Gardasil 9 Product Monograph

1 Indications

GARDASIL®9, Human Papillomavirus 9-valent Vaccine, Recombinant, is a vaccine indicated in individuals 9 through 45 years of age for the prevention of infection caused by the Human Papillomavirus (HPV) types 6, 11, 16, 18, 31, 33, 45, 52 and 58 and the following diseases associated with the HPV types included in the vaccine:

• Cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58
• Genital warts (condyloma acuminata) caused by HPV types 6 and 11

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58:

• Cervical adenocarcinoma in situ (AIS)
• Cervical intraepithelial neoplasia (CIN) grade 2 and grade 3
• Cervical intraepithelial neoplasia (CIN) grade 1
• Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
• Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
• Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.

1.1 Pediatrics (≥ 9 years of age)

Based on the data submitted and reviewed by Health Canada, the safety and efficacy of GARDASIL®9 in pediatric patients from 9 years of age has been established. Therefore, Health Canada has authorized an indication for pediatric use in individuals 9 years and above (see 1 Indications, 8 Adverse Reactions and 14 Clinical Trials).

1.2 Geriatrics (≥ 65 years of age)

The safety and efficacy of GARDASIL®9 have not been evaluated in individuals aged 65 years and over.

2 Contraindications

• GARDASIL®9 is contraindicated in patients who are hypersensitive to either GARDASIL® or GARDASIL®9 or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.
• Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of GARDASIL®9 or GARDASIL® should not receive further doses of GARDASIL®9.

4 Dosage and Administration

4.1 Dosing Considerations

Administration of GARDASIL®9 in Individuals Who Have Been Previously Vaccinated with GARDASIL®

It is recommended that individuals who receive a first dose of GARDASIL®9 complete the vaccination course with GARDASIL®9.

Studies using a mixed regimen (interchangeability) of HPV vaccines were not performed for GARDASIL®9.

Safety and immunogenicity of GARDASIL®9 were assessed in individuals who previously completed a three-dose vaccination series with GARDASIL® (see 8 Adverse Reactions and 14 Clinical Trials).

4.2 Recommended Dose and Dosage Adjustment

GARDASIL®9 should be administered intramuscularly as 3 separate 0.5 mL doses according to the following schedule:

First dose: at elected date

Second dose: 2 months after the first dose

Third dose: 6 months after the first dose

Individuals are encouraged to adhere to the 0, 2, and 6 months vaccination schedule. The second dose should be administered at least 1 month after the first dose, and the third dose should be administered at least 3 months after the second dose. All three doses should be given within a 1 year period.

Alternatively, in individuals 9 through 14 years of age, GARDASIL®9 can be administered according to a 2-dose schedule; the second dose should be administered between 5 and 13 months after the first dose. If the second vaccine dose is administered earlier than 5 months after the first dose, a third dose should always be administered.

The use of GARDASIL®9 should be in accordance with official recommendations.

4.4 Administration

For intramuscular use only.

Shake well before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine. GARDASIL®9 should not be diluted or mixed with other vaccines. After thorough agitation, GARDASIL®9 is a white, cloudy liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the product if particulates are present or if it appears discolored.

GARDASIL®9 should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.

GARDASIL®9 must not be injected intravascularly. Neither subcutaneous nor intradermal administration has been studied. These methods of administration are not recommended.

Instructions for Use

Prefilled Syringe Use

Shake well before use. Attach the needle by twisting in a clockwise direction until the needle fits securely on the syringe. Administer the entire dose as per standard protocol.

Needles

A sterile 22 to 25-gauge needle, 1 to 1-½ inch (2.5 cm – 3.8 cm) length for IM injection should be used. It is important to use a separate sterile syringe and needle for each patient to prevent transmission of infectious agents from one individual to another.

4.5 Missed Dose

If a planned dose of GARDASIL®9 is missed, it should be administered as soon as possible. The schedule of administration should be adjusted to maintain the prescribed dosing interval.

5 Overdose

There have been no reports of administration of higher than recommended doses of GARDASIL®9.

For the most recent information in the management of a suspected vaccine overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 Dosage Forms, Strengths, Composition, and Packaging

To help ensure the traceability of vaccines for patient immunization record-keeping as well as safety monitoring, healthcare professionals should record the time and date of administration, quantity of administered dose (if applicable), anatomical site and route of administration, brand name and generic name of the vaccine, the product lot number and expiry date.

Syringes

GARDASIL®9 is supplied in single-dose Type I glass prefilled Luer Lock syringes, containing 0.5 mL dose of liquid vaccine.

Available in 1 and 10 single dose syringe packages.

The components of the prefilled syringes are latex free.

Table 1 – Dosage Forms, Strengths, and Composition

7 Warnings and Precautions

General

As for any vaccine, vaccination with GARDASIL®9 may not result in protection in all vaccine recipients.

This vaccine is not intended to be used for treatment of active external genital lesions; cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers; CIN, VIN, VaIN, or AIN.

This vaccine will not protect against diseases that are not caused by HPV.

GARDASIL®9 has not been shown to protect against diseases due to HPV types not contained in the vaccine.

As with all injectable vaccines, appropriate medical treatment should always be readily available in case of rare anaphylactic reactions following the administration of the vaccine.

Syncope (fainting) may follow any vaccination, especially in adolescents and young adults. Syncope, sometimes associated with falling, has occurred after HPV vaccination. Therefore, vaccinees should be carefully observed for approximately 15 minutes after administration of GARDASIL®9.

Routine monitoring and Pap test in women should continue to be performed as indicated, regardless of GARDASIL®9 administration. Recipients of GARDASIL®9 should not discontinue screening for cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers if it has been recommended by a healthcare professional. Appropriate precautions against sexually transmitted diseases should continue to be used.

Febrile Illness

The decision to administer or delay vaccination because of a current or recent febrile illness depends largely on the severity of the symptoms and their etiology. Low-grade fever itself and mild upper respiratory infection are not generally contraindications to vaccination.

Hematologic

This vaccine should be given with caution to individuals with thrombocytopenia or any coagulation disorder because bleeding may occur following an intramuscular administration in these individuals.

Immune

Individuals with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a genetic defect, Human Immunodeficiency Virus (HIV) infection, or other causes, may have reduced antibody response to active immunization (see 9 Drug Interactions).

