Monitoring the Safety Monitoring the Safety of of Influenza A (H1N1) 2009 Influenza A (H1N1) 2009

Monovalent VaccinesMonovalent Vaccines

Claudia Vellozzi, MD, MPHClaudia Vellozzi, MD, MPHImmunization Safety OfficeImmunization Safety Office

Division of Healthcare Quality Promotion Division of Healthcare Quality Promotion Centers for Disease Control and PreventionCenters for Disease Control and Prevention

Atlanta, GAAtlanta, GA

November 18, 2009November 18, 2009

Overall Objectives 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 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

Today’s Objectives

Describe the CDC’s Immunization Safety Office surveillance systems for monitoring the safety of 2009 H1N1 vaccine

Provide preliminary data from each of these systems

Routine SystemsEnhanced for 2009

H1N1

Vaccine Adverse Event Reporting System (VAERS)

Enhanced VAERS

Real Time Immunization

Monitoring System (RTIMS)

Clinical Immunization

Safety Assessment (CISA)

Vaccine Safety Datalink (VSD)

Post licensure Rapid

Immuniztion Safety Monitoring

Monitoring Influenza A (H1N1) 2009 Monovalent Vaccine Adverse Events

Signal Detection(Identification of

Potential Vaccine Adverse Events)

Verification of Signal

Defense Medical Surveillance

System (DMSS)

GBS Active Case Findings (EIP)

Collaborations: FDA, American Academy of Neurology (AAN), International, VA, IHS, CMS

Vaccine Safety Datalink (VSD): Background

Established in 1990 A collaborative project among CDC and 8 managed care

organizations (MCOs) Allows for planned immunization safety studies as well as timely

investigations arising from– hypotheses from medical literature and pre-licensure – reports to the Vaccine Adverse Event Reporting System

(VAERS)– changes in immunization schedules, or the introduction of new

vaccines Since 2005, conducts routine Rapid Cycle Analysis (RCA) of newly

licensed and approved vaccines or modifications to existing vaccine recommendations

VSD Population

Collects medical care and vaccination data on more than 9.5 million members annually (3.1% of the US population)

As of 12/31/2008: 2,252,024 children (<18) enrolled

– 3.0% of US population

7,245,835 adults (≥18) enrolled – 3.1% of US population

Average yearly birth cohort ~ 95,000

VSD Sites: 2009

Northwest Kaiser Permanente

No. CA Kaiser Permanente

Harvard Pilgrim

Group Health Cooperative

So. CA Kaiser Permanente

Kaiser Permanente Colorado

Health Partners

Marshfield Clinic

CDC

AHIP

VSD Data Files + Chart Review

Immunizations Records

Hospital discharge

diagnosis codesEnrollment and demographics

Birth and death certificate

information

Linked by Study IDs

Outpatient and Clinic visits

+

VSD 2009 H1N1 Vaccine Safety Monitoring Specific Aims

Conduct rapid surveillance of 2009 H1N1 vaccine safety using – self controlled case series (SCCS) using binomial

maximized sequential probability ratio tests (maxSPRT) – comparisons with historical seasonal influenza vaccines

using Poisson maxSPRT

Conduct comprehensive analyses after immunization program is completed of associations between H1N1 vaccine and adverse events using a variety of statistical methods – Confirmatory Logistic Regression, SCCS, others (as

needed)

SCCS Example

Vaccination

-------------------------------------------------------------------------------------------

Days -56 -15 0 42 84

Unexposed (pre) Exposed Unexposed (post)

VSD 2009 H1N1 Vaccine Adverse Events under surveillance

GBS – first ever and first in a year diagnosis, complemented by chart review Demyelinating disease Disorders of the peripheral nervous system and neuropathies Seizures (epilepsy, convulsions) Encephalitis, myelitis, encephalomyelitis Bell’s Palsy Other cranial nerve disorders (Facial nerve disorders, Trigeminal nerve disorders) Ataxia (other cerebellar ataxia, ataxia) Anaphylaxis Angioneurotic edema, Allergic Reaction, Urticaria Myocarditis and pericarditis (LAIV only) Hemorrhagic stroke (subarachnoid hemorrhage, intracerebral hemorrhage, other and

unspecified intracranial hemorrhage) Ischemic stroke (excludes transient ischemic attack) Wheezing (LAIV only)

Asthma, wheezing, respiratory distress/insufficiency, other diseases of trachea/bronchi Multiple definitions with and without bronchiolitis

