Safety of Quadrivalent Human Papillomavirus (HPV4) Vaccine

Advisory Committee on Immunization Practices Meeting October 25, 2011

Julianne Gee, MPH Immunization Safety Office Centers for Disease Control and Prevention

Presentation Outline
Describe sources of HPV4 safety data Review of HPV4 pre-licensure data Review of US surveillance HPV4 safety data Review post-licensure commitments Review findings from 2011 Institute of Medicines report of adverse events and vaccines

Sources of Safety Data for HPV4

Pre-licensure trials Post-licensure safety monitoring and evaluation
US Vaccine Safety Surveillance Systems:
Passive :
Vaccine Adverse Event Reporting System (VAERS)

Active:
Vaccine Safety Datalink (VSD) Rapid Cycle Analysis

Manufacturer post-marketing commitments*

* Bonani P, et al. A summary of the post-licensure surveillance initiatives for GARDASIL/SILGARD. Vaccine 2010

HPV4 Pre-licensure Studies*

Entire study population: 29,323
Girls and women (9-45 yrs) Boys and men (9-26 yrs)

Serious systemic adverse events (SSAEs):

Most frequent SSAEs reported in any study arm:
Headache, gastroenteritis, appendicitis, pelvic inflammatory disease, urinary tract infection, pneumonia, pulmonary embolism, bronchospasm, asthma

0.04% SSAEs considered to be vaccine-related 40 deaths: events reported consistent with events in healthy adolescent and adult populations

HPV4 licensed in June, 2006 for females 9-26 yrs

* FDA, Product approval-prescribing information [package insert] http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM094042

Vaccine Adverse Event Reporting System (VAERS)

National post-licensure passive surveillance system Co-managed by CDC and FDA Early warning system for vaccine safety surveillance
Monitors for known adverse events (AEs) Detects signals for previously unrecognized or rare AEs Generates hypotheses for further study

Limitations
Reporting biases Incomplete data Lack of availability of denominator data Not designed to assess for causality

Summary of HPV4 VAERS US Reports

Published Post-licensure Safety Surveillance * Reporting Dates Doses Distributed Total VAERS reports Serious (%) 6/1/06-12/31/08 23,051,336 12,424 6.2% Injection site reactions, syncope, headache, hypersensitivity, Guillain Barr Syndrome (GBS), transverse myelitis, motor neuron disease, venous thromboembolic events (VTE), pancreatitis, autoimmune disorders, pregnancy , death Safety profile consistent with pre-licensure data, with exception of VTE and syncope Updated PostLicensure Safety Surveillance 6/1/06-9/15/2011 ~40 million doses** 20,096 7.2% Continued monitoring, including assessment of specified AEs

Specific AEs assessed

Assessment

No new adverse event concerns or clinical patterns identified

*SladeB,LeidelL,VellozziC,etal.JAMA.PostlicensureSafetySurveillanceforQuadrivalent Human Papillomavirus RecombinantVaccine.2009;302(7):750757 **Permissiongrantedbymanufacturertopresentdoseinformation SeriousdefinedasaneventresultinginDeath,Lifethreateningillness,Hospitalization,Prolongation ofexistinghospitalization,Persistentorsignificantdisability

Summary of VAERS HPV4 Reports June 1, 2006 - September 15, 2011

Characteristics Total reports* Median Age (Range)** Age group (years) <9 9-10 11-12 13-18 19-26 >26 Unknown
* Unknown gender= 452 (2.2%) ** Includes reports in children < 1 yr

All (N,%) 20,096

Female (N,%) 19,075 (94.9%)

Male (N,%) 569 (2.8%)

17 yrs (0-82) 109 (0.5) 289 (1.4) 2158 (10.7) 8774 (43.7) 5061 (25.2) 427 (2.1) 3278 (16.3)

17 yrs (0-82) 77 (0.4) 270 (1.4) 1994 (10.4) 8443 (44.3) 4997 (26.2) 401 (2.1) 2893 (15.2)