Reproductive Health: Female and Male Potential

• Fertility

Reproduction studies have been performed in female rats at a dose approximately 240 times the human dose (mg/kg basis) and have revealed no evidence of impaired female fertility or harm to the fetus due to GARDASIL®9 (see 7.1.1 Pregnancy, 16 Non-Clinical Toxicology).

7.1 Special Populations

• ®9 have not been evaluated in HIV-infected individuals.

7.1.1 Pregnancy

There are no adequate and well-controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response (see 16 Nonclinical Toxicology). As a precautionary measure, the administration of GARDASIL®9 during pregnancy should be avoided. Women who become or plan to become pregnant during the vaccination series should be advised to interrupt or postpone the vaccination regimen until completion of pregnancy.

A six-year pregnancy registry for GARDASIL®9 enrolled 185 women who were inadvertently exposed to GARDASIL®9 within one month prior to the last menstrual period (LMP) or at any time during pregnancy, 180 of whom were prospectively followed. After excluding elective terminations (n=1), ectopic pregnancies (n=0) and those lost to follow-up (n=110), there were 69 pregnancies with known outcomes. Frequencies of miscarriage and major birth defects were 4.3% of pregnancies (3/69) and 4.5% of live born infants (3/67), respectively. These frequencies of the assessed outcomes in the prospective population were consistent with estimated background frequencies (see 8.2 Adverse Reactions, Clinical Trials Experience of GARDASIL®9 in Pregnancy).

Pregnant women exposed to GARDASIL®9 are encouraged to report their exposure or suspected adverse reactions by contacting Merck Canada Inc., at 1-800-567-2594.

7.1.2 Breastfeeding

It is not known whether vaccine antigens are excreted in human milk.

A total of 92 women were breast feeding during the vaccination period of the clinical studies for GARDASIL®9 in women aged 16 to 26 years. There were no vaccine-related serious adverse experiences reported in infants who were nursing during the vaccination period.

7.1.3 Pediatrics (< 9 years of age)

The safety and efficacy of GARDASIL®9 have not been evaluated in children younger than 9 years.

7.1.4 Geriatrics (≥ 65 years of age)

The safety and efficacy of GARDASIL®9 have not been evaluated in individuals aged 65 years and over.

8 Adverse Reactions

8.1 Adverse Reaction Overview

Headache, fever, nausea, dizziness, fatigue, diarrhea, oropharyngeal pain, upper abdominal pain, and local injection site reactions (pain, swelling, erythema, pruritus, bruising, hematoma, mass, hemorrhage, induration) occurred after administration with GARDASIL®9.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another vaccine.

The safety of GARDASIL®9 was evaluated in 7 clinical studies (Protocols 001, 002, 003, 005, 006, 007, 009) that included 15 776 individuals who received at least one dose of GARDASIL®9 and had safety follow-up. Protocol 001 and Protocol 009 included 7 378 individuals who received at least one dose of GARDASIL® and had safety follow-up. The vaccines were administered on the day of enrollment and the subsequent doses administered approximately 2 and 6 months thereafter. Safety was evaluated using vaccination report card (VRC)-aided surveillance for 14 days after each injection of GARDASIL®9 or GARDASIL®.

The individuals who were monitored using VRC-aided surveillance included 9 102 girls and women 16 through 26 years of age, 1 394 boys and men 16 through 26 years of age and 5 280 girls and boys 9 through 15 years of age (3 481 girls and 1 799 boys) at enrollment who received GARDASIL®9; and 7 078 girls and women 16 through 26 years of age and 300 girls 9 through 15 years of age at enrollment who received GARDASIL®. The race distribution of the integrated safety population for Protocols 001, 002, 005, 006, 007 and 009 for GARDASIL®9 was similar between women (56.2% White; 25.4% Other Races or Multiracial; 14.7% Asian; 3.7% Black) and girls and boys (61.2% White; 18.9% Other Races or Multiracial; 14.6% Asian; 5.3% Black). For Protocol 003, the race distribution for boys and men was 61.9% White; 22.7% Other Races or Multiracial; 9.8% Asian; 5.5% Black. The race distribution of the safety population for GARDASIL® was determined in two studies (Protocol 001 and Protocol 009) that had different profiles. In Protocol 001, the race distribution was similar to the integrated database for GARDASIL®9: 55.3% White; 26.9% Multiracial; 14.2% Asian; 3.3% Black; 0.2% Unknown; 0.1% American Indian or Alaskan Native; and 0.1% Native Hawaiian or other Pacific Islander. Protocol 009 race distribution was 98.0% White; 1.3% Multiracial; 0.3% Asian; and 0.3% Black.

Safety of GARDASIL®9 in women 27 through 45 years of age was evaluated in a clinical trial comparing 640 women 27 through 45 years of age and 570 girls and women 16 through 26 years of age. The race distribution was similar between women 27 through 45 years of age (97.7% White, 1.6% Asian, 0.3% Other or Multiracial, 0.5% Black) and girls and women 16 through 26 years of age (94.6% White, 3.0% Asian, 1.6% Other or Multiracial, 0.9% Black).

Safety of GARDASIL®9 in men 27 through 45 years of age is inferred from the safety data of GARDASIL® and GARDASIL®9 in boys and men 9 through 26 years of age and girls and women 9 through 45 years of age.

Systemic and Injection-Site Adverse Reactions in Girls and Women

The vaccine-related adverse experiences that were observed among recipients of either GARDASIL®9 or GARDASIL® at a frequency of at least 1% are shown in Table 2. Few individuals (GARDASIL®9 = 0.1% vs. GARDASIL® < 0.1%) discontinued due to adverse experiences after receiving either vaccine.

Temperature and injection-site pain, swelling, and erythema were solicited using VRC-aided surveillance for 5 days after each injection of GARDASIL®9 during the clinical studies. The incidence and severity of solicited adverse reactions that occurred within 5 days following each dose of GARDASIL®9 are shown in Table 3.

An uncontrolled clinical trial with 640 women 27 through 45 years of age and 570 girls and women 16 through 26 years of age who received GARDASIL®9 (Protocol 004) was also conducted. Solicited and unsolicited adverse reactions reported by women 27 through 45 years of age in this study are shown in Table 4.

Table 4 - Rates (%) of Injection-Site and Systemic Adverse Reactions among Women 27 through 45 years of age and among Girls and Women 16 through 26 years of age Who Received GARDASIL®9

Systemic and Injection-Site Adverse Reactions in Boys and Men

An uncontrolled clinical trial with 662 boys and 1 923 girls 9 through 15 years of age (Protocol 002) was conducted. Solicited and unsolicited adverse reactions reported by boys in this study are shown in Table 5.

