GIÁO TRÌNH GARDASIL

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GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] GARDASIL is a registered trademark of Merck & Co., Inc. 1
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Estimated Annual Burden of Human Papillomavirus (HPV)-Related Diagnoses in the United States 9,710 new cases of cervical cancer1 330,000 new cases of high-grade cervical dysplasia (CIN 2/3)2 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. American Cancer Society; 2006:4. 2. Schiffman M et al. Arch Pathol Lab Med. 2003;127:946–949. 2 2 3. Fleischer AB et al. Sex Transm Dis. 2001;28:643–647.
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Targeting a High Disease Burden With GARDASIL HPV Type Approximate Disease Burden • 70% of cervical cancer, AIS, CIN 3, 16 and 18 VIN 2/3, and VaIN 2/3 cases • 50% of CIN 2 cases • 35%–50% of all CIN 1, VIN 1, and 6, 11, 16, and 18 VaIN 1 cases • 90% of genital warts cases AIS = adenocarcinoma in situ. VIN = vulvar intraepithelial neoplasia. 3 3 VaIN = vaginal intraepithelial neoplasia.
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Classification of Histological Findings: CIN • CIN1 – CIN 1: Mild dysplasia; includes condyloma (anogenital warts) – CIN 2: Moderate dysplasia – CIN 3: Severe dysplasia; includes carcinoma in situ (CIS) CIN 1 CIN 2 CIN 1 CIN 3 Invasive CIN1 Normal (mild (moderate (condyloma) (severe dysplasia/CIS) Cancer dysplasia) dysplasia) Histology of squamous cervical epithelium1 Basal cell Basal membrane • CIN caused by HPV can clear without treatment; however, rates of regression are dependent on grade of CIN.2 1. Bonnez W. In: Richman DD, Whitley RJ, Hayden FJ, eds. American Society for Microbiology Press; 2002:557– 596. Reprinted with the permission of the American Society for Microbiology Press. 4 4 2. Ostor AG. Int J Gynecol Pathol. 1993;12:186–192.
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Details of the Per-Protocol Efficacy (PPE) Population PPE Population Sero (+) and/or PCR (+) to the relevant Excluded vaccine HPV type at Day 1 PCR (+) to the relevant vaccine HPV type Excluded during the vaccination phase Protocol violators Excluded
Combined Analysis GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Efficacy: 100% Efficacious Against HPV 16- and 18-Related Cervical Cancer Precursors PPE-Combined Population; subjects were naïve to HPV types 6, 11, 16, and/or 18 Combined Analysis Cases: End Point: GARDASIL HPV 16/18- or HPV 16 Cases: 95% related n L1 VLP* n Placebo Efficacy CI 93– CIN 2/3 or AIS 8,487 0 8,460 53 100% 100 88– CIN 3 or AIS†‡ 8,487 0 8,460 32 100% 100 • The efficacy of GARDASIL against HPV 16-, and 18-related VIN 2/3 or VaIN 2/3 was 100%. *Analysis of CIN 2/3 and AIS endpoints included Protocol 005. † Defined by FIGO as Stage 0 cervical cancers; FIGO = International Federation of Gynecology and Obstetrics. ‡ CIN 3 or AIS analysis was a secondary end point. Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 6 6 19486-0004. Please specify information package 20651083(1).
