Summary Basis of Decision for Gardasil 9

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Gardasil 9 is located below.

Recent Activity for Gardasil 9

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Gardasil 9

Updated:

2023-03-14

The following table describes post-authorization activity for Gardasil 9, a product which contains the medicinal ingredients recombinant human papillomavirus (HPV - Types 6, 11, 16, 18, 31, 33, 45, 52, 58) L1 proteins. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

Drug Identification Number (DIN):
DIN 02437058
Each 0.5-mL dose contains:
30 µg recombinant human papillomavirus (HPV) Type 6 L1 protein,
40 µg recombinant HPV Type 11 L1 protein,
60 µg recombinant HPV Type 16 L1 protein,
40 µg recombinant HPV Type 18 L1 protein,
20 µg recombinant HPV Type 31 L1 protein,
20 µg recombinant HPV Type 33 L1 protein,
20 µg recombinant HPV Type 45 L1 protein,
20 µg recombinant HPV Type 52 L1 protein,
20 µg recombinant HPV Type 58 L1 protein,
suspension, intramuscular administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 262093 2022-03-04 Issued NOC 2022-09-23 Submission filed as a Level I – Supplement for additional facilities for the fermentation and purification of the drug substance. The submission was filed under the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q12 Pilot Program. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 264644 2022-05-27 Issued NOL 2022-06-03 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to introduce a new working cell bank. The submission was considered acceptable, and an NOL was issued.
NC # 264132 2022-05-06 Issued NOL 2022-05-11 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to introduce a new working cell bank. The submission was considered acceptable, and an NOL was issued.
SNDS # 251509 2021-04-12 Issued NOC under NOC/c Guidance 2022-04-06 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: the prevention of infection caused by the human papillomavirus (HPV) types 6, 11, 16, 18, 31, 33, 45, 52 and 58 and oropharyngeal and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58. The submission was reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance. A Regulatory Decision Summary was published.
NC # 258502 2021-11-09 Issued NOL 2022-02-10 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance, and to change the stability protocol of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 257708 2021-10-18 Issued NOL 2021-12-20 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to introduce a new working cell bank, and to change the manufacture of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 258933 2021-11-23 Issued NOL 2021-11-30 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to introduce a new working cell bank. The submission was considered acceptable, and an NOL was issued.
SNDS # 244622 2020-09-30 Issued NOC 2021-11-23 Submission filed as a Level I – Supplement to update the PM with long-term effectiveness and immunogenicity data. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials section of the PM. An NOC was issued.
NC # 250966 2021-03-22 Issued NOL 2021-03-30 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to introduce a new working cell bank. The submission was considered acceptable, and an NOL was issued.
NC # 246641 2020-11-18 Issued NOL 2021-03-17 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug substance, and in the controls applied during the drug substance manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 247139 2020-12-02 Issued NOL 2021-03-15 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to transfer quality control testing activities to a new facility. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 243346 2020-08-28 Issued NOL 2020-09-11 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to introduce a new working seed bank. The submission was considered acceptable, and an NOL was issued.
SNDS # 223244 2018-12-20 Issued NOC 2020-08-20 Submission filed as a Level I – Supplement 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 human papillomavirus (HPV) types contained in the vaccine for women aged 27-45. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 232641 2019-10-16 Issued NOL 2020-01-16 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Adverse Reactions, Action and Clinical Pharmacology, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 232285 2019-10-04 Issued NOL 2020-01-15 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the working reference standard qualification protocols, and extend the shelf-life of the reference standards. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 227604 2019-05-09 Issued NOL 2019-07-29 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf-life of the reference standards. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 228798 2019-06-19 Issued NOL 2019-07-05 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to introduce new working cell banks. The submission was considered acceptable, and an NOL was issued.
SNDS # 222666 2018-12-03 Issued NOC 2019-06-19 Submission filed as a Level I – Supplement to add alternate sites for manufacturing and testing of the drug product. The data were reviewed and considered acceptable, and an NOC was issued.
Health product advertising complaint Not applicable

