Qualifying notice for Tepmetko

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

Dossier ID: e228809

[employee name removed]
[employee title removed]
EMD Serono, a Division of EMD Inc., Canada
2695 North Sheridan Way, Suite 200
Mississauga, Ontario
L5K 2N6

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 Tepmetko (tepotinib), Control Number 242300, for the indication of the treatment of adult patients with locally advanced unresectable or metastatic non-small cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition (MET) tyrosine kinase receptor exon 14 skipping alterations, 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 EMD Serono, a Division of EMD Inc., Canada 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, EMD Serono, a Division of EMD Inc., Canada 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 EMD Serono, a Division of EMD Inc., Canada having a form and content satisfactory to Health Canada, as indicated in NOC/c Guidance, including commitments to provide the following:

Confirmatory studies

Submit, as a SNDS-c, the final reports including datasets from clinical studies to confirm and further characterize the clinical benefit of tepotinib for the treatment of patients with non-small cell lung cancer (NSCLC) harbouring MET exon 14 skipping alterations who are treatment-naïve and who have previously received systemic therapy, by providing a more precise estimation of the blinded independent central review-assessed overall response rate and duration of response. This report will contain data from patients with NSCLC harbouring MET exon 14 skipping alterations; data from at least 130 patients who are treatment naïve, after all responders have been followed for at least 12 months from the date of initial response (or until disease progression, whichever comes first); and from at least 143 patients who have been previously treated with systemic therapy, after all responders have been followed for at least 6 months from the date of initial response (or until disease progression, whichever comes first).

1. EMD Serono, a Division of EMD Inc., Canada should provide the approximate date of completion of the confirmatory study and should commit to an approximate date of filing of the SNDS-c.
2. EMD Serono, a Division of EMD Inc., Canada should acknowledge that the indication authorized under the NOC/c pathway for Tepmetko under control # 242300 can be withdrawn or revised if the aforementioned results do not confirm clinical benefit of tepotinib for the treatment of patients with non-small cell lung cancer (NSCLC) harbouring MET exon 14 skipping alterations who are treatment-naïve and who have previously received systemic therapy.

Additional studies requested by Health Canada

1. Conduct a drug interaction study to evaluate single dose pharmacokinetics when tepotinib is administered concomitantly with a strong CYP3A4 inducer and moderate CYP2C8 inducer to assess the magnitude of decreased drug exposure and determine appropriate dosing recommendations.
   1. EMD Serono, a Division of EMD Inc., Canada should provide the approximate date of completion of the confirmatory study and should commit to an approximate date of filing of the SNDS-c.
2. Conduct a drug interaction study to evaluate the effect of itraconazole on the single dose pharmacokinetics of tepotinib to assess the magnitude of increased drug exposure and determine appropriate dosing recommendations when tepotinib is administered concomitantly with a strong CYP3A4 and P-gp inhibitor.
   1. EMD Serono, a Division of EMD Inc., Canada should provide the approximate date of completion of the confirmatory study and should commit to an approximate date of filing of the SNDS-c.

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.

Additional information

1. Receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to Tepmetko (tepotinib) 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 Tepmetko (tepotinib), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
4. Copies of any current marketing authorizations for Tepmetko (tepotinib) 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 guidance documents on the Management of Drug Submissions and Applications 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 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/ha