Keytruda - Notice of Compliance with Conditions - Qualifying Notice

Biologics and Genetic Therapies Directorate
100 Eglantine Driveway
Address Locator #0601C
Ottawa, Ontario
K1A 0K9

Dossier ID: HC6-024-e171468
Control #: 209011

March 4, 2019

[Employee's name removed]
[Employee's title removed]
Merck Canada Inc.
16750 route Transcanadienne
Kirkland, QC H9H 4M7
Fax: 1-514-428-4910

Notice of Compliance with Conditions - Qualifying Notice

Dear [Employee's 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 Supplemental New Drug Submission (SNDS) for KEYTRUDA (pembrolizumab), Control Number 209011, indicated for the treatment of patients with locally advanced unresectable or metastatic urothelial carcinoma, as monotherapy, in adults who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by a validated test, or in adults who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status, 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 this 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.
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 Studies

   1. Submit, as an SNDS-c, the final report for the confirmatory study: A phase 3, randomized, active controlled trial of pembrolizumab with or without platinum-based combination chemotherapy versus chemotherapy in subjects with advanced or metastatic urothelial carcinoma (KEYNOTE-361). The sponsor should provide the approximate date of completion of the confirmatory study, KEYNOTE-361, and should commit to an approximate date of filing of the SNDS-c submission.
   2. Submit, as an SNDS-c, the final report for the confirmatory study: A phase 3, randomized, double-blind study of pembrolizumab in combination with lenvatinib versus pembrolizumab and placebo as first line treatment for locally advanced or metastatic urothelial carcinoma in cisplatin-ineligible participants whose tumors express PD-L1, and in participants ineligible for any platinum-containing chemotherapy regardless of PD-L1 expression (MK-7902-011). The sponsor should provide the approximate date of completion of the confirmatory study, MK-7902-011, and should commit to an approximate date of filing of the SNDS-c submission.
   3. The sponsor should acknowledge that the indication authorized under the NOC/c pathway for KEYTRUDA under control # 209011 can be withdrawn or revised, pending the outcomes of Study KEYNOTE-361 and/or Study MK-7902-011. The decision by BGTD on the removal of the condition and/or modification of the current proposed indication will be based on the demonstration that an overall survival benefit of pembrolizumab monotherapy in the indicated patient population can be clinically confirmed and/or if the risk/benefit analysis as determined by BGTD is positive.

   Progress Reports of Confirmatory Trials and Other Ongoing Trials

   4. 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, status reports on the progress of ongoing confirmatory trials, 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 the Merck Canada Inc. and Health Canada must be outlined in the Letter of Undertaking.

   Safety Monitoring

   5. Report all serious Adverse Reactions (AR) that occur in Canada and all serious unexpected ARs that occur outside of Canada within 15 days to the Marketed Health Products Directorate. 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, must be sent to the Biologics and Genetic Therapies Directorate. 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 the Guidance for Clinical Trial Sponsors: Clinical Trial Applications).
   6. Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Reports-C for NOC/c Products (PSUR-Cs or PBRER-Cs) on an annual basis until such time as conditions associated with the market authorisation are removed. PSUR-Cs/PBRER-Cs should be prepared in accordance with the E2C(R1) and E3C(R2) ICH Guideline, including format and content, as per section 3.4.2 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
   7. Comply with the notification and reporting of specific issues of concern as outlined in Section 3.4.4 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
   8. Implement the Risk Management Plan (RMP) in Canada and provide any updates to the RMP whenever available.

   Additional information

   9. Receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to KEYTRUDA (pembrolizumab) authorized under the NOC/c policy as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
   10. An outline of the agreed-upon advertising, labelling or distribution requirements, including a commitment to file revised Product Monographs under the appropriate submission type as information is made available as per section 4.3 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
   11. An up-to-date, complete listing of ongoing additional clinical trials related to KEYTRUDA (pembrolizumab), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
   12. Copies of any marketing authorizations for KEYTRUDA (pembrolizumab) from other major drug regulatory authority (FDA, EMA, and TGA) 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 guidances 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
Finance Building,
101 Tunney's Pasture Driveway
Address Locator 0201A1
Ottawa, Ontario, K1A 0K9

Attention: Office of Regulatory Affairs, Biologics and Genetic Therapies Directorate

Sincerely,

Celia Lourenco, Ph.D.
Director General