Qualifying Notice for Zykadia

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

Revised: February 10, 2015

Original signed: January 30, 2015

Dossier ID: E162920

[employee name removed]
Manager, Drug Regulatory Affairs
Novartis Pharmaceuticals Canada Inc.
385 Bouchard Boulevard
DORVAL, Quebec
H9S 1A9

Notice of Compliance with Conditions - Qualifying Notice

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 ZYKADIA (ceritinib), Control number 175702, indicated as monotherapy for use in patients with anaplastic lymphoma kinase (ALK)-positive locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) who have progressed on or who were intolerant to crizotinib, 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:

Novartis Pharmaceuticals Canada Inc. must submit the following to Health Canada within 30 calendar days of receipt of the NOC/c-QN:

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

Confirmatory Pivotal Studies

1. Study CLDK378A2303, titled "A phase III multicenter, randomized study of oral ceritinib versus standard chemotherapy in adult patients with ALK-rearranged (ALK-positive) locally advanced or metastatic NSCLC who have been treated previously with one chemotherapy regimen (platinum doublet) and crizotinib".
   
   The anticipated trial completion date is December 2017 and the submission of the final CSR is expected by June 2018.
   
   To evaluate the efficacy and safety of the use of ceritinib, the Sponsor should submit the final exposure-response analysis for Progression Free Survival (PFS), response rate, Overall Survival (OS) and safety endpoints utilizing data from this trial.
2. Final CSR from the first-in-human, open-label, Phase 1 study of LDK378 conducted in 304 adult patients with advanced tumors confirmed to have genetic abnormalities in ALK (Study X2101 Final CSR 4Q2016) and the ongoing Phase 1, open-label, dose-escalation and expansion study in Japanese patients with ALK-positive tumors (Study X1101 Final CSR 4Q2017).

Post Market Data

1. 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.
2. Annual developmental and periodic safety update reports (Development Safety Update Reports [DSURs] and Periodic Safety Updated Reports-confirmatory [PSUR/c's]) should be provided to the Therapeutic Products Directorate in a manner deemed consistent with the current Guidance Document: Notice of Compliance with Conditions (NOC/c).
3. A draft of the "Dear Health Care Professional Letter (DHCPL)" detailing the issuance of a Notice of Compliance in accordance with the NOC/c Guidance for ZYKADIA (ceritinib) for the indication:
   
   ZYKADIA™ (ceritinib) is indicated as monotherapy for use in patients with anaplastic lymphoma kinase (ALK)-positive locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) who have progressed on or who were intolerant to crizotinib.
   
   Marketing authorization with conditions was based on a primary efficacy endpoint of objective response rate (ORR) as well as duration of response (DR) in clinical Study CLDK378X2101, based on investigator assessment using RECIST (see CLINICAL TRIALS). There are no available data demonstrating improvement in survival or quality of life with ZYKADIATM.
4. A draft of Part III Consumer Information section of the Product Monograph outlining the potential risks, benefits and side effects of ZYKADIA (ceritinib) for the indication stated in point 3 (above).
5. 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, if applicable, a boxed text should appear on the cover page, at the beginning of each major section of the Product Monograph (Parts I, II and III), the first page, and the start of the Consumer Information section, disclosing the nature of the authorization granted for ZYKADIA (ceritinib) for the indication stated in point #3 (above).

The Bureau also requests the following, which should not be included as commitments in the Letter of Undertaking. When submitting each item below please indicate clearly how the submitted information will affect the Product Monograph:

1. Study CLDK378A2112: A Phase I, multi-center, randomized open label study to assess the systemic exposure and safety of 450 milligrams (mg) ceritinib taken with a low-fat meal and 600 mg Ceritinib taken with a low-fat meal as compared with that of 750 mg ceritinib taken in the fasted state in adult patients with ALK rearranged (ALK-positive) metastatic non-small cell lung cancer. Final Report Submission: Sep-2017
2. Study CLDK378A2110: A phase I, open label, multi-center, single dose study to evaluate the pharmacokinetics of ceritinib in subjects with hepatic impairment compared to subjects with normal hepatic function. Final Report Submission: Jun-2016
3. Study CLDK378A2103: A phase 1 multi-center, open label, drug-drug interaction study to assess the effect of ceritinib on the pharmacokinetics of warfarin and midazolam administered as a two-drug cocktail in patients with ALK-positive advanced tumors including non-small cell lung cancer. Final Report Submission: Mar-2017

Study CLDK378A2113: A phase I open-label, two-period, single-center study to assess the effect of esomeprazole (proton pump inhibitor, PPI) on the PK of ceritinib in healthy subjects. Final Report Submission: Mar-2016

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 informationwithin 30 calendar days of the original signed 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,

Barbara J. Sabourin
Director General

BJS/oh