Date received: 2018-10-03

 A health product advertising complaint was received regarding advertising of products with unauthorized claims. An explanatory letter was sent.
Health product advertising complaint Not applicable Date received: 2018-08-23 A health product advertising complaint was received regarding advertising of products with unauthorized claims. An explanatory letter was sent.
NC # 200876 2016-12-02 Issued NOL
2017-02-22		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the drug substance purification process. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 193080 2016-03-08 Issued NOC
2016-12-25		 Submission filed as a Level I - Supplement for revisions to the PM based on data provided by the clinical study Protocol V503-010 on immunogenicity which includes an alternative 2-dose regimen for individuals 9 through 14 years of age. Furthermore, three adverse events (tonsillitis, postural orthostatic tachycardia syndrome (POTS) and hypersomnia) are removed from the PM based on feedback received from the U.S Food and Drug Administration and European Medicines Agency. Overall, the benefits of the alternative 2-dose regimen outweigh the risks in 9 to 14 year old girls and boys. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 196392 2016-06-23 Issued NOL
2016-10-05		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes related to a release test for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 188266 2015-10-05 Issued NOC
2016-08-16		 Submission filed as a Level I - Supplement for revisions to the PM based on data provided by the following studies 9:
  1. Pivotal Study Protocol V503-003 with Gardasil 9 in young men;
  2. Long-term studies:
    • Two studies with Gardasil 9: end of study report for Protocol V503-001, and extension study report for Protocol V503-002
    • Four studies with Gardasil (qHPV) for protocols V501-015-21, V501-018-11, V501-019-21 and V501-020-021.
These data address both long term efficacy and the indication for males, for which a commitment was made. Study V503-003 further supports the indication in males 16-26 years old for Gardasil 9. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 188296 2015-10-06 Issued NOC
2016-05-20		 Submission filed as a Level I - Supplement for a new drug substance manufacturing site, a scale up of the drug substance manufacturing process and change to the drug substance purification process. There are no changes to the drug substance or drug product release specifications as a result of the proposed changes. The data were reviewed and considered acceptable, and an NOC was issued.
NC # 188137 2015-09-28 Issued No Objection Letter
2015-12-24		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the drug substance purification process. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 186345 2015-07-17 Issued No Objection Letter
2015-10-23		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to qualify a new lot of reference standard against the approved reference standard. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 184344 2015-05-06 Issued No Objection Letter
2015-07-30		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Adverse Reaction - Serious Adverse Events in Clinical Studies, Part I section of the Product Monograph to add postural orthostatic tachycardia syndrome and hyperinsomnia. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 186011 2015-07-07 Issued No Objection Letter
2015-07-27		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add new working seed bank lots. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 183074 2015-03-19 Issued No Objection Letter
2015-04-15		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add new working seed bank lots. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Drug product (DIN 02437058) market notification Not applicable Date of first sale:
2015-03-18		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 170006 2014-02-13 Issued NOC 2015-02-05 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Gardasil 9

Date SBD issued: 2015-08-11

The following information relates to the new drug submission for Gardasil 9.

Recombinant human papillomavirus (Types 6, 11, 16, 18, 31, 33, 45, 52, 58) L1 protein, 0.5 mL dose containing recombinant human papillomavirus:
30 µg Type 6 L1 protein
40 µg Type 11 L1 protein,
60 µg Type 16 L1 protein
40 µg Type 18 L1 protein,
20 µg Type 31 L1 protein,
20 µg Type 33 L1 protein,
20 µg Type 45 L1 protein,
20 µg Type 52 L1 protein,
20 µg Type 58 L1 protein, Suspension, Intramuscular

Drug Identification Number (DIN):

  • 02437058

Merck Canada Inc.

New Drug Submission Control Number: 170006

 

On February 5, 2015, Health Canada issued a Notice of Compliance to Merck Canada Inc. for the vaccine Gardasil 9.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Gardasil 9 is favourable for the following indications:

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 26 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 26 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.

1 What was approved?

Gardasil 9, a human papillomavirus 9-valent vaccine, recombinant, was authorized for the following indications:

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 26 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 26 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.

The safety and efficacy of Gardasil 9 have not been evaluated in individuals aged 65 years and over, or in children younger than 9 years.

