Safety Monitoring of 2009 Pandemic H1N1 Influenza Vaccines VRBPAC meeting November 18, 2009...

Safety Monitoring of2009 Pandemic H1N1 Influenza Vaccines

VRBPAC meeting

November 18, 2009

Presented by:•Hector Izurieta (FDA/CBER)Compiled by:•Laura Polakowski (FDA/CBER)

2009 Pandemic H1N1 Influenza VaccineSafety 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

Pandemic H1N1 Influenza VaccineSafety 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

Federal H1N1 Influenza Vaccine Safety Data Monitoring Sources

Vaccine Safety Program Description Population 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)



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 system 1.2 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



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 Surveillance 1.4 million

2. Signal Detection 1.4 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 study 1,100

2. Case-control surveillance 2,000

Vaccine Adverse Event Reporting System(VAERS)

Contributors:•Frank DeStefano (CDC)•Claudia Vellozzi (CDC)•Michael Nguyen (FDA/CBER)

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

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

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)

Estimated U.S. H1N1 Vaccine Distribution(as of 11/13/09)

Total H1N1 Vaccine Distributed36.9 million

Live-attenuated9.6 million (26%)

Inactivated27.3 million (74%)

H1N1 Reports to VAERS — United States, 2009(as of 11/13/09)

Total Reported Adverse Events 2,395

Nonserious2,278 (95%)

Serious109 (5%)

Live-attenuated780 (34%)

Inactivated1498 (66%)


Inactivated76 (70%)

10 Most Frequently Reported Adverse EventsAmong All Reports (as of 11/13/09)

Preferred Term

1 Pyrexia

2 Headache

3 Cough

4 Dizziness

5 Urticaria (hives)

6 Vomiting

7 Nausea

8 Pain

9 Pruritus (itching)

10 Rash

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

H1N1 Reports to VAERS — United States, 2009Anaphylaxis

• 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

H1N1 Reports to VAERS — United States, 2009Deaths

(as of 11/13/09)

Total Reported Adverse Events 2,395

Non-serious2,278 (95%)

Serious109 (5%)


Inactivated1498 (66%)


Inactivated76 (70%)

Deaths 6

Deaths 2

Reports of Death to VAERS*(as of 11/13/09)

Age (yrs)

SexVaccine(s)

Onset interval(days)

Clinical Description

1 9Female

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.

2 35Female

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

3 46Female

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.

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

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

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

GBS After H1N1 VaccinationPreliminary 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

VAERS Summary

• Daily review of all VAERS reports is ongoing• To date, no indications or signals of H1N1 vaccine

safety-related issues

Medicare Population

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

Vaccine Safety Monitoringin 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

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., 95th 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

Signal Detection AfterAccounting for Delay in Claims

Comparison of Upper Bounds With and Without Delay Window 42 days; Comparator 2004-2007

0

1

2

3

4

5

6

7

8

9

10

18/14

59/11

910/9

1311/6

1712/4

211/1

251/29

292/26

333/26

374/23

Process Week

AE

Rate

(p

er

millio

n)

.

Observed Rate 2008 Upper Bound - No delay Upper Bound - With delay

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)

Medicare Influenza Vaccine Safety MonitoringPreliminary 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

Medicare Influenza Vaccine Safety MonitoringConclusions

• 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

Department of Veterans Affairs (VA)

Contributors:•Fran Cunningham (VA)•Wei Hua (FDA/CBER)•Jerry Tokars (CDC)

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

VA ADERS National Database

• VA’s web-based Adverse Drug Event Reporting System VA’s web-based Adverse Drug Event Reporting System (ADERS)(ADERS) National Program – Initiated March 2007National Program – Initiated March 2007 StandardizationStandardization CentralizationCentralization Medications and VaccinesMedications and Vaccines Benchmarking/SurveillanceBenchmarking/Surveillance Over 100,000 reportsOver 100,000 reports

VA Integrated Databasesfor Safety Monitoring

• Prescription databasesPrescription databases• National patient care databasesNational patient care databases

Demographics, diagnoses, all visits, labsDemographics, diagnoses, all visits, labs

• Mortality databaseMortality database• OtherOther

Disease state registries (i.e. diabetes registry)Disease state registries (i.e. diabetes registry) Local/regional data packages (immunization package)Local/regional data packages (immunization package)

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

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

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)

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

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

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

IHS Enhanced Passive SurveillanceMethods

• Facilitate VAERS reporting for adverse events of interest (100% in select sites)

• Validate reports (quality control)• Facilitate VAERS report completeness

IHS H1N1 Influenza Vaccine Safety MonitoringPreliminary 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

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)

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

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

Summary of Safety Monitoring of2009 Pandemic H1N1 Influenza Vaccines

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

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

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

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