Qualifying Notice - Enhertu

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

Dossier ID: HC6-024-E231047
Control #: 242104

[employee name removed]
[employee title remove]
AstraZeneca Canada Inc.
1004 Middlegate Road, Suite 5000
Mississauga, ON L4Y 1M4
Email: [employee email removed]

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 Enhertu (Trastuzumab Deruxtecan), Control Number # 242104, indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior treatment with trastuzumab emtansine (T-DM1), 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 Astrazeneca Canada 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, Astrazeneca Canada 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 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. Submit the final clinical study report of [study name/number has been removed], a phase 3, multicentre, randomized, open-label, active-controlled study of trastuzumab deruxtecan, an anti-HER2-antibody drug conjugate, versus treatment with investigator's choice for HER2-positive, unresectable and/or metastatic breast cancer patients previously treated with T-DM1, to confirm the clinical benefit of Enhertu and to convert the NOC/c authorization to an NOC authorization.

Progress Reports of Confirmatory Trials and Other Ongoing 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 sent to the Biologic and Radiopharmaceutical Drugs 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).
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 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);
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 Enhertu (Trastuzumab Deruxtecan) authorized under the NOC/c policy as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
7. 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).
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).
10. Should the sponsor wishes to use HER2 biomarker testing in blood samples to support a future Enhertu submission, the appropriateness of the method needs to be discussed, including supporting evidence, e.g., a correlation of HER2 biomarker testing using blood samples and IHC and FISH results across different HER2 expressing subjects ranging from low HER2 expressing subjects to high HER2 expressing subjects. If the method is used other than exploratory purpose, the method may need to be properly validated and the related validation report should to be included in the submission.
11. Due to the limited number of patients who tested positive for anti-drug antibody (ADA), no conclusions can be drawn concerning a potential effect of immunogenicity on clinical pharmacology, efficacy and safety of Enhertu. The sponsor should commit to monitoring and analyzing immunogenicity in ongoing Enhertu clinical trials and in the post-market setting.
12. While no large effect on QT interval was observed in the ECG sub-study in this submission, Grade 2 or 3 QTcF prolongation were reported in some patients in the [study name/number has been removed]and [study name/number has been removed] studies. The clinical significance of this observation is unclear based on the available data. The sponsor should commit to monitoring and analyzing the risk of QT prolonging potential in ongoing Enhertu clinical trials and in the post-market setting.
13. Patients with moderate or severe hepatic or renal impairment were not adequately represented in the [study name/number has been removed] and [study name/number has been removed] studies in the current submission. The sponsor should commit to monitoring and analyzing Enhertu safety in these patient populations. In the next regulatory submission for Enhertu, provide an integrated exposure-response analysis for all patients with liver and kidney impairment using PK parameters from a noncompartmental analysis, instead of using simulated data from a POP PK analysis.

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
Biologic and Radiopharmaceutical Drugs Directorate

Sincerely,

Celia Lourenco, Ph.D.
Director General