SHOULD I VACCINATE MY CHILD AGAINST CERVICAL CANCER? Mark H. Stoler, MD

1. SHOULD I VACCINATE MY CHILD AGAINST CERVICAL CANCER?Mark H. Stoler, MD

2. Estimated Annual Burden of HPV-Related Diagnoses in the United States 9,710 new cases of cervical cancer1 3,700 deaths estimated in 20061 330,000 new cases of high-grade cervical dysplasia (CIN 2/3)2 CIN = cervical intraepithelial neoplasia. 1.4 million new cases of low-grade cervical dysplasia (CIN 1)2 1 million new cases of genital warts3 CIN = cervical intraepithelial neoplasia. 1. American Cancer Society. Cancer Facts and Figures 2006. Atlanta, Ga: American Cancer Society; 2006:4. 2. Schiffman M, Solomon D. Findings to date from the ASCUS-LSIL Triage Study (ALTS). Arch Pathol Lab Med. 2003;127:946–949. 3. Fleischer AB, Parrish CA, Glenn R, Feldman SR. Condylomata acuminata (genital warts):Patient demographics and treating physicians. Sex Transm Dis. 2001;28:643–647.

6. HPV and Cancer1 Cancer % Associated with Certain HPV Types Cervical* ≥95% Vaginal* 50% Vulvar* >50% Penile 50% Anal >70% Oropharyngeal 20% Nonmelanoma skin/cutaneous squamous cell 90%** *Includes cancer and intraepithelial neoplasia **Immunocompromised patients 1. Gonzalez Intxaurraga MA, Stankovic R, Sorli R, Trevisan G. Acta Dermatovenerol. 2002;11:1–8.

7. Natural History of HPV Infection Definitive Efficacy 0 to 1 Year 0 to 3 Years Up to 20 Years InitialHPV Infection CIN 2/3 or AIS Cervical Cancer ContinuingInfection 1 Efficacy Objective of Clinical Program for GARDASIL® – Demonstrate Prevention of HPV 16/18-CIN 2/3 and AIS CIN 1 Cleared HPV Infection

8. IN2/3 is Noninvasive cancer Clear precursor relationship HPV types the same Invasive cancer develops from IN3

9. GARDASIL: The First Cervical Cancer Vaccine in the United States • Quadrivalent HPV 6/11/16/18 L1 virus-like particle (VLP) vaccine • VLPs are produced in Saccharomyces cerevisiae. • The L1 proteins self-assemble into VLPs. • Purified VLPs are adsorbed on aluminum-containing adjuvant. • The adjuvant is amorphous aluminum hydroxyphosphate sulfate (225 μg per dose). • Each 0.5-mL dose contains HPV Types 6/11/16/18 (20/40/40/20 μg L1 protein, respectively).

10. Prophylactic Efficacy of GARDASIL CIN & AISPer-Protocol Population (Protocols 007, 013, and 015) Mean Follow-Up - 44 months

11. Prophylactic Efficacy of GARDASIL®External Genital LesionsPer-Protocol Population (Protocols 007, 013, and 015) Mean Follow-Up - 44 months * Subjects are counted only once per row, but may be in more than one row

12. 73% of subjects were naïve to all 4 vaccine HPV types. Among subjects who were positive to a vaccine HPV type, most were positive to only 1 type. Exclusion criteria: 6 or more sexual partners Subjects Exposed to Any Vaccine HPV Type at Enrollment 20% Efficacy Studies—Combined Population 93% of subjects were naïve to ≥3 vaccine HPV types (6, 11, 16, or 18) at enrollment. Baseline HPV Status Naïve to all 4 types 73% Positive to 1 type 27% of subjects had evidence of prior exposure to or ongoing infection with at least 1 of the 4 vaccine HPV types. Positive to 2 types 6% Positive to 3 types Positive to 4 types 1.2% 0.1% Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package 20651717(4)-GRD.