An uncontrolled clinical trial with 1 394 boys and men and 1 075 girls and women 16 through 26 years of age (Protocol 003) was also conducted. Solicited and unsolicited adverse reactions reported by boys and men 16 through 26 years of age in this study are shown in Table 5.

Serious Adverse Events in Clinical Studies of GARDASIL®9

Serious adverse events were collected throughout the entire study period for the seven integrated clinical studies for GARDASIL®9. Out of the 15 778 individuals who were administered GARDASIL®9 and had safety follow-up, 356 reported a serious adverse event; representing 2.3% of the population. Four individuals administered GARDASIL®9 reported at least one serious adverse event that was determined to be vaccine-related. The vaccine-related serious adverse events that occurred during the study period were pyrexia, allergy to vaccine, asthmatic crisis, and headache. No vaccine-related deaths were reported.

Clinical Trials Experience for GARDASIL®9 in Individuals Who Have Been Previously Vaccinated with GARDASIL®

A clinical study (Protocol 006) evaluated the safety of GARDASIL®9 in 12- through 26-year-old girls and women who had previously been vaccinated with 3 doses of GARDASIL®. The time interval between the last injection of GARDASIL® and the first injection of GARDASIL®9 ranged from approximately 12 to 36 months. Individuals were administered GARDASIL®9 or saline placebo and safety was evaluated using VRC-aided surveillance for 14 days after each injection of GARDASIL®9 or saline placebo in these individuals. The individuals who were monitored included 608 individuals who received GARDASIL®9 and 305 individuals who received saline placebo. Three (0.5%) individuals who received GARDASIL®9 discontinued due to adverse reactions. No individuals who received placebo discontinued due to adverse reactions. The vaccine-related adverse experiences that were observed among recipients of GARDASIL®9 at a frequency of at least 1.0% and also at a greater frequency than that observed among saline placebo recipients are shown in Table 6.

Clinical Trials Experience for Concomitant Administration of GARDASIL®9 with Other Vaccines

The safety of GARDASIL®9 when administered concomitantly with other vaccines was evaluated in clinical studies.

There was an increase in injection-site swelling reported at the injection site for GARDASIL®9 when GARDASIL®9 was administered concomitantly with Repevax* [Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content) (Tdap-IPV)]; or Adacel* [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] and Menactra* [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine], as compared to non-concomitant vaccination.

The majority of injection-site swelling seen with concomitant administration with other vaccines was reported as being mild to moderate in intensity.

Clinical Trials Experience of GARDASIL®9 in Pregnancy

In clinical studies, women underwent serum or urine pregnancy testing prior to administration of GARDASIL®9. Women who were found to be pregnant before completion of a 3-dose regimen of GARDASIL®9 were instructed to defer completion of their vaccination regimen until resolution of the pregnancy.

The overall proportion of pregnancies occurring at any time during the studies that resulted in an adverse outcome defined as the combined numbers of spontaneous abortion, late fetal death and congenital anomaly cases out of the total number of pregnancy outcomes for which an outcome was known (and excluding elective terminations), was 12.9% (174/1 353) in women who received GARDASIL®9 and 14.4% (187/1 303) in women who received GARDASIL®. The proportions of adverse outcomes observed were consistent with pregnancy outcomes observed in the general population.

Further sub-analyses were conducted to evaluate pregnancies with estimated onset within 30 days or more than 30 days from administration of a dose of GARDASIL®9 or GARDASIL®. For pregnancies with estimated onset within 30 days of vaccination, no cases of congenital anomaly were observed in women who have received GARDASIL®9 or GARDASIL®. In pregnancies with onset more than 30 days following vaccination, 30 and 24 cases of congenital anomaly were observed in women who have received GARDASIL®9 and GARDASIL®, respectively. The types of anomalies observed were consistent (regardless of when pregnancy occurred in relation to vaccination) with those generally observed in pregnancies in the general population.

For pregnancies with estimated onset within 30 days of vaccination, the proportion of pregnancies that resulted in a spontaneous abortion out of the total number of pregnancies with a known outcome (excluding elective terminations) was 27.4% (17/62) and 12.7% (7/55) in women who received GARDASIL®9 or GARDASIL®, respectively. For pregnancies with estimated onset more than 30 days following vaccination, that proportion was 10.9% (105/960) and 14.6% (136/933) in women who received GARDASIL®9 or GARDASIL®, respectively.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

The safety profile of GARDASIL®9 is consistent between children and adults (see 8.2 Clinical Trial Adverse Reactions).

8.5 Post-Market Adverse Reactions

The post-marketing adverse experiences were reported voluntarily from a population of uncertain size, therefore it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure.

The post-marketing adverse experience with GARDASIL® is relevant to GARDASIL®9 since the vaccines are similar in composition and contain HPV L1 proteins of four of the same HPV types.

In addition to the adverse reactions reported in the clinical studies, the following post-marketing adverse experiences have been spontaneously reported during post-approval use of GARDASIL®9:

Gastrointestinal disorders

Vomiting

General disorders and administration site conditions

Injection-site nodule

Nervous system disorders

Syncope sometimes accompanied by tonic-clonic movements

Additionally, the following post-marketing adverse experiences have been spontaneously reported for GARDASIL® and remain relevant to GARDASIL®9:

Blood and lymphatic system disorders

Autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, lymphadenopathy

Gastrointestinal disorders

Pancreatitis

General disorders and administration site conditions

Asthenia, chills, death, malaise

Immune system disorders

Hypersensitivity reactions including anaphylactic/anaphylactoid reactions, bronchospasm, and urticaria

Infections and infestations

Cellulitis

Musculoskeletal and connective tissue disorders

Arthralgia, myalgia

Nervous system disorders

Acute disseminated encephalomyelitis, Guillain-Barré syndrome, motor neuron disease, paralysis, transverse myelitis

Respiratory, thoracic and mediastinal disorders

Pulmonary embolus

Vascular disorders

Deep venous thrombosis

9 Drug Interactions

9.2 Drug Interactions Overview

Use with Other Vaccines

Results from clinical studies indicate that GARDASIL®9 may be administered concomitantly (at a separate injection site) with Menactra* [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel* [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)], and Repevax* [Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content) (Tdap-IPV)] (see 14 Clinical Trials).