14 yrs (0-77) 27 (4.7) 16 (2.8) 149 (26.2) 285 (50.1) 40 (7.0) 23 (4.0) 29 (5.1)

Summary of VAERS HPV4 Reports June 1, 2006 - September 15, 2011

Characteristics Total reports* Serious**- fatal - non-fatal Non-serious Reported by- Manufacturer - Provider Received HPV4 only Median onset interval from vaccination to adverse event (range) All (N, %) 20,096 71 (0.3) 1,456 (7.2) 18,569 (92.4) 12,378 (61.6) 4,152 (20.6) 15,201 (78.6) 0 days (0-1,977) Female (N, %) 19,075 (94.9%) 57 (0.3) 1,415 (7.4) 17,603 (92.2) 11,866 (62.2) 3,839 (20.1) 14,550 (76.2) 0 days (0-1,977) Male (N,%) 569 (2.8%) 3 (0.5) 30 (5.2) 530 (94.2) 135 (23.7) 288 (50.6) 251 (44.1) 0 days (0-433)

* Unknown gender= 452 (2.2%) ** Serious defined as an event resulting in Death, Life-threatening illness, Hospitalization, Prolongation of existing hospitalization, Persistent or significant disability Day 0 = Day of vaccination

Most Frequently Reported Terms for Non-serious and Serious Reports Following HPV4 in VAERS
Non-serious (N=18,569)
MedDRA Preferred Terms* Syncope Dizziness Nausea Headache Injection site pain Drug exposure during pregnancy Pyrexia Loss of consciousness Urticaria Pain in extremity % 14.5 13.7 9.3 8.3 7.0 6.8 6.3 5.9 4.9 4.9

Serious (N=1,527)
MedDRA Preferred Terms* Headache Nausea Fatigue Dizziness Vomiting Pyrexia Computerized tomogram normal Syncope Asthenia Pain % 25.0 18.6 17.4 16.8 14.7 13.7 13.0 12.6 11.7 11.6

* As coded using the MedDRA preferred terms, more than one code may be assigned to a single event

: VAERS Serious Reports of Syncope Following HPV4*

Total number of serious reports: 202 Injuries resulting from syncopal event:
Fractures (nose, skull, maxillary) Dental injuries Contusions Concussions Intracranial hemorrhages (subdural hematoma, subarachnoid hemorrhage)

No reports of death resulting from injury following a vasovagal syncopal event

* Unverified reports coded as syncope or syncope vasovagal

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VAERS Reports of Anaphylaxis

Total number of reports: 43*
All female Serious reports: 20

Median age (range): 17 years (11-27) Median onset from vaccination to event: 0 days (0-10) Confirmed anaphylaxis: 12
All treated and recovered

No confirmed deaths due to anaphylaxis

*Reports coded with MedDRA terms: anaphylactic shock, anaphylactic reaction, anaphylactoid shock, anaphylactoid reaction

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VAERS: Reports of Death Following HPV4

Total Death Reports N= 71

Verified* N= 34

Unconfirmed N= 37

Female N= 32

Male N=2

Hearsay** N=28

Other** N=9

*Deaths verified by autopsy, death certificate, or provider confirmation ** Hearsay: Reports with no identifying information for follow-up. Other: Under investigation

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VAERS Verified Reports of Death (N=34)

Characteristic Female Median age (range) Median days vaccination to death HPV dose closest to death Dose 1 Dose 2 Dose 3 Concomitant vaccinations Received HPV4 only Received concomitant vaccination Not documented 15 13 6 15 8 11 32(94%) 17 yrs (10-37) 15 days (2-745)

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VAERS Verified Reports of Death

Reported causes of death after clinical review with median onset interval:
Neurological: 7 (seizures [5]; ALS [2])
53 days (13-745)

Cardiac: 7 (arrhythmia [3]; myocarditis [3]; congenital)

9 days (2-25)

Pulmonary embolism: 4
14.5 days (13-181)

Infectious: 5 (Group A Strep [2]; N. meningitidis, MRSA; HIV-CNS vasculitis)

29 (4-117)

