Qualifying notice for Gardasil 9

Biologic and Radiopharmaceutical Drugs Directorate
100 Eglantine Driveway
LCDC Building
Tunney’s Pasture, A.L. 0601C
Ottawa ON  K1A 0K9

Dossier ID: HC6-024-e170006
Control #: 251509

[employee name removed]
[employee title removed]
Merck Canada Inc.
16750 route Transcanadienne
Kirkland QC  H9H 4M7
Email: [employee email removed]

Dear [employee name removed]:

This Notice of Compliance with Conditions (NOC/c)-Qualifying Notice, issued in accordance with the Health Canada NOC/c Policy, is to advise you that information submitted in support of the Supplement to a New Drug Submission (SNDS) for Gardasil 9 [Human Papillomavirus 9-valent Vaccine, Recombinant], Control Number 251509, indicated for the prevention of head and neck cancers, qualifies to be considered for authorisation under the NOC/c policy. In keeping with the provisions outlined in the NOC/c policy, the following additional information is required to complete the assessment:

1. A letter signed by the Chief Executive Officer, or designated signing authority of Merck Canada Inc. indicating that you agree to have the submission considered under the NOC/c Policy. Please be reminded that in agreeing to accept an NOC under the NOC/c Policy, Merck Canada Inc. consents to the posting of the NOC/c-QN on Health Canada’s website with all propriety information redacted.
2. A draft Letter of Undertaking signed by the Chief Executive Officer, or designated signing authority, of Merck Canada Inc., having a form and content satisfactory to Health Canada as indicated in the “Guidance Document: Notice of Compliance with Conditions (NOC/c)”, including commitments to provide the following:

Confirmatory study

1. A Supplement to a New Drug Submission-confirmatory (SNDS-c) containing the final clinical study report of the pivotal study ([trial identifier removed]) titled: A Phase 3, International, Multi-center, Randomized, Double-blind, Placebo controlled Clinical Trial to Study the Efficacy, Immunogenicity, and Safety of the 9vHPV Vaccine, a Multivalent L1 Virus-like Particle Vaccine, in the prevention of oral persistent infection with HPV Types 16, 18, 31, 33, 45, 52, or 58 in adult males, 20 to 45 years of age (YOA). The final clinical trial study report is planned to contain the following from the [trial identifier removed] pivotal study:
   1. Final primary efficacy endpoint analysis for HPV 16/18/31/33/45/52/58-related oral persistent infection 6 months (± 1-month window) or longer.
   2. Secondary endpoint analysis of 1) HPV 6/11-related oral persistent infection 6 months (± 1-month window) or longer, 2) Serum antibody titer to each of HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 at Month 7, and 3) Solicited injection-site adverse events, Systemic adverse events, and serious adverse events.
2. Analysis of efficacy results in men 20-45YOA extrapolated to other demographic groups including females 9-45 YOA and males 9-19 YOA based on cross-study immuno-bridging analysis using immunogenicity data from prior studies. This information can be provided in either the CSR or an appropriate eCTD section.

The target submission date for the above would be Q4-2026. If there is a change in this date, the Sponsor will provide an update to Health Canada. The Sponsor should acknowledge that the indication for Gardasil 9 [Human Papillomavirus 9-valent Vaccine, Recombinant] for the prevention of head and neck cancers may be withdrawn if study V503-049 does not determine that Gardasil 9 is able to demonstrate vaccine efficacy of HPV 16/18/31/33/45/52/58-related oral persistent infection 6 months (± 1-month) or longer with a statistical criterion for success requiring that the lower bound of the 2-sided 95% CI for VE be >20%.

Progress reports of confirmatory trials and other ongoing trials

3. On an annual basis, within 60 calendar days of the market authorization anniversary or a date agreed upon at the time of the issuance of the market authorization, submit status reports on the progress of the ongoing confirmatory trial, as per section 3.2 and Appendix 4 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The details of the requirements for filing and termination of the annual status report as agreed upon by Merck Canada Inc. and Health Canada must be outlined in the Letter of Undertaking.

Safety monitoring

4. Report all serious ARs that occurred in Canada and all serious unexpected ARs that occurred outside of Canada within 15 days to the Marketed Health Products Directorate, in accordance with current regulations (C.01.016) and guidelines. Adverse events (AE) and AR reports on marketed drugs occurring as part of confirmatory trials subject to clinical trial applications, as outlined in the Letter of Undertaking, should not be sent to the Canada Vigilance Program. These reports should be sent to the Biologic and Radiopharmaceutical Drugs Directorate (BRDD). Reporting must be conducted as per section 3.4.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c) and in accordance with current regulations and guidelines (e.g. Guidance for Industry - Reporting Adverse Reactions to Marketed Health Products and Guidance for Clinical Trial Sponsors: Clinical Trial Applications).
5. Submit Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Reports-C for NOC/c Products (PSUR-Cs or PBRER-Cs) on a semi-annual basis until such time as conditions associated with the market authorisation have been fulfilled and removed from the NOC by Health Canada. PSUR-Cs/PBRER-Cs should be prepared in accordance with the standards defined in the ICH E2C(R2) guideline, including format and content as per section 3.4.2 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The PBRER-Cs will include an analysis of the adverse drug reactions as per the Pharmacovigilance Plan and safety updates from all ongoing clinical trials with Gardasil 9.
6. Comply with the notification and reporting on specific issues of concern as outlined in section 3.4.4 of the “Guidance Document: Notice of Compliance with Conditions (NOC/c)”.
7. Submit one updated core RMP and Canadian addendum that include data related to the new Head and Neck indication to the Marketed Health Products Directorate for review.

Additional information

8. Receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to Head and Neck indication for Gardasil 9 authorized under the NOC/c policy as per section 5.1 of the “Guidance Document: Notice of Compliance with Conditions (NOC/c)”.
9. Submit an outline of the agreed-upon advertising, labelling or distribution requirements imposed on the Head and Neck indication for Gardasil 9, including a commitment to file revised Product Monographs as information is made available as per section 4.3 of the “Guidance Document: Notice of Compliance with Conditions (NOC/c)”.
10. Submit an up-to-date, complete listing of ongoing additional clinical trials related to Head and Neck indication for Gardasil 9 appended to the “Letter of Undertaking” as per section 4.5 of the “Guidance Document: Notice of Compliance with Conditions (NOC/c)”.
11. Submit copies of any marketing authorizations for Head and Neck indication for Gardasil 9 from any other drug regulatory authority as per section 4.6 of the “Guidance Document: Notice of Compliance with Conditions (NOC/c)”.

I wish to advise you that this Qualifying Notice is being issued in accordance with Health Canada's guidance on the Management of Drug Submissions and Notice of Compliance with Conditions, respectively. Sponsors are instructed to submit a complete response (refer to Guidance Document: Notice of Compliance with Conditions) to the outstanding information within 30 calendar days of the date of this letter.

Your response to the above should be submitted with a copy of this letter to the Office of Submissions and Intellectual Property. In order to facilitate and ensure proper processing of your response, please include a revised Submission Certificate, quoting the product name, assigned dossier ID, and control number of the original submission, and address your response to:

Director, Office of Submissions and Intellectual Property
Resource Management and Operations Directorate
Address Locator: 1908A
8th Floor – Room 811A Jeanne Mance Building
200 Eglantine Driveway
Ottawa ON  K1A 0K9

Attention: Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate

Sincerely,

Celia Lourenco, Ph.D.
Director General