Keytruda - Notice of Compliance with Conditions - Qualifying Notice

Biologic and Radiopharmaceutical Drugs Directorate
100 Eglantine Driveway
LCDC Building
Tunneys' Pasture, A.L. 0601C
Ottawa, Ontario
K1A 0K9

Dossier ID: HC6-024-e171468
Control #: 236910

[employee's name removed]
[employee's title removed]
16750 Route Transcanadienne
Kirkland, QC H9H 4M7

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 236910, indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in-situ (CIS) with or without papillary tumours in adults who are ineligible for or have elected not to undergo cystectomy, 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, Keynote-676, entitled: A Phase 3, Randomized, Comparator-controlled Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination with Bacillus Calmette Guerin (BCG) in Participants with High-risk Non muscle Invasive Bladder Cancer (HR NMIBC) that is Persistent or Recurrent Following BCG Induction. The estimated study enrollment is 550 patients and the primary endpoint of the study is complete response (CR) rate in patients with CIS. The key secondary endpoints of the study is event-free survival (EFS) in all patients. As per the study protocol both endpoints are statistically powered.
   1. The Sponsor should provide the approximate date of completion (month/year) of the confirmatory study (Keynote-676) and should commit to an approximate date (month/year) of filing the SNDS-c.
   2. The Sponsor should acknowledge that the indication for Keytruda may be withdrawn if the results of the Keynote-676 study comparing Keytruda plus BCG versus BCG alone do not demonstrate both a statistically significant and clinically meaningful improvement in both the CR rate in CIS patients and EFS in all patients. That is, the findings of the CR rate and EFS will be equally weighted in the assessment of benefit/risk.

Progress Reports of Confirmatory Trials and Other Ongoing Trials

2. 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 and Health Canada must be outlined in the Letter of Undertaking.

Safety Monitoring

3. 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 Biologic and Radiopharmaceutical Drugs 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
4. 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);
5. 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

6. 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).
7. 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).
8. 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).
9. Copies of any marketing authorizations for Keytruda (pembrolizumab) from any other drug regulatory authority as per Section 4.6 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).

3. A draft of the Product Monograph that is consistent with the requirements outlined in sections 5.2.1 and 5.2.2 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). Please note that a boxed text must appear on the cover page, at the beginning of each major section of the Product Monograph (Parts I, II and III), and the first page, disclosing the nature of the authorization granted for (Keytruda (pembrolizumab) and the need to conduct confirmatory studies.

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
Finance Building,
101 Tunney's Pasture Driveway
Address Locator 0201A1
Ottawa, Ontario, K1A 0K9

Attention: Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate

Sincerely,

Celia Lourenco, Ph.D.
Director General