Gardasil 9 is contraindicated in patients who are hypersensitive to either Gardasil or Gardasil 9 or to any ingredient in the formulation or component of the container. 

Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of Gardasil 9 or Gardasil should not receive further doses of Gardasil 9.

Gardasil 9 was approved for use under the conditions stated in the Gardasil 9 Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Gardasil 9 [0.5 mL dose containing recombinant human papillomavirus Type 6 L1 protein (30 µg), Type 11 L1 protein (40 µg ), Type 16 L1 protein (60 µg ), Type 18 L1 protein (40 µg ), Type 31 L1 protein (20 µg ), Type 33 L1 protein (20 µg ), Type 45 L1 protein (20 µg ), Type 52 L1 protein (20 µg ), and Type 58 L1 protein (20 µg )] is presented as a powder for suspension. In addition to the medicinal ingredient, the powder contains aluminum hydroxyphosphate sulfate (AAHS Adjuvant), L-histidine, polysorbate 80, sodium borate, sodium chloride, and water for injection.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Gardasil 9 Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Gardasil 9 approved?

Health Canada considers that the benefit/risk profile of Gardasil 9 is favourable for the following indications:

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 26 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 26 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.

Infection with HPV causes benign and malignant dysplastic disease in both men and women, primarily in the anogenital area and the aerodigestive tract. Persistent HPV infection significantly increases the risk of cervical, other anogenital cancers, and oropharyngeal cancers. Different HPV types are classified as high-risk or low-risk based on their potential to cause cancer. Low-risk types cause generally benign lesions. The International Agency for Research on Cancer has identified 12 HPV types as carcinogens. These include the 7 high-risk HPV types represented in Gardasil 9 (HPV types 16, 18, 31, 33, 45, 52, and 58).

Gardasil 9 is a 9-valent HPV vaccine that is comparable to Gardasil, a quadrivalent HPV vaccine that contains 4 of the same HPV types and that is currently authorized for sale in Canada. The two vaccines are manufactured in a similar way and contain the same antigens from HPV Types 6, 11, 16, and 18. In addition, Gardasil 9 also contains antigens from HPV Types 31, 33, 45, 52, and 58. The Gardasil 9 development program was designed based on pre-marketing and post-marketing experience with Gardasil. The proposed indications for Gardasil 9 are similar to those of Gardasil, including all the current Gardasil indications plus indications related to the five new HPV types.

Gardasil 9 has been demonstrated to prevent both persistent infection and high-grade cervical, vulvar and vaginal disease (CIN 2, VIN 2, VaIN 2, or worse) related to HPV Types 31, 33, 45, 52, and 58, in 16-26 year old women who were naïve to the relevant HPV type(s) at the time of vaccination and through one month post-dose 3 (Month 7). These high-grade lesions have been used as surrogate markers for the relevant cancers.

The efficacy of Gardasil 9 with respect to HPV Types 6, 11, 16, and 18 has been inferred by demonstrating that the immune responses elicited by Gardasil 9 were non-inferior to the immune responses to these HPV types elicited by Gardasil in 16-26 year old women. The efficacy findings for Gardasil 9 in women 16 to 26 years of age were bridged to girls and boys 9 to 15 years of age based on the demonstration of non-inferior immunogenicity to all 9 HPV types included in Gardasil 9.

There were no clinical studies for Gardasil 9 in women 27 to 45 years of age or men 16 to 26 years of age at the time of review. Health Canada has determined that it is likely that Gardasil 9 will have an acceptable safety profile and confer prophylactic protection in these two populations, because of similar immunogenicity (with respect to HPV Types 6, 11, 16, and 18) and safety profiles of Gardasil 9 compared to those of Gardasil in several other groups (including women 16 to 26 years of age, and girls 9 to 15 years of age), as well as the efficacy data for Gardasil 9 in women 16 to 26 years of age, and the efficacy data in women 16-45 years of age for Gardasil. A Phase III immunogenicity and safety study in men 16 to 26 years of age (Protocol 003) was ongoing at the time of review and the study report will be submitted when available.

