Regulatory Decision Summary for Gardasil 9
Review decision
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
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What was the purpose of this submission?
The purpose of this supplemental new drug submission (SNDS) was to expand the age range for Gardasil 9 to include men aged 27-45 and to add an indication for prevention of anal dysplasia and cancer caused by HPV types contained in the vaccine for women aged 27-45. No changes were proposed to the drug dosage or regimen.
After evaluation of the submitted data package, Health Canada authorized Gardasil 9 for these additional indications. The proposed indications for Gardasil 9 are as follows:
Girls and Women
Gardasil 9 is a vaccine indicated in girls and women 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, and vaginal cancer 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
- Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
- Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
- Cervical intraepithelial neoplasia (CIN) grade 1
Gardasil 9 is indicated in girls and women 9 through 45 years of age for the prevention of:
- Anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58
- Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.
Boys and Men
Gardasil 9 is indicated in boys and men 9 through 45 years of age for the prevention of infection caused by 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:
- Anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58
- Genital warts (condyloma acuminata) caused by HPV types 6 and 11
And anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58.
Why was the decision issued?
Three clinical studies and one third-party study were submitted to support the indication. One of the clinical studies (501-019-021) and the third party (MAM) study were studies of Gardasil in women aged 24-35 and men aged 27-45 respectively. The remaining two studies (503-004 and 503-020) were Gardasil 9 studies. Gardasil studies are considered relevant to Gardasil 9 due to similar manufacturing processes and overlapping product compositions.
One study, 503-004, provided the most relevant clinical data for the proposed expansion of indications as it investigated immunogenicity and safety in women aged 27-45. Study 503-004 was a European multicentre open label phase 3 clinical trial comparing immunogenicity and safety of Gardasil 9 in women aged 27-45 with women aged 16-26. 640 subjects aged 27-45 and 570 subjects aged 16-26 received at least one dose of Gardasil 9. Immune response (by cLIA) was measured one month after the third dose of the vaccine, and safety endpoints were followed up to 6 months post-vaccination. Immune response to each of the 7 oncogenic strains among 27-45-year-old women was found to be statistically-lower but non-inferior to immune response to these strains among women aged 16-26. The most common local adverse events in 27-45 year-old women were injection site pain (83%), injection site swelling (23%), and injection site erythema (17%). Headache (14%) was the most common vaccine-related adverse event reported in this group. The safety profile of Gardasil 9 in women 27-45 was similar to the safety profile in other populations, and no safety concerns were identified.
There are some limitations to the available clinical data including no direct evidence for efficacy of Gardasil 9 for prevention of anal dysplasia or cancer, nor for efficacy of Gardasil 9 in men or women aged 27-45. Given the statistically-lower immune response in women aged 27-45 vs women aged 16-26 in Study 503-004, and the absence of immune persistence data, uncertainty remains regarding level of efficacy in older age groups as well as duration of protection. However, this uncertainty is mitigated by the known pathophysiology of HPV disease and mechanisms of protection that are conserved across ages, genders, and HPV infection endpoints.
Based on the totality of the data in the Gardasil and Gardasil 9 development programs, Gardasil 9 is likely to provide benefit in men aged 27-45 and against anal endpoints in men and women aged 27-45. Additionally, the clinical trial and post-marketing safety data for both Gardasil and Gardasil 9 support the safety of Gardasil 9 in both genders and up to age 45.
In conclusion, the benefit-risk assessment is favourable for expansion of the Gardasil 9 indications to include prevention of HPV infection, EGW, and anal dysplasia and cancer caused by vaccine strains in men aged 27-45 and prevention of anal dysplasia and cancer caused by vaccine strains in women aged 27-45.
Decision issued
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.