Qualifying notice for Opdivo

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

Dossier ID: HC6-024-e177442
Control number: 253652

[employee title removed]
Bristol-Myers Squibb Canada Co.
2344 Alfred-Nobel, Suite 300
Montreal QC H4S 0A4

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 Supplemental New Drug Submission (SNDS), Control Number 253652, for Opdivo (Nivolumab), indicated as a monotherapy for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC, 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 Bristol-Myers Squibb Canada Co. 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, Bristol-Myers Squibb Canada Co. 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 Bristol-Myers Squibb Canada Co. 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. Bristol-Myers Squibb Canada Co. commits to submit, as a Supplemental New Drug Submission-confirmatory (SNDS-c), from the pivotal study, CA209274 (CheckMate-274), entitled: A Phase 3 Randomized, Double-Blind, Multi-centre Study of Adjuvant Nivolumab versus Placebo in Subject with High Risk Invasive Urothelial Carcinoma, the following:
   1. interim and final analyses of Overall Survival (OS) for both the all-randomized population and the PD-L1 ≥1% population. The target filing date will be Q1 2023 and Q1 2025 for the all-randomized and PD-L1 ≥1% interim analysis report, respectively and Q2 2026 and Q4 2027 for the final report, respectively. The target filing date for the safety interim analysis for the all-randomized population will be Q1 2023.
   2. annual interim and final reports including meeting minutes and the charter from the Data Monitoring Committee analyzing the overall survival results of the upper tract urothelial carcinoma subgroup population. The target filing dates would be Q4 of every year from 2022 - 2027.

   Bristol-Myers Squibb Canada Co. acknowledges that:

   3. the indication authorized under the NOC/C pathway for Opdivo under control #253652 can be withdrawn or revised pending the outcomes of study CheckMate-274 (CA209274). The decision on the removal of the condition and/or modification of the current indication will be based on the demonstration of an overall survival benefit with nivolumab monotherapy in the indicated patient population being clinically confirmed and/or if the risk/benefit analysis, as determined by BRDD, is positive.
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 Bristol-Myers Squibb Canada Co. 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 Clinical Trial Sponsors: Clinical Trial Applications).
4. Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Reports-C for NOC/c Products (PSUR-Cs or PBRER-Cs) should be provided 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).
6. Implement the Risk Management Plan (RMP) in Canada and provide any updates to the RMP whenever available.

Additional information

7. Receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to Opdivo (Nivolumab) authorized under the NOC/c policy as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
8. Provide 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).
9. Provide an up-to-date, complete listing of ongoing additional clinical trials related to Opdivo (Nivolumab), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
10. Copies of any marketing authorizations for Opdivo (Nivolumab), 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 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 quote the product name, assigned dossier ID, and control number of the original submission, and send directly to the Office of Submissions and Intellectual Property (OSIP) via the Common Electronic Submissions Gateway (CESG) using the Regulatory Enrolment Process (REP).

Sincerely,

Celia Lourenco, Ph.D.
Director General