Pregnancy Outcomes – Spontaneous Abortions, Stillborn & Pre-eclampsia, eclampsia

Adjuvanted Outcomes – Autoimmune hepatitis and Thrombocytopenia

VSD 2009 H1N1 Vaccine Pregnancy Studies

Active surveillance in pregnant women– Outcomes: Fever (>100° F),allergic

reactions, miscarriage, stillbirth, premature labor and preeclampsia (includes 2 VSD sites)

Retrospective analysis evaluating the safety of 2009 H1N1 vaccines in pregnant women and their offspring (includes all VSD sites)

VSD 2009 H1N1 Vaccine Pregnancy Studies

Conduct a survey of pregnant women who receive any combination of seasonal or H1N1 vaccines or refuse

vaccination (includes one VSD site)

Specific Aims Assess where and when pregnant women are vaccinated

and if not vaccinated—why not Accurately capture pregnancy related start dates for future

linkage with the electronic medical record Assess non-medically attended AEs

– Systemic and local reactions (Fever, chills, headache, swelling, etc.)

– ILI and URI symptoms, GI symtoms, sleep disturbances, other

VSD 2009 H1N1 Vaccine Doses Administered as of Nov 13, 2009

Age Group

Novel H1N1-09,

nasal (LAMV)

Novel H1N1-09, preservative-free

Novel H1N1-09, unknown formulatio

ns

Novel H1N1-09, inactivated

, no adjuvant Total

< 25 104,741 2,275 4,948 92,019 203,983

25-49 15,619 1,429 5,898 54,315 77,261

50-64 446 740 4,840 34,915 40,941

65+ 137 67 491 4,213 4,908

Total 120,943 4,511 16,177 185,462 327,093

206,150 Inactivated Doses

VSD 2009-10 Seasonal Vaccine Doses Administered as of Nov

13, 2009

Age Group LAIV TIV Total

<25 81,838 524,549 606,387

25-49 17,749 455,141 472,890

50-64 498 507,813 508,311

65+ 281 557,624 557,905

Total 100,366 2,045,127 2,145,493

VSD 2009-10 Seasonal Influenza Vaccine Safety

Preliminary Findings

2009-10 Seasonal Trivalent Inactivated Influenza Vaccine

(TIV): SCCS –preliminary results

Outcome Window

(days) ObservedComparison

Window RR Signal

Demyelinating Disease 1-42 87 245 0.71 No

Disorders of Peripheral Nervous System 1-42 1108 2689 0.82 No

Seizures 0-7 61 48 1.27 No

Encephalitis/myelitis/encephalomyelitis 1-21 1 6 0.33 No

Bell's Palsy, 1-42 1-42 125 148 0.84 No

Bell's Palsy, 1-60 1-60 128 153 0.84 No

Other Cranial Nerve Disorders 1-42 140 439 0.64 No

Ataxia 1-42 9 19 0.95 No

Anaphylaxis 0-2 1 2 0.50 No

Allergic reactions 1-2 234 175 1.34 No

Total Doses Administered– 2,045,127

2009-10 Seasonal TIV Historical Comparison-

preliminary results

OutcomeWindow (Days)

Age Group Observed Expected RR Signal

GBS 1-42 >=6m 7 7.5 0.9 No Demyelinating diseas 1-42 6m-24y 4 3.8 1.0 NoDisorders of Peripheral Nervous System 1-42 6m-24y 18 22.1 0.8 No Encephalitis 1-21 >=6m 1 3.6 0.3 No Bell's palsy 1-42 1-42 6m-24y 4 13.2 0.3 No Bell's palsy 1-60 1-40 6m-24y 4 11.7 0.3 No Other Cranial Nerve Disorders 1-42 6m-24y 4 5.8 0.7 No Ataxia 1-42 >=6m 9 13.8 0.7 No Anaphylaxis 0-2 >=6m 1 2.1 0.5 No

Total Doses Administered: 2,045,127

VSD 2009 H1N1 Safety Preliminary Findings

2009 H1N1 MIV: Historical Comparison- Preliminary Results

OutcomeWindow (Days)

Age Group Observed Expected RR Signal

GBS 1-42 >=6m 0 0.1 0.0 No Demyelinating Disease 1-42 6m-24y 0 0.1 0.0 NoDisorders of Peripheral Nervous System 1-42 6m-24y 2 0.4 4.8 No Encephalitis 1-21 >=6m 0 0.1 0.0 No Bell's palsy 1-42 1-42 6m-24y 0 0.2 0.0 No Bell's palsy 1-60 1-60 6m-24y 0 0.2 0.0 No Other Cranial Nerve Disorders 1-42 6m-24y 1 0.1 11.8 No Ataxia 1-42 >=6m 0 0.1 0.0 No Anaphylaxis 0-2 >=6m 1 0.1 15.6 No

