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
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

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):
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

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
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

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
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:

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%)
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

7. 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

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
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.

9. 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

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
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

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 the CDC Vaccine safety web site):
Gardasil ® Package Insert:
VAERS information:
VAERS public search tool:   
CDC. General Recommendations on Immunization; MMWR 2006; 55(RR15);

14. Thank You