Post-Licensure Safety Data: Monitoring Two Human Papillomavirus (HPV) Vaccine Products: Gardasil® (HPV4) and CervarixTM (HPV2) Barbara A. Slade, MD Julianne Gee, MPH Immunization Safety Office DHQP/NCEZID/OID/CDC

Vaccine Adverse Event Reporting System (VAERS) National post-licensure passive surveillance system for reporting vaccine adverse events Co-managed by CDC and FDA Early warning system for vaccine safety surveillance Monitors for known adverse events (AEs) Detects signals for previously unrecognized/rare AEs Generates hypotheses for further study Limitations Risk of underreporting and other 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

Review of HPV4 Reports to VAERS Aggregate summaries of VAERS reports were evaluated for reporting patterns and potential “signal” identification Reports of select serious adverse events (SAEs)*, including deaths and other medically important conditions were reviewed in detail * VAERS defines serious adverse events as those involving death, hospitalization, life-threatening illness, persistent or significant disability/incapacity, or certain other medically important conditions

Aggregate Summary of HPV4 AEs Reported to VAERS, June ‘06----Dec ‘09 Outcome Doses Distributed 30 million Total # VAERS HPV4 Reports 15,672 # Serious VAERS HPV4 Reports (% of total reports) 1,208 (7.7%) # (%) Most Frequently Reported Syncope, Syncope Vasovagal 2592 (16.5%) Dizziness 2451 (15.6%) Nausea 1611 (10.3%) Headache 1501 (9.6%) Injection site reactions 1554 (9.9%) Syncope: 2,592 reports Serious reports: 158 Head injuries (Fractures, dental injuries, contusions, lacerations, intercranial hemorrages) Reported increase in syncope for all adolescent vaccines

Select HPV4 Serious Adverse Event (SAE) Reports, confirmed by medical review 26 deaths No clustering by cause of death, by time since vaccination, or by age 57 thromboembolic events* 41/57 (72%) had known risk factor(s) 29 had history of estrogen-containing birth control measures 11/24 (46%) of cases tested for genetic coagulation mutation tested positive Increased reporting rates compared to females of the same age range who received other vaccines Pulmonary embolus, deep venous thrombosis, cerebral venous sinus thrombosis, cerebral vascular accident 50 deaths, 81 thromboemboli * pulmonary embolus, deep venous thrombosis, cerebral venous sinus thrombosis, cerebral vascular accident

Select HPV4 Serious Adverse Event (SAE) Reports, confirmed by medical review 18 cases of Guillain Barre Syndrome met Brighton case definition* 12 cases of pancreatitis All confirmed cases had known risk factors** 2 cases of a juvenile ALS-like disorder Autopsy: destruction of anterior horn cells in spinal cord Rapidly progressive course 57 GBS, 19 pancreatitis, 5 ALS-like *http://www.brightoncollaboration.org/internet/en/index/definition____guidelines/document_download.html#G **gallstones, alcohol, increased lipids, Coxsackie infection, estrogen use, obesity, ulcerative colitis, post colectomy

Vaccine Safety Datalink (VSD) Project Collaboration: CDC and 8 Managed Care Organizations (MCOs) in the US 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 7

VSD: HPV4 Rapid Cycle Analysis FOR INTERNAL VSD DISCUSSION ONLY VSD: HPV4 Rapid Cycle Analysis Objective: Identify associations between HPV4 and a pre-specified list of adverse outcomes in females age 9-26 years Weekly analyses conducted using sequential statistical methodologies Outcomes monitored: GBS Stroke Venous Thromboembolism (VTE) Appendicitis Seizures Syncope Allergic Reactions Anaphylaxis

VSD: HPV4 Rapid Cycle Analysis Monitored for ~ 3 years: August 6, 2006 – October 4, 2009 Total HPV4 doses administered Youth (9-17 yrs): 419,942 Adults (18-26 yrs): 186,616 Total utilization by dose: Dose 1: 45.1% Dose 2: 32.4% Dose 3: 22.4% 9