Total Doses Administered – 206,150

Summary

No potential associations or signals have been identified following the monitoring of 2009-10 Seasonal TIV (2,045,127) and LAIV (100,366) doses

2009 H1N1 influenza vaccines have only recently

begun to be administered in the VSD MCOs and data are insufficient to assess the safety of the vaccines

The VSD will continue to monitor both seasonal and H1N1 influenza vaccines on a weekly basis

EIP Guillain-Barré Syndrome (GBS) Surveillance Project:

Association of Influenza A (H1N1) 2009 Vaccine and GBS

EIP GBS Surveillance Sites, 2009-2010

Connecticut

Colorado

Oregon

California

Tennessee

Georgia

Maryland

New YorkMinnesota

Population: ~ 44.9 million

New Mexico

EIP Guillain-Barré Surveillance (GBS) Surveillance Project

CDC's Emerging Infections Program (EIP)– partnership of state and local health departments, academic

centers, and CDC – performs surveillance and public health research on emerging

infections October 1, 2009 time limited surveillance for GBS Objectives:

– Rapidly detect cases of GBS and report (with vaccination status)– Assess and measure if there is an association between 2009

(H1N1) vaccine and GBS Methods:

– Population ~45 million persons (statewide in CT, MD, MN, NM, TN and selected regions of CA, CO, GA, NY, and OR)

– Active network of neurologists and acute care facilities contacted weekly

– Report all GBS cases, standardized case finding, medical record abstraction, patient interviews

– Calculation of measures of association

EIP Guillain-Barre Surveillance Case Finding

* Weekly query with established network of neurology providers, sentinel pharmacies

Additional: Hospital dischargesPassive provider reporting (reportable condition)AAN educational initiative;VAERS

10 EIP (40 million)

Exclusion (non-cases)[Brighton not met or other

neurologic diagnosis]

reported weeklyto CDC

Clinical Network * Active Case-Finding Possible

Cases

Confirmed

Probable

Indeterminate

Record review; contact provider;

antecedent & vaccine history

Brighton1, 2

Brighton3

Info pending

Re-assess at 14 days

Pat

ient

Inte

rvie

ws

Descriptive Epidemiology of GBS Active Case Finding, Oct 1-Nov 9,

2009Confirmed (Brighton Case Definition* Level 1 /2) 9

Probable (Brighton Case Definition Level 3) 1

Indeterminate (Brighton Criteria Not Available) 6

Non-Case (Brighton Clinical Criteria Not Met) 8

Case under investigation 17

TOTAL 41

*www.Brightoncollaboration.org

Descriptive Epidemiology of GBS Active Case Finding, Nov 9, 2009

Characteristic + H1N1 vaccine

- H1N1 vaccine

Vaccine unknown/ missing/

Total

n (%) n (%) n(%) n (%)

Case Status

Confirmed (Brighton Level 1 and 2)

0 (0.0) 5 (83.3) 4(100.0) 9 (90.0)

Probable (Brighton Level 3)

0 (0.0) 1 (16.7) 0 (0.0) 1 (10.0)

TOTAL 0 (0.0) 6(100.0) 4(100.0) 10(100.0)

Age (years)

0-24 0 (0.0) 2 (33.3) 1 (25.0) 3 (30.0)

25-49 0 (0.0) 2 (33.3) 1 (25.0) 3 (30.0)

50-64 0 (0.0) 2 (33.3) 2 (50.0) 4 (40.0)

65+ 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Select Methods Using Vaccine Coverage Data

Observed vs. historical GBS rates– Compares observed no. GBS cases occurring within 42 days of H1N1

vaccination to expected no. among vaccinees– Earliest incidence metric– Limitations:

historical rate comparison (may not be valid comparison, different case finding)

Initially only crude, or age-specific with assumptions on vaccine administration

With BFRSS data, fewer assumptions needed for age-specific comparisons

GBS rates in vaccinated vs. unvaccinated persons– Use BFRSS vaccine coverage data, calculate person-time exposed and

unexposed to vaccine, calculate rates– Strength: rates in vaccinated and unvaccinated persons will both be

calculated from active surveillance data– Limitations

BRFSS data not available until mid-November and may only be available at the state level (not EIP catchment area specific)

