Transcript Slide 1

Post-Marketing Safety
Surveillance for Quadrivalent
Human Papillomavirus Vaccine
(HPV4)
Julianne Gee, MPH
Immunization Safety Office
Division of Healthcare Quality Promotion
Centers for Disease Control and Prevention
CDC’s Immunization Safety Office
Vaccine Safety Monitoring Systems
 Vaccine Adverse Event Reporting System:
 National passive reporting system that accepts reports from the
public on adverse events (AEs) following vaccination
 Vaccine Safety Datalink (VSD) Project:
 Collaboration between CDC and 8 managed care organizations
that allows for rigorous monitoring and evaluation of the safety
of vaccines
 Clinical Immunization Safety Assessment (CISA)
Network:
 Studies the pathophysiology of adverse events following
immunization, identifies risk factors, and develops guidance to
assist clinicians
Monitoring HPV4 Vaccine Safety
 VAERS:
 Monitors and reviews reports on a daily basis
 Follow-up on serious reports and deaths
 Post licensure Safety Surveillance for Quadrivalent
Human Papillomavirus Recombinant Vaccine JAMA.
2009; 302(7):750-757
 CISA:
 Conduct clinical case reviews of reports received by
the CISA Network and to VAERS
 VSD
 Active surveillance of selected outcomes
VAERS
 National post-licensure passive surveillance
system for vaccine adverse events operated by
CDC and FDA
 Serves as an early warning system for vaccine
safety surveillance
 Permits monitoring for known AEs
 Detects signals for previously unrecognized/rare AEs
 Generates hypotheses for further study
 Limitations
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Risk of underreporting and reporting biases
Incomplete data
Lack of availability of denominator data
Cannot assess causality
Summary of HPV4 Adverse Event
Reports Published in JAMA
 First published HPV post licensure study
 AEs reported to VAERS from June 1, 2006-December 31, 2008 (US
reports only)
 Methods:
 Reported signs/symptoms were assigned MedDRA codes and
classified as serious or non-serious
 Serious Adverse Event: an adverse event that is life threatening, results
in death, permanent disability, congenital anomaly, hospitalization, or
prolonged hospitalization
 Describe characteristics of adverse event reports
 Datamining: detects disproportionality in reporting (as compared to
other vaccines)
 Proportional reporting ratios (PRR)
 Empirical Bayesian geometric mean (EBGM)
 Detailed case reviews conducted on select AEs
*Medical Dictionary for Regulatory Activities:
http://www.meddramsso.com
Summary of HPV4 Adverse Event
Reports Published in JAMA
 Total HPV4 VAERS reports: 12,424
 Most frequently reported AEs included:
 Syncope (n=1847, 15%)
 Dizziness (n=1763, 14%)
 Nausea (n=1170, 9%)
 Headache (n=957, 8%)
 Injection site reactions (n=926, 7.5%)
 Serious adverse events: 772 (6%)
Summary of Select HPV4 Adverse Event
Reports Published in JAMA
Adverse Event
Syncope
Anaphylaxis
GBS
Death
Transverse
Myelitis
VTE
Total
No.
Serious
HPV4 only
AE
RR*
1896
28
42
32
10
1396
18
25
23
9
93
8
31
32
10
8.2
0.1
0.3
0.1
0.04
56
55
39
0.2
*RR= Reporting Rate (total reports) per 100,000 doses distributed
23 million doses distributed
Summary of HPV4 Adverse Event
Reports Published in JAMA
 Conclusions
 Vast majority of reports were non-serious
 Disproportional reporting of syncope and venous thrombotic events
(VTE)
 Syncope: 1896 reports
 200 Head injuries (Fractures, dental injuries, contusions,
lacerations, intercranial hemorrages)
 Serious reports: 93
 VTE: 56 reports
 31 with sufficient information for clinical review
 30 reports with HPV4 alone
 Risk factors associated with VTE reports
 Results generally consistent with pre-licensure trials
 Post-licensure monitoring is continuing and epidemiologic studies
considered to assess potential signals
Vaccine Safety Datalink (VSD)
Project
• Collaboration: CDC and Managed Care
Organizations (MCOs) in the US
• 8 participating MCOs
• Annual population > 9.2 million
• Advantages of VSD for vaccine safety research
• Large, well-defined population
• Computerized, linkable administrative data files
• Powerful tool for controlled population-based studies
VSD Rapid Cycle Analysis: HPV4
 Near real-time monitoring to evaluate the associations
between HPV4 and pre-specified list of outcomes in
females aged 9-26 yrs
 Using sequential statistical methodologies, outcomes
are evaluated on a weekly basis
 Comparison groups:
 Historical:
 Background rates
 Outcomes: GBS, Appendicitis, Stroke, VTE
 Concurrent:
 Females in the same age range who had a preventative or
vaccination visit during the same time period as the exposed group
 Outcomes: Seizures, Syncope, Allergic reactions
 Descriptive analysis for anaphylaxis
 Medical record review:
 GBS, VTE, and Anaphylaxis cases identified in automated
data
VSD RCA: Preliminary Results
 Total number of HPV4 doses administered
(through August 30, 2009): 562,988
 9-17 yrs: 389,706
 18-26 yrs: 173,282
 We did not find any statistically significant
differences for the outcomes being
monitored following HPV4 and their
comparison groups.
VSD: Next Steps
 Formal weekly analyses will end soon
 Long-term surveillance for VTE, Stroke, and
GBS
 Monitor outcomes until 1 million doses
administered
HPV4 Vaccine and
General Vaccine Safety References
Reports of Adverse Events Following Gardasil ® (on the CDC
Vaccine safety web site):
http://www.cdc.gov/vaccinesafety/vaers/gardasil.htm
Gardasil ® Package Insert:
http://www.fda.gov/cber/label/gardasilLB.pdf
VAERS information: http://vaers.hhs.gov/info.htm
VAERS public search tool: http://wonder.cdc.gov/vaers.html
CDC. General Recommendations on Immunization; MMWR 2006;
55(RR15);1-48
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5515a1.htm
Thank You