Qualifying Notice - Opdivo

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

Dossier ID: HC6-024-e177442
Control #: 239474

[employee's name removed]
[employee's title removed]
Bristol-Myers Squibb Canada
2344 Alfred-Nobel, Suite 300
Saint-Laurent, Quebec, Canada H4S 0A4
Fax : 514-333-9955

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), Control Number 239474, for "Opdivo (nivolumab) in combination with ipilimumab. Indicated for the treatment of adult patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer after prior fluoropyrimidine-based therapy in combination with oxaliplatin or irinotecan. The marketing authorization with conditions is primarily based on tumour objective response rate and durability of response. An improvement in survival has not been established", which warrants it 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 (3-12):

Confirmatory Study (requirement)

• 3. Submit the Final Report for [study name/number has been removed]. The study enrolls participants across lines of therapy except the chemotherapy arm which is open to participants who have not received prior therapy or only received one line of prior therapy. This study shall need to verify the clinical benefits of nivolumab in combination with Ipilimumab versus investigator's choice chemotherapy based on an improvement of Blinded Independent central Review (BICR)-assessed progression-free survival (PFS) (primary endpoint) in patients who have not received prior treatment, with centrally confirmed MSI-H or dMMR mCRC. Key secondary endpoints of this study would include Objective Response Rate (ORR), Duration of Response (DoR) as assessed by BICR and Overall survival (OS).
  • a. The Sponsor should provide the approximate date of completion of the confirmatory study [study name/number has been removed] and should commit to an approximate date of filing the SNDS-c.
  • b. The Sponsor should acknowledge that the indication for Opdivo plus Ipilimumab may be withdrawn if study [study name/number has been removed] does not demonstrate that Opdivo plus Ipilimumab in patients who have not received prior therapy, is associated with a PFS that is both statistically significant and clinically meaningful over investigator's choice chemotherapy.

Progress Reports of Confirmatory Studies and Other Ongoing Studies

• 4. In accordance with section 3.2 and Appendix 4 of the Guidance Document: Notice of Compliance with Conditions (NOC/c) the sponsor is required to submit on an annual basis status reports on the progress of ongoing confirmatory trials. This annual status report should be submitted within 60 calendar days of the market authorization anniversary or a date agreed upon at the time of the issuance of the market authorization.

Safety Monitoring

• 5. The sponsor must report all serious Adverse Reactions (ARs) that occurred in Canada and all serious unexpected ARs that occurred 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).
• 6. Submit a risk management plan (RMP) whenever safety updates have been made to the RMP.
• 7. Provide a Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Reports-C for NOC/c Products (PSUR-Cs or PBRER-Cs) on annual basis 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 Opdivo (nivolumab) authorized under the NOC/c policy as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
• 10. 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).
• 12. 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).
• 13. Provide 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, Ontario, K1A 0K9

Attention: Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate

Sincerely,
Celia Lourenco, Ph.D.
Director General