Qualifying Notice - DARZALEX

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

May 27, 2016

Dossier ID #: HC6-024-e182292
Control #: 187648
Document #: 1107660

[employee name removed]
Manager, Regulatory Affairs
Janssen Inc.
19 Greenbelt Drive
Toronto, ON   M3C 1L9

Fax: 1-800-791-8047

Notice of Compliance with Conditions - Qualifying Notice

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 DARZALEX (daratumumab), Control Number 187648, indicated for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are refractory to both a PI and an IMiD, 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 Janssen 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, Janssen 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 Janssen 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. Submit by the end of 2016 (4Q2016) as an SNDS-c, the interim analysis report of the confirmatory study (MMY3003) entitled “Phase 3, randomized, open-label, active-controlled, parallel-group, multicentre study of daratumumab, lenalidomide, and low-dose dexamethasone (DRd) compared with lenalidomide and low-dose dexamethasone (Rd) in subjects with relapsed or refractory multiple myeloma”. The final report will be submitted when available.

      It is recommended that the trial be sufficiently powered for the key secondary endpoint Overall Survival (OS). The sponsor should acknowledge that they are aware that the indication for DARZALEX can be withdrawn in the event of an unsuccessful study.
    2. Submit by the end of 2016 (4Q2016) as an SNDS-c, the interim analysis report of the confirmatory study (MMY3004) entitled “Phase 3 Study Comparing Daratumumab, Bortezomib an Dexamethasone (DVd) vs Bortezomib and Dexamethasone (Vd) in Subjects With Relapsed or Refractory Multiple Myeloma”. The final report will be submitted when available.

      It is recommended that the trial be sufficiently powered for the key secondary endpoint OS. The sponsor should acknowledge that they are aware that the indication for DARZALEX can be withdrawn in the event of an unsuccessful study.
    3. Provide a subgroup analysis of ORR by ISS staging for both confirmatory studies MMY3003 and MMY3004. The role of disease stage as a potential prognostic and/or predictive marker of response should be further investigated in the confirmatory trials. The results should be submitted to Health Canada in the final reports of the confirmatory studies (see 1a and 1b).

    Final Reports

    1. Submit as an SNDS-c, when available the final report of the completed trial MMY2002 entitled: “An Open-label, Multicenter, Phase 2 Trial Investigating the Efficacy and Safety of Daratumumab in Subjects With Multiple Myeloma Who Have Received at Least 3 Prior Lines of Therapy (Including a Proteasome Inhibitor and IMiD) or are Double Refractory to a Proteasome Inhibitor and an IMiD”.
    2. Submit as an SNDS-c, when available the final report of the completed trial GEN501 entitled: “Daratumumab (HuMax-CD38) Safety Study in Multiple Myeloma – Open-label, Dose-Escalation Followed by Open-Label, Single-Arm Study”.
    3. Submit as an SNDS-c, when available the final report of the completed trial MMY1001 entitled: “An Open-label, Multicenter, Phase 1b Study of JNJ-54767414 (HuMax® CD38) (Anti-CD38 Monoclonal Antibody) in Combination with Backbone Regimens for the Treatment of Subjects with Multiple Myeloma”.
    4. Submit as an SNDS-c, when available the final report of the completed trial MMY1002 entitled: “A Phase 1 Study of JNJ-54767414 (Daratumumab) in Japanese Patients With Relapsed or Refractory Multiple Myeloma.”
    5. Submit as an SNDS-c, when available the final report of the completed trial GEN503 entitled: “An Open label, International, Multicenter, Dose Escalating Phase 1/2 Trial Investigating the Safety of Daratumumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma”.
    6. Submit as an SNDS-c, when available the validation reports to accurately detect binding antibodies and neutralizing antibodies to DARZALEX with an appropriate level of tolerance to concentrations of DARZALEX in clinical trial serum samples. Along with these validation reports, an evaluation of antibody-drug antibodies (ADA) response to DARZALEX (both binding and neutralizing) in clinical trials should be performed.

    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 Janssen Inc. and Health Canada must be outlined in the Letter of Undertaking.

    Safety Monitoring

    1. Submit when available the safety analysis of DARZALEX in multiple myeloma patients with baseline hepatic impairment from clinical studies MMY3003 and MMY3004.
    2. If the results of the confirmatory studies MMY3003 or MMY3004, and/or of other DARZALEX clinical trials reveals greater safety risks for any subgroups and/or AEs (e.g. cardiac AEs), appropriate risk mitigation strategies will be required (e.g. PM labelling and RMP).
    3. Provide an evaluation of the relationship between daratumumab and QT from study SMM2001 when the SMM2001 study report is available.
    4. Based on the mechanism of action of DARZALEX, there is a potential risk of hemolysis. Continue to monitor this as a potential safety signal in clinical studies and post-marketing safety data.
    5. 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).
    6. Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Reports- 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 PSUR-Cs/PBRER-Cs should include an analysis of the Adverse Drug Reactions as per the Pharmacovigilance Plan and safety updates from ALL ongoing clinical trials with DARZALEX.
    7. 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).
    8. Implement the Risk Management Plan (RMP) in Canada and provide any updates to the RMP whenever available.
    9. Submit to MHPD education materials for DARZALEX regarding the interference with blood compatibility testing within 2 months after product launch.

    Additional information

    1. Receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to DARZALEX (daratumumab) 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 DARZALEX (daratumumab), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
    4. Submit to Health Canada any other analyses that have been designated as post-marketing commitments to other international authorisation granting agencies as per section 3.4.4 of the Guidance for Industry, Notice of Compliance with Conditions (NOC/c).
    5. Copies of any marketing authorizations or other regulatory actions for DARZALEX (daratumumab) from any other drug regulatory authority as per Section 4.6 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
  3. A draft "Dear Health Care Professional Letter" detailing the issuance of a Notice of Compliance under the NOC/c Policy for DARZALEX (daratumumab) indicated for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are refractory to both a PI and an IMiD, as per section 5.3 and Appendix 3 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
  4. A draft of the Product Monograph that is consistent with the requirements outlined in sections 5.2.1 and 5.2.2 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). Please note that a boxed text must appear on the cover page, at the beginning of each major section of the Product Monograph (Parts I, II and III), and the first page, disclosing the nature of the authorization granted for DARZALEX (daratumumab) and the need to conduct confirmatory studies.

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 file number 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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