Bosulif - Notice of Compliance with Conditions - Qualifying Notice


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

Dossier Identifier: E141793
Control No.: 152211

January 10, 2014

[employee name removed]
Manager, Regulatory Affairs
Pfizer Canada Inc.
17,300 Trans Canada Highway
Kirkland, Quebec, H9J 2M5
Direct: (514) 426-7047
Fax: (514) 426-6824

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 BOSULIF (bosutinib), Control Number 152211, for the indication of, "the treatment of chronic, accelerated, or blast phase Ph+ CML in adult patients with resistance or intolerance to prior tyrosine kinase inhibitor therapy, and for whom subsequent treatment with imatinib, nilotinib, and dasatinib is not clinically appropriate", 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 Pfizer 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, Pfizer Canada Inc. consents to the posting of the NOC/c-QN on Health Canada's website.
  2. A draft Letter of Undertaking signed by the Chief Executive Officer or designated signing authority of Pfizer Canada Inc., having a form and content satisfactory to Health Canada, as indicated in NOC/c Guidance, including commitments to supply the following:

Confirmatory Studies

  • To confirm the long-term clinical benefit of BOSULIF, the Sponsor should submit final analysis of efficacy and safety data from Study 200-WW with minimum 48 months follow-up for all Ph+CP CML patients previously treated with imatinib. For Ph+ CP CML patients previously treated with imatinib and at least one additional TKI and the advanced phase patients, the final study report will include more than 36 months, but less than 48 months efficacy and safety data, since patients judged to be deriving clinical benefit from bosutinib are enrolled in the bosutinib extension study B1871040. Special emphasis should include analyses of renal and cardiovascular function (including ECG analysis and multi-unit gated analysis (MUGA)). The final clinical study report is expected in June 2015.
  • To confirm the long-term safety of BOSULIF, the Sponsor should submit analysis of safety data (including ECG and MUGA analyses) from Phase 3 Study 3000-WW with minimum 48 months follow-up for all patients. It is expected that patients will be followed for a maximum 6 years, with the anticipated CSR planned to be available by the end of 2015.

Post Market Safety Monitoring Studies

  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 safety summary reports 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" detailing the issuance of a Notice of Compliance in accordance with the NOC/c Guidance for BOSULIF (bosutinib) for the indication of the treatment of chronic, accelerated, or blast phase Ph+ CML in adult patients with resistance or intolerance to prior tyrosine kinase inhibitor therapy, and for whom subsequent treatment with imatinib, nilotinib, and dasatinib is not clinically appropriate.
  4. A draft of Part III Consumer Information section of the Product Monograph outlining the potential risks, benefits and side effects of BOSULIF (bosutinib) for the indication of the treatment of chronic, accelerated, or blast phase Ph+ CML in adult patients with resistance or intolerance to prior tyrosine kinase inhibitor therapy, and for whom subsequent treatment with imatinib, nilotinib, and dasatinib is not clinically appropriate.
  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 BOSULIF (bosutinib) for the indication of the treatment of chronic, accelerated, or blast phase Ph+ CML in adult patients with resistance or intolerance to prior tyrosine kinase inhibitor therapy, and for whom subsequent treatment with imatinib, nilotinib, and dasatinib is not clinically appropriate.

The Bureau requests the Sponsor to submit the following studies (below) when available and as per the instructions below. These studies are not considered commitments as part of the NOC/c and should not be included in the Letter of Undertaking (LOU). The Sponsor should submit these studies only in the event that the results change the benefit:risk profile. If/when submitting this information, the Sponsor should clearly indicate how the submitted study data will affect the product monograph:

