Vaccine Information: GARDASIL 9 (Page 4 of 8)

14.2 Clinical Trials for GARDASIL 9

Efficacy and/or immunogenicity of the 3-dose regimen of GARDASIL 9 were assessed in seven clinical trials. Study 1 evaluated the efficacy of GARDASIL 9 to prevent HPV-related cervical, vulvar, and vaginal disease using GARDASIL as a comparator.

The analysis of efficacy for GARDASIL 9 was evaluated in the per-protocol efficacy (PPE) population of 16- through 26-year-old girls and women, who received all three vaccinations within one year of enrollment, did not have major deviations from the study protocol, and were naïve to the relevant HPV type(s) by serology and PCR of cervicovaginal specimens prior to dose one and who remained PCR negative for the relevant HPV type(s) through one month post-dose 3 (Month 7). Overall, approximately 52% of subjects were negative to all vaccine HPV types by both PCR and serology at Day 1.

The primary analysis of efficacy against HPV Types 31, 33, 45, 52, and 58 is based on a combined endpoint of Cervical Intraepithelial Neoplasia (CIN) 2, CIN 3, Adenocarcinoma in situ (AIS), invasive cervical carcinoma, Vulvar Intraepithelial Neoplasia (VIN) 2/3, Vaginal Intraepithelial Neoplasia (VaIN) 2/3, vulvar cancer, or vaginal cancer. Other endpoints evaluated include cervical, vulvar and vaginal disease of any grade, persistent infection, cytological abnormalities and invasive procedures. For all endpoints, the efficacy against the HPV Types 31, 33, 45, 52 and 58 in GARDASIL 9 was evaluated compared with GARDASIL. Efficacy of GARDASIL 9 against anal lesions caused by HPV Types 31, 33, 45, 52, and 58 was not assessed due to low incidence. Effectiveness of GARDASIL 9 against anal lesions was inferred from the efficacy of GARDASIL against anal lesions caused by HPV types 6, 11, 16 and 18 in men and antibody responses elicited by GARDASIL 9 against the HPV types covered by the vaccine.

Effectiveness against disease caused by HPV Types 6, 11, 16, and 18 was assessed by comparison of geometric mean titers (GMTs) of type-specific antibodies following vaccination with GARDASIL 9 with those following vaccination with GARDASIL (Study 1 and Study 3). The effectiveness of GARDASIL 9 in girls and boys 9 through 15 years old and in boys and men 16 through 26 years old was inferred based on a comparison of type-specific antibody GMTs to those of 16 through 26-year-old girls and women following vaccination with GARDASIL 9. Immunogenicity analyses were performed in the per-protocol immunogenicity (PPI) population consisting of individuals who received all three vaccinations within pre-defined day ranges, did not have major deviations from the study protocol, met pre-defined day range for serum collection for assessment of antibody response and were naïve [PCR negative (in girls and women 16 through 26 years of age; Studies 1 and 2) and seronegative (Studies 1, 2, 3, 5, 7 and 8)] to the relevant HPV type(s) prior to dose 1 and among 16- through 26-year-old girls and women (Studies 1 and 2) remained PCR negative to the relevant HPV type(s) through Month 7. Pre-defined day ranges for vaccinations were relative to Day 1 (dose 1). For the 3-dose schedule, dose 2 was at 2 months (± 3 weeks) and dose 3 was at 6 months (± 4 weeks). For the 2-dose schedule, dose 2 was at 6 or 12 months (± 4 weeks). Pre-defined day range for serum collection for assessment of antibody response was 21 to 49 days after the last dose.

Study 1 evaluated immunogenicity of GARDASIL 9 and efficacy to prevent infection and disease caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in 16- through 26-year-old girls and women. Study 2 evaluated immunogenicity of GARDASIL 9 in girls and boys 9 through 15 years of age and women 16 through 26 years of age. Study 3 evaluated immunogenicity of GARDASIL 9 compared with GARDASIL in girls 9 through 15 years of age. Study 4 evaluated administration of GARDASIL 9 to girls and women 12 through 26 years of age previously vaccinated with GARDASIL. Study 5 evaluated GARDASIL 9 concomitantly administered with Menactra and Adacel in girls and boys 11 through 15 years of age. Together, these five clinical trials evaluated 12,233 individuals who received GARDASIL 9 (8,048 girls and women 16 through 26 years of age at enrollment with a mean age of 21.8 years; 2,927 girls 9 through 15 years of age at enrollment with a mean age of 11.9 years; and 1,258 boys 9 through 15 years of age at enrollment with a mean age of 11.9 years. Study 7 evaluated immunogenicity of GARDASIL 9 in boys and men, including 1,106 self-identified as heterosexual men (HM) and 313 self-identified as men having sex with men (MSM), 16 through 26 years of age at enrollment (mean ages 20.8 years and 22.2 years, respectively) and 1,101 girls and women 16 through 26 years of age at enrollment (mean age 21.3 years). Study 9 evaluated immunogenicity of GARDASIL 9 in 640 women 27 through 45 years of age and 570 girls and women 16 through 26 years of age (mean ages 35.8 years and 21.6 years, respectively).

The race distribution of the 16- through 26-year-old girls and women in the clinical trials was as follows: 56.8% White; 25.2% Other; 14.1% Asian; and 3.9% Black. The race distribution of the 9- through 15-year-old girls in the clinical trials was as follows: 60.3% White; 19.3% Other; 13.5% Asian; and 7.0% Black. The race distribution of the 9- through 15-year-old boys in the clinical trials was as follows: 46.6% White; 34.3% Other; 13.3% Asian; and 5.9% Black. The race distribution of the 16- through 26-year-old boys and men in the clinical trials was as follows: 62.1% White; 22.6% Other; 9.8% Asian; and 5.5% Black.

