[Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]
I. THERAPEUTIC CLASS
GARDASIL™ is a recombinant, quadrivalent vaccine that protects against Human Papillomavirus (HPV).
II. CLINICAL PHARMACOLOGY
Disease Burden: Worldwide, over 490,000 cases of cervical
cancer are diagnosed annually. Cervical cancer prevention focuses on repeat screening
(eg, Papanicolaou's [Pap] testing and/or Human Papillomavirus [HPV] testing) and early intervention.
This strategy has reduced cancer rates by approximately 75% in the developed world but has shifted
the burden from managing cervical cancer to monitoring and treating a large number of premalignant lesions.
Cervical cancer is caused by Human Papillomavirus (HPV) infection. HPV infection is necessary for
the development of squamous cell cervical cancer (and its precursor lesions Cervical Intraepithelial Neoplasia
[CIN] 1 and CIN 2/3) and cervical adenocarcinoma (and its precursor lesion adenocarcinoma in situ [AIS]).
HPV also causes a subset of vulvar and vaginal cancers and their precursor lesions
Vulvar Intraepithelial Neoplasia (VIN) and Vaginal Intraepithelial Neoplasia (VaIN).
HPV infection is very common. In the absence of vaccination, over 50% of sexually active
adults will become infected with HPV during their lifetime. Most HPV infections clear without sequelae but some progress to cervical cancer.
Infection with HPV Types 6, 11, 16, and 18 can cause abnormal Pap test results and low-grade
dysplastic lesions (CIN 1, VIN 1, and VaIN 1). HPV 6and HPV 11-related lesions are unlikely to progress
to cancer but are clinically indistinguishable from premalignant lesions caused by HPV 16 and HPV 18.
HPV 16 and HPV 18 cause 70% of anal and HPV related penile cancers and their precursor lesions.
Infection with HPV 6 and HPV 11 also causes genital warts (condyloma acuminata) which are growths of
the cervicovaginal, vulvar, and perianal mucosa and the external genitalia that rarely progress to cancer.
The lifetime risk for acquisition of genital warts has been estimated to exceed 10%.
The incidence of this lesion is generally comparable between men and women.
Recurrent Respiratory Papillomatosis (RRP), a disease of infants and adults,
is also caused by HPV 6 and HPV 11. RRP is characterized by repeated growth of warts in the respiratory tract.
In the U.S., 5,900 cases are diagnosed annually. Therapy requires repeated surgery.
GARDASIL is a recombinant vaccine directed against
HPV 6, 11, 16, and 18. These types are responsible for:
• 70% of cervical cancer, AIS, CIN 2/3, and
HPV-related vulvar and vaginal cancer cases;
• 35 to 50% of all CIN 1, VIN 1, and VaIN 1 cases; and
• 90% of genital wart and RRP cases.
Mechanism of Action: GARDASIL contains L1 VLPs, which are proteins that resemble wild-type virions.
Because the virus-like particles contain no viral DNA, they cannot infect cells or reproduce.
In preclinical studies, induction of anti-papillomavirus antibodies with L1 VLP vaccines
resulted in protection against infection. Administration of serum from vaccinated to unvaccinated
animals resulted in the transfer of protection against HPV to the unvaccinated animals.
These data suggest that the efficacy of L1 VLP vaccines is mediated by the development of humoral immune responses.
Clinical Studies: CIN 2/3 and AIS are the immediate precursors of invasive squamous
cell carcinoma and invasive adenocarcinoma of the cervix, respectively. Their detection and removal
has been shown to prevent invasive cancer (secondary prevention); thus, their primary prevention
through vaccination will prevent invasive cancer.
Invasive cervical cancer cannot be used as an endpoint for efficacy studies of HPV
vaccines because of the importance of employing secondary prevention measures.
Therefore, the immediate precursors, CIN 2 (moderategrade cervical dysplasia),
CIN 3 (high-grade cervical dysplasia including carcinoma in situ), and AIS are the most appropriate
endpoints for the demonstration of the prevention of cervical cancer by HPV vaccines.
CIN 3 and AIS are classified as Stage 0 cervical cancers according to FIGO
(International Federation of Obstetrics and Gynaecology). VIN 2/3 and VaIN 2/3 are the immediate
precursors to HPV-related vulvar and vaginal cancer, respectively.
The efficacy of GARDASIL was assessed in 4 placebo-controlled, doubleblind, randomized
Phase II and III clinical studies. The first Phase II study evaluated the HPV 16 component of
GARDASIL (Protocol 005, N = 2,391) and the second evaluated all components of GARDASIL
(Protocol 007, N = 551). The Phase III studies, termed FUTURE (Females United To Unilaterally Reduce Endo/Ectocervical Disease),
evaluated GARDASIL in 5,442 (FUTURE I) and 12,157 (FUTURE
II) subjects. Together, these studies evaluated 20,541 women 16 to 26 years of age at enrollment.
