1. Safety Monitoring of 2009 Pandemic H1N1 Influenza Vaccines VRBPAC meeting November 18, 2009 Presented by: Hector Izurieta (FDA/CBER) Compiled by: Laura Polakowski (FDA/CBER)

2. 2009 Pandemic H1N1 Influenza Vaccine Safety Issues New strain, monovalent vaccine Large numbers of vaccinees expected Heightened public attention Expected increase in adverse event reporting, regardless of causal association to vaccination Expectation for robust safety monitoring  Need for adaptable toolbox

3. Pandemic H1N1 Influenza Vaccine Safety Monitoring Strategy Enhanced/more timely pharmacovigilance tools  Signal detection (passive surveillance systems)  Signal strengthening and confirmation  Rapid cycle analysis (RCA) – statistical methods accounting for multiple sequential analyses of cumulative data in near real-time Increased communication/collaboration among U.S. agencies and internationally  Methods  Sharing of preliminary safety surveillance results  Signal validation and confirmation of potential associations

4. Federal H1N1 Influenza Vaccine Safety Data Monitoring Sources Vaccine Safety ProgramDescriptionPopulation Monitored CDC Vaccine Safety Datalink (VSD)A national active surveillance system monitoring medical record data of eight managed care organizations. 9.5 million Population-based active surveillance for Guillain-Barré Performs active case finding to detect Guillain-Barré syndrome following vaccination 45 million Clinical Immunization Safety Assessment (CISA) Network CISA will review case reports and has the potential to use repositories to collect specimens for in-depth investigation of selected AEFI for future study. US population Real-Time Immunization Monitoring System (RTIMS) An internet-based system conducted by Johns Hopkins University on behalf of CDC for active monitoring of health events after vaccination focusing on a sampling of school children, health care workers, and pregnant women. US population FDA & CDC Vaccine Adverse Event Reporting System (VAERS) A national surveillance system; accepts AEFI reports from providers, patients, family members, pharmaceutical companies and others. US population Post-Licensure Rapid Immunization Safety Monitoring (PRISM) An active surveillance system to link vaccination and subsequent health outcomes data from state vaccine registries and large health plans in several states. 30 million (17 million registry enhanced)

5. Federal H1N1 Influenza Vaccine Safety Data Monitoring Sources Vaccine Safety ProgramDescriptionPopulation Monitored DoD Defense Medical Surveillance System (DMSS) An executive information system whose database contains up-to- date and historical data on diseases and medical events (e.g., hospitalizations, ambulatory visits, etc) and longitudinal data on U.S. active duty military personnel 1.4 million VA Department of Veterans Affairs Databases (VA) Veterans (VA ADERs) & employees using VA health system1.2 million Integrated database of predominately VA patients for prospective tracking 918,000 CMS Centers for Medicare and Medicaid Services Database (CMS) CMS Medicare data (National Claims History File and Enrollment Database) can be used for retrospective and prospective vaccine safety studies, primarily among the elderly (age 65+ ). Data are for persons enrolled in fee-for-service Medicare. 38 million

6. Federal H1N1 Influenza Vaccine Safety Data Monitoring Sources Vaccine Safety ProgramDescriptionPopulation Monitored IHS Indian Health Service (IHS)The IHS will use its electronic health records to monitor selected health events that occur in temporal association with vaccination. 1. Enhanced VAERS Surveillance1.4 million 2. Signal Detection1.4 million BARDA Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) A collaboration of academic and professional investigators that currently monitors exposures such as medications taken during pregnancy. This system will monitor the relationship between receipt of 2009 H1N1 influenza vaccines, seasonal influenza vaccines, and influenza antiviral medications in pregnancy and subsequent maternal and fetal outcomes. 1. Prospective cohort study1,100 2. Case-control surveillance2,000

7. Vaccine Adverse Event Reporting System (VAERS) Contributors: Frank DeStefano (CDC) Claudia Vellozzi (CDC) Michael Nguyen (FDA/CBER)

8. Vaccine Adverse Event Reporting System (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

9. VAERS Methods Signal Detection  Case reviews (daily, CDC & FDA medical officers)  Disproportionality/data mining  Reporting rates (compare with seasonal vaccine) System enhancements  Improved communications with healthcare providers for more timely reporting  Increased staffing for more rapid VAERS report processing  Provision of influenza vaccination card upon vaccine receipt to facilitate reporting of manufacturer and lot number  Established system for electronic transmission of state-specific VAERS report data to states

10. 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 increase with heightened public awareness (e.g., media attention, serious event occurrence, MMWR release, other)

11. Estimated U.S. H1N1 Vaccine Distribution (as of 11/13/09) Total H1N1 Vaccine Distributed 36.9 million Live-attenuated 9.6 million (26%) Inactivated 27.3 million (74%)