Health Canada has also determined that efficacy of Gardasil 9 against anal diseases can be inferred from the efficacy of Gardasil 9 against genital lesions, because HPV-associated genital and anal lesions share similar pathophysiology, Gardasil has previously been demonstrated to prevent anal lesions related to HPV Types 16 and 18, and Gardasil 9 has been demonstrated to prevent persistent infection related to HPV Types 31, 33, 45, 52, and 58.

The safety profile of Gardasil 9 is generally comparable to that of Gardasil, except the use of Gardasil 9 is associated with an increase in injection-site adverse experiences compared with Gardasil. Most injection-site adverse experiences in people administered Gardasil 9 were mild or moderate in intensity.  

Potential safety concerns are adequately addressed in post-licensure activities and the Product Monograph labelling.

A Risk Management Plan (RMP) for Gardasil 9 was submitted by Merck Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. The RMP for Gardasil 9 includes the following additional studies:

  • A post-marketing pregnancy registry in the United States of America to monitor pregnancy outcomes in women exposed to Gardasil 9.
  • A 10-Year extension in vaccine recipients from Protocol 001 (V503-021 Nordic Long-term Follow-Up Study).
  • A 10-Year Post-dose 3 extension in vaccine recipients from Protocol 002 (V503-002-20 Long-term Follow-Up Study).
  • An Observational Post Authorization Safety Study with the objective of assessing the general safety of Gardasil 9 in the course of routine clinical practice (The PASS Study).

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

Currently there is no vaccine licensed for the prevention of anogenital cancers caused by HPV types other than HPV 16 and 18, in Canada. The clinical benefits of Gardasil 9 outweigh its risks for the indicated populations.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to theClinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Gardasil 9?

Submission Milestones: Gardasil 9

Submission Milestone Date
Pre-submission meeting: 2011-12-15
Submission filed: 2014-02-28
Screening  
Screening Acceptance Letter issued: 2014-04-11
Review  
Quality Evaluation complete: 2015-01-30
Clinical Evaluation complete: 2015-02-03
Labelling Review complete: 2015-01-27
Notice of Compliance issued by Director General: 2015-02-05

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for Gardasil 9?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Gardasil 9 is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

Gardasil 9 is a vaccine indicated for the prevention of infection and related diseases caused by human papilloma virus (HPV) types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in girls and women 9 through 45 years of age and in boys and men 9 through 26 years of age.

Gardasil 9 is comparable to Gardasil, a quadrivalent HPV vaccine that contains 4 of the same HPV types and that is currently authorized for sale in Canada. The two vaccines are manufactured in a similar way and contain the same antigens from HPV Types 6, 11, 16, and 18. In addition, Gardasil 9 also contains antigens from HPV Types 31, 33, 45, 52 and 58. The Gardasil 9 development program was designed based on pre-marketing and post-marketing experience with Gardasil.

Clinical Pharmacology

Human beings develop a humoral immune response to the vaccine, although the exact mechanism of protection is unknown. The minimum anti-HPV titre that confers protective efficacy has not been determined.

The pharmacodynamics of Gardasil 9 were assessed through the analysis of immunogenicity described in the Clinical Efficacy section. Pharmacokinetic studies are not directly applicable to vaccines.

For further details, please refer to the Gardasil 9 Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy and immunogenicity of Gardasil 9 were assessed in 6 clinical studies. The major efficacy and immunogenicity findings for the six studies are summarised below.

Protocol 001: Pivotal Efficacy, Immunogenicity, and Safety Study in Women, 16 to 26 Years of Age

This was a Phase IIb/III, randomized, double-blind, Gardasil-controlled, multicenter, multinational study designed to evaluate the safety, immunogenicity and efficacy of Gardasil 9. A total of 14,204 women (7,099 received Gardasil 9 and 7,105 received Gardasil), 16 - 26 years of age, were enrolled and vaccinated without pre-screening for the presence of HPV infection. Both groups received their assigned vaccine as intramuscular injection of 0.5 mL on Day 1, Month 2 and Month 6. Individuals were followed up with a median duration of follow-up of 40 months (range 0 to 64 months) after Day1. Serum samples were collected to detect the presence of antibodies against the HPV types contained in the vaccines. The following specimens were collected from study participants for the purpose of detecting vaccine-type HPV deoxyribonucleic acid (DNA) or clinical disease: cervicovaginal and external genital swabs, ThinPrep Pap test, cervical or external genital biopsy if clinically indicated, endocervical curettage specimen at the investigator's discretion, and definitive therapy specimen if clinically indicated.

