Qualifying notice for Bavencio

Biologics and Genetic Therapies Directorate
100 Eglantine Driveway
Address Locator #0601C
Ottawa ON K1A 0K9

Dossier ID: HC6-024-e196892
Control #: 208742

[employee name removed]
[employee title removed]
EMD Serono, A Division of EMD Inc., Canada
200-2695 North Sheridan Way
Mississauga ON L5K 2N6
Fax: [employee fax 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 Bavencio (avelumab), Control Number 208742, qualifies to be considered for authorisation under the NOC/c policy for the following indication:

Bavencio (avelumab) is indicated:

• for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-based chemotherapy.

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 EMD Serono, A Division of EMD Inc., Canada, 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, EMD Serono, A Division of EMD Inc., Canada 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 EMD Serono, A Division of EMD Inc., Canada, 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 [study name/number has been removed]. The study is designed to evaluate the effect, on overall survival, of avelumab combined with best supportive care (BSC) vs. BSC alone in a maintenance setting.
   1. Provide the approximate date of completion of the confirmatory study [study name/number has been removed] and commit to an approximate date of filing of the SNDS-c.
   2. Acknowledge that the indication for Bavencio (avelumab) may be withdrawn if study [study name/number has been removed] does not demonstrate that Bavencio (avelumab) plus BSC is associated with an overall survival (OS) benefit that is both statistically and clinically significant (compared to BSC alone).
   3. With regards to the PD-L1 biomarker, commit to explore treatment outcomes by PD-L1 expression level. 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, estimates of efficacy endpoints including the Objective Response Rate (ORR) for the urothelial carcinoma cohorts of [study name/number has been removed], based on sufficient follow-up of the population of 242 platinum experienced urothelial carcinoma patients. This report should also provide mature estimates of the duration of response (DoR).

Progress reports of confirmatory trials and other ongoing trials

3. 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).

Post market safety monitoring

4. Ensure that the risk management plan (RMP) filed under submission control number 208742 (urothelial carcinoma indication) is updated and amalgamated with the information contained in the RMP filed and reviewed under submission control number 204052 (Merkel cell carcinoma indication). The amalgamated RMP should contain all information that was agreed to during the review of 204052 as well as the additional information proposed within submission 208742.
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 Food and Drug 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) for Bavencio (avelumab) to BGTD with the following submission schedule:
   • Every 6 months during the first 2 years following the initial marketing authorization,
   • Annually for the following 2 years,
   • Every 3 years thereafter until such time as conditions associated with the market authorization are removed.

     PBRER-Cs will be prepared in accordance with the E2C(R1) and E2C(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 Bavencio (avelumab).

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 Bavencio (avelumab) 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 an up-to-date, complete listing of ongoing additional clinical trials related to Bavencio (avelumab), 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 (FDA, EMA and TGA) 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 Bavencio (avelumab) 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 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 ON K1A 0K9

Attention: Office of Regulatory Affairs
Biologics and Genetic Therapies Directorate

Sincerely,

Catherine Parker
Director General