GBS rates in H1N1 vaccinated vs. seasonal vaccine recipients– Use BFRSS vaccine coverage data– Age-adjust

Real Time Immunization Monitoring System (RTIMS)

Contributors: Johns Hopkins Bloomberg School of Public Health

(JHU) CDC ISO (AHIP) WorldAPP (WA) State and local health departments (HD) Hospitals, schools, clinics, pharmacies

RTIMS Automated web-based surveillance system Captures self reported data from vaccine recipients Predecessor: Telewatch

– Used for monitoring patients with chronic diseases– Modified for monitoring yellow fever vaccine1

– Piloted for influenza vaccine November 2008 Capacity:

– On line and database: 1-10 million vaccine recipients– Follow-up personnel: expandable

Objectives

1. To monitor influenza vaccine recipients for adverse events (early signal detection)

2. To identify host factors associated with adverse events

3. To compare rates of adverse events associated with different influenza vaccine products

4. To expedite reporting of AEs to VAERS

Study Population

Seasonal & 2009 H1N1 Influenza vaccine recipients Target population – Pregnant women, health care workers, school

aged children

State & local health departments, hospitals, schools and OB clinics

Timeline for Surveys

2nd Follow-up

1st Follow up

Day 2 Day 7 Day 42

Baseline survey

PregnancyFollow-up?

Study Information CardProvided at Time of

Vaccination Front Back

RTIMS Information Flow

Electronic(Registries)

RTIMS Survey

Permission to Contact at Time of Vaccination

JHUData entryFormatting

VaccineRecipient

WorldAPP

WeblinksCDC, JHU, HDs

Paper

or

linkwww.myflushot.org

or

www.myflushot.orgwebsite sign-up

3-4 min initial<1 min follow-up

State Participation - Active Capture

(31 Contacted)

On Board Considering Declined PRISM

CO, IN, MD, RI, UT, WV, NC, NJ, KS

IL, WA AK, AR, CT, DC, IA, MA, ME, MT, MS, ND,NY, OK, SC, TN, VA, VT

AZ, FL, GA, MI, MN, PA, WI

4,730 Baseline Surveysby Risk Group and Gender

as of Nov 9, 2009

Type of Vaccine Received by Risk Group

as of Nov 9, 2009

Diagnoses after Flu Vaccineby Vaccine

as of Nov 9, 2009

Limitations

Surveys after vaccination Possible selection bias:

– Females more likely to participate– Persons with reactions more likely to complete?– Drop outs?

Some reluctance to have VAERS form filed– name and contact information

Active solicitation of symptoms– Some multiple symptoms

Acknowledgements VSD

– Eric Weintraub– James Baggs– Frank DeStefano

CDC/EIP– Melissa Viray– Paige Lewis– Oliver Morgan– Scott Fridkin

RTIMS– Neal Halsey– Rosanna Setse

Extra slides

The VSD Distributed Data Model

CDC

Hub

“Direct”

“Indirect”

SAS Programs,

Logs, Output, & Analytical Datasets

VSD 2009 H1N1 Vaccine Study Design and Analytic Plan

Challenges for studying the safety of influenza vaccines – Confounding by indication – Vaccine recommendations have expanded and changed – Influenza vaccines are often given over a very short period

of time.– Individuals may have received vaccine outside their MCO

(count as unvaccinated) – Seasonality of adverse events may confound interpretation

To address the challenges to monitor 2009 H1N1 safety more than one approach will be included in both:– Rapid Cycle Analyses (RCA) weekly surveillance (near real

time and critical to rapid safety assessment)– End of season analysis

VSD Methodological approaches in evaluating H1N1 vaccine

safety

VSD 2009 H1N1 Vaccine Adverse Event Definitions

Risk periods (windows)– AE-specific as described in published studies or

biologic plausibility – Length of windows – vary from 2 to 60 days– Day of vaccination included in the risk period if it is

biologically plausible for AE to occur same day of vaccination (e.g., anaphylaxis).

