hpv gardasil vaccine

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GARDASIL is a registered trademark of Merck & Co., Inc.
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]
Estimated Annual Burden of Human
Papillomavirus (HPV)-Related Diagnoses in
the United States




9,710 new cases of cervical cancer
1
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 warts

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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.
3. Fleischer AB et al. Sex Transm Dis. 2001;28:643–647.

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HPV Type Approximate Disease Burden
16 and 18
• 70% of cervical cancer, AIS, CIN 3,
VIN 2/3, and VaIN 2/3 cases
• 50% of CIN 2 cases
6, 11, 16, and 18
• 35%–50% of all CIN 1, VIN 1, and
VaIN 1 cases
• 90% of genital warts cases
Targeting a High Disease Burden
With GARDASIL
AIS = adenocarcinoma in situ.
VIN = vulvar intraepithelial neoplasia.
VaIN = vaginal intraepithelial neoplasia.
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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Classification of Histological Findings: CIN
•

CIN
1
–
CIN 1: Mild dysplasia; includes condyloma (anogenital warts)
–
CIN 2: Moderate dysplasia
–
CIN 3: Severe dysplasia; includes carcinoma in situ (CIS)
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.
2. Ostor AG. Int J Gynecol Pathol. 1993;12:186–192.
CIN
1
Normal
CIN 1
(condyloma)
CIN 1
(mild
dysplasia)
CIN 2
(moderate
dysplasia)
CIN 3
(severe dysplasia/CIS)
Invasive
Cancer
Histology of
squamous
cervical
epithelium

1
Basal
cell
Basal
membrane
•
CIN caused by HPV can clear without treatment; however, rates of
regression are dependent on grade of CIN.
2
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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PPE Population
Sero (+) and/or PCR (+) to the relevant
vaccine HPV type at Day 1
Excluded
PCR (+) to the relevant vaccine HPV type
during the vaccination phase
Excluded
Protocol violators Excluded
<3 doses Excluded
Case counting
1 month
Postdose 3
Details of the Per-Protocol Efficacy (PPE)
Population
GARDASIL

®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]
PCR = polymerase chain reaction.

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End Point:
HPV 16/18-
related n
Cases:
GARDASIL
or HPV 16
L1 VLP* n
Cases:
Placebo Efficacy
95%
CI
CIN 2/3 or AIS 8,487 0 8,460 53 100%
93–
100
CIN 3 or AIS
†‡
8,487 0 8,460 32 100%
88–
100
Efficacy: 100% Efficacious Against HPV 16-
and 18-Related Cervical Cancer Precursors
*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
19486-0004. Please specify information package 20651083(1).
PPE-Combined Population; subjects were naïve to HPV types 6, 11, 16, and/or 18
Combined Analysis
Combined Analysis
•
The efficacy of GARDASIL against HPV 16-, and 18-related VIN 2/3 or VaIN
2/3 was 100%.
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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Efficacy Against HPV 6/11/16/18-Related
Lesions
End Point:
HPV 6/11/16/18-related
Cases:
GARDASIL
(n=7,858)
Cases:
Placebo
(n=7,861)
Vaccine
Efficacy 95% CI
CIN or AIS 4 83 95% 87–99
End Point:

HPV 6/11/16/18-related
Cases:
GARDASIL*
(n=7,897)
Cases:
Placebo*
(n=7,899)
Vaccine
Efficacy 95% CI
Genital warts 1 91 99% 94–100
PPE-Combined Population; subjects were naïve to HPV types 6, 11, 16, and/or 18
•
The efficacy of GARDASIL against HPV 6-, 11-, 16-, and 18-related VIN 1 or
VaIN 1 was 100%.
Combined Analysis
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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Subjects Exposed to Any Vaccine HPV Type
at Enrollment
Day 1 Composite HPV Status
Total
(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%
Efficacy Studies—Combined Population
Data on file, MSD.
Combined Analysis
•
93% of subjects had 0 or 1 of the HPV vaccine types (6, 11, 16, or
18) at enrollment.
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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MITT-2 MITT-3
Sero (-) and/or PCR (-) to the relevant
vaccine HPV type at Day 1
Included Included
Sero (+) and/or PCR (+) to the relevant
vaccine HPV type at Day 1
Excluded Included
PCR (+) to the relevant vaccine HPV type
during the vaccination phase
Included Included
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
Modified Intention to Treat (MITT)

Populations Used to Evaluate GARDASIL
ASCUS = atypical squamous cells of undetermined significance.
Data on file, MSD.
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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Contribution of Subpopulations to Overall
Incidence of CIN 2/3 or AIS
Naïve to relevant vaccine HPV
types at Day 1 (MITT-2)
•
May acquire new infection prior
to completion of vaccination
regimen
•
Takes time for disease to develop
Early on, few disease
cases observed
MITT-2 + those infected with ≥1
vaccine HPV type or nonvaccine
type at Day 1 (MITT-3)
•
May have disease at Day 1
OR
•
May develop disease after Day 1
Most disease in clinical

trials of GARDASIL was
observed early
Impact of GARDASIL is masked due
to early prevalence of disease
Prophylactic efficacy of GARDASIL is high
Data on file, MSD.
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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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
End Points Analysis
Cases:
GARDASIL
or HPV 16
Vaccine
Cases:
Placebo
% Reduction
(95% CI)
HPV 16/18-
related CIN
2/3 or AIS
HPV-naïve efficacy 1 81 99 (93, 100)
HPV 16(+) and/or 18(+) at Day 1 121 120
General population impact 122 201 39 (23, 52)

