Post-Marketing Safety Surveillance for Quadrivalent Human Papillomavirus Vaccine (HPV4)

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

2. 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

3. 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

4. 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 • Risk of underreporting and reporting biases • Incomplete data • Lack of availability of denominator data • Cannot assess causality

5. 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

6. 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%)

7. Summary of Select HPV4 Adverse Event Reports Published in JAMA *RR= Reporting Rate (total reports) per 100,000 doses distributed 23 million doses distributed

8. 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

9. VaccineSafety 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

10. 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

11. 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.

12. VSD: Next Steps • Formal weekly analyses will end soon • Long-term surveillance for VTE, Stroke, and GBS • Monitor outcomes until 1 million doses administered

13. HPV4 Vaccine and General Vaccine Safety References Reports of Adverse Events Following Gardasil ® (on theCDC 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

14. Thank You