Qualifying notice for Opdivo (203286)

Biologics and Genetic Therapies Directorate
100 Eglantine Driveway
Address Locator #0601C
Ottawa ON KIA 0K9

• Dossier ID: HC6-024-E177442
• Control number: 203286
• Document number: 1265369

[employee name removed]
[employees title removed]
Bristol-Myers Squibb Canada
2344 Alfred-Nobel, Suite 300
St-Laurent QC H4S 0A4
Fax: 1-514-333-9955

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) for OPDIVO (nivolumab), Control Number 203286, indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) after failure of autologous stem cell transplant (ASCT), 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, 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 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, 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 SNDS-c, the Primary PFS Report of CA209812 Trial in September 2024 and the Final Clinical Study Report of the trial in December 2026.

   Study CA209812: Randomized, Open-label, Phase 3 Trial of Nivolumab plus Brentuximab vedotin versus Brentuximab vedotin alone in Participants with Relapsed Refractory or Ineligible for Autologous Stem Cell Transplant (ASCT) Advanced Stage Classical Hodgkin Lymphoma.

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 Bristol-Myers Squibb Canada and Health Canada must be outlined in the Letter of Undertaking.

Safety monitoring

3. commit to implement safety monitoring as per requirements of the Guidance Document: Notice of Compliance with Conditions (NOC/c). 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 Biologies 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).
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).
6. implement the Risk Management Plan (RPM) in Canada and provided updates to the RPM whenever available.

Additional information

7. Submit the Clinical Study Reports for the following on-going and planned studies in accordance with Health Canada's guidance document entitled Post-Notice of Compliance (NOC) Changes: Safety and Efficacy Document.
   1. CA209205 Trial titled "Non-Comparative, Multi-Cohort, Single-Arm, OpenLabel, Phase 2 Study of Nivolumab in Classical Hodgkin Lymphoma (cHL) Subjects After Failure of Autologous Stem Cell Transplant (ASCT)".
      1. Final reports for Cohorts A, B, and C based on 16 Dec 2016 DBL by 2Q 2018.
      2. Addenda to the above final clinical study report whenever the information from any additional data-cutoffs becomes available.
   2. Safety study to characterize complications after allogeneic hematopoietic stem cell transplantation (HSCT) following nivolumab therapy. The Interim Report by June 2019 and the Final Report by December 2022.
   3. CA209744 Trial titled "Risk-based, response-adapted, Phase II open-label trial of nivolumab + brentuximab vedotin (N + Bv) for children, adolescents, and young adults with relapsed/refractory (R/R) CD30 + classic Hodgkin lymphoma (cHL) after failure of first-line therapy, followed by brentuximab +bendamustine (Bv + B) for participants with a suboptimal response.". The final CSR: by 2nd Quarter 2022.
8. 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).
9. 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).
10. 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).
11. 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 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 ON KIA 0K9

Attention: Office of Regulatory Affairs
Biologics and Genetic Therapies Directorate

Sincerely,

Catherine Parker
Director General