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 The CDC’s Immunization Safety Office has monitors the safety of vaccines through 3 systems: VAERS: National passive surveillance system for reporting adverse events that is co-managed by CDC and FDA VSD: a collaborative project between the CDC and 8 managed care organizations that allows for rigorous monitoring and evaluation of vaccine safety Clinical immunization safety assessment network: A project that focuses on vaccine safety at the individual level in which it studies the pathophysiology of adverse events following immunization, indentifies 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 In ISO, the safety of HPV4 has been monitored and evaluated through our three systems by the following activities: Through VAERS, reports are reviewed on a daily basis and aggregate summaries of VAERS reports are evaluated for reporting patterns and potential signal identification Reports of serious adverse events, including deaths and other medically important conditions will be reviewed in detail in which medical charts and autopsy reports are requested and reviewed In August 2009, VAERS published a 2 year surveillance summary of HPV4 in Jama that I will highlight later in this presentation The CISA project has served as a resource for specific clinical case reviews that have been referred to the CISA network through providers. They have also been involved in reviewing GBS, anaphylaxis, along with TM cases reported to VAERS. The VSD is conducting near real time monitoring of select outcomes following HPV4

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 Briefly, for those who are not familiar with VAERS, as I mentioned it s a national passive surveillance system for vaccine adverse events. Jointly operated by the CDC and FDA. The system accepts reports from physicians, other health care providers, and the public It serves as an early warning system for vaccine safety surveillance in which is allows for: - Signal detection Previously unrecognized and/or rare adverse events -Monitoring known adverse events It is a voluntary, passive surveillance system and therefore faces some limitations. - there are reporting biases s - data are sometimes incomplete, missing critical pieces of information - it does not provide denominator data - and we cannot assess causality using VAERS

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 As I mentioned, VAERS has recently published a paper in JAMA describing the reports received to VAERS from June 2006 to December 31, 2008. The findings from this paper were generally not that different from what is seen in the safety reviews of other vaccines recommended for this age group. The next couple of bullets describe the methods that were used in the paper. Symptoms were assigned a medra code and classified as serious or non-serious, based on FDA’s regulatory definition of a serious adverse event. Because no denominator is available through VAERS, the authors used the number of doses distributed in the US, during the study time period, which was 23, 051,336. This served as a denominators to assess reporting rates and proportional reporting ratios Detailed case reviews were conducted for select serious AEs, in which the investigators from CISA played an integral role in reviewing and confirming many of the outcomes. *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%) There were 12,424 reports following HPV4 vaccine received to VAERS in the study time period Of which, the majority were considered non-serious. 6% were considered serious. The most frequently reported AEs have been listed in this slide

Summary of Select HPV4 Adverse Event Reports Published in JAMA Total No. HPV4 only Serious AE RR* Syncope 1896 1396 93 8.2 Anaphylaxis 28 18 8 0.1 GBS 42 25 31 0.3 Death 32 23 Transverse Myelitis 10 9 0.04 VTE 56 55 39 0.2 On this slide, I wanted to highlight select serious reports that were presented in the table and their reporting rate per 100,000 doses *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 As I mentioned previously, the vast majority of reports anaylzed in this paper were non serious. It was concluded that there was increased reporting of sycnope and VTE events. Meaning that ????? And to describe these two outcomes in a little more detail, there were 1896 syncopal reports to VAERS, of which 200 resulted in a head injury, 93 considered serious. Among the 56 VTE reports, 31 had sufficient information for clinical review. 30/31 were reports in which the female recevied only HPV4. the majority had one or more risk factor for vte.

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 The Vaccine Safety Datalink has developed a near real-time monitoring system to evaluate the associations between HPV4 and a prespecified list of outcomes in females 9-26 years of age. We use sequential statistical methodologies to evaluate these outcomes on a weekly basis. We selected either historical or concurrent comparison groups for outcomes, depending on their rarity. For the more rate outcomes like GBS, Appendicitis, Stroke, and VTE we used background rates as the comparison. For more common outcomes such as seizures, syncope, and allergic reactions, we used concurrent comparisons in which we compare females in the same age range who have either a preventative care visit or a vaccination visit during the same time period as the exposed group. We did not conduct a formal comparison for anaphylaxis because the primary ICD-9 code for this outcome is non-specific and generates a lot of false positives. So instead, we validated each anaphylaxis case identified in the automated data through chart abstraction and calculated an incident rate

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