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Efficacy Against HPV 6/11/16/18-Related Lesions PPE-Combined Population; subjects were naïve to HPV types 6, 11, 16, and/or 18 Combined Analysis Cases: Cases: End Point: GARDASIL Placebo Vaccine HPV 6/11/16/18-related (n=7,858) (n=7,861) Efficacy 95% CI CIN or AIS 4 83 95% 87–99 Cases: Cases: End Point: GARDASIL* Placebo* Vaccine HPV 6/11/16/18-related (n=7,897) (n=7,899) Efficacy 95% CI Genital warts 1 91 99% 94–100 • The efficacy of GARDASIL against HPV 6-, 11-, 16-, and 18-related VIN 1 or VaIN 1 was 100%. 7 7
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Subjects Exposed to Any Vaccine HPV Type at Enrollment Efficacy Studies—Combined Population Combined Analysis Total Day 1 Composite HPV Status (N=18,478) Negative to HPV 6/11/16/18 73% By serology 80% By PCR only 85% Positive to at least 1 HPV type 27% By serology 20% By PCR 15% • 93% of subjects had 0 or 1 of the HPV vaccine types (6, 11, 16, or 18) at enrollment. Data on file, MSD. 8 8
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Modified Intention to Treat (MITT) Populations Used to Evaluate GARDASIL MITT-2 MITT-3 Sero (-) and/or PCR (-) to the relevant Included Included vaccine HPV type at Day 1 Sero (+) and/or PCR (+) to the relevant Excluded Included vaccine HPV type at Day 1 PCR (+) to the relevant vaccine HPV type Included Included during the vaccination phase Day 1 (+) to nonvaccine HPV type Included Included Day 1 Pap ≥ASCUS Included Included Protocol violators/< 3 doses Included Included Case counting After Day 30 After Day 30 ASCUS = atypical squamous cells of undetermined significance. Data on file, MSD. 9 9
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Contribution of Subpopulations to Overall Incidence of CIN 2/3 or AIS Naïve to relevant vaccine HPV MITT-2 + those infected with ≥1 types at Day 1 (MITT-2) vaccine HPV type or nonvaccine type at Day 1 (MITT-3) • May acquire new infection prior to completion of vaccination • May have disease at Day 1 regimen OR • Takes time for disease to develop • May develop disease after Day 1 Most disease in clinical Early on, few disease trials of GARDASIL was cases observed observed early Impact of GARDASIL is masked due Prophylactic efficacy of GARDASIL is high to early prevalence of disease Data on file, MSD. 10 10
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] General Population Impact: In Young Women Aged 16 to 26 Years GARDASIL Reduced the Incidence of Cervical Cancer, Cervical Dysplasia, and Genital Warts Caused by Vaccine HPV Types Cases: GARDASIL Cases: % Reduction End Points Analysis or HPV 16 Placebo (95% CI) Vaccine HPV-naïve efficacy 1 81 99 (93, 100) HPV 16/18- related CIN HPV 16(+) and/or 18(+) at Day 1 121 120 -- 2/3 or AIS General population impact 122 201 39 (23, 52) HPV HPV-naïve efficacy 9 143 94 (88, 97) 6/11/16/18- HPV 6, 11, 16, and/or 18 (+) at Day 1 161* 174* -- related CIN or AIS General population impact 170 317 46 (35, 56) HPV HPV-naïve efficacy 9 136 93 (87, 97) 6/11/16/18- HPV 6, 11, 16, and/or 18 (+) at Day 1 49 48† -- related genital warts General population impact 58 184 69 (58, 77) *Includes 2 subjects who underwent colposcopy for reasons other than an abnormal Pap and 1 subject with missing serology/PCR data at Day 1. † Includes 1 subject with missing data at Day 1. 11 11
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] General Population Impact: GARDASIL Reduced the Likelihood of HPV 16/18-Related CIN 2/3 or AIS in 16- to 26-Year-Old Females Within 2 to 4 Years MITT-3 Population 6 Placebo and 95% CI 5 GARDASIL and 95% CI Cumulative 4 Incidence of HPV 16/18- 3 High rates of 39% ↓ Related CIN prevalent disease early 2/3 or AIS, % 2 1 0 0 6 12 18 24 30 36 42 48 Time Since Month 1, Months • With each screening round, the impact of the vaccine became more apparent. Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486- 12 0004. Please specify information package 20651480(1). 12
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] General Population Impact: GARDASIL Reduced the Likelihood of HPV 6/11/16/18-Related VIN, VaIN, and Genital Warts in 16- to 26-Year Old Females Within 2 to 4 Years MITT-3 Population 7 Placebo and 95% CI Cumulative Incidence of HPV VaIN, or Genital Warts, % 6 GARDASIL and 95% CI 6/11/16/18-Related VIN, 5 4 3 High rates of prevalent disease 69% ↓ 2 early 1 0 0 6 12 18 24 30 Time Since Month 1, Months • With each screening round, the efficacy of the vaccine became more apparent. 13 13 Data on file, MSD.