Use with Hormonal Contraceptives

In 7 269 women (aged 16 through 26 years, from Protocols 001 and 002), 60.2% used hormonal contraceptives during the vaccination period of the clinical studies. Use of hormonal contraceptives did not appear to affect the type specific immune responses to GARDASIL®9.

Use with Systemic Immunosuppressive Medications

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune responses to vaccines (see 7 Warnings and Precautions, 7.1 Special Populations).

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

10 Clinical Pharmacology

10.1 Mechanism of Action

Efficacy of GARDASIL® 9 against anogenital diseases related to the vaccine HPV types is thought to be mediated by humoral immune responses induced by the vaccine. The exact mechanism of protection is unknown.

HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 (vs. types 6, 11, 16, and 18) cause approximately 90% (vs. 70%) of cervical cancers, 75 - 85% (vs. 50%) of cervical precancerous lesions, and 50 - 60% (vs. 30 - 35%) of low-grade cervical lesions, respectively. Among HPV-related cases, these HPV types also cause 85 - 90% (vs. 70 - 75%) of vulvar cancers, 80 - 85% (vs. 65%) of vaginal cancers, 90 - 95% (vs. 85 - 90%) of anal cancers, and at least 75% (vs. 60%) of these cancers’ precursor lesions as well as 95% (vs 85%) of oropharyngeal cancers.

CIN 2/3 and AIS have been accepted as precursors of invasive cervical cancer. VIN 2/3, VaIN 2/3, AIN 2/3 and PIN 2/3 have been accepted as precursors of vulvar, vaginal, anal and penile cancer, respectively.

HPV infection can also cause non-malignant lesions. HPV types 6 and 11 cause 90% of genital warts (condyloma acuminata) and 90% of recurrent respiratory papillomatosis (RRP) cases. These conditions rarely progress to cancer, but are associated with significant morbidity and psychosocial impacts, including a low health related quality of life.

10.2 Pharmacodynamics

Duration of Effect

Duration of effectiveness of GARDASIL®9 has been observed up to 8.2 years and 9.5 years in 9 to 15-year-olds and 16 to 26-year-olds postdose 3, respectively. Persistence of immune response has been observed for up to 7 years and 5 years in 9 to 15-year-olds and 16 to 26-year-olds postdose 3, respectively.

11 Storage, Stability, and Disposal

Store refrigerated at 2° to 8°C. Do not freeze. Protect from light.

GARDASIL®9 should be administered as soon as possible after being removed from refrigeration. GARDASIL®9 can be administered provided total (cumulative multiple excursion) time out of refrigeration (at temperatures between 8°C and 25°C) does not exceed 72 hours. Cumulative multiple excursions between 0°C and 2°C are also permitted as long as the total time between 0°C and 2°C does not exceed 72 hours. These are not, however, recommendations for storage.

Discard the product if it is frozen, particulates are present, or if it appears discolored.

12 Special Handling Instructions

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

PART 2: Scientific Information

13 Pharmaceutical Information

Drug Substance

Human Papillomavirus 9-valent Vaccine, Recombinant

Product Characteristics:

GARDASIL®9, Human Papillomavirus 9-valent Vaccine, Recombinant, is a non-infectious recombinant 9-valent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The L1 proteins are produced by separate fermentations using recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (Amorphous Aluminum Hydroxyphosphate Sulfate or AAHS). The 9-valent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant and the final purification buffer.

After thorough agitation, GARDASIL®9 is a white, cloudy liquid.

14 Clinical Trials

14.1 Clinical Trials by Indication

Study Results

GARDASIL®9 includes the same four HPV types contained in GARDASIL® (HPV 6, 11, 16, 18) and five additional HPV types (31, 33, 45, 52, and 58).

Efficacy Data for GARDASIL®

Efficacy of GARDASIL® was assessed in 6 AAHS-controlled, double-blind, randomized Phase II and III clinical studies evaluating 28 413 individuals (20 541 girls and women 16 through 26 years of age, 4 055 boys and men 16 through 26 years of age, and 3 817 women 24 through 45 years of age).

Individuals 16 through 26 Years of Age

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 girls and women who were PCR negative and seronegative at baseline (Table 7). In addition, girls and women who were already infected with 1 or more vaccine-related HPV types prior to vaccination appears to be protected from precancerous cervical lesions and external genital lesions caused by the other vaccine HPV types. Individuals who had prior infection that had been resolved before vaccination (PCR negative and seropositive at baseline) appears to be protected from reinfection or recurrence of infection leading to clinical disease with the same HPV type. There was no evidence of protection from disease caused by vaccine HPV types for which individuals were PCR positive and seropositive at baseline.

GARDASIL® was efficacious in reducing the incidence of genital warts related to vaccine HPV types 6 and 11 in boys and men who were PCR negative and seronegative at baseline. Efficacy against penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer was not demonstrated as the number of cases was too limited to reach statistical significance (Table 7). GARDASIL® was efficacious in reducing the incidence of anal intraepithelial neoplasia (AIN) grades 1 (both condyloma and non-acuminate), 2, and 3 related to vaccine HPV types 6, 11, 16, and 18 in boys and men who were PCR negative and seronegative at baseline (Table 7).

A minimum anti-HPV level that provides protection against HPV infection and disease has not been defined. Also, immune responses to vaccines are typically lower in older individuals compared to younger individuals. Therefore, to confirm the utility of GARDASIL® to prevent cervical, vulvar, and vaginal cancers and related diseases caused by the types targeted by the vaccine in individuals up to and including age 45 years, an efficacy study was conducted.

Individuals 24 through 45 Years of Age

GARDASIL® was highly efficacious in reducing the combined incidence of persistent infection; CIN (any grade); and external genital lesions (EGL) caused by HPV types 6, 11, 16, and 18, which was primarily driven by prevention of persistent infection (Table 8). The primary analyses of efficacy, with respect to HPV types 6, 11, 16, and 18, were conducted in the per-protocol efficacy (PPE) population. Efficacy was measured starting after the Month 7 visit (Table 8).

Effectiveness of GARDASIL® in men 27 through 45 years of age is inferred from efficacy data in women 24 through 45 years of age as described above. In addition, a published study provided immunogenicity data in 150 men, 27 through 45 years of age who received a 3-dose regimen of GARDASIL® (0, 2, 6 months)¹.

¹ Giuliano AR, Isaacs-Soriano K, Torres BN, Abrahamsen M, Ingles DJ, Sirak BA, et al. Immunogenicity and safety of Gardasil among mid-adult aged men (27-45 years) - The MAM Study. Vaccine. 2015 Oct 13;33(42):5640-6.