To improve the specificity– Limit to AEs occuring in inpatient or ED settings– First event to occur in a year

For AEs that may have more than one “new” onset in a year a shorter period of time will be included in analysis (ex;wheezing, seizures)

How the VSD Evaluates Signals

1. Check data quality

2. Check inputs, background incidences, i.e. temporal trends

3. Check whether comparison groups are defined appropriately

4. Conduct the analysis using a different control group (e.g., concurrent vs. historical) or different vaccine

4. Conduct a temporal scan to see if outcomes cluster during a post-vaccination time window

5. Conduct a definitive study using logistic regression analysis

6. Review charts to confirm or exclude cases as true cases

Weekly maxSPRT Results for GBS, Age ≥6 Months, 2007/08 Season

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800

1200

1600

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IV d

oses (

1000s)

LLR critical value for maxSPRT

Relative risk

Log likelihood ratio (LLR)

Cumulative TIV doses

VSD Investigators and Collaborators - Partial List

Centers For Disease Control, VSD team James Baggs, PhD Julianne Gee, MPH Natalie McCarthy, MPH Eric Weintraub, MPH

Kaiser Permanente of No. California (NCK), Oakland CA Roger Baxter, MD Nicky Klein, MD, PhD Ned Lewis

Northwest Kaiser Permanente (NWK), Portland OR Allison Naleway, PhD John Mullooly, PhD Karen Riedlinger Lois Drew

Harvard Pilgrim /Harv. Vanguard (HAR)Boston, MA Tracy Lieu, MD, MPH Richard Platt, MD, MSc Katherine Yih, PhD, MPH Richard Fox Grace Lee, MD, MPH Sharon Greene, MD, MPH

Group Health Cooperative (GHC), Seattle WA Lisa Jackson, MD, MPH Jennifer Nelson, PhD Lora Bounds

Marshfield Clinic Rsch. Foundation (MFC)Marshfield WI Edward Belongia, MD James Donahue, MD Nick Berger

Health Partners Rsch Foundation (HPM)Minneapolis MN Jim Nordin, MD Amy Butani

Kaiser Permanente of Colorado (KPC)Denver, CO Simon Hambidge, MD, PhD Jason Glanz, MS, PhD David McClure, PhD Matt Daley, MD David Ryerson

So. California Kaiser Permanente (SCK), CALos Angeles, CA Steven Jacobson, MD, PhD Wansu Chen, MS Sungching Glenn, MS

Sites include > 125 staff working on VSD

EIP Guillain-Barre Surveillance Timeline

Vaccine Delivered

OCT NOV DEC JAN MARFEB MAYAPR

Case Only Methods:

Descriptive Epidemiology

Observed vs. Background Rates of GBS:

Crude and Age-Specific Comparisons

Estimated GBS Rates in Vaccinated vs. Unvaccinated Persons:

Crude and Age-Specific Comparisons

Case-Cohort analysisBRFSS Vaccine

Coverage Data Available

Potential Analytic Studies:

Self Control Case Series (SCCS)

4,790 Completed Baseline Surveysby Risk Group and Age Group

as of Nov 9, 2009

Diagnoses after Flu Vaccineby Gender

as of Nov 9, 2009

Daily Visits to http://www.myflushot.org

Links clicked on to arrive at http://www.myflushot.org

HITS Entry Link________________________________________________________

3615 http://www.cdc.gov/h1n1flu/vaccination/public/vaccination_qa_pub.htm3486 Unknown1240 http:// www.cdc.gov/h1n1flu/vaccination/vaccine_safety_qa.htm1123 Entered URL directly917 http:// www.cdc.gov/h1n1flu/vaccination/589 http:// www.cdc.gov/h1n1flu/vaccination/vaccine_keyfacts.htm564 http:// www.cdc.gov/H1N1flu/vaccination/pregnant_qa.htm358 http:// www.cdc.gov/h1n1flu/vaccination/gbs_qa.htm327 http:// www.cdc.gov/h1n1flu/vaccination/vaccine_safety.htm303 http:// www.in.gov/flu/178 http:// www.cdc.gov/h1n1flu/vaccination/general.htm105 http:// cdc.gov/h1n1flu/vaccination/public/vaccination_qa_pub.htm103 http:// www.in.gov/flu/2443.htm94 http:// www.vaccinesafety.edu/

>60% of traffic comes from the CDC

2009-10 Seasonal TIV Historical Comparison-

preliminary results

Window

(days)

Age Observed Expected RR signal

GBS 1-42 >6 mos 7 7.5 0.9 NO

Encephalitis 1-21 >6 mos 1 3.6 0.3 NO

Ataxia 1-42 >6 mos 9 13.8 0.7 NO

Anaphylaxis 0-2 >6 mos 1 2.1 0.5 NO

Total Doses Administered: 2,045,127