Qualifying notice for Ojemda

Pharmaceutical Drugs Directorate
Holland Cross, Tower "B"
6th Floor, 1600 Scott Street
Address Locator #3106B
Ottawa ON K1A 0K9

Dossier ID: e294323
Control number: 301603

[name of employee removed]
Associate Director, Regulatory Affairs
Ipsen Biopharmaceuticals Canada Inc.
500 – 5050 Satellite Drive
Mississauga ON L4W 0G1
Email: regulatory.canada@ipsen.com

Dear [name of employee removed]:

This Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN), issued in accordance with the Health Canada Guidance Document: Notice of Compliance with Conditions (NOC/c), is to advise you that information submitted in support of the New Drug Submission for Ojemda (tovorafenib), control number 301603, qualifies to be considered for authorization in accordance with the above guidance document for the following indication:

Ojemda (tovorafenib tablets and tovorafenib for oral suspension) is indicated as monotherapy for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harbouring a BRAF fusion or rearrangement, or BRAF V600 mutation, who have received one or more prior systemic therapies.

In keeping with the provisions outlined in the Guidance Document: Notice of Compliance with Conditions (NOC/c), the following additional information is requested to complete the assessment:

1. A letter, signed by the Chief Executive Officer or designated signing authority of Ipsen Biopharmaceuticals Canada Inc., indicating that you agree to have this submission considered under the Guidance Document: Notice of Compliance with Conditions (NOC/c). Please be reminded that in agreeing to accept a Notice of Compliance (NOC) under the Guidance Document: Notice of Compliance with Conditions (NOC/c), Ipsen Biopharmaceuticals Canada Inc. consents to the posting of this NOC/c-QN on Health Canada's website once market authorization has been received.
2. A draft Letter of Undertaking signed by the Chief Executive Officer or designated signing authority of Ipsen Biopharmaceuticals Canada Inc., having a form and content satisfactory to Health Canada, as indicated in Guidance Document: Notice of Compliance with Conditions (NOC/c), including commitments to provide the following:

Confirmatory studies

The Sponsor will submit to Health Canada a Supplement to a New Drug Submission - Confirmatory (SNDS-C) which will include the final clinical study report of the following Confirmatory Study:

1. Study DAY101-002 (LOGGIC/FIREFLY-2): Phase 3, randomized, international multicentre trial comparing tovorafenib monotherapy with standard of care chemotherapy in patients with pediatric low-grade glioma harbouring an activating rapidly accelerated fibrosarcoma gene (RAF) alteration requiring first line systemic therapy. The intent is to verify the clinical benefit of Ojemda by assessing the objective response rate (ORR) as the primary efficacy endpoint and progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) as key secondary endpoints. The ORR, PFS, and EFS should be assessed according to the Response Assessment in Pediatric Neuro-Oncology for Low-grade Glioma (RAPNO-LGG) criteria by Independent Review Committee (IRC). The SNDS-C is to be filed by 30 April 2032.

Progress reports of confirmatory 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 Ipsen Biopharmaceuticals Canada Inc. and Health Canada should 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 reported 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. Annual PSUR/PBRER, covering the second year of marketing in Canada, as per the ICH E2C (R2). Subsequent PSUR/PBRER submission frequency to Health Canada would be determined thereafter. PSUR-Cs/PBRER-Cs should be prepared in accordance with the E2C(R2)ICH Guideline, including format and content, as per section 3.4.2 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). Please note that once all the commitments are fulfilled, Periodic Benefit-Risk Evaluation Reports-Pharmacovigilance (PBRER-PV) or Periodic Safety Update Reports-Pharmacovigilance (PSUR-PV) should be submitted as stipulated in the regulations (subsection C.01.018(5)), upon request. Furthermore, in situations where the Market Authorization Holder (MAH) identifies significant change in the product's overall benefit-risk and safety profiles, the MAH must notify Health Canada without delay (subsection C.01.018(4)).
   • The PSUR should include updates and discussion of relevant safety finding for all safety concerns listed in the RMP in addition to: long term safety with attention and detailed discussion of all cases related to Growth retardation, Hemorrhages, Non-hematological malignant tumors, Eye disorders (SOC), Ventricular tachyarrhythmias, Rhabdomyolysis/myopathy, Pregnancy exposure/outcomes, and Fertility disorders.
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 Ojemda (tovorafenib) as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). For more information on the regulatory requirements for advertising, please visit: https://www.canada.ca/en/health-canada/services/drugs-health-products/regulatory-requirements-advertising.html.
7. An up-to-date, complete listing of ongoing additional clinical trials related to Ojemda (tovorafenib), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
8. Copies of any marketing authorizations for Ojemda (tovorafenib) from any other drug regulatory authority as per Section 4.6 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).

3. A draft of the Product Monograph that is consistent with the requirements in accordance with the Guidance Document: Product Monograph (2020) and the Product Monograph Master Template, disclosing the nature of the authorization granted for Ojemda (tovorafenib) and the need to conduct confirmatory trials.
4. A final mock-up of the Package Insert (if applicable), in line with the requirements outlined in Health Canada's Questions and Answers: Plain Language Labelling Regulations (Q&A: PLL) for Prescription Drugs - document, containing boxed text disclosing the nature of the authorization granted for Ojemda (tovorafenib) for the indication listed above.

I wish to advise you that this Qualifying Notice is being issued in accordance with Health Canada's guidance documents on the Management of Drug Submissions and Applications and Notice of Compliance with Conditions (NOC/c), respectively.

Sponsors are instructed to submit a complete response (refer to Guidance Document: Notice of Compliance with Conditions (NOC/c)) with the requested information within 30 calendar days of the date of this letter directly to the Office of Submissions and Intellectual Property (OSIP) via the Common Electronic Submissions Gateway using Regulatory Enrolment Process.

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.

Yours sincerely,

Kelly Robinson
Director General
Pharmaceutical Drugs Directorate