Qualifying Notice - Replagal

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

December 13, 2016

Dossier ID: HC6-024-E133485
Control #: 188407
Document #: 1162892

[employee name removed]
Director, Global Regulatory Affairs
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421
Fax: 781-482-2958

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 Replagal (agalsidase alfa), Control Number 188407, indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry Disease, 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 Shire Human Genetic Therapies, 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, Shire Human Genetic Therapies, 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 Shire Human Genetic Therapies, Inc., 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
   1. conduct a new clinical study in patients with Fabry disease. The proposed study protocol SHP-REP-401 provided in the submission is acceptable, in principle; however, amend the protocol to include ERT-naive patients at the recommended dose of 0.2 mg/kg every other week (EOW), to confirm efficacy. Prior to conducting the trial, obtain Health Canada/BGTD concurrence regarding the clinical trial design, efficacy endpoints, sample size, statistical analysis methods, Patient Reported Outcomes (PRO) and Quality of Life (QoL) indicators. Submit Protocol SHP-REP-401 as a Clinical Trial Application (CTA).
   Progress Reports of Confirmatory Trials and Other Ongoing Trials
   2. provide an up-to-date benefit/risk analysis for Replagal across all markets and regulatory agencies within six months.
   3. on an annual basis, within 60 calendar days of the market authorization anniversary or a date agreed upon at the time of the issuance of the market authorization, status reports on the progress of the ongoing confirmatory trial, 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 Shire Human Genetic Therapies, Inc. and Health Canada must be outlined in the Letter of Undertaking.
   
   Safety Monitoring
   4. report all serious Adverse Reactions (AR) that occur in Canada and all serious unexpected ARs that occur outside of Canada within 15 days to the Marketed Health Products Directorate. Adverse Events (AE) and AR reports on marketed drugs occurring as part of the confirmatory trial subject to clinical trial applications, as outlined in the Letter of Undertaking, must be sent to the Biologics and Genetic Therapies Directorate. 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).
   5. Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Reports-C for NOC/c Products (PSUR-Cs or PBRER-Cs) on an annual basis until such time as conditions associated with the market authorisation are removed. PSUR-Cs/PBRER-Cs should be prepared in accordance with the E2C(R1) and E3C(R2) ICH Guideline, including format and content, as per section 3.4.2 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
   6. 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).
   
   Additional information
   7. receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to Replagal (agalsidase alfa) authorized under the NOC/c policy as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
   8. 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).
   9. an up-to-date, complete listing of ongoing additional clinical trials related to Replagal (agalsidase alfa, appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
   10. copies of any marketing authorizations or other regulatory actions for Replagal (agalsidase alfa) from any other drug regulatory authority as per Section 4.6 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
3. 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, disclosing the nature of the authorization granted for Replagal (agalsidase alfa) and the need to conduct a confirmatory study.

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