VSD: HPV4 Rapid Cycle Analysis (RCA) Conducting final analyses Finish manuscript Long-term surveillance for VTE, Stroke, and GBS Monitor outcomes until 1 million doses administered 10

Summary of HPV2 VAERS Adverse Event Reports 264 VAERS reports 2 from US; 262 foreign* reports 263 Cervarix alone 259 females; 4 males Age ranges 6—17 yo: 184 (70%) 18—29 yo: 32 (12%) No reports in VSD to date I case with other vaccines: HepA, Tdap, varicella *Foreign reports = reports submitted from foreign countries

Summary of HPV2 (Cervarix) VAERS Adverse Event Reports Outcome Number (% of Total Reports) Total # VAERS Reports 264 # (%) Most Frequently Reported Dizziness 50 (19%) Headache 40 (15%) Malaise 35 (13%) Syncope 28 (11%) Dyspnea 23 (9%) Pyrexia 22 (8%)

Summary of HPV2 (Cervarix) VAERS Serious Adverse Event (SAE) Reports Outcome Number (% of Total Reports) # Serious VAERS Reports (% of total reports) 94 (36%) Grouping of SAEs Deaths 3 Life-threatening Illnesses 20 Hospitalizations 54 Permanent disabilities 17 Foreign reports do not contain enough information to do detailed medical review.

Comparative Data on Safety of HPV2 and HPV4 Vaccines in Healthy Women Aged 18--45 years* Percentage of women reporting specific solicited local symptoms at least once within 7 days after any vaccine dose Symptom CervarixTM (n=524) Gardasil® Pain 93% 72% Redness 44% 26% Swelling 36.5% 22% The incidence of solicited symptoms was generally higher after Cervarix™, injection site reactions being most common. However, compliance rates with the three-dose schedules were similarly high (= 84%) for both vaccines. 11 clinical trial of 30,000 Most frequent local rxn: injection site pain Clinical trials: generally safe and tolerable ASO4-adjuvanted vaccine *Einstein MH et al. Human Vaccines 2009;5(10):705-719.

Comparative Data on Safety of HPV2 and HPV4 Vaccines in Healthy Women Aged 18--45 years* Percentage of women reporting specific solicited general symptoms at least once within 7 days after any vaccine dose Symptom CervarixTM (n=526) Gardasil® (n=526) Arthralgia 21.7% 15.4% Fatigue 49.8% 39.8% Fever 14.4% 11.0% Gastrointestinal 32.7% 26.5% Headache 47.5% 41.9% Myalgia 27.6% 19.6% Rash 4.8% 3.4% Urticaria 4.9% 4.0% The incidence of solicited symptoms was generally higher after Cervarix™, injection site reactions being most common. However, compliance rates with the three-dose schedules were similarly high (= 84%) for both vaccines. *Einstein MH et al. Human Vaccines 2009;5(10):705-719.

Summary: Vaccine Safety of HPV Vaccines VAERS reports for HPV4 similar to findings reported in JAMA 2009 article. VSD RCA completing Rapid Cycle Analyses for HPV4. Inadequate use of HPV2 vaccine in the US to identify the types of rare SAEs seen with post-licensure safety assessment. Post-licensure monitoring of both HPV4 and HPV2 is continuing in both VAERS and VSD. * compared to females of the same age range who received other vaccines

HPV 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/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM111263.pdf CervarixTM Package Insert: http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM186981.pdf VAERS information: http://vaers.hhs.gov/info.htm   VAERS public search tool: http://wonder.cdc.gov/vaers.html    CDC. Syncope after Vaccination. MMWR 2008;57(17):457-460 Slade BA et al. Human Papillomavirus Recombinant Vaccine Postlicensure Safety Surveillance for Quadrivalent Human Papillomavirus Recombinant Vaccine. JAMA 2009;302(7):750-757