12. H1N1 Reports to VAERS — United States, 2009 (as of 11/13/09) Total Reported Adverse Events 2,395 Nonserious 2,278 (95%) Serious 109 (5%) Live-attenuated 780 (34%) Inactivated 1498 (66%) Live-attenuated 33 (30%) Inactivated 76 (70%)

13. 10 Most Frequently Reported Adverse Events Among All Reports (as of 11/13/09) Preferred Term 1Pyrexia 2Headache 3Cough 4Dizziness 5Urticaria (hives) 6Vomiting 7Nausea 8Pain 9Pruritus (itching) 10Rash

14. CDC Review of VAERS Reports 205 reports currently under CDC review  All serious reports  Non-serious reports on adverse events of interest 70 of the 205 reports were among pregnant females  13 serious reports  57 non-serious reports  No maternal deaths Reviews complete in 40% of cases

15. H1N1 Reports to VAERS — United States, 2009 Anaphylaxis 29 reports were identified as potentially compatible with anaphylaxis based on review of VAERS  Medical records for these reports have been requested  The CDC team is currently reviewing these medical records to assess whether they are consistent with anaphylaxis  To date, after review, 7 are considered as consistent with anaphylaxis Reported rate consistent with published estimates of anaphylaxis after other vaccinations

16. H1N1 Reports to VAERS — United States, 2009 Deaths (as of 11/13/09) Total Reported Adverse Events 2,395 Non-serious 2,278 (95%) Serious 109 (5%) Live-attenuated 780 (34%) Inactivated 1498 (66%) Live-attenuated 33 (30%) Inactivated 76 (70%) Deaths 6 Deaths 2

17. Reports of Death to VAERS* (as of 11/13/09) Age (yrs) Sex Vaccine(s) Onset interval (days) Clinical Description 19 Female Oct 8 LAMV Oct 8 TIV 6 History of Down’s syndrome and leukemia (remission) Cough and limp several days before vaccination. Day of vaccination: white blood cell count = 2500/µL, hemoglobin = 7.5 g/dL Died in hospital 10/14/2009 Preliminary autopsy results: Growth of Streptococcus pneumoniae in lung tissue and molecular evidence of wild-type H1N1 influenza virus infection. No evidence for vaccine strain infection. 235 Female Oct 22 LAMV Oct 9 TIV 2 History of hereditary spherocytosis, post-splenectomy Received pneumococcal vaccination Dec 2007. Developed influenza-like symptoms 2 days after LAMV Admitted to hospital in respiratory distress w/multiorgan failure; died of septic shock (Streptococcus pneumoniae isolated on blood culture) Preliminary autopsy results: Molecular evidence of pneumoccocal infection in lung tissue. No evidence of wild-type H1N1 or vaccine strain infection 346 Female Oct 26 MIV Sept 10 TIV 1 History of hypertension, obesity, hyperlipidemia, deep venous thrombosis, and pulmonary embolism Seen as outpatient 1 day after MIV; diagnosed with URI, essential hypertension, low blood pressure, weight loss and fatigue Died 10/28/2009 at home. Preliminary autopsy results: Pulmonary embolus; negative for H1N1 influenza virus * Final autopsy reports and cause of death on death certificate are pending.

18. Guillain-Barré Syndrome After H1N1 Vaccination Guillain-Barré syndrome (GBS)  Autoimmune disorder causing injury to peripheral nerves  Associated with viral and bacterial infections and certain chronic medical conditions  Usually treatable  Affects both genders and occurs at any age  Background rate (U.S. population): ~140 cases/week  Shares features with other conditions; medical tests needed to confirm diagnosis 7 reports of potential GBS (as of 11/13/09)  2 cases consistent with GBS  1 classified as Brighton case definition Level 3 or “possible” GBS  1 classified as Brighton case definition Level 2 or “probable” GBS  2 reports did not meet diagnostic criteria  3 reports under review

19. Guillain-Barré Syndrome (GBS) – Case 1 69 yr male  Received 2009 H1N1 monovalent inactivated vaccine  Received seasonal TIV one month prior Pertinent history & clinical course  No history of other antecedent illnesses  Weakness ~12 hours following H1N1 vaccination  Physical exam: bilateral upper & lower extremity weakness; slightly diminished reflexes  Lumbar puncture: within normal limits  Nerve conduction studies: not completed Brighton case definition criteria  Level 3 (“Possible” GBS)  Clinical exam consistent with GBS Treatment  Received IVIG (as outpatient) and recovered

