Qualifying notice for Amtagvi (293019)

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

Dossier ID: e279570
Control number: 293019

Iovance Biotherapeutics, Inc.
c/o [employee name removed]
[employee title removed]
PPD Development L.P.
3900 Paramount Parkway
Morrisville, NC, United States of America, 27560
Email: [employee email removed]

Dear [employee name 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 (NDS) for Amtagvi (lifileucel), Control Number 293019, qualifies to be considered for authorization in accordance with the above guidance document for the following indication: Amtagvi (lifileucel) is a tumour-derived autologous T-cell immunotherapy indicated for the treatment of adult patients with unresectable or metastatic melanoma that has progressed on or after at least one prior systemic therapy including a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor, and who have no satisfactory alternative treatment options. 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 Iovance Biotherapeutics, 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), Iovance Biotherapeutics, 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 Iovance Biotherapeutics, 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. The sponsor commits to submit, as a Supplemental New Drug Submission-confirmatory (SNDS-c), the clinical study report (CSR) of the confirmatory study IOV-MEL-301: A Phase 3, randomized, open-label study to assess the efficacy and safety of the lifileucel regimen in combination with pembrolizumab compared with pembrolizumab monotherapy in participants with untreated, unresectable or metastatic melanoma. The CSRs of the Interim Analysis 2 (final progression-free survival [PFS] analysis and interim overall survival [OS] analysis) and the Final Analysis (final OS analysis) should be submitted.
   1. The sponsor should provide the approximate dates of completion of each of the analyses and should commit to an approximate date of filing for each SNDS-c;
   2. The sponsor should acknowledge that the indication authorized under the NOC/c pathway for Amtagvi under control no. 293019 can be withdrawn or revised, pending the outcome of Study IOV-MEL-301. The decision by BRDD on the removal of the condition and/or modification of the current proposed indication will be based on the demonstration of an improvement in overall survival and/or a positive benefit – risk profile of the combination of lifileucel plus pembrolizumab in the confirmatory study.
2. The sponsor commits to submit, as an SNDS-c, the final CSR of Study C-144-01.
1. The sponsor should provide the approximate date of completion of the confirmatory study and should commit to an approximate date of filing of the SNDS-c.

Progress reports of confirmatory trials

3. 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 Iovance Biotherapeutics, Inc. and Health Canada must be outlined in the Letter of Undertaking.

Safety monitoring

4. 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).
5. Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Reports-C for NOC/c Products (PSUR-Cs or PBRER-Cs) should be submitted on a semi-annual basis covering the periods from February 16, 2025 to August 15, 2025 and August 16, 2025 to February 15, 2026. 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(4)), upon request or in situations where the Market Authorization Holder (MAH) identifies any negative safety findings and/or significant change in the product's overall benefit-risk and safety profiles.
6. Please provide interval and cumulative analyses of all cases of death, including summaries of the case narratives and the reporter's and the Market Authorization Holder's causality assessments with both requested PSUR-Cs or PBRER-Cs.
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).

Additional information

8. Receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to Amtagvi (lifileucel) 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.
9. An up-to-date, complete listing of ongoing additional clinical trials related to Amtagvi (lifileucel), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
10. Copies of any marketing authorizations for Amtagvi (lifileucel) 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 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 (CESG) using Regulatory Enrolment Process (REP).

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.
Sincerely,

Sophie Sommerer
Director General