Immunogenicity against HPV Types 6, 11, 16, and 18

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 Titres (GMT)] of Gardasil 9 compared with Gardasil for these HPV types. The efficacy findings from the pivotal clinical studies for Gardasil against HPV Types 6, 11, 16, and 18 were bridged to Gardasil 9 by demonstrating that the immune responses elicited by Gardasil 9 were non-inferior to the immune responses elicited by Gardasil. The statistical criterion for non-inferiority with respect to GMT required that the lower bound of the 95% Confidence Interval (CI) for the fold-difference in anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs [Gardasil 9 versus (vs.) Gardasil] be above 0.67.

The Per Protocol Immunogenicity (PPI) population consisted of individuals who received all 3 vaccinations within pre-defined day ranges, did not have major deviations from the study protocol, met pre-defined criteria for the interval between the Month 6 and Month 7 visit, and who 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 post dose 3 (Month 7). In the per protocol immunogenicity population, non-inferiority of the GMT responses for each of the HPV Types 6, 11, 16, and 18 in the group administered Gardasil 9, relative to the group administered Gardasil, at 4 weeks post-dose 3 was established; the GMT ratios (Gardasil 9/ Gardasil) for HPV types 6, 11, 16, and 18 ranged from 0.80 to 1.19. Non-inferiority of immune responses with respect to the percentages of subjects who became seropositive to HPV Types 6, 11, 16, and 18 was also demonstrated in the Gardasil 9 group, compared to the Gardasil group. Therefore, the data support bridging prior efficacy findings for Gardasil to Gardasil 9 with respect to persistent infection and anogenital disease related to HPV types 6/11/16/18, in females, 16 to 26 Years of Age. Detailed results of the analysis for the immunogenicity of Gardasil 9 with respect to HPV Types 6, 11, 16, and 18 are included in the Gardasil 9 Product Monograph.

Efficacy against HPV Types 31, 33, 45, 52 and 58

Analysis of efficacy against HPV Types 31, 33, 45, 52, and 58 was based primarily on a combined endpoint of CIN 2/ 3, AIS, invasive cervical carcinoma, VIN 2/3, VaIN 2/3, vulvar cancer, or vaginal cancer, related to these HPV types, and compared with that of the Gardasil group. The primary analysis of efficacy for Gardasil 9 against HPV Types 31, 33, 45, 52, and 58 was evaluated in the per protocol efficacy population of 16 through 26 year old women, who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and who were naïve to the relevant HPV type(s) prior to dose one and through 1 month post dose 3 (Month 7).

In the per protocol efficacy population, Gardasil 9 was 96.7% efficacious (95% CI: 80.9%, 99.8%), relative to Gardasil, in preventing high-grade cervical, vulvar and vaginal disease (CIN 2, VIN 2, VaIN 2, or worse) related to HPV 31, 33, 45, 52, and 58; the results met the success criterion for the endpoint (the lower bound of the two-sided 95% CI greater than 25%). Gardasil 9 was also efficacious in reducing persistent infection related to these types of HPV after both 6 months [96.0%, (95% CI: 94.4%, 97.2%)] and 12 months [96.3%, (95% CI: 94.4%, 97.7%)]. Detailed results of the analysis for the efficacy of Gardasil 9 with respect to HPV Types 31, 33, 45, 52, and 58 are included in the Gardasil 9 Product Monograph.

Protocol 002: Immunological Bridging in Females and Males, 9 to 15 Years of Age, and Lot Consistency Study

No efficacy study was conducted in adolescents due to the ethical constraints in collecting samples and performing examinations with children. Gardasil 9 efficacy and immunogenicity findings in women 16 to 26 years of age from Protocol 001 were bridged to girls and boys 9 to 15 years of age, based on the demonstration of non-inferior immunogenicity.