Long-term follow-up studies

A subset of subjects who received 3 doses were followed up for an extended period after GARDASIL® vaccination for safety, immunogenicity and protection against clinical diseases related to HPV types 6/11/16/18.

Persistence of antibody response was observed for 10 years in adolescents who were 9 through 15 years of age at time of vaccination; 14 years in girls and women, 16 through 23 years of age at time of vaccination; 9.5 years in boys and men, 16 through 26 years of age at time of vaccination, and 9.5 years in women, 24 through 45 years of age at time of vaccination.

In a selection of subjects in the PPE population of a registry-based extension of a base clinical trial, no cases of HPV 16/18-related high grade CIN were reported postdose 3 of GARDASIL® during a period with a median length of 11.8 years (range from 3.7 to 14 years) in 16-23 year old females (N = 2,121; 24,099 person-years at risk). In a selection of subjects in the PPE population of long-term extension of clinical studies, no cases of HPV 6-, 11-, 16-, or 18-related high-grade anogenital dysplasia and/or external genital lesions were observed postdose 3 of GARDASIL® during a period with a median length of 9.5 years (range from 3.1 to 11.4 years) in 16-26 year old men (N = 732; 6,538 person-year at risk); no cases of HPV 6-, 11-, 16-, or 18-related cervical dysplasia or external genital warts during a period with a median length of 9.1 years (range from 5.5 to 10.1 years) in 24-45 year old women (N = 601; 5,390 person-years at risk).

Persistence of antibody response to GARDASIL® was also assessed in a clinical trial using a 2-dose regimen. One month after the last dose, antibody responses to the 4 HPV types were non-inferior among girls 9 through 13 years of age who received 2 doses of GARDASIL^® 6 months apart compared with girls and women 16 through 26 years of age who received 3 doses of the vaccine within 6 months. In post hoc analyses at 3 and 10 years of follow-up, non-inferiority criteria were also met for all 4 HPV types.

Clinical Trials for GARDASIL®9

Table 9 - Summary of patient demographics from clinical trials that contributed efficacy data

Efficacy and/or immunogenicity of the 3-dose regimen of GARDASIL®9 were assessed in eight clinical studies. Clinical studies evaluating the efficacy of GARDASIL®9 against placebo were not acceptable because HPV vaccination represents the standard of care for protection against HPV infection and disease in many countries. Therefore, the pivotal clinical study (Protocol 001) evaluated the efficacy of GARDASIL®9 to prevent HPV-related cervical, vulvar, and vaginal disease using GARDASIL® as a comparator.

Efficacy against HPV Types 6, 11, 16, and 18 was primarily assessed using a bridging strategy that demonstrated comparable immunogenicity (as measured by Geometric Mean Titers [GMT]) of GARDASIL®9 compared with GARDASIL® (Protocol 001 and 009).

The analysis of efficacy for GARDASIL®9 was evaluated in the per-protocol efficacy population (PPE) of 16- through 26-year-old girls and women, who were naïve to the relevant HPV type(s) prior to dose one and through 1 month Postdose 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 cervical, vulvar and vaginal disease of any grade, persistent infection, cytological abnormalities and invasive procedures. For all endpoints, the efficacy against the HPV Types in GARDASIL®9 (31, 33, 45, 52, and 58) was evaluated compared to GARDASIL®.

The efficacy is further extended to 9- through 15-year-old girls and boys and to 16- through 26-year-old boys and men, for all endpoints studied, using immunological bridging. The immunogenicity bridging analyses were performed in the per-protocol immunogenicity population consisting of individuals who received all 3 vaccinations within pre-defined day ranges, met pre-defined criteria for the interval between the Month 6 and Month 7 visit, did not have major deviations from the study protocol, and were naïve [PCR negative (in girls and women 16 through 26 years of age; Protocols 001 and 002) and seronegative (Protocols 001, 002, 003, 005, 007 and 009)] to the relevant HPV type(s) prior to dose 1 and through 1 month postdose 3 Month 7.

P001 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. P002 evaluated immunogenicity of GARDASIL®9 in girls and boys 9 through 15 years of age and women 16 through 26 years of age. Protocol 009 evaluated immunogenicity of GARDASIL®9 compared with GARDASIL® in girls 9 through 15 years of age. Protocol 003 evaluated immunogenicity of GARDASIL®9 in boys and men 16 through 26 years of age and in girls and women 16 through 26 years of age (N = 2 515: 1 103 Heterosexual Men [HM]; 313 Men Who Have Sex with Men [MSM]; and 1 099 women receiving GARDASIL®9). P006 evaluated administration of GARDASIL®9 to girls and women 12 through 26 years of age previously vaccinated with GARDASIL®. Protocol 005 and Protocol 007 evaluated GARDASIL®9 concomitantly administered with Menactra* and Adacel*; or Repevax*, respectively, in girls and boys 11 through 15 years of age. Together, these seven clinical trials evaluated 15 875 individuals who received GARDASIL®9 (9 152 girls and women 16 through 26 years of age at enrollment with a mean age of 21.7 years; 3 498 girls 9 through 15 years of age at enrollment with a mean age of 12.0 years; 1 416 boys and men 16 through 26 years of age at enrollment with a mean age of 21.1 years; and 1 809 boys 9 through 15 years of age at enrollment with a mean age of 12.1 years. The race distribution of the 16 through 26-year-old girls and women in the clinical trials was as follows: 56.2% White; 25.4% Other; 14.7% Asian; and 3.7% Black. The race distribution of the 9- through 15-year-old girls in the clinical trials was as follows: 63.2% White; 16.2% Other; 14.6% Asian; and 5.9% Black. The race distribution of the 9- through 15 year-old boys in the clinical trials was as follows: 57.2% White; 24.0% Other; 14.6% Asian; and 4.1% Black. In Protocol 003, the race distribution was as follows: 16- through 26-year-old boys and men: 61.9% White; 22.7% Other; 9.8% Asian; and 5.5% Black; 16-through 26-year-old girls and women: 60.4% White; 23.7% Other; 10.0% Asian; and 5.9% Black.

