Qualifying notice for Enhertu (285834)

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

Dossier ID: e231047
Control number: 285834

[employee name removed]
Project Manager, Regulatory Affairs
Astra Zeneca Canada Inc.
1004 Middlegate Road, Suite 5000
Mississauga ON  L4Y 1M4
[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) or Supplemental New Drug Submission (SNDS)) for Enhertu (trastuzumab deruxtecan) Control Number 285834, qualifies to be considered for authorization in accordance with the above guidance document for the following indication: Enhertu (trastuzumab deruxtecan) as monotherapy is indicated for the treatment of adult patients with unresectable, locally advanced or metastatic Her2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. 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 commits to submit, as a Supplemental New Drug Submission-confirmatory (SNDS-c), the complete Clinical Study Report for the pivotal study, U306/Destiny- Gastric04 entitled: A Phase 3, Multicenter, 2-arm Randomized, Open-label Study of Trastuzumab Deruxtecan in subjects with Her2-Positive Metastatic and/or Unresectable Gastric or Gastro Esophageal Junction (GEJ) Adenocarcinoma Subjects who have progressed on or after a Trastuzumab-containing Regimen.
   • Statistically significant results from either the interim or final analyses of Overall Survival (OS) and accompanying safety analyses.
   • Full Pharmacokinetic analysis report for U306/Destiny-Gastric04.
     The sponsor should provide the approximate date of completion of the confirmatory study, U306, and should commit to an approximate date of filing(s) of the SNDS-c submission(s).
2. The sponsor should acknowledge that the indication authorized under the NOC/c pathway for Enhertu under control number 285834 can be withdrawn or revised, pending the outcome of Study U306. The decision by BRDD on the removal of the condition and/or modification of the current proposed indication will be based on the demonstration that an overall survival benefit of Enhertu monotherapy in the indicated patient population can be clinically confirmed and/or if the risk/benefit analysis as determined by BRDD is positive.

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 AstraZeneca Canada 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 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 a once-every-three-years 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(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.
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 Enhertu (trastuzumab deruxtecan) 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 Regulatory Requirements for Advertising.
8. An up-to-date, complete listing of ongoing additional clinical trials related to Enhertu (trastuzumab deruxtecan), 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 Enhertu (trastuzumab deruxtecan) 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 Guidance Document: Product Monograph (2020) and the Product Monograph Master Template, disclosing the nature of the authorization granted for Enhertu (trastuzumab deruxtecan) and the need to conduct confirmatory trials.

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 original date of issuance 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