Vaccine Information: GARDASIL (Page 3 of 8)

14 CLINICAL STUDIES

CIN 2/3 and AIS are the immediate and necessary precursors of squamous cell carcinoma and adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent cancer; thus, they serve as surrogate markers for prevention of cervical cancer. In the clinical studies in girls and women aged 16 through 26 years, cases of CIN 2/3 and AIS were the efficacy endpoints to assess prevention of cervical cancer. In addition, cases of VIN 2/3 and VaIN 2/3 were the efficacy endpoints to assess prevention of HPV-related vulvar and vaginal cancers, and observations of external genital lesions were the efficacy endpoints for the prevention of genital warts.

In clinical studies in boys and men aged 16 through 26 years, efficacy was evaluated using the following endpoints: external genital warts and penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer. In addition, cases of AIN grades 1/2/3 and anal cancer made up the composite efficacy endpoint used to assess prevention of HPV-related anal cancer.

Anal HPV infection, AIN, and anal cancer were not endpoints in the studies conducted in women. The similarity of HPV-related anal disease in men and women supports bridging the indication of prevention of AIN and anal cancer to women.

Efficacy was assessed in 6 AAHS-controlled, double-blind, randomized Phase 2 and 3 clinical studies. The first Phase 2 study evaluated the HPV 16 component of GARDASIL (Study 1, N = 2391 16- through 26-year-old girls and women) and the second evaluated all components of GARDASIL (Study 2, N = 551 16- through 26-year-old girls and women). Two Phase 3 studies evaluated GARDASIL in 5442 (Study 3) and 12,157 (Study 4) 16- through 26-year-old girls and women. A third Phase 3 study, Study 5, evaluated GARDASIL in 4055 16- through 26-year-old boys and men, including a subset of 598 (GARDASIL = 299; placebo = 299) men who self-identified as having sex with men (MSM population). A fourth Phase 3 study, Study 6, evaluated GARDASIL in 3817 24- through 45-year-old women. Together, these six studies evaluated 28,413 individuals (20,541 girls and women 16 through 26 years of age at enrollment with a mean age of 20.0 years, 4055 boys and men 16 through 26 years of age at enrollment with a mean age of 20.5 years, and 3817 women 24 through 45 years of age at enrollment with a mean age of 34.3 years). The race distribution of the 16- through 26-year-old girls and women in the clinical trials was as follows: 70.4% White; 12.2% Hispanic (Black and White); 8.8% Other; 4.6% Black; 3.8% Asian; and 0.2% American Indian. The race distribution of the 16- through 26-year-old boys and men in the clinical trials was as follows: 35.2% White; 20.5% Hispanic (Black and White); 14.4% Other; 19.8% Black; 10.0% Asian; and 0.1% American Indian. The race distribution of the 24- through 45-year-old women in the clinical trials was as follows: 20.6% White; 43.2% Hispanic (Black and White); 0.2% Other; 4.8% Black; 31.2% Asian; and 0.1% American Indian.

The median duration of follow-up was 4.0, 3.0, 3.0, 3.0, 2.3, and 4.0 years for Study 1, Study 2, Study 3, Study 4, Study 5, and Study 6, respectively. Individuals received vaccine or AAHS control on the day of enrollment and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies in girls and women combined according to a prospective clinical plan.

Overall, 73% of 16- through 26-year-old girls and women, 67% of 24- through 45-year-old women, and 83% of 16- through 26-year-old boys and men were naïve (i.e., PCR [Polymerase Chain Reaction] negative and seronegative for all 4 vaccine HPV types) to all 4 vaccine HPV types at enrollment.

A total of 27% of 16- through 26-year-old girls and women, 33% of 24- through 45-year-old women, and 17% of 16- through 26-year-old boys and men had evidence of prior exposure to or ongoing infection with at least 1 of the 4 vaccine HPV types. Among these individuals, 74% of 16- through 26-year-old girls and women, 71% of 24- through 45-year-old women, and 78% of 16- through 26-year-old boys and men had evidence of prior exposure to or ongoing infection with only 1 of the 4 vaccine HPV types and were naïve (PCR negative and seronegative) to the remaining 3 types.

In 24- through 45-year-old individuals, 0.4% had been exposed to all 4 vaccine HPV types.

In individuals who were naïve (PCR negative and seronegative) to all 4 vaccine HPV types, CIN, genital warts, VIN, VaIN, PIN, and persistent infection caused by any of the 4 vaccine HPV types were counted as endpoints.

Among individuals who were positive (PCR positive and/or seropositive) for a vaccine HPV type at Day 1, endpoints related to that type were not included in the analyses of prophylactic efficacy. Endpoints related to the remaining types for which the individual was naïve (PCR negative and seronegative) were counted.