One additional immunological bridging study was conducted. Protocol 004 evaluated immunogenicity of GARDASIL®9 in girls and women 16 through 26 years of age compared to women 27 through 45 years of age (N = 1 210: 640 women 27 through 45 years and 570 girls and women 16 through 26 years). In Protocol 004, the race distribution was as follows: women 27 through 45 years of age: 97.7% White, 1.6% Asian, 0.3% Other or Multiracial, 0.5% Black; girls and women 16 through 26 years of age : 94.6% White, 3.0% Asian, 1.6% Other or Multiracial, 0.9% Black.

One clinical trial (Protocol 010) assessed the 2-dose regimen of GARDASIL®9. Protocol 010 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 girls and women 16 through 26 years of age; (N = 1 516; 751 girls 9 through 14 years of age; 451 boys 9 through 14 years of age; and 314 girls and women 16 through 26 years of age). 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.

Anogenital Indication

Prophylactic 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 women was assessed in an active comparator-controlled, double-blind, randomized clinical study (Protocol 001) 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 follow-up of 40 months post-dose 3 (range 0 to 64 months) after the last vaccination.

The primary efficacy was based on evaluation of 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. The efficacy is further supported by evaluation 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 Pap tests, cervical and external genital procedures (i.e., biopsies) and cervical definitive therapy procedures.

Efficacy was evaluated in the PPE population of 16- through 26-year-old women, who were naïve to the relevant HPV type(s) prior to dose one and through Month 7. Efficacy was measured starting after the Month 7 visit. GARDASIL®9 was efficacious in preventing HPV 31-, 33-, 45-, 52-, and 58-related persistent infection and disease (Table 10). GARDASIL®9 also reduced the incidence of HPV 31-, 33-, 45-, 52-, and 58-related Pap test abnormalities, cervical procedures (i.e., biopsies), and cervical definitive therapy procedures (including loop electrosurgical excision procedure [LEEP] or conization). See Table 10.

Table 10 - Analysis of Efficacy of GARDASIL®9 Against HPV Types 31, 33, 45, 52, and 58 in the PPE* Population 16- through 26-Year-old Women

At the end of study, efficacy analyses were conducted in the efficacy substudy cohort with a median follow-up time of 3.5 years post-dose 3 (with a range of 0.0 to 5.6 years). For the HPV 31-, 33-, 45-, 52-, 58-related CIN 2/3, AIS, Cervical Cancer, VIN 2/3, VaIN 2/3, Vulvar Cancer, and Vaginal Cancer, there was 1 case in the GARDASIL®9 group and 38 cases in the GARDASIL® group representing an efficacy of 97.4%. With respect to 12 month persistent infection, there were 23 cases in the GARDASIL®9 group and 657 cases in the GARDASIL® group representing an efficacy of 96.7%. There were 37 cases in the GARDASIL®9 group and 506 cases in the GARDASIL® group of HPV31-, 33-, 45-, 52- and 58-related Pap test abnormalities representing an efficacy of 92.9%. There were 4 cases in the GARDASIL®9 group and 41 cases in the GARDASIL® group of HPV 31-, 33-, 45-, 52- and 58-related cervical definitive therapy representing an efficacy of 90.2%.

Immunogenicity

Table 11 - Summary of patient demographics from clinical trials that contributed immunogenicity data

Assays to Measure Immune Response

The minimum anti-HPV titer that confers protective efficacy has not been determined.

Because there were few disease cases in individuals naïve (PCR negative and seronegative) to vaccine HPV types at baseline in the group that received GARDASIL®9 it has not been possible to establish minimum antibody levels that protect against clinical disease caused by vaccine HPV types.

Type-specific 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; thus, comparisons across types and to other assays are not appropriate.

Immunogenicity was measured by (1) the percentage of individuals who were seropositive for antibodies against the relevant vaccine HPV type, and (2) the Geometric Mean Titer (GMT).

In these studies, seropositive is defined as anti-HPV titer greater than or equal to the pre-specified serostatus cutoff for a given HPV type. Seronegative is defined as anti-HPV titer less than the pre-specified serostatus cutoff for a given HPV type (Table 12). The serostatus cutoff is the antibody titer level above the assay’s lower limit of quantification that reliably distinguishes sera samples classified by clinical likelihood of HPV infection and positive or negative status by previous versions of Competitive Luminex Immunoassay (cLIA).

Studies Supporting the Efficacy of GARDASIL®9 Against HPV Types 6, 11, 16, 18

GARDASIL®9 efficacy against HPV 6-, 11-, 16-, and 18-related infection and disease was inferred from comparative studies to the quadrivalent (Types 6, 11, 16 18) vaccine, GARDASIL®, in which GARDASIL®9 elicited immune responses as measured by GMT. These studies were designed to evaluate immunologic non-inferiority of GARDASIL®9 to GARDASIL®. Therefore, the efficacy findings from the pivotal clinical studies for GARDASIL® against HPV Type 6-, 11-, 16-, and 18-related disease were extended to GARDASIL®9 by demonstrating that the immune responses elicited by GARDASIL®9 were non-inferior to the immune responses elicited by GARDASIL®.

Comparison of GARDASIL®9 with GARDASIL® immunogenicity with respect to HPV types 6, 11, 16, and 18 were conducted in a population of 16- through 26-year-old women from Protocol 001 (N = 13 587), and 9- through 15-year-old girls from Protocol 009 (N = 600). The primary analyses were conducted in the per-protocol immunogenicity population.

A statistical analysis of non-inferiority was performed based on Month 7 comparing cLIA anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs between individuals administered GARDASIL®9 and individuals administered GARDASIL®. Immune responses, measured by GMT, for GARDASIL®9 were non-inferior to immune responses for GARDASIL® (Tables 13 and 14). Therefore, efficacy for GARDASIL®9 against persistent infection and disease related to HPV Types 6, 11, 16, or 18 can be inferred to be comparable to that of GARDASIL®.

In addition, a published study provided immunogenicity data in 500 heterosexual men, 16 through 26 years of age who received a 3-dose regimen of GARDASIL® or GARDASIL®9 (0, 2, 6 months)².

Study Supporting the Effectiveness of GARDASIL®9 against Vaccine HPV Types in 9- through 15-Year-Old Girls and Boys

Effectiveness of GARDASIL®9 against persistent infection and disease related to vaccine HPV types in 9- through 15-year-old girls and boys was inferred from non-inferiority comparison in Protocol 002 of GMTs following vaccination with GARDASIL®9 among 9- through 15-year-old girls and boys with those among 16- through 26-year-old girls and women. The primary analyses were conducted in the per-protocol population. Anti-HPV GMTs at Month 7 among 9- through 15-year-old girls and boys were non-inferior to anti-HPV GMTs among 16- through 26-year-old girls and women (Table 15).