Other non-infectious: 4 (suicide; type 1 DM DKA; drug overdose; dermatomyositis)

35 (2-594)

Undetermined cause of death: 7

17 (2-121)

No patterns in verified death events

* Median onset interval from vaccination to death (range)

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Summary of HPV4 VAERS Reports: Males

Total VAERS reports: 569*
Pre-licensure reports (6/1/06-10/15/09): 65 Post-licensure reports (10/16/09-9/15/11): 504

Serious Reports: 33 (5.8%) HPV4 given alone: 44% Median age (range) 14 yrs (0-77) Median onset interval from vaccination to event (range): 0 days (0-433)

* Reports from June 1, 2006-Sept 15, 2011

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Most Frequently Reported Terms for Non-serious and Serious Reports Among Males Following HPV4 in VAERS
Non-serious (N=536)
MedDRA Preferred Terms* %

Serious (N=33)
MedDRA Preferred Terms* %

Dizziness Syncope Injection site erythema Pallor Nausea Pyrexia Headache Wrong drug administered Injection site swelling Fall

18.8 15.3 10.0 9.0 8.4 7.7 7.6 7.4 7.2 6.3

Pyrexia White blood cell count increased Nausea Pain in extremity Blood glucose increased Dyspnea Cough Muscular weakness Abdominal pain Chest pain

27.3 24.2 24.2 21.2 21.2 18.2 18.2 18.2 18.2 18.2

* As coded using the MedDRA preferred terms (PT), More than one code may be assigned to a single event

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HPV4 Male Serious Reports

Total male serious reports: 33
3 deaths: 2 verified; 1 hearsay 1 female incorrectly coded as male

Serious non-fatal reported categories (n=29)

Neurological: 9 (Guillain Barr syndrome
[4]; seizures [2]; altered mental status; transverse myelitis; acute dystonic reaction)

Immune/Allergic: 4 (Stevens-Johnson syndrome; allergic reaction [2],

serum sickness)

Cardiac: 2 (myocarditis; pericarditis) Gastrointestinal: 4 (acute pancreatitis [2]; appendicitis; colon cancer) Infectious: 2 (cellulitis; diarrhea) Other: 8 (syncope/presyncope [3]; pulmonary embolism; osteitis pubis;
DM type 1; sickle cell disease; spontaneous pneumothorax)

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VAERS Verified Male Reports of Death

Myocarditis
Age: 10 yrs Days from vaccination to death: 9 days Received other vaccines on same day
Meningococcal, Hepatitis A, Tdap, HPV4 (Dose 1)

No past medical history

Obstructive congenital subaortic membrane

Age: 15 yrs Days from vaccination to death: 25 days Received only HPV4, Dose 1 Past medical history: asthma; cardiac disorder
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Vaccine Safety Datalink (VSD)

Collaboration between CDC and 10 managed care organizations
Data from ~9.8 million members captured annually (~3% of US population)
Group Health Cooperative Northwest Kaiser Permanente HealthPartners Harvard Pilgrim

No. CA Kaiser Permanente Kaiser Permanente Colorado

Marshfield Clinic

So. CA Kaiser Permanente

Kaiser Permanente Georgia CDC

Kaiser Permanente Hawaii

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Rapid Cycle Analysis (RCA)

Alternative to traditional post-licensure vaccine safety study methods, which generally take years to complete Basics of RCA vaccine safety monitoring:
Tests specific hypotheses with well-defined outcomes Each week, evaluate the number of events in vaccinated persons Compare to the expected number of events based on a comparison group
Historical or concurrent

Weekly analyses with statistical adjustment for multiple looks

RCA is not intended to be final answer

Potential associations (signals) need further study to determine whether signals are real or spurious
Lieu TA, et al. Real-time vaccine safety surveillance for the early detection of adverse events. Med Care. 2007 Oct;45:S89-95.