13. Efficacy of GARDASIL in Subjects Who Were Positive to ≥1 Vaccine HPV Type at Day 1 Individuals with current or past infection with 1 vaccine-related HPV types prior to vaccination were protected from disease caused by the remaining vaccine HPV types for which they were naïve at Day 1. Case-counting Postdose 1 Ph III–FUTURE I (P013) and FUTURE II (P015) CIN = cervical intraepithelial neoplasia; VIN = vulvar intraepithelial neoplasia; VaIN = vaginal intraepithelial neoplasia *Among subjects who were positive to ≥ 1 vaccine HPV type, efficacy against HPV types for which they were naïve at Day 1. n = Number of subjects in the given population with at least 1 follow-up visit following 30 days after Day 1. Subjects are counted once in each applicable end-point category. A subject may appear in more than 1 category. Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package 20651717(5)-GRD.

14. Impact of GARDASIL Against HPV 6/11/16/18-Related CIN (Any Grade)Based on HPV Status at Day 1; Combined Analysis • GARDASILis a prophylactic vaccine. • There is no clear evidence of protection from disease caused by HPV types for which subjects were seropositive and/or PCR positive at baseline. Seropositive and PCR-positive at baseline AIS = adenocarcinoma in situ. CIN = cervical intraepithelial neoplasia. Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package 20651717(6)-GRD.

15. Overall Conclusions for GARDASIL • Highly effective in preventing cervical cancer, CIN 2/3, AIS, and other anogenital diseases including genital warts caused by HPV 6, 11, 16, and 18 in 16- to 26-year-old women naïve to the relevant HPV types • Individuals with current or past infection with 1 vaccine-related HPV types prior to vaccination were protected from disease caused by the remaining vaccine HPV types • Successful immunogenicity bridge between female adolescents and young adult women • Antibody response in 9- to 15-year-old females is higher, compared with response observed in young adult women (16–26 years old) • Duration of efficacy is demonstrated between 2 and 4 years • Favorable tolerability profile AIS = adenocarcinoma in situ. CIN = cervical intraepithelial neoplasia.

16. Summary of US Vaccine Recommendations aACIP = Advisory Committee on Immunization Practices. bACOG = American College of Obstetricians and Gynecologists. cAAFP = American Academy of Family Practitioners. dACP = American College of Physicians. eAAP = American Academy of Pediatrics. 1.Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2007;56(RR-2):1-24. 2. American College of Obstetricians and Gynecologists (ACOG). Obstet Gynecol. 2006;108:699–705. 3. Advisory Committee on Immunization Practices. Ann Intern Med. 2007;147(10):725-729. 4. Committee on Infectious Diseases. Pediatrics. 2007; 120(3);666-668.

17. Important Information About GARDASIL GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] • GARDASIL is a vaccine indicated in girls and women 9 to 26 years of age for the prevention of cervical cancer, precancerous or dysplastic lesions, and genital warts caused by human papillomavirus (HPV) Types 6, 11, 16, and 18. • GARDASIL is contraindicated in individuals who are hypersensitive to the active substances or to any of the excipients of the vaccine. • GARDASIL does not substitute for routine cervical cancer screening, and women who receive GARDASIL should continue to undergo screening per standard of care.

18. Important Information About GARDASIL (cont) GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] • Vaccination with GARDASIL may not result in protection in all vaccine recipients. • GARDASIL is not recommended for use in pregnant women. • GARDASIL is not intended to be used for treatment of active genital warts; cervical cancer; CIN, VIN, or VaIN.a • GARDASIL has not been shown to protect against diseases due to non-vaccine HPVb types. • The vaccine-related adverse experiences that were observed among recipients of GARDASIL at a frequency of at least 1.0% and greater than placebo were pain, swelling, erythema, fever, nausea, pruritus, and dizziness. In addition, common postmarketing reports include vomiting and syncope. aCIN = cervical intraepithelial neoplasia; VIN = vulvar intraepithelial neoplasia; VaIN = vaginal intraepithelial neoplasia. bHPV = human papillomavirus.