Qualifying Notice - Verity - BCG

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

Dossier ID: HC6-024-e215162
Control #: 221579

[employee's name removed]
[employee's title removed]
Verity Pharmaceuticals Inc.
2560 Matheson Blvd E. Suite 220
Mississauga, Ontario, Canada, L4W 2Y9
Fax: 4162866851

Dear [employee's 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 (Verity-BCG Bacillus Calmette-Guérin (BCG): Russian BCG-I (Russian or Moscow) strain), Control Number 221579, qualifies to be considered for authorization under the NOC/c policy. Verity-BCG is indicated as an adjuvant therapy after transurethral resection (TUR) of a primary or relapsing superficial papillary urothelial cell carcinoma of the bladder stage Ta (grade 2 or 3) or T1 (grade 1, 2, or 3), without concomitant carcinoma in situ. It is only recommended for stage Ta grade 1 papillary tumors, when there is judged to be a high risk (>50%) of tumor recurrence. 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 Verity Pharmaceuticals 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, Verity Pharmaceuticals 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 Verity Pharmaceuticals 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 (3-12):

Confirmatory Studies

• 3. Submit, as an SNDS-C, the final report for the confirmatory study entitled: "A multicenter, randomized, double-blind, controlled phase 3 noninferiority study assessing efficacy and safety of VERITY-BCG vs. OncoTICE in the management of intermediate and high-risk nonmuscle invasive bladder cancer (NMIBC) in BCG-naïve patients". The estimated study enrollment is 518 patients and the primary endpoints of the study are: the cumulative Recurrence Free Survival (RFS) at 24 months following 1st intravesical instillation as estimated using the Kaplan - Meier estimator of the survival function. And recurrence will be defined as the reappearance of any of the NMIBC tumors as confirmed by biopsy performed at the time of cystoscopy or TURBT. The non - inferiority Hazard Ratio (HR) for the primary endpoint has been set as 1.32. Key secondary endpoints of this study are: RFS at 36 months as estimated using the Kaplan - Meier estimator of the survival function. Progression Free Survival (PFS) at 24 - months as estimated using the Kaplan - Meier estimator of the survival function. PFS at 36 - months as estimated using the Kaplan - Meier estimator of the survival function. Overall Survival (OS) at 36 months as estimated using the Kaplan - Meier estimator of the survival function. Change in Quality of Life as measured by the EORTCQLQ-NMIBC24 over 36 months. Change in functioning and symptom status as measured by the EORTC-QLQ-C30 over 36 months. For all endpoints the hypotheses tested are that Verity-BCG is non - inferior to OncoTICE.
  1. In the Letter of Undertaking, the sponsor should provide the expected date of initiation and the approximate date of completion of the confirmatory study and should commit to an approximate date of filing the SNDS-c.
  2. The Sponsor should acknowledge that the indication for Verity-BCG, may be withdrawn if the confirmatory study does not meet it's endpoints for both statistical significance and clinical meaningfulness.

Progress Reports of Confirmatory Trials and Other Ongoing Trials

• 4. 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 (Verity Pharmaceuticals Inc.) and Health Canada must be outlined in the Letter of Undertaking.
  1. The Independent Data Monitoring Committee will perform periodic interim analyses of safety and futility that will be based on the between group distribution of the number of recurrence or progression events. The number and intervals between interim analyses conducted as well as the futility boundaries will be pre-specified but may be changed depending on the observed number and between group distribution of recurrence or progression events.

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 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).
• 6. Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Reports-C for NOC/c Products (PSUR-Cs or PBRER-Cs) on a semi-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);
  1. Canadian data in PSUR-Cs or PBRER-Cs should be analysed and reported separately from pooled data.
• 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 (Verity-BCG Bacillus Calmette-Guérin (BCG): Russian BCG-I (Russian or Moscow) strain) authorized under the NOC/c policy as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
• 10. 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. An up-to-date, complete listing of ongoing additional clinical trials related to (Verity-BCG Bacillus Calmette-Guérin (BCG): Russian BCG-I (Russian or Moscow) strain), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
• 12. Copies of any marketing authorizations for (Verity-BCG Bacillus Calmette-Guérin (BCG): Russian BCG-I (Russian or Moscow) strain) 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, Ontario, K1A 0K9

Attention: Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate

Sincerely,
Celia Lourenco, Ph.D.
Director General