Notice of Compliance with Conditions - Qualifying Notice Kanuma

Biologics and Genetic Therapies Directorate
100 Eglantine Driveway
Address Locator #0601C
Ottawa, Ontario
K1A 0K9

November 07, 2017

Dossier ID: HC6-024-e199066
Control #: 204085
Document #: 1264334

[employee name removed]
Manager, Regulatory Affairs
Alexion Pharma Canada
3100 Rutherford Road, Suite 300
Vaughan, Ontario, L4K 0G6
Fax: 905-553-2995

Notice of Compliance with Conditions - Qualifying Notice

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 New Drug Submission (NDS) for Kanuma (sebelipase alfa), Control Number 204085, indicated for the treatment of lysosomal acid lipase deficiency (LALD), qualifies to be considered for authorisation 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 Alexion Pharma GmbH, 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, Alexion Pharma GmbH 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 Alexion Pharma GmbH, having a form and content satisfactory to Health Canada, as indicated in the Guidance Document: Notice of Compliance with Conditions (NOC/c), including commitments to provide the following:

    I. Additional study

    Lysosomal acid lipase deficiency (LALD) is a rare disease. Traditional confirmatory outcome studies would not be feasible in a rare disease population. However, to support a favourable benefit/risk profile of Kanuma in this population, the following data are still required:

    • The long term prospective clinical outcomes of Kanuma treated infants who survived beyond 12 months.
    • The long term prospective clinical outcomes of Kanuma treatment in children and adults with LALD including but not limited to progression of liver and cardiovascular diseases and changes in anthropometric assessments (e.g. length/height z-scores and weight z-scores).
    • The impact of Kanuma on the liver. The assessments should include liver imaging studies, liver biopsies, liver synthetic function evaluation and provide data on the clinical progression of liver disease (e.g. delay or reversal liver disease or progression to end stage liver disease [e.g. utilising the Model for End-Stage Liver Disease {MELD} score], receipt of liver transplantation and fatal outcomes).
    • The impact of improving dyslipidemia on cardiovascular outcomes including incidence rates of non-fatal stroke, myocardial infarction and cardiovascular death.
    • The impact of Kanuma on spleen related complications (splenomegaly, anemia).
    • Additional evaluations for dosing regimens and dosing modification criteria.
    • Long term safety of Kanuma including occurrence of serious hypersensitivity reactions (e.g. anaphylaxis), immunogenicity and data on neutralizing antibodies.

    Similar to the US-FDA commitment, Health Canada/BGTD requires a study to collect the above data in order to support a favourable risk/benefit profile of Kanuma use in the long term. Eligible patients will be enrolled over an initial 3-year period and followed by a minimum of 10 years from the time of enrollment or until death whichever comes first. This study may be conducted as a separate study or a sub-study within the LALD registry.

    Prior to conducting the study, submit your proposed study to BGTD, Clinical Evaluation Division, Autoimmune-Endocrinology (CED-AE) for comments regarding the clinical trial design, efficacy endpoints, sample size, statistical analysis method…etc. After receiving agreement from CED-AE on the study, submit the protocol as a Clinical Trial Application (CTA).

    In light of the rarity of the disease, Health Canada would accept the sponsor’s proposal to share the results of the registry commitment made to the US-FDA.

    The final CSR of the above study should be submitted as a SNDS-c by April 30, 2030.

    Progress Reports of Confirmatory Trials and Other Ongoing Trials

    II. The CSRs of ongoing trials

    In addition, the following study reports are required to be submitted as a SNDS-c by December of 2019 in order to provide additional data (e.g. children 2-4 years of age), to support the favourable risk/benefit profile of Kanuma and to update the prescribing information in the initial Product Monograph.

    1. Estimated completion by July 2018, the final CSR for Study LAL-CL04: a Phase 2, single-arm, open-label extension for subjects who completed Study LAL-CL01 (Phase 1/2, single arm, open-label, dose escalation PK and PD study in adults with LALD.

    2. Estimated completion by December 2018:
      1. the final CSR for the pivotal study LAL-CL02: a Phase 3, randomised, double-blind (20 weeks), placebo-controlled trial; followed by an open-label extension (up to 130 weeks) study in children (> 4 years) and adults with LALD and ALT elevation (> 1.5 ULN)
      2. The final CSR for the pivotal study LAL-CL03: a Phase 2/3, single-arm, open-label study in infants with LALD and growth failure diagnosed before the first 6 months of age.
      3. the final CSR for Study LAL-CL06: an open-label, Phase 2/3 study in pediatric and adult subjects with LALD who are not eligible for other concurrent Kanuma clinical pivotal studies due to age (2-4 years age), advanced liver disease, previous treatment by HSCT or liver transplantation or less common disease manifestations.

    3. Estimated completion by July 2019, the final CSR for Study LAL-CL08: an open-label, Phase 2 study in infants less than 8 months of age with rapidly progressive LALD. The objectives of this study are to evaluate hepatic function over time up to 3 years and survival at 12 months, and to assess the long term safety of Kanuma, specifically hypersensitivity reactions and anti-drug antibodies’ impact on efficacy and safety.

