Qualifying notice for Voxzogo (290788)

Biologic and Radiopharmaceutical Drugs Directorate
100 Eglantine Driveway
LCDC Building
Tunney's Pasture, A.L. 0601C
Ottawa ON K1A 0K9

Dossier ID: e283698
Control number: 290788

[employee name removed]
[employee title removed]
BioMarin International Limited
Shanbally, Ringaskiddy County
Cork, Ireland P43 R298

c/o: [employee name removed] [employee title removed]
BioMarin (UK) Limited
10 Bloomsbury Way
London, United Kingdom WC1 A2SL
Email: [employee email removed]

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 (NDS) for Voxzogo (vosoritide injection), control number 290788, qualifies to be considered for authorization in accordance with the above guidance document for the following indication: Voxzogo (vosoritide for injection) is indicated to increase linear growth in patients with achondroplasia who are 4 months of age and older whose epiphyses are not closed. The diagnosis of achondroplasia should be confirmed by appropriate genetic testing. In keeping with the provisions outlined in the Guidance Document: Notice of Compliance with Conditions (NOC/c), the following additional information is requested to complete the assessment:

1. A letter, signed by the Chief Executive Officer, or designated signing authority of BioMarin International Limited, indicating that you agree to have this submission considered under the Guidance Document: Notice of Compliance with Conditions (NOC/c). Please be reminded that in agreeing to accept a Notice of Compliance (NOC) under the Guidance Document: Notice of Compliance with Conditions (NOC/c), BioMarin International Limited consents to the posting of this NOC/c-QN on Health Canada's website once market authorization has been received.
2. A draft Letter of Undertaking signed by the Chief Executive Officer or designated signing authority of BioMarin International Limited, 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. Submit as an SNDS-c, the final study report for the Study 4134-2 (111-confirm): To measure the effect of vosoritide on final adult height in pediatric subjects with achondroplasia (ACH), whose epiphyses are not closed. The trial should also evaluate disproportionality and bone age as secondary endpoints. The safety endpoints related to the drug (e.g., blood pressure) or to the disease itself that may improve or worsen with long-term treatment (e.g., neurological complications, bone deformities, sleep apnea) should also be included.
2. As Study 4134-2 (111-confirm) is now complete, with a final data cut in October 2025, the sponsor should confirm the expected timeline for finalizing the study report (anticipated by the end of April 2026) and commit to the proposed target date for filing the SNDS-c submission in Canada, currently planned for November 30, 2026 (Response to clinical clarification request dated 2025-11-24). The sponsor should also acknowledge that the indication authorized under the NOC/c pathway for Voxzogo (vosoritide injection) under control # 290788 can be withdrawn or revised, pending the outcome of Study 4134-2 (111-confirm). The decision by BRDD to remove the condition and/or modify the currently proposed indication will depend on the confirmation of clinical outcome benefit (i.e. final adult height) and the demonstration that there are no long-term safety concerns associated with the use of vosoritide in the pediatric subjects older than 4 months of age with ACH, resulting in an overall favourable benefit-risk profile, upon review of the requested additional evidence.

Progress reports of confirmatory trials

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 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 BioMarin International Limited 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 confirmatory trials subject to clinical trial applications, as outlined in the Letter of Undertaking, must be reported 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(R2) ICH Guideline, including format and content, as per section 3.4.2 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). Please note that once all the commitments are fulfilled, Periodic Benefit-Risk Evaluation Reports-Pharmacovigilance (PBRER-PV) or Periodic Safety Update Reports-Pharmacovigilance (PSUR-PV) should be submitted as stipulated in the regulations (subsection C.01.018(5)), upon request. Furthermore, in situations where the Market Authorization Holder (MAH) identifies a significant change in the product's overall benefit-risk and safety profiles, the MAH must notify Health Canada without delay (subsection C.01.018(4)).
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 Voxzogo (vosoritide injection) as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). For more information on the regulatory requirements for advertising, please visit: https://www.canada.ca/en/health-canada/services/drugs-health-products/regulatory-requirements-advertising.html.
8. An up-to-date, complete listing of ongoing additional clinical trials related to Voxzogo (vosoritide injection), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
9. Copies of any marketing authorizations for Voxzogo (vosoritide injection) from any other drug regulatory authority as per Section 4.6 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).

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 Applications and Notice of Compliance with Conditions (NOC/c), respectively.

Sponsors are instructed to submit a complete response (refer to Guidance Document: Notice of Compliance with Conditions (NOC/c)) with the requested information within 30 calendar days of the date of this letter directly to the Office of Submissions and Intellectual Property (OSIP) via the Common Electronic Submissions Gateway (CESG) using Regulatory Enrolment Process (REP).

In order to facilitate and ensure proper processing of your response, please quote the product name, assigned dossier ID and control number of the original submission.

Sincerely,

Sophie Sommerer
Director General