In Study 9 the race distribution of 27- through 45-year-old women was as follows: 97.7% White, 1.6% Asian, 0.3% Other or Multiracial, and 0.5% Black. The race distribution of girls and women 16 through 26 years of age in this study was as follows: 94.6% White, 3.0% Asian, 1.6% Other or Multiracial, and 0.9% Black.

One clinical trial (Study 8) assessed the 2-dose regimen of GARDASIL 9. Study 8 evaluated the immunogenicity of 2 doses of GARDASIL 9 in girls and boys 9 through 14 years of age and 3 doses of GARDASIL 9 in girls 9 through 14 years of age and women 16 through 26 years of age; (N=1,518; 753 girls; 451 boys and 314 women). The mean age for the girls and boys 9 through 14 years of age was 11.5 years; the mean age for girls and women 16 through 26 years of age was 21.0 years. In Study 8, the race distribution was as follows: 61.1% White; 16.3% Asian; 13.3% Other; and 8.9% Black.

14.3 Efficacy – HPV Types 31, 33, 45, 52 and 58 in Girls and Women 16 through 26 Years of Age

Studies Supporting the Efficacy of GARDASIL 9 against HPV Types 31, 33, 45, 52, and 58

The efficacy of GARDASIL 9 in 16- through 26-year-old girls and women was assessed in an active comparator-controlled, double-blind, randomized clinical trial (Study 1) that included a total of 14,204 women (GARDASIL 9 = 7,099; GARDASIL = 7,105) who were enrolled and vaccinated without pre-screening for the presence of HPV infection. Subjects were followed up with a median duration of 40 months (range 0 to 64 months) after the last vaccination.

The primary efficacy evaluation was conducted in the PPE population based on a composite clinical endpoint of HPV 31-, 33-, 45-, 52-, and 58-related cervical cancer, vulvar cancer, vaginal cancer, CIN 2/3 or AIS, VIN 2/3, and VaIN 2/3. Efficacy was further evaluated with the clinical endpoints of HPV 31-, 33-, 45-, 52-, and 58-related CIN 1, vulvar and vaginal disease of any grade, and persistent infection. In addition, the study also evaluated the impact of GARDASIL 9 on the rates of HPV 31-, 33-, 45-, 52-, and 58-related abnormal Papanicolaou (Pap) tests, cervical and external genital biopsy, and definitive therapy [including loop electrosurgical excision procedure (LEEP) and conization]. Efficacy for all endpoints was measured starting after the Month 7 visit.

GARDASIL 9 prevented HPV 31-, 33-, 45-, 52-, and 58-related persistent infection and disease and also reduced the incidence of HPV 31-, 33-, 45-, 52-, and 58-related Pap test abnormalities, cervical and external genital biopsy, and definitive therapy (Table 7).

Table 7: Analysis of Efficacy of GARDASIL 9 against HPV Types 31, 33, 45, 52, and 58 in the PPE * Population of 16- through 26-Year-old Girls and Women (Study 1)

Disease Endpoint	GARDASIL 9N †=7099		GARDASILN †=7105		GARDASIL 9 Efficacy%(95% CI)
	n ‡	Number of cases	n ‡	Number of cases
CI=Confidence Interval
CIN=Cervical Intraepithelial Neoplasia, VIN=Vulvar Intraepithelial Neoplasia, VaIN=Vaginal Intraepithelial Neoplasia, AIS=Adenocarcinoma In Situ , ASC-US=Atypical squamous cells of undetermined significance
HR=High Risk
* The PPE population consisted of individuals who received all three vaccinations within one year of enrollment, did not have major deviations from the study protocol, were naïve (PCR negative and seronegative) to the relevant HPV type(s) (Types 31, 33, 45, 52, and 58) prior to dose 1, and who remained PCR negative to the relevant HPV type(s) through one month post-dose 3 (Month 7); data from Study 1 (NCT00543543). † N=Number of individuals randomized to the respective vaccination group who received at least one injection ‡ n=Number of individuals contributing to the analysis § Persistent infection detected in samples from two or more consecutive visits at least six months apart ¶ Persistent infection detected in samples from two or more consecutive visits over 12 months or longer # Papanicolaou test Þ Including loop electrosurgical excision procedure (LEEP) and conization
HPV 31-, 33-, 45-, 52-, 58-related CIN 2/3, AIS, Cervical Cancer, VIN 2/3, VaIN 2/3, Vulvar Cancer, and Vaginal Cancer	6016	1	6017	30	96.7(80.9, 99.8)
HPV 31-, 33-, 45-, 52-, 58-related CIN 1	5948	1	5943	69	98.6(92.4, 99.9)
HPV 31-, 33-, 45-, 52-, 58-related CIN 2/3 or AIS	5948	1	5943	27	96.3(79.5, 99.8)
HPV 31-, 33-, 45-, 52-, 58-related Vulvar or Vaginal Disease	6009	1	6012	16	93.8(61.5, 99.7)
HPV 31-, 33-, 45-, 52-, 58-related Persistent Infection ≥6 Months §	5939	26	5953	642	96.2(94.4, 97.5)
HPV 31-, 33-, 45-, 52-, 58-related Persistent Infection ≥12 Months ¶	5939	15	5953	375	96.1(93.7, 97.9)
HPV 31-, 33-, 45-, 52-, 58-related ASC-US HR-HPV Positive or Worse Pap # Abnormality	5881	35	5882	462	92.6(89.7, 94.8)
HPV 31-, 33-, 45-, 52-, 58-related Biopsy	6016	7	6017	222	96.9(93.6, 98.6)
HPV 31-, 33-, 45-, 52-, 58-related Definitive Therapy Þ	6012	4	6014	32	87.5(65.7, 96.0)