Protocol 002 was an open-label, multicentre, multinational study to assess the safety, immunogenicity and manufacturing consistency of Gardasil 9, with a target enrollment of approximately 2,800 participants (1,800 girls of 9-15 years old, 600 boys of 9-15 years old, and 400 women of 16-26 years old). All participants received Gardasil 9 as a series of three intramuscular injections of 0.5 mL on Day 1, Month 2 and Month 6.

Immunobridging

A non-inferiority analysis was performed in the Per Protocol Immunogenicity population that consisted of individuals who received all 3 vaccinations within one year of enrollment, did not have major deviations from the study protocol, and were HPV naïve (seronegative for all participants and PCR negative in cervicovaginal specimens in women aged 16 to 26) to the relevant HPV types prior to dose 1 and through 1 month post dose 3 (Month 7). The statistical criterion for non-inferiority with respect to GMT for each HPV type (6, 11, 16, 18, 31, 33, 45, 52, and 58) required that the lower bound of the 95% CI for the GMT ratio relative to 16 to 26 year old women be greater than 0.67. In the Per Protocol Immunogenicity population, the immunogenicity of Gardasil 9 in girls aged 9 to 15 and in boys aged 9 to 15 was non-inferior to that of Gardasil 9 in women aged 16 to 26 for all HPV types included in the vaccine at 4 weeks post-dose 3 (Month 7), with respect to GMT and with respect to the percentages of individuals who became seropositive to each vaccine HPV Type. These data support the bridging of the efficacy of Gardasil 9 against persistent infection and disease related to vaccine HPV types from 16 to 26 year old women to girls and boys aged 9 to 15 years.

Lot Consistency

In the lot consistency sub-study, the GMT responses for each of the 9 HPV vaccine types at 4 weeks post-dose 3 were similar among girls, 9 to 15 years of age, randomized to 1 of 3 manufacturing lots of Gardasil 9. Per protocol, the statistical criterion for equivalence required that the two-sided 95% CI for the ratio of the GMTs between the lots be entirely contained within (0.5, 2), and equivalence was established in all 3 pairwise comparisons for each vaccine HPV type.

Protocol 009: Immunological Bridging in Females, 9 to 15 Years of Age

This was a randomized, double-blind, Gardasil-controlled study to assess the immunogenicity and safety of Gardasil 9 in girls aged 9 to 15 years. A total of 600 girls were enrolled (300 received Gardasil 9, 300 received Gardasil). This study demonstrated that the immunogenicity of Gardasil 9 was non-inferior to Gardasil in girls aged 9 to 15 for HPV Types 6, 11, 18, and 18, further supporting the immunological bridging conclusions from Protocol 002.

Protocol 006: Study of Gardasil 9 in Prior Gardasil Vaccine Recipients

This was a safety and immunogenicity, placebo-controlled study in prior Gardasil recipients. The study was conducted in girls and women12 to 26 years of age.

Gardasil 9 was immunogenic in prior Gardasil recipients, as shown by high seroconversion rates (>98%) for all vaccine HPV types. However, GMTs for the five new HPV types were lower in prior Gardasil recipients administered Gardasil 9 compared with subjects naïve to HPV vaccination administered Gardasil 9 in other studies. The clinical relevance of this finding is unknown.

Protocols 005 and 007: Concomitant Use Studies

Both Protocol 005 and Protocol 007 were conducted to document the immunogenicity and safety profile of Gardasil 9 when administered concomitantly with vaccines recommended for routine vaccination of adolescents.

Concomitant administration of Gardasil 9 with Menactra and Adacel (Protocol 005) or with Repevax (Protocol 007) did not show any adverse impact on immune response to any of the four vaccines.

Overall Analysis of Efficacy

Gardasil 9 has been demonstrated to prevent both persistent infection and high-grade cervical, vulvar and vaginal disease (CIN 2, VIN 2, VaIN 2, or worse) related to HPV Types 31, 33, 45, 52, and 58, in 16-26 year old women who were naïve to these relevant HPV type(s) at the time of vaccination and throughout the follow-up period (Month 7). These high-grade lesions have been used as surrogate markers for the relevant cancers.

