no new safety concerns emerged following this comprehensive review *Vellozzi, et al (2009)

42. Goals for 2009 H1N1 Vaccine Safety Monitoring Identify clinically significant adverse events following receipt of 2009 HINI vaccine in a timely manner Rapidly evaluate serious adverse events following receipt of 2009 H1N1 vaccine and determine the public health importance Evaluate if there is a risk of Guillain-Barré syndrome (GBS) associated with the 2009 H1N1 vaccine Communicate vaccine safety information in a clear and transparent manner to healthcare providers, public health officials, and the public

43. Vaccine Adverse Event Reporting System (VAERS) VAERS: Voluntary reporting system jointly managed by CDC and FDA Signal detection National in scope Flexible Scalable Encourages reports from healthcare providers and accepts reports from vaccinees, others System enhancements underway Increase in staffing to process VAERS reports more rapidly

44. VAERS Limitations Usually cannot assess causality Variable quality of data No unvaccinated comparison group Denominator data lacking Under-reporting (voluntary, passive reporting) Variation of reporting: Stimulated reporting can occur during times of heightened awareness (e.g. Media attention, serious event occurs, MMWR release, other)

45. Vaccine Safety Datalink (VSD) Eight managed care organizations representing approximately 9 million US individuals Sequential Analytical methods Allows rapid assessment of pre-specified adverse events Simultaneous analysis with appropriate comparison group Chart confirmation is feasible Requires accurate vaccination information within the managed care database Outcome linked with exposure

46. VSD Limitations Up to a 2 week delay for available outcome data Adverse events with longer risk windows add to delay of analysis Power may not be sufficient for rare outcomes with limited vaccine use Vaccination information within the MCO is necessary

47. Clinical Immunization Safety Assessment (CISA) Network Collaboration between CDC and 6 academic centers with vaccine safety experts Provide vaccine safety clinical expertise in the evaluation of serious adverse events following 2009 H1N1 vaccination (e.g., assist with review of complex serious cases reported to VAERS)

48. Other Surveillance Systems Collaboration with DoD/CDC/FDA utilizing the Defense Medical Surveillance System (DMSS) U.S. military personnel (~1.5 million active duty personnel) Real Time Immunization Monitoring System (RTIMS) Automated web-based active surveillance Collaboration between CDC and Johns Hopkins School of Public Health Post-Licensure Rapid Immunization Safety Monitoring (PRISM) Collaboration National Vaccine Program Office (NVPO), FDA, and CDC

49. Guillain-Barré Syndrome (GBS)  Immune-mediated acute demyelinating polyneuropathy affecting the peripheral nervous system Estimated annual incidence rate: 1 case per 100,000 population In 1976, a type of influenza vaccine was causally associated with GBS* 1 additional case per 100,000 persons vaccinated Subsequent studies of influenza vaccines have found small or no increased risk of GBS if there is a risk of GBS from seasonal influenza vaccines, it would be no more than ~1 additional case per million people vaccinated

50. GBS Active Case-Finding Emerging Infections Program (existing hospital based surveillance system) Active GBS case finding (other adverse events as necessary) Ascertainment of vaccination status Identify risk factors for GBS (e.g., antecedant infection) >50 million US population 10 states American Academy of Neurology (AAN) collaboration Increase VAERS awareness to enhance reporting Enhanced GBS reporting in the EIP surveillance sites GBS standard case definition being used*

51. CDC Support of Public Health Officials participating in H1N1 Vaccine Monitoring Collaboration between CDC’s Immunization Safety Office and Vaccine Safety Coordinators in 62 state, territorial and local health departments Assist states with technical and epidemiologic investigation as needed Regular communications with ASTHO, NACCHO, CSTE and other partners

53. What to Report to VAERS Report any clinically significant adverse event following immunization (www.vaers.hhs.gov) Submit reports of concern even when not sure whether the vaccine caused the adverse event Include as much information as possible (e.g., vaccination location, date, vaccine type, lot number and dose number) Incomplete reports are accepted Report as soon as possible but there is no time limit

54. How to submit a VAERS report  1) Online via a secure website at https://vaers.hhs.gov 2) Download a form from: www.vaers.hhs.gov/pdf/vaers_form.pdf Fax a completed form: 877-721-0366 Mail a completed VAERS form to: VAERS P.O. Box 1100 Rockville, MD, 20849 3) VAERS assistance: 800-822-7967 or email: info@vaers.org

55. Clinician’s Role in Vaccine Safety Monitoring during the 2009 H1N1 vaccination campaign Properly store and administer vaccine Screen for contraindications and precautions Educate vaccinee (or caregiver) about risks and benefits of vaccine Vaccine Information Statements (VIS)* Use Influenza Vaccination Record (card) Evaluate and treat patient if an adverse event occurs Report clinically significant adverse events promptly to VAERS https://vaers.hhs.gov

56. CDC Resources for 2009 H1N1 Vaccine Safety General Questions and Answers on 2009 H1N1 Influenza A Vaccine Safety http://www.cdc.gov/h1n1flu/vaccination/vaccine_safet_qa.htm General Questions and Answers on Thimerosal http://www.cdc.gov/h1n1flu/vaccination/thimerosal_qa.htm General Questions and Answers on Guillain-Barré Syndrome (GBS) http://www.cdc.gov/h1n1flu/vaccination/gbs_qa.htm

57. Summary2009 H1N1 Vaccine Safety Monitoring Established vaccine safety infrastructure will be utilized, enhancements in process New collaborations being developed CDC to provide support to states and territories during 2009 H1N1 vaccination program Vaccine risk communication is an important component of the vaccine safety monitoring effort. Clinicians play an important role in vaccine safety monitoring

58. Questions

59. Rapid Communication with Clinicians During EmergenciesRapid Communication with Clinicians During Emergencies