Qualifying Notice for Strensiq

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

File #: 9427-A2454\1-23

June 30, 2015

[employee name removed]
Associate Director, Regulatory Affairs
Alexion Pharma Canada
3100 Rutherford Road, Suite 300
Vaughan, Ontario, L4K 0G6
Facsimile: 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 STRENSIQ (asfotase alfa), Control Number 179340, filed by Alexion Pharma Canada on behalf of Alexion Pharma International Sarl, indicated for the enzyme replacement therapy for patients with confirmed diagnosis of paediatric-onset hypophosphatasia, 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 International Sarl, 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 International Sarl consents to the posting of the NOC/c-QN on Health Canada's web site.

  2. A draft Letter of Undertaking signed by the Chief Executive Officer, or designated signing authority, of Alexion Pharma International Sarl, 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:

    • Confirmatory Studies

      By November 2017, submit as SNDS-c the following:

      1. The final Clinical Study Report (CSR) for studies ENB-006-09/ENB-008-10 entitled : ENB-006-09: "A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Historical Control Study of the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of ENB-0040 (Human Recombinant Tissue-Nonspecific Alkaline Phosphatase Fusion Protein) in Children with Hypophosphatasia (HPP)" and ENB-008-10 "Extension Study of Protocol ENB-006-09 Evaluating the Long-Term Safety and Efficacy of ENB-0040 (Human Recombinant Tissue-Nonspecific Alkaline Phosphatase Fusion Protein) in Children with Hypophosphatasia (HPP)".

        In addition, these studies should provide efficacy and safety data in patients who will be reaching 13 to 18 years of age by the time of the study completion.

      2. The final CSR of completed Study ENB-010-10 entitled: "An Open-Label, Multicenter, Multinational Study of the Safety, Efficacy, and Pharmacokinetics of Asfotase Alfa (human recombinant tissue-nonspecific alkaline phosphatase fusion protein) in Infants and Children ≤ 5 Years of Age with Hypophosphatasia (HPP)".

      3. The final CSR of completed Study ENB-009-10 entitled" A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Concurrent Control Study of the Safety, Efficacy, and Pharmacokinetics of ENB-0040 (Human Recombinant Tissue-Nonspecific Alkaline Phosphatase Fusion Protein) in Adolescents and Adults with Hypophosphatasia (HPP)".

      4. The final CSR of completed Studies ENB-002-008/ ENB-003-08 entitled: ENB-002-008 "A multicenter, open-label study of the safety, tolerability, and pharmacology of Study ENB-0040 (Enobia's human recombinant tissue-nonspecific alkaline phosphatase fusion protein) in up to 10 severely affected patients with infantile hypophosphatasia (HPP)" and ENB-003-08 entitled: "Extension study of ENB-0040 (human recombinant tissue-nonspecific alkaline phosphatase fusion protein) in severely affected infants and young children with hypophosphatasia (HPP)".

      5. In order to evaluate pharmacokinetic profile of asfotase alfa in adult at the authorised dose, to demonstrate the dose response on plasma inorganic pyrophosphate (PPi) and pyridoxal 5-phosphate (PLP) and to explore evidence of clinical benefit, a PK/PD study of asfotase alfa in adult patients with HPP should be conducted and CSR should be submitted to BGTD as an SNDS-c (as per commitment to the EMEA).

    • Progress Reports of Confirmatory Trials and Other Ongoing Trials

      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, 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 the Alexion Pharma International Sarl and Health Canada must be outlined in the Letter of Undertaking.

      2. Safety updates for ALL on-going clinical trials with STRENSIQ (asfotase alfa).

      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 STRENSIQ (asfotase 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.

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

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

    • Additional information

      1. Copies of any marketing authorizations or other regulatory actions for STRENSIQ (asfotase 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 to the BGTD with STRENSIQ (asfotase alfa) Medical educational materials.

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

      4. 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. A draft "Dear Health Care Professional Letter" detailing the issuance of a Notice of Compliance under the NOC/c Policy for STRENSIQ (asfotase alfa) indicated for the enzyme replacement therapy for patients with confirmed diagnosis of paediatric-onset hypophophatasia, as per section 5.3 and Appendix 3 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).

  4. A draft of the 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 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), and the first page, and the start of the Consumer Information section, disclosing the nature of the authorization granted for STRENSIQ (asfotase alfa) and the need to conduct confirmatory 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 file number 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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