    III. In addition to the above CSRs, the following assessments are to be submitted in the SNDS-c by December 2019:

    1. Provide a table showing the completion of the above ongoing studies and whether or not they have met their primary endpoint(s) and key secondary endpoints. If they were not completed, submit the rationale for the delay and the revised completion date. If they failed to meet the primary and key secondary endpoints, provide the rationale for failing to meet the endpoints.

    2. An evaluation of the benefit-risk profile of KANUMA based on the data from the CSRs.

    3. A determination on any change to the benefit-risk profile of KANUMA in LALD populations. Infants with rapidly progressive LALD and children/adults with LALD are to be evaluated separately.

    4. Identify new safety signals. Provide assessment determining whether the risk mitigation strategy remains adequate for safe use of KANUMA or additional risk mitigation strategies are required and the implementation plan for these additional strategies.

    IV. Progress Reports of Ongoing Trials

    To further characterise the long term safety profile (including hypersensitivity/anaphylaxis reactions immunogenicity, cardiovascular disorders, etc.) of KANUMA in infants, children and adults; and to detect treatment differences between 2-4 years of age group and other age groups, address the following:

    1. On an annual basis, within 60 calendar days of the market authorization anniversary or a date agreed upon at the time of issuance of market authorization, provide status reports on the progress of ongoing confirmatory trials, as per section 3.2 and Appendix 4 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The details of the requirements for filing and termination of the annual status report as agreed upon by Alexion Pharma Canada Inc. and Health Canada must be outlined in the Letter of Undertaking.

    2. Include safety updates for ALL on-going clinical trials with KANUMA (sebelipase alfa) in the above status reports.

    3. Provide to Health Canada any other analyses that have been designated as post-marketing commitments to other international agencies and comply with the notification and reporting of specific issues of concern as per Section 3.3.3 of the Guidance for Industry, Notice of Compliance (NOC/c).

    Safety Monitoring

    1. Report of all serious Adverse Reactions (AR) that occurred in Canada and all serious unexpected ARs that occurred outside of Canada should be forwarded within 15 days to the Marketed Health Products Directorate (MHPD). Adverse Events (AE) and AR reports on marketed drugs occurring as part of confirmatory trials subject to clinical trial applications, as outlined in the Letter of Undertaking, must be sent to the Biologics and Genetic Therapies Directorate (BGTD). Reporting must be conducted as per section 3.4.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c) and in accordance with current regulations and guidelines (e.g. Guidance for Industry: Reporting Adverse Reactions to Marketed Health Products and the Guidance for Clinical Trial Sponsors: Clinical Trial Applications).

    2. Submit to the BGTD Periodic Benefit-Risk Evaluation Reports- for NOC/c Products (PBRER-Cs) for KANUMA (sebelipase alfa) on an annual basis until such time as conditions associated with the market authorisation are removed. The PBRER-Cs should be prepared in accordance with the E2C ICH Guideline, including format and content, as per section 3.4.2 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).

    3. Implement the Risk Management Plan (RMP) in Canada and provide any updates to the Canadian RMP when available. Please note that the Canadian addendum is to be submitted for MHPD review with the next RMP.

    4. Comply with the notification and reporting of specific issues of concern as outlined in Section 3.4.4 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).

    5. Establish a patient registry and provide annual interim reports and the final report to the MHPD.

    Additional information

    1. Provide copies of any marketing authorizations or other regulatory actions for KANUMA (sebelipase alfa) from any other drug regulatory authority as per Section 4.6 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).

    2. Submit a copy of the educational materials for KANUMA (sebelipase alfa) to MHPD for review.

    3. Receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to KANUMA (sebelipase alfa) authorized under the NOC/c policy as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).

    4. Provide 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).

    Work with Health Canada to finalise KANUMA Product Monograph that is consistent with the requirements outlined in sections 5.2.1 and 5.2.2 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). Please note that boxed text must appear on the cover page, at the beginning of each major section of the Product Monograph (Parts I, II and III), and the first page, and the start of the Consumer Information section, disclosing the nature of the authorization granted for KANUMA (sebelipase alfa) and the need to conduct additional studies.

I wish to advise you that this Qualifying Notice is being issued in accordance with Health Canada's guidances on the Management of Drug Submissions and Notice of Compliance with Conditions, respectively. Sponsors are instructed to submit a complete response (refer to Guidance Document: Notice of Compliance with Conditions) to the outstanding information within 30 calendar days of the date of this letter.

Your response to the above should be submitted with a copy of this letter to the Office of Submissions and Intellectual Property. In order to facilitate and ensure proper processing of your response, please include a revised Submission Certificate, quoting the product name, assigned dossier ID, and control number of the original submission, and address your response to:

Director, Office of Submissions and Intellectual Property
Therapeutic Products Directorate
Finance Building,
101 Tunney's Pasture Driveway
Address Locator 0201A1
Ottawa, Ontario, K1A 0K9

Attention: Office of Regulatory Affairs
Biologics and Genetic Therapies Directorate

Sincerely,

Catherine Parker
Director General

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