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 #: 218779

[Employee's name removed]
[Employee's title removed]
Merck Canada Inc.
16750 route Transcanadienne
Kirkland, QC  H9H 4M7
Fax: 1-866-348-6715

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 218779 indicated for the treatment of adults with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, or MSI-H or dMMR endometrial cancer that has progressed following prior therapy and who have no satisfactory alternative treatment options, 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. Enrollment of additional patients to and completion of pivotal study KN-164:
      • An additional 63 evaluable patients should be enrolled to pivotal study KN-164 under eligibility criteria of either cohort A or cohort B.
      • On completion of enrolment and at the time of submission, all responding patients should be followed for a minimum of 12 months.
      • These conditions should be completed and Health Canada (HC) notified of their completion by September 2022, with a final report submitted to HC in March 2023.
    2. The following conditions need to be met in order for the MSI-H/dMMR endometrial cancer indication to achieve full authorisation without conditions:
      • Enrollment of additional patients with MSI-H/dMMR endometrial cancer into study KN-158 should be continued beyond the 24 patients reported in this submission. HC would expect a total of at least 50 patients with MSI-H/dMMR endometrial cancer to have been enrolled. These patients should be analyzed for safety, objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) as specified in the last amended version of the protocol and conducted in the current interim analysis in this submission. These conditions should be completed and HC notified of their completion by September 2022, with a final report submitted to HC in March 2023.
      • All responding patients should be followed for a minimum of 12 months to ensure maturity of the data for these endpoints.
    3. Additional patients enrolled under points a and b above should be selected for treatment for MSI-H/dMMR mCRC and endometrial cancer based on the presence of MSI-H or dMMR expression as determined by an experienced laboratory using a test authorized in Canada.

      In addition, the sponsor is reminded of the following:

    4. Merck Canada Inc. may wish to consider re-submitting additional MSI-H/dMMR histological tumour types that have enrolled a minimum of 20 evaluable patients for consideration of NOC/c status under the NOC/c policy. Authorization will be considered upon completion of review for those tumour types that show sufficient promise of efficacy as defined by ORR and DOR. Patients should be selected for MSI-H/dMMR expression as determined by an experienced laboratory using a test authorized in Canada.

      Progress Reports of Confirmatory Trials and Other Ongoing Trials

    5. 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 Merck Canada Inc. and Health Canada must be outlined in the Letter of Undertaking.

      Safety Monitoring

    6. 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).
    7. 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).
    8. 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).

      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
Therapeutic Products Directorate
Health Canada
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

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