20. Guillain-Barré Syndrome (GBS) – Case 2 14 year old male  Received 2009 H1N1 monovalent inactivated vaccine 1 day prior Pertinent history & clinical course  Presentation: lower extremities: decreased strength and sensation, no reflexes; Arms: decreased strength  Physical exam: bilateral upper & lower extremity weakness, slightly diminished reflexes  Electromyography: positive for slowing  MRI-negative for transverse myelitis  Lumbar Puncture: negative for infection Brighton case definition criteria  Level 2 (“Probable” GBS) Treatment  Received IVIG (admitted to hospital) and discharged 4 days later

21. GBS After H1N1 Vaccination Preliminary Conclusions 2 cases confirmed as “possible or probable” GBS Short interval to symptom onset (≤1 day) decreases but does not eliminate the possibility that H1N1 vaccine caused the event To date: Rate of GBS reported < background GBS rate

22. VAERS Summary Daily review of all VAERS reports is ongoing To date, no indications or signals of H1N1 vaccine safety-related issues

23. Medicare Population Main Contributors: Dale Burwen (FDA/CBER) Jeffrey Kelman (CMS) H1N1 Influenza Vaccine Safety Team (FDA, SafeRx, Acumen LLC)

24. Vaccine Safety Monitoring in the Medicare Population Collaborative SafeRx project  Food and Drug Administration (FDA)  Centers for Medicare & Medicaid Services (CMS)  Acumen, LLC (CMS contractor) Population  38 million persons >65 years of age  8 million persons with disability or end-stage renal disease Objective  Develop rapid system to actively monitor vaccine safety

25. Medicare GBS Vaccine Safety Monitoring Methods Define risk interval  0–42 (also 0–21) days post-vaccination Define expected adverse event (AE) rate  Weighted mean of 5 prior flu seasons Monitor number of vaccinees  Total (sample size) and those with adverse events Define critical limits (e.g., 95 th percentile) of rates among sampling distribution Conduct group sequential testing  Accounts for testing multiple times Adjust for delay in claims accrual  Expected AE rate modified by delay in AEs derived from historical distribution of delay times

26. Signal Detection After Accounting for Delay in Claims

27. Next Steps if System Signals Signal does not indicate causal association Further evaluation may include  Data quality checks  Assessment of temporal clustering  Comparison with results from other surveillance systems  If further evaluation warranted, assess whether any of the available systems could be used for hypothesis confirmation (e.g., ICD-9-CD code validation)

28. Medicare Influenza Vaccine Safety Monitoring Preliminary Results ~9.2 million seasonal flu vaccinations (as of 11/10/09) ~56,000 H1N1 vaccine doses administered (as of 11/17/09) No GBS signal to date  Observed rate < Critical limit Monitoring is ongoing

29. Medicare Influenza Vaccine Safety Monitoring Conclusions Capable of near real-time surveillance Potential to add other clinical conditions if needed Provides powerful new tool for projects of benefit to Medicare population and public May serve as model for safety monitoring of other medical products received by the Medicare population

30. Department of Veterans Affairs (VA) Contributors: Fran Cunningham (VA) Wei Hua (FDA/CBER) Jerry Tokars (CDC)

31. VA Health Care System 153 medical centers ~800 outpatient clinics Population  ~ 4.9 million Veterans ( using VA for medications and health care )  Complex health care needs  Multiple morbidities  Disabilities  Mental health issues

32. VA ADERS National Database VA’s web-based Adverse Drug Event Reporting System (ADERS)VA’s web-based Adverse Drug Event Reporting System (ADERS)  National Program – Initiated March 2007  Standardization  Centralization  Medications and Vaccines  Benchmarking/Surveillance  Over 100,000 reports

33. VA Integrated Databases for Safety Monitoring Prescription databasesPrescription databases National patient care databasesNational patient care databases  Demographics, diagnoses, all visits, labs Mortality databaseMortality database OtherOther  Disease state registries (i.e. diabetes registry)  Local/regional data packages (immunization package)

34. VA H1N1 Influenza Vaccine Safety Activities: Passive Surveillance To facilitate reporting of H1N1 adverse events to VAERS Database: VA web-based ADERS Inactivated H1N1 vaccine  29,000 doses administered (as of 11/09/09)  4 adverse events total (as of 11/09/09)  All non-serious, including 1 whole-body rash Seasonal influenza vaccine  2.6 million doses ordered (as of 11/17/09)  47 adverse events total (as of 11/09/09)  1 GBS, 1 anaphylaxis, 1 angiodema*, 1 shortness of breath Summary:  No signals of concern from the VA passive surveillance * Use of ACE inhibitor reported in angioedema case

35. VA H1N1 Vaccine Safety Activities: Signal Detection and Confirmation Signal detection and confirmation  Rapid cycle analysis (RCA) (performed by CDC/VSD)  End of season analysis  Comparison with previous season rates  Risk interval analysis  Case series analysis Data  ~500,000 individuals  Pilot dataset with complete electronic data  Vaccinations  Hospitalizations  Outpatient and ED visits RCA anticipated to start late November 2009