² Van Damme P, Meijer CJ, Kieninger D, Schuyleman A, Thomas S, Luxembourg A, et al. A phase III clinical study to compare the immunogenicity and safety of the 9-valent and quadrivalent HPV vaccines in men. Vaccine. 2016 Jul 29;34(35):4205-12.

On the basis of this immunogenicity bridging, the efficacy of GARDASIL®9 in 9- through 15-year-old girls and boys is inferred.

Study Supporting the Effectiveness of GARDASIL®9 against Vaccine HPV Types in 16 -through 26-Year-Old Boys and Men

Effectiveness of GARDASIL®9 against persistent infection and disease related to vaccine HPV types in 16- through 26-year-old boys and men was inferred from non-inferiority comparison in Protocol 003 of GMTs following vaccination with GARDASIL®9 among 16- through 26-year-old boys and men with those among 16- through 26-year-old girls and women. The primary analyses were conducted in the per-protocol population. Anti-HPV GMTs at Month 7 among 16- through 26-year-old boys and men (HM) appeared non-inferior to anti-HPV GMTs among 16- through 26-year-old girls and women (Table 16). Anti-HPV GMTs at Month 7 among 16- through 26-year-old MSM (HIV-negative) were lower than in 16- through 26-year-old HM. The GMT fold difference in 16- through 26-year-old MSM relative to the HM was 0.6 to 0.8.

On the basis of this immunogenicity bridging, the efficacy of GARDASIL®9 in 16- through 26-year-old boys and men is inferred.

Study Supporting the Effectiveness of GARDASIL®9 against Vaccine HPV Types in 27 -through 45-Year-Old Women

Effectiveness of GARDASIL®9 against persistent infection and disease related to vaccine HPV types in 27- through 45-year-old women was inferred based on non-inferiority of GMTs following vaccination with GARDASIL®9 in 27- through 45-year-old women compared to 16- through 26-year-old girls and women and demonstration of efficacy of GARDASIL® in girls and women 16 through 45 years of age.

Protocol 004 provided immunogenicity bridging between 27 through 45-year-old women and 16 through 26-year-old girls and women who received GARDASIL®9. Non-inferiority (defined as less than 2-fold decrease) was demonstrated at Month 7 for each of HPV 16, 18, 31,33, 45, 52 and 58 anti-HPV GMTs in women 27 through 45 years of age compared with girls and women 16 through 26 years of age, with GMT ratios between 0.66 and 0.73 (Table 17). These results support the efficacy of GARDASIL®9 in women 27 through 45 years of age.

Table 17 - Comparison of Immune Responses (Based on cLIA) Between the PPI* Populations of 27 through 45-Year-Old Women and 16- through 26-Year-Old Girls and Women for GARDASIL®9 Vaccine HPV Types

Men 27 Years of Age and Older

GARDASIL®9 has not been studied in men 27 years of age and older. In men 27 years of age and older, efficacy of GARDASIL®9 is inferred based on (1) efficacy of GARDASIL® in girls and women 16 through 45 years of age, (2) efficacy of GARDASIL® in boys and men 16 through 26 years of age, (3) comparable efficacy of GARDASIL® and GARDASIL®9 in girls and women 16 through 26 years of age, (4) comparable immunogenicity of GARDASIL® and GARDASIL®9 in girls and women 9 through 26 years of age and (5) immunogenicity of GARDASIL® and GARDASIL®9 in boys and men 16 through 26 years of age.

Immune Responses to GARDASIL®9 Using a 2-dose Schedule in Individuals 9- through 14 Years of Age

Protocol 010 measured HPV antibody responses to the 9 HPV types after GARDASIL®9 vaccination in the following cohorts: girls and boys 9 through 14 years of age receiving 2 doses at a 6-month or 12-month interval (+/- 1 month); girls 9- through 14 years of age receiving 3 doses (at 0, 2, 6 months); and women 16- through 26 years of age receiving 3 doses (at 0, 2, 6 months).

GMTs were non-inferior in girls and boys who received 2 doses of GARDASIL®9 (at either 0, 6 months or 0, 12 months) to GMTs in 16- through 26-year old-girls and women who received 3 doses of GARDASIL®9 (at 0, 2, 6 months) for each of the 9 vaccine HPV types. On the basis of this immunogenicity bridging, the efficacy of a 2-dose regimen of GARDASIL®9 in 9 through 14-year-old girls and boys is inferred. One month following the last dose of the assigned regimen, between 97.9% and 100% of subjects across all groups became seropositive for antibodies against the 9 vaccine HPV types (Table 18).

In the same study, in girls and boys 9 through 14 years of age, GMTs at one month after the last vaccine dose were numerically lower for some vaccine types after a 2-dose schedule than in girls 9 through 14 years of age after a 3-dose schedule (HPV types 18, 31, 45, and 52 after 0, 6 months and HPV type 45 after 0, 12 months; Table 18). The clinical relevance of these findings is unknown.

Persistence of antibody response to GARDASIL®9 was observed for 3 years in girls and boys who were 9 through 14 years of age at time of vaccination receiving 2 doses at 6-month or 12-month interval. At Month 36, non-inferiority criteria were also met for GMTs in girls and boys 9 through 14 years of age receiving 2 doses at a 6-month interval (+/-1 month) compared to GMTs in girls and women 16 through 26 years of age receiving 3 doses of GARDASIL^®9

Duration of protection of a 2-dose schedule of GARDASIL®9 has not been established.

Variation in Dosing Regimen in 16- through 26-Year-Old Women

All individuals evaluated for efficacy in the PPE population of Study 1 received all 3 vaccinations within a 1-year period, regardless of the time interval between doses. An analysis of immune response data suggests that flexibility of ±1 month for dose 2 (i.e., Month 1 to Month 3 in the vaccination regimen) and flexibility of ±2 months for dose 3 (i.e., Month 4 to Month 8 in the vaccination regimen) do not substantially impact the immune responses to GARDASIL®9 (see 4 DOSAGE AND ADMINISTRATION).

