Qualifying notice amendment for Imfinzi

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

Dossier ID: HC6-024-e195931
Control #: 259689

[employee name removed]
[employee title removed]

AstraZeneca Canada Inc.
1004 Middlegate Road, Suite 5000
Mississauga ON L4Y 1M4
Fax: 905-275-6271

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 for Imfinzi (durvalumab for injection), Control Number 202953, indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:

• Have disease progression during or following platinum containing chemotherapy.
• Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

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, as an SNDS-c, the final report for the confirmatory study titled [study name/number has been removed].
   1. Provide the approximate date of completion of the confirmatory study and commit to an approximate date of filing of the SNDS-c.
   2. Acknowledge that the indication for Imfinzi may be withdrawn if study [study name/number has been removed] does not demonstrate that durvalumab in combination with standard of care chemotherapy is associated with an overall survival (OS) benefit in the ITT population that is both statistically and clinically significant (compared to standard of care) and does not permit BRDD to make a positive risk/benefit assessment in the indicated population.
   3. With regards to the PD-L1 biomarker, commit to explore treatment outcomes by PD-L1 expression level as assessed by the Ventana SP263 assay in [study name/number has been removed]. The predictive value of PD-L1 expression on both tumour infiltrating immune cells and tumour cells should be explored
2. Submit, as an SNDS-c, mature estimates of the secondary analyses (i.e., duration of response) of the study, [study name/number has been removed], for patients with UC. Provide the approximate date of completion of study follow-up and commit to an approximate date of filing of the SNDS-c.

3. Other Ongoing Studies

   The assay used to determine the rate of binding ATA and binding ATA that were neutralizing in [study name/number has been removed] was determined to be inadequate. Therefore, AstraZeneca Canada Inc. should develop and validate assays with improved sensitivity for the detection of binding and neutralising antibodies against durvalumab in the presence of durvalumab concentrations that are expected to be present in samples at the time of patient sampling after first dose and during steady state. Patient samples should be banked for storage until the improved method is available, and the rate of development of binding ATA and the proportion of binding ATA that are neutralizing should be determined for the advanced cancer population. The results of the investigation should be submitted to the BGTD as an SNDS-c. Alternatively, the characterization of binding and neutralizing antibodies could be conducted using patient samples from [study name/number has been removed] and included in the SNDS-c noted in commitment A if the assays were to be available soon enough to facilitate such an assessment.

Progress reports of confirmatory trials and other ongoing trials

4. Submit, 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.

Post market safety monitoring

5. 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 this Letter of Undertaking, will be sent to the Biologics and Genetic Therapies Directorate. Reporting will 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).
6. Submit Periodic Benefit-Risk Evaluation Reports for NOC/c Products (PBRER-Cs) on an annual basis until such time as conditions associated with the market authorization are removed. PBRER-Cs will be prepared in accordance with the E2C(R1) and E3C(R2) ICH Guidelines, including format and content, as per section 3.4.2 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The PBRER-Cs will include an analysis of the adverse drug reactions as per the Pharmacovigilance Plan and safety updates from all ongoing clinical trials with Imfinzi.
7. 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).
8. Implement the Risk Management Plan (RMP) in Canada and provide any updates to the RMP whenever available.

Additional information

9. Receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to Imfinzi (durvalumab) authorized under the NOC/c policy as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
10. Provide 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).
11. Provide up-to-date, complete listing of ongoing additional clinical trials related to Imfinzi (durvalumab), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
12. Submit to Health Canada any other analyses that have been designated as post-marketing commitments to other international authorisation granting agencies as per section 3.4.4 of the Guidance for Industry, Notice of Compliance with Conditions (NOC/c).
13. Provide copies of any marketing authorizations or other regulatory actions for Imfinzi (durvalumab) 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 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 quote the product name, assigned dossier ID, and control number of the original submission, and send directly to the Office of Submissions and Intellectual Property (OSIP) via the Common Electronic Submissions Gateway (CESG) using the Regulatory Enrolment Process (REP).

Sincerely,

Cynthia Colapinto, Ph.D. (for) Celia Lourenco, Ph.D.

Director General