Vitrakvi - 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: E213708

[employee name removed]
[employee titled removed]
Bayer Inc.
2920 Matheson Blvd East
Mississauga, Ontario
L4W 5R6

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 VITRAKVI (larotrectinib), control number 219998, indicated for: the treatment of adult and pediatric patients with solid tumours that have a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion without a known acquired resistance mutation; are metastatic or where surgical resection is likely to result in severe morbidity; and have no satisfactory treatment options,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 Bayer 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, Bayer 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 Bayer Inc., having a form and content satisfactory to Health Canada, as indicated in NOC/c Guidance, including commitments to provide the following:

   Confirmatory Studies

   • The final report from the 73 patients (extended Primary Analysis Set) with NTRK-fusion solid tumours enrolled across Study LOXO-TRK-14001, Study LOXO-TRK-15002 (NAVIGATE), and Study LOXO-TRK-15003 (SCOUT), to further characterize the duration of response in patients who achieved a complete or partial response to larotrectinib. All responding patients will be followed for at least 2 years from the onset of response and duration of response will be assessed by independent central review.
   • The final report from ongoing and proposed trials conducted to verify and describe the clinical benefit of larotrectinib, through more precise estimation of the overall response rate and mature response duration per independent review assessment, in adult and pediatric patients with solid tumours that have a NTRK-gene fusion and without a known acquired resistance mutation; are metastatic or where surgical resection is likely to result in severe morbidity; and have no satisfactory treatment options. A sufficient number of patients will be evaluated to characterize response and durability of response for each of the following tumour types: colorectal cancer, non-small cell lung cancer, central nervous system tumours, and melanoma. A minimum of 40 patients with cancers other than colorectal cancer, non-small cell lung cancer, central nervous system tumours, melanoma, soft tissue sarcoma, thyroid cancer, infantile fibrosarcoma, and salivary cancers (e.g., breast cancer, gastrointestinal stromal tumours, cholangiocarcinoma, biliary tract cancers) 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.

   The timelines for these studies should be included in the Letter of Undertaking. Indicate the earliest anticipated availability of the data.

   Additional Studies

   • Results of the [trial identifier removed] of larotrectinib which will include a sufficient number of pediatric patients with NTRK-fusion solid tumours to evaluate the potential serious risk of adverse long-term effects of larotrectinib on the growth and development of pediatric patients. Patients will be evaluated for growth and developmental milestones using age-appropriate screening tools and undergo neurological examination at appropriate intervals (for example, every six months) until larotrectinib is discontinued or for minimum of five years, whichever occurs first. Evaluations should include a neurologic exam, developmental milestone assessment, Karnofsky/Lansky score, growth as measured by weight and height, height velocity, height standard deviation scores (SDS), age at adrenarche if applicable (males), age at menarche if applicable (females), and Tanner Stage.

   The timelines for this additional study should be included in the Letter of Undertaking. Indicate the earliest anticipated availability of the data.

   Post Market Safety Monitoring Studies

   • 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.
   • 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.
   • 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.
   • Implement and maintain the Risk Management Plan (RMP) in accordance with the published Health Canada Guidance.
3. A draft of the Product Monograph 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 VITRAKVI.
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 VITRAKVI.

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 toGuidance Document: Notice of Compliance with Conditions (NOC/c)] with the requested informationwithin 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 the Office of Submissions and Intellectual Property, Therapeutic Products Directorate, Health Canada, Finance Building, 101 Tunney's Pasture Driveway, Address Locator 0201A1, Ottawa, Ontario, K1A 0K9.

Yours sincerely,

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

JPS/or