Rozlytrek - 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: E221250

Dear [Employee name removed]
Hoffmann-La Roche Limited
7070 Mississauga Road
Mississauga, Ontario
L5N 5M8

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 ROZLYTREK (entrectinib), control number 227517, indicated for: the treatment of adult patients with unresectable locally advanced or metastatic extracranial solid tumours, including brain metastases, that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, and with no satisfactory treatment options. Clinical effectiveness is based on tumour objective response rate (ORR) and duration of response (DOR) in an integrated analysis of efficacy data from three studies in adults (see Clinical Trials). Prior to initiation of ROZLYTREK therapy, NTRK fusion-positive status should be established using a validated test. ROZLYTREK should only be administered under the supervision of a health professional experienced in the use of antineoplastic agents, 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 Hoffmann-La Roche Limited, 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, Roche 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 Hoffmann-La Roche Limited having a form and content satisfactory to Health Canada, as indicated in NOC/c Guidance, including commitments to provide the following: 

    Confirmatory Studies

    • Submit the final report as an SNDS-C, from the first 54 patients with neurotrophic tyrosine receptor kinase (NTRK)-fusion solid tumours enrolled across the ALKA, STARTRK-1, and STARTRK-2 studies to verify and describe the clinical benefit and further characterize the duration of response in patients who achieved a complete or partial response to entrectinib. All responding patients will be followed for at least 2 years from the onset of response or until disease progression, whichever comes first. Duration of response will be assessed by independent central review.
    • Submit the final report as an SNDS-C, from ongoing and proposed trials conducted to verify and describe the clinical benefit of entrectinib, through more precise estimation of the overall response rate and mature response duration per independent review assessment, in adult patients with unresectable locally advanced or metastatic extracranial solid tumours, including brain metastases, that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, and with no satisfactory treatment options. A sufficient number of patients will be evaluated to more precisely characterize response and durability of response for each of the following tumour types: colorectal cancer, gynecological cancers, and melanoma. A minimum of 40 patients with cancers other than pediatric solid tumours, colorectal cancer, central nervous system cancers, gynecological cancers, melanoma, soft tissue sarcoma, non-small cell adenocarcinoma lung cancer, mammary analogue secretory carcinoma, and secretory breast cancer will also be studied. Overall response rate and duration of response will be assessed by independent central review and all responding patients will be followed for at least 12 months from the onset of response.

    Other Studies

    • Determine functional activation or inhibition of off-target receptors, transporters, and/or channels that, at concentrations of 10 µM, showed greater than 50% inhibition by entrectinib or M5 in the secondary pharmacology studies submitted in the NDS. As part of an integral safety assessment, include EC50 or IC50 data for target receptors, transporters, and channels that are still significantly affected at a concentration less than 1 µM, particularly those involved in suicidal intent and behavior, as described in Muller et al., 2015.Footnote 1
    • Submit integrated safety analyses and supporting data from an adequate number of patients enrolled in clinical trial(s) designed to characterize the cardiac risks and its sequelae in patients exposed to entrectinib with reasonable precision; to identify risk factors for development of these sequelae; and to support labeling instructions for dose modification and monitoring. The design of the trial should include sufficient cardiac monitoring to achieve these objectives.
    • Submit integrated safety analyses and supporting data from an adequate number of patients enrolled in clinical trial(s) designed to characterize the risk of fractures and its sequelae in patients exposed to entrectinib with reasonable precision; to identify risk factors for development of these sequelae; and to support labeling recommendations to mitigate the risk of skeletal fractures. The design of the trial should include sufficient bone monitoring to achieve these objectives, including but not limited to initial and serial assessment of bone mineral density (BMD) with dual x-ray absorptiometry (DXA) scans, and markers of bone formation, bone resorption, and calcium metabolism.
    • 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 or for a minimum of 3 years following marketing in Canada, whichever is later. 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.
      4. Implement and maintain the Risk Management Plan (RMP) in accordance with the published Health Canada Guidance.
  3. 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 ROZLYTREK.

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

JPS/oh 

Footnotes

Footnote 1

Muller PY, Dambach D, Gemzik B, et al. Integrated risk assessment of suicidal ideation and behavior in drug development. Drug Discovery Today 2015;20:1135-1142.

Return to footnote 1 referrer

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