For example, in individuals who were HPV 18 positive (PCR positive and/or seropositive) at Day 1, lesions caused by HPV 18 were not counted in the prophylactic efficacy evaluations. Lesions caused by HPV 6, 11, and 16 were included in the prophylactic efficacy evaluations. The same approach was used for the other types.

14.1 Prophylactic Efficacy – HPV Types 6, 11, 16, and 18 in Girls and Women 16 through 26 Years of Age

GARDASIL was administered without prescreening for presence of HPV infection and the efficacy trials allowed enrollment of girls and women regardless of baseline HPV status (i.e., PCR status or serostatus). Girls and women with current or prior HPV infection with an HPV type contained in the vaccine were not eligible for prophylactic efficacy evaluations for that type.

The primary analyses of efficacy with respect to HPV types 6, 11, 16, and 18 were conducted in the per-protocol efficacy (PPE) population, consisting of girls and women who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative in cervicovaginal specimens and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit.

GARDASIL was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN (any grade); and VaIN (any grade) related to vaccine HPV types 6, 11, 16, or 18 in those who were PCR negative and seronegative at baseline (Table 11).

In addition, girls and women who were already infected with 1 or more vaccine-related HPV types prior to vaccination were protected from precancerous cervical lesions and external genital lesions caused by the other vaccine HPV types.

Table 11: Analysis of Efficacy of GARDASIL in the PPE * Population of 16- Through 26-Year-Old Girls and Women for Vaccine HPV Types
Population GARDASIL AAHS Control % Efficacy (95% CI)
N Number of cases N Number of cases
N = Number of individuals with at least 1 follow-up visit after Month 7
CI = Confidence Interval
Note 1: Point estimates and confidence intervals are adjusted for person-time of follow-up.
Note 2: The first analysis in the table (i.e., HPV 16- or 18-related CIN 2/3, AIS or worse) was the primary endpoint of the vaccine development plan.
Note 3: Table 11 does not include cases due to non-vaccine HPV types.
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate
*
The PPE population consisted of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month postdose 3 (Month 7).
See Table 14 for analysis of vaccine impact in the general population.
Evaluated only the HPV 16 L1 VLP vaccine component of GARDASIL
§
Analyses of the combined trials were prospectively planned and included the use of similar study entry criteria.
HPV 16- or 18-related CIN 2/3 or AIS
Study 1 755 0 750 12 100.0 (65.1, 100.0)
Study 2 231 0 230 1 100.0 (-3744.9, 100.0)
Study 3 2201 0 2222 36 100.0 (89.2, 100.0)
Study 4 5306 2 5262 63 96.9 (88.2, 99.6)
Combined Protocols § 8493 2 8464 112 98.2 (93.5, 99.8)
HPV 16-related CIN 2/3 or AIS
Combined Protocols § 7402 2 7205 93 97.9 (92.3, 99.8)
HPV 18-related CIN 2/3 or AIS
Combined Protocols § 7382 0 7316 29 100.0 (86.6, 100.0)
HPV 16- or 18-related VIN 2/3
Study 2 231 0 230 0 Not calculated
Study 3 2219 0 2239 6 100.0 (14.4, 100.0)
Study 4 5322 0 5275 4 100.0 (-50.3, 100.0)
Combined Protocols § 7772 0 7744 10 100.0 (55.5, 100.0)
HPV 16- or 18-related VaIN 2/3
Study 2 231 0 230 0 Not calculated
Study 3 2219 0 2239 5 100.0 (-10.1, 100.0)
Study 4 5322 0 5275 4 100.0 (-50.3, 100.0)
Combined Protocols § 7772 0 7744 9 100.0 (49.5, 100.0)
HPV 6-, 11-, 16-, or 18-related CIN (CIN 1, CIN 2/3) or AIS
Study 2 235 0 233 3 100.0 (-138.4, 100.0)
Study 3 2241 0 2258 77 100.0 (95.1, 100.0)
Study 4 5388 9 5374 145 93.8 (88.0, 97.2)
Combined Protocols § 7864 9 7865 225 96.0 (92.3, 98.2)
HPV 6-, 11-, 16-, or 18-related Genital Warts
Study 2 235 0 233 3 100.0 (-139.5, 100.0)
Study 3 2261 0 2279 58 100.0 (93.5, 100.0)
Study 4 5404 2 5390 132 98.5 (94.5, 99.8)
Combined Protocols § 7900 2 7902 193 99.0 (96.2, 99.9)
HPV 6- and 11-related Genital Warts
Combined Protocols § 6932 2 6856 189 99.0 (96.2, 99.9)

Prophylactic efficacy against overall cervical and genital disease related to HPV 6, 11, 16, and 18 in an extension phase of Study 2, that included data through Month 60, was noted to be 100% (95% CI: 12.3%, 100.0%) among girls and women in the per protocol population naïve to the relevant HPV types.

GARDASIL was efficacious against HPV disease caused by HPV types 6, 11, 16, and 18 in girls and women who were naïve for those specific HPV types at baseline.

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