36. Indian Health Service (IHS) Contributors: Amy Groom (IHS) John Redd (IHS) Jerry Tokars (CDC) Yandong Qiang (FDA/CBER) Andrea Sutherland (FDA/CBER) Hector Izurieta (FDA/CBER/AEB)

37. Indian Health Service (IHS) American Indian / Alaskan Native population 560 federally-recognized tribes from 35 states Eligible population: 1.9 million User population (>1 visit in last 3yrs): 1.4 million

38. IHS Influenza Vaccine Safety Data Resource & Patient Management System (RPMS) electronic health records at most sites Locally collected and maintained, with periodic exports to National Data Warehouse H1N1 & seasonal influenza vaccine status Pre-specified outcomes and onset intervals

39. IHS H1N1 Influenza Vaccine Safety Activities Passive surveillance  Enhanced reporting of H1N1 adverse events to VAERS Signal detection and confirmation  Rapid cycle analysis (RCA)  End-of-season analysis (risk interval analysis planned) Objectives  Proof-of-concept of IHS active surveillance for vaccine adverse events  Understand and respond to influenza vaccine adverse events among IHS patients

40. IHS Enhanced Passive Surveillance Methods Facilitate VAERS reporting for adverse events of interest (100% in select sites) Validate reports (quality control) Facilitate VAERS report completeness

41. IHS H1N1 Influenza Vaccine Safety Monitoring Preliminary Results 51,290 doses administered (as of 11/15/09) 39 adverse events reported (as of 11/15/09)  3 verified, reported to VAERS  1 Anaphylaxis: 31 yrs, received LAIV H1N1  1 Bell’s palsy: 33 yrs, received inactivated H1N1  1 Thrombocytopenia: 19 yrs, received inactivated H1N1  30 not related to vaccination  6 pending review Summary:  So far, system provides timely and thorough reporting of adverse events to VAERS

42. International Collaboration Main contributors: Hector Izurieta (FDA/CBER) Judith Badoo (FDA/CBER) Steve Black (NVPO) Robert Davis (Kaiser Permanente) Maria de los Angeles Cortes (PAHO) Dina Pfeiffer (WHO) Patrick Zuber (WHO)

43. Background Multiple H1N1 influenza vaccines developed/distributed worldwide in response to pandemic H1N1 vaccines used extensively in population groups not often vaccinated against influenza Limited capacity for epidemiological vaccine safety studies in many countries  Often rely on passive surveillance for post-marketing safety

44. Objectives Collaboration of U.S. federal agencies and WHO for worldwide 2009 pandemic H1N1 vaccine safety monitoring  Exchange information weekly on H1N1 vaccine safety surveillance  Improve vaccine safety surveillance systems for future use Proof-of-concept international epidemiological study  Using case series methodology  End-of-season analysis to investigate the association between GBS and H1N1 vaccines

45. Summary of Safety Monitoring of 2009 Pandemic H1N1 Influenza Vaccines

46. Pandemic H1N1 Influenza Vaccine Safety Monitoring Strengthened collaboration and communication among government agencies and internationally Enhanced capacity for timely signal detection, strengthening and confirmation Ongoing passive and near real-time safety surveillance Initial stages of end-of-season analyses have begun So far, no safety signals of concern in U.S.-licensed H1N1 vaccines nationally or internationally

47. Acknowledgements NVPO  Daniel Salmon  Steve Black CDC  Claudia Vellozzi  Frank DeStefano  Jerry Tokars  Karen Broder  Paul Gargiullo  Cindy Weinbaum KP  Robert Davis DoD  Patrick Garman VA  Fran Cunningham IHS  Amy Groom  John Redd CMS  Jeffrey Kelman  Chris Worrall Acumen, LLC  Thomas MaCurdy  Jonathan Gibbs  Bruno Garcia  Emil Rusev  Rosalind Gullett WHO  Patrick Zuber  Dina Pfeiffer Canada  Barbara Law PAHO  Maria Cortes Spain  Xavier Diez  Francisco Gimenez UK  Paddy Farrington

48. Acknowledgements FDA  Robert Ball  Rick Wilson  Hector Izurieta  Robert Wise  Andrea Sutherland  Douglas Pratt  Michael Nguyen  Dale Burwen  Wei Hua  Yandong Qiang  Laura Polakowski  Aysha Akhtar  Sukhminder Sandhu  Geetha Senthil  Judith Badoo  David Cho  Joan Blair  Jean Hu-Primmer  Marianthi Markatou  Richard Forshee  Sanjaya Dhakal