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VSD HPV4 Rapid Cycle Analysis Results

VSD active surveillance confirmed no significant risk for any of the pre-specified adverse events after vaccination
GBS, seizures, syncope, appendicitis, stroke, VTE, and other allergic reactions Additional study is needed for a possible non-statistical association between HPV4 and VTE
All confirmed cases had other risk factors for VTE

No increase in rate of anaphylaxis following HPV4 as compared to previous VSD studies

* Gee J, et al. Monitoring the Safety of Quadrivalent Human Papillomavirus Vaccine: Findings from the Vaccine Safety Datalink Vaccine. 2011 (in press)

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VSD HPV4 Vaccine Monitoring and Evaluation: Next Steps

Long-term surveillance of GBS and stroke
Currently ongoing

VTE self-controlled case series analysis

Currently ongoing

RCA of HPV4 in males

Awaiting sufficient uptake

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Manufacturer HPV4 Post-Licensure Commitments

Multiple ongoing studies*
A Post-Licensure Surveillance Program for the Safety of GARDASIL in a Managed Care Organization Setting (Protocol 31) The Nordic long-term follow up study (Protocol 15) A long-term immunogenicity, safety, and effectiveness study of GARDASIL among adolescents who received GARDASIL at 9-15 yrs of age (Protocol 18)
* Bonani P, et al. A summary of the post-licensure surveillance initiatives for GARDASIL/SILGARD. Vaccine 2010

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Nordic Long-term Follow-up Study:

Population: 5400 women vaccinated between ages 16-26 yrs
Includes 600 that received placebo only

Duration of planned study follow-up: ~14 yrs Safety endpoints:

Death, cancers, hospitalizations and other safety outcomes assessed by using patient registries

Interim analysis findings:

Vaccine is generally safe and is well-tolerated for a mean of 6 years following vaccination

Saah A. HPV4 vaccine: Duration of Protection presentation to ACIP. June 2011

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Long-term Study of Gardasil in Adolescents

Population: 1661 adolescents vaccinated between ages 9-15 yrs Duration of planned study follow-up: ~10 yrs Findings at first interim analysis:
Safety is similar to that observed in pre-licensure studies HPV4 is generally well-tolerated over the long-term

Saah A. HPV4 vaccine: Duration of Protection presentation to ACIP. June 2011

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2011 Institute of Medicine (IOM) Report on Adverse Events of Vaccines

Syncope following vaccination:
IOM concluded that data convincingly support a causal relationship between injection of a vaccine and syncope

Anaphylaxis following HPV4:

IOM concluded that the weight of published evidence favored an acceptance of a causal relationship between HPV vaccine and anaphylaxis*
* http://www.iom.edu/Reports/2011/Adverse-Effects-of-Vaccines-Evidence-and-Causality.aspx

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Post-Vaccination Syncope
VAERS :
Majority of syncope occurs within 15 min of vaccination

VSD: Rates of syncope on day 0 following Td, Tdap, varicella, meningococcal or HPV vaccination among Rate per 10,000 9-26 yrs:*
Gender vaccinations 12.5 17.9 15.3 Male Female Both

HPV4 Package insert: listed as a warning/precaution ACIP recommends:

Providers should consider observation of patients for 15 minutes after vaccine administration**
* Unpublished rates from one VSD site using electronic data only, 2005-2011 ** Kroger AT, et al. General Recommendations on Immunization, Recommendations of ACIP. MMWR 2011

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Summary
Monitoring and evaluation are ongoing for HPV4 VAERS continues reviewing reports following HPV4
No new adverse event concerns or clinical patterns identified

VSD rapid cycle analysis confirmed no significant risk for any of the pre-specified adverse events after vaccination for two age groups (9-17yrs and 18-26 yrs)
Further evaluation of VTE and HPV4 is ongoing

Long-term follow-up of adolescents have not identified any safety concerns

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Acknowledgements
Immunization Safety Office Jorge Arana Karen Broder Jonathan Duffy Theresa Harrington Zanie Leroy Paige Lewis Pedro Moro Claudia Vellozzi Eric Weintraub DSTDP Eileen Dunne Lauri Markowitz FDA Thomas Buttolph David Martin Michael Nguyen Andrea Sutherland

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