Qualifying Notice for Tasigna

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Contact: Bureau of Metabolism, Oncology and Reproductive Sciences

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

9427-N0846-305

May 17, 2011 (signed)

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

Dear [employee name removed]:

This Notice of Compliance with Conditions (NOC/C) - Qualifying Notice, issued in accordance with the Health Canada NOC/c Policy, is to advise you that information submitted in support of the Supplement to a New Drug Submission (SNDS) for TASIGNA (nilotinib hydrochloride monohydrate), Control Number 138440, qualifies to be considered for authorization, under the NOC/c Policy. In keeping with the provisions outlined in the NOC/c Policy, the following additional information is required to complete the assessment:

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 Policy.  Please be reminded that in agreeing to accept an NOC under the NOC/c Policy, 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, including commitments to supply the following:

Confirmatory Studies:

1. Second Interim Report for pivotal Phase III Study A2303 ENESTnd (based on 24 month follow-up) which is available as of February 2011.
2. Final Clinical Study Report for pivotal Phase III Study A2303 ENESTnd (based on 5 year follow-up) planned in March 2014. The dataset should provide final results showing the safety and efficacy for the TASIGNA 300 milligram (mg) two times per day (bid) arm, TASIGNA 400 mg bid arm, and Gleevec 400 mg one time per day (qd) arm, including the primary endpoint, major molecular response (MMR), and all secondary endpoints as per the study protocol.  Population pharmacokinetics (PK) data should also be included.
   
   This requirement is based on the finding (from the IRIS study with Gleevec) that the highest frequency of progression events were reported within 3 years of treatment with Gleevec, and the need to investigate whether a similar trend might occur with TASIGNA. It is expected that longer follow-up data will provide this information. It is expected the product monograph will reflect the updated efficacy data and patient numbers, when available.
   1. Subanalysis should include a mutational data analysis (in patients who failed treatment with TASIGNA) of the frequency, nature and time course of development of Bcr-Abl mutations which confer resistance to TASIGNA. This requirement is based on the reported 15% failure rate in patients treated with Gleevec (IRIS study) and commonly associated with the development of mutations in the Bcr-Abl gene and the uncertainty regarding the potential for a similar trend in patients treated with TASIGNA.

Post Market Safety Monitoring Studies:

1. Reports of serious unexpected and expected Adverse Drug Reactions (ADRs) that occurred within Canada and outside of Canada should be forwarded within 15 calendar days to Health Canada in accordance with the Guidance for Industry: Notice of Compliance with Conditions.
2. Periodic Safety Update Reports (PSUR-Cs) requirements referenced in a manner deemed appropriate by the review division. Semi-annual PSUR-Cs in a manner deemed consistent with E2C International Conference on Harmonisation (ICH) Guidelines, until the conditions for the newly diagnosed philadelphia chromosome positive chronic myeloid leukemia in chronic phase (CML-CP) NOC/c have been fulfilled. The semi-annual PSUR-Cs will include cumulative data on relevant unlisted and listed adverse reactions (ARs) (including sudden cardiac deaths) from the date of Marketing ([that is (i.e.)] International Birth Date, July 25, 2007) to the time of the report.
3. A draft of the "Dear Health Care Professional Letter" detailing the issuance of a Notice of Compliance under the NOC/c Policy for TASIGNA for the indication of "the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (CML) in chronic phase".
4. A draft of the Product Monograph that is consistent with the requirements outlined in Section 5.2.1of the Notice of Compliance with Conditions Guidance.Please note that, if applicable, a boxed text must 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 TASIGNA and the need to conduct confirmatory studies.

Other Comments:

1. For information purposes only, you are requested to submit to Health Canada a copy of the final accepted publication, when available [Jennings, Smith, Halling, Persons and Kamel-Reid. Design and Analytical Validation of BCR-ABL1 Quantitative RT-PCR Assay for Monitoring Minimal Residual Disease (submitted in March 2011)].

I wish to advise you that this Qualifying Notice is being issued in accordance with Health Canada's guidance and policy on the Management of Drug Submissions and Notice of Compliance with Conditions, respectively. Sponsors are instructed to submit a complete response (refer to Guidance for Industry; Notice of Compliance with Conditions) to the outstanding 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 Submission and Information Policy Division, Therapeutic Products Directorate, Finance Building, 101 Tunney's Pasture Driveway, Address Locator 0201A1, Tunney's Pasture, Ottawa, Ontario, K1A 0K9.

Enclosed, please find the reviewer reports for this submission.

Yours sincerely,

Original signed by

Supriya Sharma, MD MPH FRCPC
Director General