The efficacy of Gardasil 9 with respect to HPV Types 6, 11, 16, and 18 has been inferred by demonstrating that the immune responses elicited by Gardasil 9 were non-inferior to the immune responses to these HPV types elicited by Gardasil in 16-26 year old women. The efficacy findings for Gardasil 9 in women 16 to 26 years of age were bridged to girls and boys 9 to 15 years of age based on the demonstration of non-inferior immunogenicity to all 9 HPV types included in Gardasil 9.

There were no clinical studies for Gardasil 9 in women 27 to 45 years of age or men 16 to 26 years of age at the time of review. Health Canada has determined that it is likely that Gardasil 9 will have an acceptable safety profile and confer prophylactic protection in these two populations, because of similar immunogenicity (with respect to HPV Types 6, 11, 16, and 18) and safety profiles of Gardasil 9 compared to those of Gardasil in several other groups (including women 16 to 26 years of age, and girls 9 to 15 years of age), as well as the efficacy data for Gardasil 9 in women 16 to 26 years of age, and the efficacy data in women 16-45 years of age for Gardasil. A Phase III immunogenicity and safety study in men 16 to 26 years of age (Protocol 003) was ongoing at the time of review and the study report will be submitted when available. 

Health Canada has also determined that efficacy of Gardasil 9 against anal diseases can be inferred from the efficacy of Gardasil 9 against genital lesions, because HPV associated genital and anal lesions share similar pathophysiology, Gardasil has previously been demonstrated to prevent anal lesions related to HPV Types 16 and 18, and Gardasil 9 has been demonstrated to prevent persistent infection related to HPV Types 31, 33, 45, 52, and 58.

For more information, refer to the Gardasil 9 Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The Gardasil 9 clinical studies were conducted in girls and women 9 to 26 years of age and boys and men 9 to 15 years of age. The data presented in the NDS on the use of Gardasil 9 in over 13,000 subjects in six clinical trials show that the vaccine is generally well tolerated.

The safety profile of Gardasil 9 is generally comparable to that of Gardasil, except for the use of Gardasil 9 is associated with an increase in injection-site adverse experiences compared with Gardasil. However, most of the injection-site adverse experiences in subjects administered Gardasil 9 are mild or moderate in intensity.

Administration of Gardasil 9 is generally well-tolerated in girls and women, 12 to 26 years of age, who previously received a 3-dose regimen of Gardasil. In addition, administration of Gardasil 9 concomitantly with Menactra and Adacel or Repevax is generally well tolerated.

Five study participants who received Gardasil 9 died (all from Protocol 001); none of the deaths were considered to be vaccine-related. Five participants who received Gardasil 9 had at least one serious adverse experience that was determined by the investigator to be related to the vaccine (one event each of pyrexia, allergy, asthmatic crisis, headache, and tonsillitis). Complete details regarding all vaccine related adverse events that were observed in either the Gardasil 9 or Gardasil groups at a frequency of at least 1% are included in the Gardasil 9 Product Monograph.

The percentages of subjects who developed new medical conditions were generally comparable between Gardasil 9 and Gardasil groups. The most commonly reported new medical conditions were vaginal infections, nasopharyngitis and influenza. However, there were 5 multiple sclerosis (MS) cases in the Gardasil 9 group (n = 7,089) and 2 cases in the Gardasil treatment group (n = 7,093, all from Protocol 001). The number of the cases in each group is small, and the clinical significance of this imbalance is unclear. The incidence rate of MS in the Gardasil 9 group is within the range of incidence rates of MS reported in the literature for the general population.

Generally comparable pregnancy outcomes were observed in subjects who received Gardasil 9 or Gardasil. However, exploratoryanalyses showed that 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.These rates are consistent with published spontaneous abortion rates and previously observed rates in the placebo group of the Gardasil clinical development program.

Appropriate warnings and precautions are in place in the approved Gardasil 9 Product Monograph to address the identified safety concerns.

