PostLicensure Safety Data Monitoring Two Human Papillomavirus HPV

Post-Licensure Safety Data: Monitoring Two Human Papillomavirus (HPV) Vaccine Products: Gardasil® (HPV 4) and Cervarix. TM (HPV 2) 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

Review of HPV 4 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 HPV 4 AEs Reported to VAERS, June ‘ 06 ----Dec ‘ 09 Outcome Doses Distributed 30 million Total # VAERS HPV 4 Reports 15, 672 # Serious VAERS HPV 4 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%)

Select HPV 4 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

Select HPV 4 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 *http: //www. brightoncollaboration. org/internet/en/index/definition____guidelines/do cument_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

VSD: HPV 4 Rapid Cycle Analysis • Objective: Identify associations between HPV 4 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: HPV 4 Rapid Cycle Analysis • Monitored for ~ 3 years: – August 6, 2006 – October 4, 2009 • Total HPV 4 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%

VSD: HPV 4 Rapid Cycle Analysis (RCA) § Conducting final analyses § Finish manuscript § Long-term surveillance for VTE, Stroke, and GBS § Monitor outcomes until 1 million doses administered

Summary of HPV 2 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 *Foreign reports = reports submitted from foreign countries

Summary of HPV 2 (Cervarix) VAERS Adverse Event Reports Outcome Number (% of Total Reports) Total # VAERS Reports # (%) Most Frequently Reported 264 Dizziness Headache Malaise Syncope Dyspnea Pyrexia 50 (19%) 40 (15%) 35 (13%) 28 (11%) 23 (9%) 22 (8%)

Summary of HPV 2 (Cervarix) VAERS Serious Adverse Event (SAE) Reports Outcome # Serious VAERS Reports (% of total reports) Grouping of SAEs Number (% of Total Reports) 94 (36%) Deaths 3 Life-threatening Illnesses 20 Hospitalizations 54 Permanent disabilities 17

Comparative Data on Safety of HPV 2 and HPV 4 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 Cervarix. TM Gardasil® (n=524) Pain 93% 72% Redness 44% 26% Swelling 36. 5% 22% *Einstein MH et al. Human Vaccines 2009; 5(10): 705 -719.

Comparative Data on Safety of HPV 2 and HPV 4 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 Arthralgia Fatigue Fever Cervarix. TM (n=526) 21. 7% 49. 8% 14. 4% Gardasil® (n=526) 15. 4% 39. 8% 11. 0% Gastrointestinal Headache Myalgia Rash Urticaria 32. 7% 47. 5% 27. 6% 4. 8% 4. 9% 26. 5% 41. 9% 19. 6% 3. 4% 4. 0% *Einstein MH et al. Human Vaccines 2009; 5(10): 705 -719.

Summary: Vaccine Safety of HPV Vaccines § VAERS reports for HPV 4 similar to findings reported in JAMA 2009 article. § VSD RCA completing Rapid Cycle Analyses for HPV 4. § Inadequate use of HPV 2 vaccine in the US to identify the types of rare SAEs seen with post-licensure safety assessment. § Post-licensure monitoring of both HPV 4 and HPV 2 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/Biologics. Blood. Vaccines/Appro ved. Products/UCM 111263. pdf Cervarix. TM Package Insert: http: //www. fda. gov/downloads/Biologics. Blood. Vaccines/Appro ved. Products/UCM 186981. 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 HPV 4 AEs Reported to VAERS: June ‘ 06 – Dec ‘ 09 5000 # Reports 4000 3000 Death SAE non-SAE 2000 1000 0 <9 9 --10 11 --12 12 --17 Age (yrs. ) 18 --26 >26

Select HPV 4 Serious Adverse Event (SAE) Reports, June ‘ 06—Dec ‘ 09 Serious Adverse Event Death Thromboembolic Events Guillain Barre Syndrome Pancreatitis “juvenile Amyotropic Lateral Sclerosis”-like Total No. of SAEs 50 81 Total No. of Confirmed SAEs* 26 57 57 18 (plus 9 pending review) 19 5 * After medical review, removing hearsay reports, cases with no identifying information for follow-up, and cases with insufficient information. 12 2

Summary of HPV Adverse Event Reports § Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant = Gardasil ® = q. HPV § 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 = Cervarix. TM = b. HPV § Through 4/1/10 , m

Adverse Events Following HPV 2 (Cervarix) Vaccine • Literature Report – Einstein MH et al. Comparison of the immunogenicity and safety of Cervarix. TM and Gardasil ® human papillomavirus (Hp. V) 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

Classification of Reporter Type to VAERS q. HPV: 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 HPV 4 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

Confirmed Selected SAEs Reported to VAERS for HPV 4, 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 VAERS reports do not establish a causal relationship between the vaccine and the adverse event

Age Distribution of HPV 4 AEs Reported to VAERS: June ‘ 06 – Dec ‘ 09 10000 # of Reports (log) 1000 Death 100 SAE non-SAE 10 1 <9 9 --10 11 --12 12 --17 Axis Age in Years 18 --26 >26