IDHIFA - Notice of Compliance with Conditions - Qualifying Notice

Therapeutic Product Directorate
Holland Cross, Tower "B"
6th Floor, 1600 Scott Street
Address Locator #3106B
OTTAWA, Ontario
K1A 0K9

Dossier ID: E210847

[employee name removed]
[employee titled removed]
Celgene Inc.
6755 Mississauga Road, Suite 600
Mississauga, Ontario
L5N 7Y2

Dear [employee name removed]:

This Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN), issued in accordance with the Health Canada Guidance Document: Notice of Compliance with Conditions (NOC/c), is to advise you that information submitted in support of the New Drug Submission for IDHIFA (enasidenib mesylate), control number 217033, indicated for the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia (AML) with an isocitrate dehydrogenase-2 IDH2 mutation, qualifies to be considered for authorization in accordance with the NOC/c Guidance. In keeping with the provisions outlined in the NOC/c Guidance, the following additional information is requested to complete the assessment:

  1. A letter, signed by the Chief Executive Officer or designated signing authority of Celgene Inc., indicating that you agree to have this submission considered under the NOC/c Guidance. Please be reminded that in agreeing to accept a Notice of Compliance (NOC) under the NOC/c Guidance, Celgene Inc. consents to the posting of this NOC/c-QN on Health Canada's website once market authorization has been received.
  2. A Letter of Undertaking signed by the Chief Executive Officer or designated signing authority of Celgene Inc., having a form and content satisfactory to Health Canada, as indicated in NOC/c Guidance, including commitments to provide the following:

    Confirmatory studies

    1. The report of the final analysis of Study AG221-AML-004 - A phase 3, multicenter, open-label, randomized study comparing the efficacy and safety of AG-221 versus conventional care regimens in patients 60 years or older with R/R AML after second- or third-line AML therapy and positive for an isocitrate dehydrogenase 2 (IDH2) mutation should be submitted as confirmatory data. The outline of this confirmatory trial and the timelines should be included in the Letter of Undertaking. Indicate the earliest anticipated availability of the data.

    Additional Studies

    1. The report of the final analysis of Study CC-90007-CP-004, a drug-drug interaction study in AML subjects with an IDH2 mutation.
    2. The report of the final analysis of Study CC90007-CP-003, a single dose, pharmacokinetic study in subjects with moderate and severe hepatic impairment and healthy matched subjects.

    The timelines for these additional studies should be included in the Letter of Undertaking.

    Indicate the earliest anticipated availability of the data.

    Post Market Safety Monitoring Studies

    1. Provision of annual Periodic Benefit-Risk Evaluation Reports (PBRER-Cs) or Periodic Safety Update Reports (PSUR-Cs) in a manner deemed consistent with E2C ICH Guidelines, until such time as all conditions for market authorization under the NOC/c Guidance have been removed. The annual PBRER-Cs or PSUR-Cs should include cumulative data on relevant unlisted Adverse Reactions (ARs) from the date of marketing to the time of the report.
    2. Notification and reporting on specific issues of concern, as outlined in Section 3.4.4, Post-Market Commitments: Notification and Reporting of Specific Issues of Concern, of the Health Canada NOC/c Guidance.
    3. Report(s) of all serious adverse drug reactions (ADRs) that occurred in Canada and all serious unexpected ADRs that occurred outside of Canada should be forwarded within 15 days to the Marketed Health Products Directorate, in accordance with the current Food and Drug Regulations (C.01.017) and guidance documents.
  3. A draft of the Product Monograph (PM) that is consistent with the requirements outlined in section 5.2.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). Please note that boxed text should appear on the cover page as well as at the beginning of each major section of the Product Monograph (Parts I, II and III, as applicable), disclosing the nature of the authorization granted for Idhifa for the indication of the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation. Treatment with Idhifa should be initiated following confirmation of IDH2 mutation through a validated test.
  4. A final mock-up of the Package Insert in line with the requirements outlined in Health Canada's Guidance Document, Questions and Answers: Plain Language Labelling Regulations (Q&A: PLL), containing boxed text disclosing the nature of the authorization granted for Idhifa for the indication of the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation. Treatment with Idhifa should be initiated following confirmation of IDH2 mutation through a validated test.
  5. Patient and caregiver Wallet Cards with information related to symptoms and management of differentiation syndrome are to be distributed in all 100 mg and 50 mg cartons of Idhifa.

I wish to advise you that this Qualifying Notice is being issued in accordance with Health Canada's guidance documents on the Management of Drug Submissions and Notice of Compliance with Conditions. Sponsors are instructed to submit a complete response [refer to Guidance Document: Notice of Compliance with Conditions (NOC/c)] with the requested information within 30 calendar days of the date of this letter.

In order to facilitate and to ensure proper processing, please include a revised Submission Certificate with your response, quote the product name and control number, and address all correspondence to:

Office of Submissions and Intellectual Property
Therapeutic Products Directorate
Health Canada, Finance Building, Address Locator 0201A1
101 Tunney's Pasture Driveway
Ottawa, Ontario
K1A 0K9

Yours sincerely,

Dr. J. Patrick Stewart, MD, CCFP(EM)
Director General
Therapeutic Products Directorate

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