Biologics and Genetic Therapies Directorate
100 Eglantine Driveway
Address Locator #0601C
March 7, 2017
Dossier ID: HC6-024-E186968
Control #: 196843
Document #: 1187938
[employee name removed]
Project Manager, Regulatory Affairs
Hoffmann-La Roche Limited
7070 Mississauga Road
Mississauga, ON L5N 5M8
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 Tecentriq (atezolizumab), Control Number 196843, 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:
- A letter, signed by the Chief Executive Officer, or designated signing authority of Hoffmann-La Roche Limited, 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, Hoffmann-La Roche Limited consents to the posting of the NOC/c-QN on Health Canada's website.
- A draft Letter of Undertaking signed by the Chief Executive Officer, or designated signing authority, of Hoffmann-La Roche Limited, 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:
- Submit by the second quarter of 2018 (Q2 2018), as an SNDS-c, the final report for the primary analysis of the confirmatory study: A Phase III, open-label, multicenter, randomized study to investigate the efficacy and safety of atezolizumab compared with chemotherapy in patients with locally advanced or metastatic urothelial carcinoma after failure with platinum containing chemotherapy (IMvigor211). This study is designed to evaluate the effect of atezolizumab on overall survival (OS) when compared to chemotherapy (investigator's choice of docetaxel, paclitaxel or vinflunine).
The sponsor should acknowledge that the indication for TECENTRIQ can be withdrawn if study IMvigor211 does not demonstrate an improvement in overall survival (OS).
With regards to the PD-L1 biomarker, the sponsor should commit to explore treatment outcomes by PD-L1 expression level as assessed by the Ventana sp142 assay in IMvigor211. The predictive value of PD-L1 expression on both tumour infiltrating immune cells and tumour cells should be explored.
- Submit by the second quarter of 2018 (Q2 2018), as an SNDS-c, mature estimates of the secondary analyses (i.e., duration of response) of the pivotal study, IMvigor210 (Cohort 2).
Other Ongoing Studies
- Submit the final clinical study report of a clinical study to evaluate the effect of TECENTRIQ on thyroid function tests and clinical thyroid disease. The sponsor should provide the approximate date of completion of the study and commit to an approximate date of filing.
- The assay used to determine the rate of binding ATA that were neutralizing in IMvigor210 was determined to be inadequate. Therefore, the sponsor should develop and validate an assay with improved sensitivity for the detection of neutralising antibodies against atezolizumab in the presence of atezolizumab levels that are expected to be present in samples at the time of patient sampling. Patient samples should be banked for storage until the improved method is available, and the proportion of binding ATA that are neutralizing should be determined for the locally advanced and metastatic urothelial carcinoma population. The results of the investigation should be submitted to the BGTD. Alternatively, the characterization of neutralizing antibodies could be conducted using patient samples from IMvigor211 and included in the SNDS-c, noted in commitment (a.), if the assay were to be available soon enough to facilitate such an assessment.
- Submit the final study report for the study entitled "Investigation of the Immune Response to Keyhole Limpet Hemocyanin (KLH) Challenge in Male and Female Cynomolgus Monkeys Following Administration of Atezolizumab"
Progress Reports of Confirmatory Trials and Other Ongoing Trials
- 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 Hoffmann-La Roche Limited and Health Canada must be outlined in the Letter of Undertaking.
- 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 Biologics and Genetic Therapies 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).
- The sponsor should submit 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);
- 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).
- Implement the Risk Management Plan (RMP) in Canada and provide any updates to the RMP whenever available.
- Receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to TECENTRIQ (atezolizumab) authorized under the NOC/c policy as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
- 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).
- Provide an up-to-date, complete listing of ongoing additional clinical trials related to TECENTRIQ (atezolizumab), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
- Submit to Health Canada any other analyses that have been designated as post-marketing commitments to other international authorisation granting agencies.
- Provide copies of any marketing authorizations for TECENTRIQ (atezolizumab) 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
101 Tunney's Pasture Driveway
Address Locator 0201A1
Ottawa, Ontario, K1A 0K9
Attention: Office of Regulatory Affairs
Biologics and Genetic Therapies Directorate