Qualifying Notice - Opdivo

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

September 22, 2016

Dossier ID: HC6-024-E177442
Control #: 189307
Document #: 1138869

[Employee's name removed]
Senior Manager, Regulatory Affairs
Bristol-Myers Squibb Canada
2344 Alfred-Nobel, Suite 300
St-Laurent, Quebec   H4S 0A4
Fax: 514-333-9955

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 OPDIVO (nivolumab), Control Number 189307, qualifies to be considered for authorisation under the NOC/c policy for the following indications:

  • OPDIVO (nivolumab) is indicated for the treatment of patients with unresectable or metastatic BRAF V600 mutation-positive melanoma in previously untreated adults. An improvement in survival has not yet been established; and
  • OPDIVO (nivolumab) is indicated for the treatment of patients with unresectable or metastatic melanoma in previously untreated adults when used in combination with ipilimumab. Relative to OPDIVO monotherapy, an increase in progression-free survival (PFS) for the combination of OPDIVO with ipilimumab is established only in patients with low tumour PD-L1 expression (based on the predefined expression level of <5%). An improvement in survival has not yet been established.

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 Canadaconsents 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. As a SNDS-c for study CA209067, the results of a multicenter, randomized trial or trials establishing the superiority of nivolumab over standard therapy in adult patients with unresectable or metastatic BRAF V600 mutation-positive melanoma in previously untreated adults.
    2. As a SNDS-c for study CA209067, the results of a multicenter, randomized trial or trials establishing the superiority of nivolumab in combination with ipilimumab over standard therapy in adult patients with unresectable or metastatic melanoma in previously untreated adults.

      Bristol-Myers Squibb Canada has indicated that the final report of the completed trial CA209067 entitled "A Phase 3, randomized, double-blind study of nivolumab monotherapy or nivolumab combined with ipilimumab versus ipilimumab monotherapy in subjects with previously untreated unresectable or metastatic melanoma" will be submitted to fulfill this commitment. This report is expected to be submitted in the first quarter of 2017 (Q1 2017).

    3. The sponsor should acknowledge that they are aware that the two indications authorized under the NOC/c pathway for OPDIVO under control # 189307 can be withdrawn if the final report of Study CA209067 fails to demonstrate an overall survival benefit in these patient populations and/or if the risk/benefit analysis as determined by BGTD is not positive.

    Progress Reports of Confirmatory Trials and Other Ongoing Trials

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

    Safety Monitoring

    1. 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).
    2. 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);
    3. 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).
    4. implement the Risk Management Plan (RMP) in Canada and provide any updates to the RMP whenever available.

    Additional information

    1. 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).
    2. 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).
    3. 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).
    4. copies of any marketing authorizations or other regulatory actions 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 the official Qualifying Notice will be 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 the official 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, Biologics and Genetic Therapies Directorate

Sincerely,

Catherine Parker
Director General

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