Qualifying notice for Rybrevant

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

Dossier ID: HC6-024-e245921
Control #: 254440

[employee name removed]
[employee title removed]
Janssen Inc.
19 Green Belt Drive,
Toronto ON  M3C 1L9

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 Rybrevant (amivantamab for injection), Control Number 254440, indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal-growth factor receptor (EGFR) Exon 20 insertion mutations whose disease has progressed on or after platinum-based 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:

1. A letter, signed by the Chief Executive Officer, or designated signing authority of Janssen 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, Janssen 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 Janssen 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. Submit, as an SNDS-c, the final report for the [study name/number has been removed]. The estimated study enrollment is 300 patients and the primary endpoint of the study is progression-free survival (PFS) based on blinded independent central review (BICR) per RECIST v1.1. The key secondary endpoints of this study would include objective response rate (ORR) per BICR, including duration of response, and overall survival (OS). While OS is a secondary endpoint in the study, it will be considered a key outcome in the conformation of benefit for the indicated patient population.
   1. The Sponsor should provide the approximate date of completion of the confirmatory study and should commit to an approximate date of filing this SNDS-c.
   2. The Sponsor should acknowledge that the indication for Rybrevant may be withdrawn if the results of the [study name/number has been removed] does not demonstrate that Rybrevant in combination with carboplatin plus pemetrexed is associated with a PFS that is both statistically significant and clinically meaningful over carboplatin plus pemetrexed alone. Additionally, the OS result will be a key element evaluated in the confirmation of benefit, and assessment of benefit/risk, for the indicated patient population.
2. Submit, as an SNDS-c, the final report from the [study name/number has been removed]. This is to provide confirmation, and a more precise estimation of the ORR per BICR and duration of response in a high number of patients with longer follow-up. The data submitted should be an analysis after all responders in the target patient population (at least 129 patients with exon 20 insertion mutations + prior platinum-based chemotherapy) have been followed for at least 6 months from the date of initial response (or until disease progression, whichever comes first). Safety will be evaluated for consistency.
   3. The Sponsor should provide the approximate date of completion of the confirmatory study and should commit to an approximate date of filing this SNDS-c.

Progress reports of confirmatory trials and other ongoing 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 Janssen 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 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).
5. 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);
6. 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

7. receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to Rybrevant (amivantamab for injection) authorized under the NOC/c policy as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
8. 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).
9. an up-to-date, complete listing of ongoing additional clinical trials related to Rybrevant (amivantamab for injection), 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 Rybrevant (amivantamab for injection) 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
Resource Management and Operations Directorate
Address Locator: 1908A
8th Floor – Room 811A Jeanne Mance Building
200 Eglantine Driveway
Ottawa ON  K1A 0K9

Attention: Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate

Sincerely,

Celia Lourenco, Ph.D.
Director General