Thank You

Additional Slides

Age Distribution of HPV4 AEs Reported to VAERS: June ‘06 – Dec ‘09

Select HPV4 Serious Adverse Event (SAE) Reports, June ‘06—Dec ‘09 Total No. of SAEs Total No. of Confirmed SAEs* Death 50 26 Thromboembolic Events 81 57 Guillain Barre Syndrome 18 (plus 9 pending review) Pancreatitis 19 12 “juvenile Amyotropic Lateral Sclerosis”-like 5 2 26 deaths: No clustering by cause of death, by time since vaccination, or by age Thromboembolic events: PE (31;alone=21;+DVT=10), DVTs (UE=10; LE=7), CVA, GBS: 18 met Brighton case definition 12 confirmed pancreatitis all had known risk factor: Gallstones (2), Alcohol use (2), inc TG (1), Coxsackie infxn (1), estrogen use (2), obesity (3), ulcerative colitis, s/p colectomy (1) 2 ALS-like: rapidly progressive---not typical, autopsy----destruction anterior horn cells * After medical review, removing hearsay reports, cases with no identifying information for follow-up, and cases with insufficient information.

Summary of HPV Adverse Event Reports Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant = Gardasil ® = qHPV Females: June 8, 2006—Dec. 31, 2009 Males: June 8, 2006---Oct. 15, 2009 licensed 10/16/2009 Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant = CervarixTM = bHPV Through 4/1/10 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. ,m

Adverse Events Following HPV2 (Cervarix) Vaccine Literature Report Einstein MH et al. Comparison of the immunogenicity and safety of CervarixTM and Gardasil ® human papillomavirus (HpV) cervical cancer vaccines in healthy women aged 18–45 years. Human Vaccines 2009;5(10):705-719. VAERS Reports No reports to date in VSD randomized, observer-blind study compared the two vaccines in a single, well-defined population of healthy women aged 18–45 years, using identical methodology for assessment of immunogenicity and safety.

Classification of Reporter Type to VAERS qHPV: 6/1/06----12/31/2009 Type of Reporter Frequency Percent Patient/Parent 746 4.8% Provider 2825 18% State Health Dept. 212 1.35% Manufacturer 9989 63.7% Other 1896 12% Unknown 4 0.03%

Summary of HPV4 AEs in Males Reported to VAERS, pre-FDA approved indication (Oct ‘09) Total Number of VAERS Reports n = 75 1 female 34 medical errors 6 HIV positives 4 injection site reactions 7 male babies exposed in utero 2 enrolled in study, experienced AE 3 syncope 1 pulmonary embolus Total SAEs n = 10 6 male babies exposed in utero

57 thromboembolic events 18 cases of GBS 12 cases of pancreatitis Confirmed Selected SAEs Reported to VAERS for HPV4, June ‘06---Dec ’09, cont. 26 deaths 57 thromboembolic events 18 cases of GBS 12 cases of pancreatitis 2 cases of a “juvenile ALS-like” disorder Causes of death: Cardiac (8), PE (4)“juvenile ALS” (2); seizure disorder (2); unable to assess (no identifiers [6], hearsay [16], insuff info [1]);drugs (2); diabetic ketoacidosis (1); meningoencephalitis (1); cerebral vasculitis (1); undet (4); influ B sepsis (1); necrotizing fasciitis (1) VTE: 81 reports 31 pulmonary emboli 8 with DVTs 11 strokes 2 SSST 24 DVTs 9 upper extremities 15 lower extremities 8 with PEs 5 manufacturer reports with no identifiers 10 hearsay reports 34 reports with HPV4 alone 28 reports serious Most associated with known risk factors associated with VTE reports VAERS reports do not establish a causal relationship between the vaccine and the adverse event 26

Age Distribution of HPV4 AEs Reported to VAERS: June ‘06 – Dec ‘09