HPV
6/11/16/18-
related CIN
or AIS
HPV-naïve efficacy 9 143 94 (88, 97)
HPV 6, 11, 16, and/or 18 (+) at Day 1 161* 174*
General population impact 170 317 46 (35, 56)
HPV
6/11/16/18-
related
genital warts
HPV-naïve efficacy 9 136 93 (87, 97)
HPV 6, 11, 16, and/or 18 (+) at Day 1 49 48
†

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

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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
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 20651480(1).
MITT-3 Population
Cumulative
Incidence of
HPV 16/18-
Related CIN
2/3 or AIS, %
•
With each screening round, the impact of the vaccine became
more apparent.
Time Since Month 1, Months
High rates of
prevalent
disease early
39% ↓
0 6 12 18 24 30 36 42 48
0
1
2
3
4
5
6
Placebo and 95% CI
GARDASIL and 95% CI
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

13

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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
Time Since Month 1, Months
Cumulative Incidence of HPV
6/11/16/18-Related VIN, VaIN,
or Genital Warts, %
MITT-3 Population
High rates of
prevalent disease
early
0 6 12 18 24 30
0
1
2
3
4
5
6
7
69% ↓
Data on file, MSD.
Placebo and 95% CI
GARDASIL and 95% CI
•
With each screening round, the efficacy of the vaccine became
more apparent.
GARDASIL
®

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

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

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*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
19486-0004. Please specify information package 20651100(1).
684 684 663 649 609 533 481

680 680 661 638 604 532 489
Number of
Subjects
Month Since Enrollment
GARDASIL Maintained Type-Specific,
Neutralizing Antibody Responses
0 7 12 18 30 42 48
1
10
100
1,000
3,000
5,000
Serum
cRIA
GMT,
mMU/mL
GARDASIL (Per Protocol)
Per-Protocol Placebo
Vaccination
Ph II–P005 Proof of Principle 16- to 23-year-old women
The duration
of protection
of GARDASIL
is unknown
beyond 48
months.
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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Ph III–P016, 018 Safety/Immunogenicity
9- to 15-year-old adolescents
Age at Enrollment, Years
Efficacy ProgramImmunogenicity Bridge
*Inclusive of 5 study protocols; all GMTs measured using cLIA.
Data on file, MSD.
Per-protocol immunogenicity population (aged 9–26)*
Neutralizing anti-HPV 6 GMTs at Month 7
Neutralizing Antibodies by Age
at Enrollment
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
500
700
900
1,100
1,300
1,500
1,600
Adolescent Females (aged 9–17)
Young Adult Females (aged 18–26)
Serum cLIA GMT with 95% CI,
mMU/mL
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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Injection Site (1 to 5 days postvaccination)
GARDASIL
(n=5,088)
Placebo (Aluminum)
(n=3,470)
Placebo (Saline)
(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

(n=5,088)
Placebo
(n=3,790)
Fever 10.3% 8.6%
Nausea 4.2% 4.1%
Dizziness 2.8% 2.6%
Vaccine-Related Experiences
•
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.
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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Summary of Pregnancies in the
Phase III Program for GARDASIL
GARDASIL
(n=10,418)
Placebo
(n=9,120)
Subjects with pregnancies 1,115 1,151
Number of pregnancies 1,244 1,272
Pregnancies with unknown
outcomes/ongoing pregnancies
258 263
Pregnancies with known outcomes 996 1,018
Live births
(% of pregnancies with known outcomes)
621 (62) 611 (60)
Fetal loss
(% of pregnancies with known outcomes)
375 (38) 407 (40)
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.
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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Summary of Known Pregnancy Outcomes in
the Phase III Program for GARDASIL
Estimated EOP could not be precisely ascertained in 10 women.
EOP = onset of pregnancy.
Data on file, MSD.
GARDASIL Placebo
Pregnancies with known
outcomes/EOP within 30 days of
vaccination
112 115
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
vaccination
879 898
Spontaneous loss 236 (26.8%) 237 (26.4%)
Elective termination 93 (10.6%) 117 (13.0%)
Live birth 549 (62.5%) 544 (60.6%)
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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Results
Cases:
GARDASIL
Cases:

Placebo
Congenital anomalies 15 16
Estimated onset of
pregnancy ≤30 days
of vaccination
5* 0
Estimated onset of
pregnancy >30 days
following vaccination
10 16
Pregnancy Outcomes:
Congenital Anomalies
•
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.
Data on file, MSD.
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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Selected Information About
GARDASIL
•
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 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.
•
Vaccination with GARDASIL may not result in protection in all vaccine
recipients.
•
GARDASIL is not intended to be used for treatment of active genital warts;
cervical cancer; CIN, VIN, or VaIN.
•
GARDASIL has not been shown to protect against diseases due to non-
vaccine HPV 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.
1. Data on file, MSD.
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

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Overall Conclusions for GARDASIL

•
Highly effective in preventing cervical cancer, CIN 2/3, AIS,
and other anogenital diseases caused by HPV 6, 11, 16,
and 18 in 16- to 26-year-old women naïve to the relevant
HPV types
•
Successful immunogenicity bridge between female
adolescents and young adult women
–
Antibody response in 10- 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
GARDASIL
®
[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]
Before administering GARDASIL, please read the accompanying Prescribing
Information.
a
Copyright © 2006 Merck & Co., Inc. All rights reserved. 20607234-08/06-GRD
GARDASIL PI
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