For more information, refer to the Gardasil 9 Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

There are a total of four non-clinical studies with Gardasil 9: one pharmacology study, one repeat-dose toxicity study and two reproductive/developmental toxicity studies. The submitted non-clinical studies were sufficient to support the licensure of Gardasil 9, based on the relevant regulatory guidelines for vaccines. In addition, more extensive non-clinical studies had been performed with Gardasil previously. There are no special concerns identified from the toxicity studies, and Gardasil 9 induced HPV-specific antibody responses in animals.

For more information, refer to the Gardasil 9 Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

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.

Gardasil 9 is supplied in single-dose vials or single-dose prefilled syringes. After thorough agitation, Gardasil 9 is a white, cloudy, liquid. The product does not contain a preservative or antibiotics.

Gardasil 9 contains VLPs of L1 protein for HPV Types 6, 11, 16, and 18, which are also included in the authorized product Gardasil. The sponsor indicated that the manufacturing of the drug substances for HPV Types 6, 11, 16 and 18 in Gardasil 9 is the same as that for Gardasil (Control # 102682). The sponsor provided a complete submission however previously reviewed portions such as drug substance development and manufacturing for HPV Types 6, 11, 16, and 18, facilities and previously approved Quality Control testing were not reviewed.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that all 9 medicinal ingredients consistently exhibit the desired characteristic structure and biological activity. The strategy and methods used in characterizing HPV Types 31, 33, 45, 52, and 58 are the same used to characterize HPV Types 6, 11, 16, 18 in the previously approved product, Gardasil. The results confirm the protein primary structures, characterize the higher order structures, and demonstrate the relationship between VLP structure and biological activity.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

Manufacturing Process and Process Controls of the Drug Substance and Final Product

Papillomaviruses, which are small, nonenveloped, icosahedral deoxyribonucleic acid (DNA) viruses, are classified according to their L1 protein sequence homology. The L1 capsid polypeptide of each of the nine vaccine types is expressed in a separate fermentation of a recombinant strain of baker's yeast, Saccharomyces cerevisiae. The L1 monomer self-assembles to form virus-like particles (VLPs), which mimic the capsid structure of the native virions. The VLPs of each HPV type are purified to produce the monovalent Final Aqueous Product (FAP). The FAP is then adsorbed onto an amorphous aluminum hydroxyphosphate sulfate adjuvant to prepare the Monovalent Bulk Adsorbed Product (MBAP), for each HPV Type included in the vaccine.

The manufacturing process of HPV MBAP consists of a series of stages which include fermentation, harvest of the recombinant yeast cell slurry, purification of the VLPs and adsorption of the purified VLPs onto aluminum-containing adjuvant to from the MBAP. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.

The formulated drug product is prepared by blending excipients with the HPV Type 6, 11, 16, 18, 31, 33, 45, 52, and 58 MBAPs. The Final Formulated Bulk (FFB) is mixed and cooled to 2-8°C before filling or storage.

In-process controls and lot release tests for Gardasil 9 were established and validated.

The materials used in the manufacture of Gardasil 9 (including biological-sourced materials) are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and the final product are valid and considered to be adequately controlled within justified limits.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the HPV Type 6, 11, 16, 18, 31, 33, 45, 52, and 58 MBAPs with the excipients is supported by the stability data provided.

Control of the Drug Substance and Final Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with International Conference on Harmonisation (ICH) guidelines.

Each lot of Gardasil 9 drug product is tested for appearance, content, identity, and potency. Established test specifications and validated analytical test methods are considered acceptable.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.

The results for all of the batches were within the proposed specification limits; however, the sponsor has been asked to make a commitment to address a few outstanding issues post-approval to ensure that products manufactured in the future continue to meet the proposed specification limits.

Stability of the Drug Substance and Final Product

Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 30 month shelf-life at 2-8°C, with time out of refrigeration (TOR) allowances of temperatures between 8°C and 25°C that do not exceed 72 hours is considered acceptable.

The compatibility of the final product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of Gardasil 9 drug product was waived because the bulk manufacturing processes for the five additional HPV types included in Gardasil 9 are essentially the same as for Gardasil.

Both sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The Gardasil 9 manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control.

Raw materials of human and animal origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the Gardasil 9 product formulation are not of animal or human origin.

Report a problem or mistake on this page
Please select all that apply:
Date modified: