Qualifying notice for Ondexxya

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

Dossier ID: HC6-024-E251431
Control number: 266464

[employee name removed]
[employee title removed]
AstraZeneca Canada Inc.
1004 Middlegate Road, Suite 5000
Mississauga ON L4Y 1M4 Canada
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 Ondexxya (andexanet alfa), Control Number 266464, indicated for adult patients treated with FXa inhibitors (rivaroxaban or apixaban) when rapid reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding, qualifies to be considered for authorisation in accordance with the above guidance document. 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 Astrazeneca Canada Inc., 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), Astrazeneca Canada Inc. 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 Astrazeneca Canada 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. The sponsor will submit, as an SNDS-c, the results of the randomized clinical trial, titled: A phase 4 randomized trial of andexanet alfa (andexanet alfa for injection) in acute intracranial hemorrhage in patients receiving an oral factor Xa inhibitor, [study name/number has been removed].

   The study is designed to compare the hemostatic efficacy and anti-FXa activity of andexanet alfa vs. usual care. The sponsor should acknowledge that the Notice of Compliance with conditions may be revoked if the study fails to demonstrate an improved benefit-risk balance over usual care.

   The sponsor will provide an estimated date of study completion (i.e., completed evaluation of the primary study outcome) and study submission for [study name/number has been removed].

Progress reports of confirmatory trials

2. 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 Astrazeneca Canada Inc. and Health Canada must be outlined in the Letter of Undertaking.

Safety monitoring

3. 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).
4. Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Reports-C for NOC/c Products (PSUR-Cs or PBRER-Cs) on an annual basis for the next three years (including all reporting periods ending in 2026). 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). 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(4)), upon request or in situations where the Market Authorization Holder (MAH) identifies any negative safety findings and/or significant change in the product's overall benefit-risk and safety profiles.
5. 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

6. Receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to Ondexxya (andexanet alfa) 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.
7. An up-to-date, complete listing of ongoing additional clinical trials related to Ondexxya (andexanet alfa), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
8. Copies of any marketing authorizations for Ondexxya (andexanet alfa) 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
Acting Director General