  • Food effect study (high fat versus low fat). The current proposed labelling includes the recommendation to administer Bosulif 500 mg tablet with meal (i.e. standard medium-calorie meal). The Bureau is aware of a new food effect Study B1871035 entitled 'A Phase 1, Open-Label, Randomized, Single-Dose, 2-Cohort, 2-Way Crossover Bioequivalence Study to Compare the Bosutinib Clinical Tablet and Clinical Capsule and Investigate Food Effect on Bosutinib Commercial Formulation in Healthy Subjects' to allow comparison of low-fat and high-fat meals on bioavailability of Bosulif. Should the Sponsor wish to revise the current wording to further specify the type of meal (high fat versus low fat) with Bosulif dosing, evidence based on the results of this study would need to be submitted (expected in May 2014).
  • Clinical drug-drug interaction study with a moderate CYP3A4 inhibitor study (e.g. Erythromycin) to evaluate the effect on the pharmacokinetics of Bosulif. The final study report is expected in March 2015.
  • Clinical drug-drug interaction study to evaluate inhibition of P-gp. In vitro data suggest the possibility of drug-drug interactions with concomitant P-gp substrates. The final clinical study report is expected by the end of 2015.
  • Post-hoc analysis of the incidence of diarrhea after study patients switch to the commercial formulation. A high incidence of diarrhea was reported in the clinical studies, thus the potential for QT prolongation due to hypokalemia and hypomagnesemia. The final report is expected at the end of 2015.
  • Clinical study to evaluate the absolute bioavailability of the commercial formulation of Bosulif tablet in fed state in healthy subjects. Absolute bioavailability has not been established. The final study report is expected at the end of 2015.
  • If the analyses which are outlined in the Special Safety Concern letter become relevant to the market authorized indication for Bosulif, please confirm that these data will be provided in a submission, and confirm whether there is an effect on labelling.
  • The Sponsor indicated that there is ongoing safety review of all reported events due to commercial use of Bosulif in patients with Ph+CML in the United States and European Union. Upon planned completion of Study 200-WW and Study 3000-WW, patients undergoing active treatment with bosutinib will be allowed entry into a planned extension protocol (Study B1871040) which will enable long-term monitoring of safety signals.
  • In future RMP submission, the Sponsor should address the following issues which have been raised by MHPD:

    With regard to the RMP, it is recommended that Pfizer:

    • Update the RMP and Canada Specific Addendum as appropriate when further information becomes available from planned or ongoing studies, as well a post-marketing information
    • Clarify and/or modify the RMP and the PM regarding the use of bosutinib in patients with hepatic impairment [contraindicated in the RMP] so that the documents are accurate and consistent with each other
    • Provide a plan for the evaluation of the effectiveness of the RMP in accordance with EMA guidelines. Health Canada recommends that Pfizer specify outcome measures to assess the effectiveness of the risk minimization activities, including details of the implementation of the investigation adapted to the Canadian context.

With regard to future reporting, the recommendations made in the initial review of the bosutinib RMP (Version 1.1 and associated documents) continue to be recommended:

  1. Include all important identified risks, important potential risks, and important missing information as "Designated Medical Events", as well as data pertaining to special patient populations in the first Periodic Safety Update Report (PSUR).
  2. It is also expected that PSURs will provide:
    • A more detailed description of the intended post-hoc analysis of diarrhea, along with the most recent available results.
    • Case narratives reporting the use of bosutinib by children (under the age of 20), regardless of the occurrence of adverse reactions.
    • Case narratives reporting exposure to bosutinib through pregnancy and lactation. Details regarding the trimester during which exposure occurred and the outcome of the pregnancy should be provided.
    • Case narratives reporting the use of bosutinib by patients with background diseases, regardless of the occurrence of adverse reactions.
  3. The pharmacovigilance plan proposed to monitor the occurrence of the important potential risk "Tumour Lysis Syndrome" should be expanded to include the monitoring of events such as hyperkalemia, hyperphosphatemia, hyperuricemia, hyperuricosuria, hypocalcemia, and acute renal failure, as these adverse drug reactions could suggest the occurrence of "Tumour Lysis Syndrome".
  4. Pfizer is also requested to submit:
    • The projected timelines for the pediatric study currently postponed.
    • The synopsis of the drug-drug interaction study to evaluate inhibition of P-gp as well as projected timelines for initiation and completion, as well as the Final Clinical Study Report (CSR) as soon as it is available (expected date by end of 2015).
    • The projected timelines for the completion and final CSR for the post-marketing (Phase 4) study to be initiated in 2014 (as per CMHP requirements). This will be a single-arm open-label multi-centre efficacy and safety study of bosutinib in Ph+CML patients previously treated with one or more TKIs and for whom imatinib, nilotinib, or dasatinib are not considered appropriate treatment options (final report expected September 30, 2018).

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 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,

[original signed by]

Barbara J. Sabourin
Director General
Therapeutic Product Directorate

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