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Assays to Measure Immune Response to GARDASIL • Type-specific competitive immunoassays with type-specific standards were used to assess immunogenicity to each vaccine HPV type. • These assays measured antibodies against neutralizing epitopes for each HPV type. • The scales for these assays are unique to each HPV type. – Comparisons across types and to other assays are not appropriate. 14 14
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] GARDASIL Maintained Type-Specific, Neutralizing Antibody Responses Ph II–P005 Proof of Principle 16- to 23-year-old women 5,000 GARDASIL (Per Protocol) 3,000 Per-Protocol Placebo 1,000 The duration Serum of protection cRIA of GARDASIL GMT, 100 is unknown mMU/mL beyond 48 months. 10 Vaccination 1 0 7 12 18 30 42 48 Month Since Enrollment Number of 684 684 663 649 609 533 481 Subjects 680 680 661 638 604 532 489 *Evaluated only the HPV 16 L1 VLP vaccine component of GARDASIL. GMT = Geometric mean titer; cRIA = Competitive radioimmunoassay. Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 15 15 19486-0004. Please specify information package 20651100(1).
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Neutralizing Antibodies by Age at Enrollment Per-protocol immunogenicity population (aged 9–26)* Ph III–P016, 018 Safety/Immunogenicity Neutralizing anti-HPV 6 GMTs at Month 7 9- to 15-year-old adolescents Immunogenicity Bridge Efficacy Program 1,600 1,500 Serum cLIA GMT with 95% CI, 1,300 1,100 mMU/mL 900 700 500 Adolescent Females (aged 9–17) Young Adult Females (aged 18–26) 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Age at Enrollment, Years *Inclusive of 5 study protocols; all GMTs measured using cLIA. Data on file, MSD. 16 16
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Vaccine-Related Experiences Injection Site (1 to 5 days postvaccination) GARDASIL Placebo (Aluminum) Placebo (Saline) (n=5,088) (n=3,470) (n=320) Pain 83.9% 75.4% 48.6% Swelling 25.4% 15.8% 7.3% Erythema 24.6% 18.4% 12.1% Pruritus 3.1% 2.8% 0.6% Systemic Adverse Event (1 to 15 days postvaccination) GARDASIL Placebo (n=5,088) (n=3,790) Fever 10.3% 8.6% Nausea 4.2% 4.1% Dizziness 2.8% 2.6% • Few subjects (0.1%) discontinued because of adverse events. The vaccine-related adverse experiences that were observed among recipients of GARDASIL were at a frequency of at least 1.0% and also at a greater frequency than that observed among placebo recipients. 17 17
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Summary of Pregnancies in the Phase III Program for GARDASIL GARDASIL Placebo (n=10,418) (n=9,120) Subjects with pregnancies 1,115 1,151 Number of pregnancies 1,244 1,272 Pregnancies with unknown 258 263 outcomes/ongoing pregnancies Pregnancies with known outcomes 996 1,018 Live births 621 (62) 611 (60) (% of pregnancies with known outcomes) Fetal loss 375 (38) 407 (40) (% of pregnancies with known outcomes) n = number of subjects who received 1, 2, or 3 doses of only the clinical material in the given column. The group receiving GARDASIL included more 9- to 15-year-olds than the group receiving placebo. Data on file, MSD. 18 18
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Summary of Known Pregnancy Outcomes in the Phase III Program for GARDASIL GARDASIL Placebo Pregnancies with known outcomes/EOP within 30 days of 112 115 vaccination Spontaneous loss 21 (18.8%) 26 (22.6%) Elective termination 21 (18.8%) 23 (20.4%) Live birth 70 (62.5%) 66 (57.4%) Pregnancies with known outcomes/EOP beyond 30 days of 879 898 vaccination Spontaneous loss 236 (26.8%) 237 (26.4%) Elective termination 93 (10.6%) 117 (13.0%) Live birth 549 (62.5%) 544 (60.6%) Estimated EOP could not be precisely ascertained in 10 women. EOP = onset of pregnancy. 19 19 Data on file, MSD.
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Pregnancy Outcomes: Congenital Anomalies Cases: Cases: Results GARDASIL Placebo Congenital anomalies 15 16 Estimated onset of pregnancy ≤30 days 5* 0 of vaccination Estimated onset of pregnancy >30 days 10 16 following vaccination • The types of anomalies observed were consistent (regardless of when pregnancy occurred in relation to vaccination) with those generally observed in pregnancies in women aged 16 to 26 years. *Congenital anomalies included pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia, and club foot. 20 20 Data on file, MSD.