Libtayo - Notice of Compliance with Conditions - Qualifying Notice

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

Dossier ID: HC6-024-e212731
Control #: 218718

March 12, 2019

[employee name removed]
Head, Regulatory Affairs
Sanofi-Aventis Canada Inc.
2905 Place Louis-R-Renaud
Laval, QC   H7V 0A3
Fax: 1-514-333-3699

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 New Drug Submission (NDS) for LIBTAYO (cemiplimab), Control Number 218718, indicated for the treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation, 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 Sanofi-Aventis 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, Sanofi-Aventis 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 Sanofi-Aventis 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. A Supplemental New Drug Submission-confirmatory (SNDS-c) containing the following from the pivotal study (R2810-ONC-1540) titled: A Phase 2 Study of REGN2810, a Fully Human Monoclonal Antibody to Programmed Death-1 (PD-1) in Patients With Advanced Cutaneous Squamous Cell Carcinoma.
      1. Final primary endpoint efficacy analyses for Group 2 (3 mg/kg Q2W; locally advanced cutaneous squamous cell carcinoma [CSCC]) and Group 3 (350 mg Q3W; metastatic CSCC) (Objective Response Rate [ORR] by central review).
      2. Secondary endpoint analyses of Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS), Safety, Pharmacokinetics (PK) [including updated E-R analyses for efficacy and safety].
      3. An update for Group 1 (3 mg/kg Q2W; metastatic CSCC) of DOR, PFS, OS, Safety and PK.
      4. An updated integrated efficacy analysis with the advanced CSCC data from R2810-ONC-1423 and R2810-ONC-1540.

      The target submission date for the above would be Q4 2019.

    2. An SNDS-c containing the final clinical trial report for Trial R2810-ONC-1540 (Groups 1, 2 and 3), that includes the final analysis of objective response rate and duration of response in patients with advanced cutaneous squamous cell carcinoma (CSCC) including patients with metastatic disease and patients with locally advanced CSCC who are not candidates for surgery or radiation.

      The target submission date for the above would be Q2 2022.

    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 Sanofi-Aventis Canada Inc. 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). The PBRER-Cs will include an analysis of the adverse drug reactions as per the Pharmacovigilance Plan and safety updates from all ongoing clinical trials with LIBTAYO.
    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 LIBTAYO (cemiplimab) 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 LIBTAYO (cemiplimab), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
    4. Any other analyses that have been designated as post-marketing commitments to other international authorisation granting agencies.
    5. Copies of any marketing authorizations for LIBTAYO (cemiplimab) 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
Resource Management and Operations 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,

Celia Lourenco, Ph.D.
Director General

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