The median duration of follow-up was 4.0, 3.0, 2.4, and 2.0 years for Protocol 005, Protocol 007,
FUTURE I, and FUTURE II, respectively. Subjects received vaccine or placebo on the day of enrollment
and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies combined.
The studies did not have a screening phase. Thus, individuals who had been exposed to a vaccine
HPV type prior to enrollment were included in the studies. Overall, 73% of subjects were naive to all 4 vaccine HPV types
at enrollment. These subjects were at risk for infection and disease caused by all 4 vaccine HPV types.
Prophylactic Efficacy: GARDASIL was highly efficacious in reducing the incidence of
CIN (any grade); AIS; non-invasive cervical cancer (CIN 3 and AIS); and external genital lesions,
including condyloma acuminata, VIN (any grade) and VaIN (any grade) related to vaccine HPV types.
Based on a pre-specified analysis of lesions evident beginning 30 days Postdose 1, there was evidence
that the vaccine was already efficacious during the course of the 3-dose vaccination regimen.
The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population,
consisting of individuals who received all 3 vaccinations within 1 year of enrollment, did not have
major deviations from the study protocol, and were naive to the relevant HPV type(s) prior to dose one
and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit.
The efficacy of GARDASIL against HPV 16- or 18-related CIN 2/3 or AIS was 100% (95% CI: 65.1%, 100.0%)
in Protocol 005, 100% (95% Cl: <0.0%, 100.0%) in Protocol 007,100% (95% CI: 78.5%, 100.0%) in FUTURE
I,100% (95% CI: 80.9%, 100.0%) in FUTURE II, and 100% (95% CI: 92.9%,100.0%) in the combined protocols.
The efficacy of GARDASIL against HPV 6-, 11-, 16-, 18-related CIN (CIN 1, CIN 2/3) or AIS was 100% (95% CI: <0.0%, 100.0%)
in Protocol 007, 100% (95% CI: 89.5%, 100.0%) in FUTURE I, 90.7% (95% CI: 74.4%,97.6%) in
FUTURE II, and 95.2% (95% CI: 87.2%, 98.7%) in the combined protocols. The efficacy of GARDASIL against
HPV 6-, 11-, 16-, or 18-related genital lesions (genital warts, VIN, VaIN) was 100% (95% CI: <0.0%, 100.0%)
in Protocol 007,100% (95% CI: 90.3%, 100.0%) in FUTURE I, 98.6% (95% CI: 91.8%, 100.0%) in FUTURE
II, and 99.1% (95% CI: 95.0%, 100.0%) in the combined protocols.
GARDASIL was equally efficacious against HPV disease caused by each of the four vaccine HPV types.
In a supplemental analysis, the efficacy of GARDASIL against HPV 16/18-related disease
was 100% (95% CI: 87.9%, 100.0%) for FIGO Stage
0 cervical cancer (CIN 3 or AIS) and 100% (95% CI: 55.5%, 100.0%) for VIN 2/3 or VaIN 2/3.
Efficacy in Subjects with Current or Prior Infection: Individuals who were already
infected with one or more vaccine-related HPV types prior to vaccination were protected from clinical
disease caused by the remaining vaccine HPV types.
Individuals who received GARDASIL, but had ongoing HPV infection at the time of vaccination
had a 26% (95% CI: <0.0%, 47.0%) lower incidence of CIN (CIN 1 or CIN 2/3) or AIS resulting from this infection as compared with placebo.
Ongoing infection was defined as infection with a vaccine HPV type at enrollment, but no evidence of immune response to it.
Overall Impact on Cervical and Genital Disease and Procedures: The impact of GARDASIL
was also evaluated in broader groups of women enrolled in the clinical trials. In addition to HPV naive women,
these groups included women who had been exposed to HPV prior to enrollment or had ongoing infection or
disease caused by any HPV type. The impact of GARDASIL was lower in these groups compared with only HPV naive individuals.
GARDASIL reduced the overall rate of CIN (CIN 1 or CIN 2/3) or AIS, CIN 2/3 or AIS, and HPV-related
external genital lesions (caused by vaccine HPV types or non-vaccine HPV types), compared with placebo.
The magnitude of the differences increased over time.
GARDASIL reduced the incidence of atypical squamous cells of undetermined significance (ASC-US)
with positive Hybrid Capture II high-risk probe, and the combined incidence of atypical glandular cells
(AGC) and low- and high-grade squamous intraepithelial lesions (LSIL and HSIL), compared with placebo.
GARDASIL reduced the incidence of definitive therapy (eg, loop electrosurgical excision procedure)
and surgery to excise genital lesions, compared with placebo.
Because GARDASIL has not been shown to protect against the consequences of all HPV types and will
not protect against established disease caused by the HPV types contained in the vaccine, the overall
efficacy of GARDASIL, described above, will depend on the baseline prevalence of HPV infection and disease in the population vaccinated.