Persistence of Immune Response to GARDASIL®9

The persistence of antibody response following a complete schedule of vaccination with GARDASIL®9 was studied in two Protocols, Protocol 001 and Protocol 002. In both studies, Anti-HPV cLIA GMTs were highest at 1 month postdose 3 (Month 7) and decreased by approximately 70% at Month 12. In 16 through 26-year-old girls and women (Protocol 001), at Month 42, GMTs were approximately 10-20% of Month 7 GMTs and 78-100% of subjects were seropositive for each of the 9 vaccine HPV types. In 9- through15-year-old boys and girls (Protocol 002), at Month 90, GMTs were approximately 10-20% of Month 7 GMTs and 91-99% of subjects were seropositive for each of the 9 vaccine HPV types.

Administration of GARDASIL®9 to Individuals Previously Vaccinated with GARDASIL®

Protocol 006 evaluated administration of GARDASIL®9 to girls and women 12- through 26 years of age previously vaccinated with GARDASIL® (N = 921; 615 receiving GARDASIL®9 and 306 receiving placebo). Prior to enrollment in the study, over 99% of subjects had received 3 injections of GARDASIL® within a one year period. The time interval between the last injection of GARDASIL® and the first injection of GARDASIL®9 ranged from approximately 12 to 36 months.

Seropositivity to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in the per protocol population ranged from 98.3 to 100% by Month 7 in individuals who received GARDASIL®9. The GMTs to HPV Types 31, 33, 45, 52 and 58 were lower than in the population who had not previously received GARDASIL® in Protocols 001, 002, 005, 007 and 009. Efficacy of GARDASIL®9 in preventing infection and disease related to HPV Types 31, 33, 45, 52, and 58 in individuals previously vaccinated with GARDASIL® has not been assessed.

Studies with Menactra* [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel* [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)]

In Protocol 005, the safety and immunogenicity of co-administration of GARDASIL®9 with Menactra* [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel* [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] (same visit, injections at separate sites) were evaluated in 1,237 boys and girls 11 through 15 years of age at enrollment. The race distribution of the study subjects was as follows: 47.4% White; 35.0% Multiracial; 9.6% American Indian or Alaska Native; 6.4% Black; 1.1% Asian; and 0.6% Native Hawaiian or Other Pacific Islander.

One group received GARDASIL®9 in one limb and both Menactra* and Adacel*, as separate injections, in the opposite limb concomitantly on Day 1 (N = 619). The second group received the first dose of GARDASIL®9 on Day 1 in one limb then Menactra* and Adacel*, as separate injections, at Month 1 in the opposite limb (N = 618). Subjects in both vaccination groups received the second dose of GARDASIL®9 at Month 2 and the third dose at Month 6. Immunogenicity was assessed for all vaccines 1 month post completion of the vaccination series (1 dose for Menactra* and Adacel* and 3 doses for GARDASIL®9).

Concomitant administration of GARDASIL®9 with Menactra* and Adacel* did not interfere with the antibody response to any of the vaccine antigens when GARDASIL®9 was given concomitantly with Menactra* and Adacel* or separately.

Repevax* [Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content) (Tdap-IPV)]

In Protocol 007, the safety and immunogenicity of co-administration of GARDASIL®9 with Repevax* [Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content) (Tdap-IPV)] (same visit, injections at separate sites) were evaluated in a study of 1053 boys and girls 11 through 15 years of age at enrollment.

One group received GARDASIL®9 in one limb and Repevax* in the opposite limb concomitantly on Day 1 (N = 525). The second group received the first dose of GARDASIL®9 on Day 1 in one limb then Repevax* at Month 1 in the opposite limb (N = 528). Subjects in both vaccination groups received the second dose of GARDASIL®9 at Month 2 and the third dose at Month 6. Immunogenicity was assessed for all vaccines 1 month post completion of the vaccination series (1 dose for Repevax* and 3 doses for GARDASIL®9).

Concomitant administration of GARDASIL®9 with Repevax* did not interfere with the antibody response to any of the vaccine antigens when GARDASIL®9 was given concomitantly with Repevax* or separately.

Head and Neck Indication

Effectiveness in Prevention of HPV-Related Oropharyngeal and Other Head and Neck Cancers

The effectiveness of GARDASIL®9 against oropharyngeal and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52 and 58, is based on the effectiveness of GARDASIL® and GARDASIL®9 to prevent persistent infection and anogenital disease caused by HPV types covered by the vaccine (see Tables 7, 8, 10 and 14).

Long-term effectiveness studies

A subset of subjects who received 3 doses were followed up for an extended period after GARDASIL® 9 vaccination for safety, immunogenicity and protection against clinical diseases related to HPV types 6/11/16/18/31/33/45/52/58.

In a selection of subjects in the PPE population in the long-term extension of Protocol 001 registry study, 1 case of HPV 16/18/31/33/45/52/58-related high-grade CIN was reported postdose 3 of GARDASIL®9 during a period with a median length of 6.7 years (range from 3.6 to 9.5years) in 16 to 26 year old females (N = 1 509; 9 378 person-years at risk). In a selection of subjects in the PPE population in the long-term extension of Protocol 002, no cases of HPV 16/18/31/33/45/52/58-related high-grade intraepithelial neoplasia or genital warts were identified postdose 3 of GARDASIL®9 during a period with a median length of 7.6 years (range from 3.5 to 8.2 years) in 9-15 year old girls (N = 856; 2 866 person-years at risk). Note: the age of an individual stated above is the age at time of vaccination for the individual.

15 Microbiology

No microbiological information is required for this vaccine.

16 Non-Clinical Toxicology

General Toxicology:

A repeat dose toxicity study has been performed in rats at a dose approximately 250 times the human dose (mg/kg basis) and revealed no special hazards to humans.

Carcinogenicity:

GARDASIL®9 has not been evaluated for the potential to cause carcinogenicity.

Genotoxicity:

GARDASIL®9 has not been evaluated for the potential to cause genotoxicity.

Reproductive and Developmental Toxicology:

GARDASIL®9 administered to female rats at a dose approximately 240 times the human dose (mg/kg basis) had no effects on mating performance, fertility, or embryonic/fetal survival.

GARDASIL®9 administered to female rats at a dose approximately 160 times the human dose (mg/kg basis) had no effects on development, behavior, reproductive performance or fertility of the offspring.

An evaluation of the effect of GARDASIL®9 on embryo-fetal, pre- and postweaning development was conducted in studies using rats. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre- and postweaning development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted. In addition, there were no treatment-related effects on developmental signs, behavior, reproductive performance, or fertility of the offspring. GARDASIL®9 induced a specific antibody response against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in pregnant rats following one or multiple intramuscular injections. Antibodies against all 9 HPV types were transferred to the offspring during the period of gestation and lactation.