Qualifying notice for Eylea (278211)

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

Dossier ID: e144515
Control number: 278211

[employee name removed]
[employee title removed]
Bayer Inc.
2920 Matheson Blvd East
Mississauga ON L4W 5R6
[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 Supplemental New Drug Submission (SNDS) for Eylea (aflibercept), Control Number 278211, qualifies to be considered for authorization in accordance with the above guidance document for the following indication: Eylea (aflibercept injection) is indicated in preterm infants for the treatment of retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 2+ or 3+) or AP-ROP (aggressive posterior ROP) disease. 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 Bayer 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), Bayer 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 Bayer 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 study report for the Study 20275 (Firefleye Next): An extension study to evaluate the long-term outcomes of subjects who received treatment for retinopathy of prematurity in Study 20090 to confirm the clinical benefit, including visual acuity (VA), and safety of intravitreal (IVT) injection of aflibercept in preterm infants for the treatment of retinopathy of prematurity (ROP). Ideally, the VA should be assessed using validated age-appropriate tools by assessors who are blinded to the assigned treatment allocation. If the VA is assessed by ophthalmologists or optometrists who are not blinded to the assigned treatment allocation, rigorous adherence to standard procedures should be implemented and every effort should be made to ensure a comprehensive and objective eye examination, and to minimize the risk of bias related to treatment unblinding. Evidence is required to show that VA results are not significantly impacted by subjective bias. The adverse events (AEs) including ocular, non-ocular and AEs potentially related with systemic risks (e.g., neurodevelopmental disorders, etc.,) should be comprehensively assessed.
   The sponsor should provide the estimated date of completion of Study 20275 (Firefleye Next), and should commit to provide an approximate date for filing their SNDS-c submission.
   The sponsor should also acknowledge that the indication authorized under the NOC/c pathway for Eylea (aflibercept) under control # 278211 can be withdrawn or revised, pending the outcome of Study 20275 (Firefleye Next). The decision by BRDD to remove the condition and/or modify the currently proposed indication will depend on the confirmation of clinical outcome benefit (i.e. visual acuity) and the demonstration that there are no long-term safety concerns associated with the use of aflibercept in the preterm infants with ROP, resulting in an overall favourable benefit-risk profile, upon review of the requested additional evidence. The methodology of VA assessment may need to be reflected in the future product monograph updates.

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 Bayer Inc. and Health Canada must 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. 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(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.
   The sponsor is requested to include a safety review on events associated with ROP indication, including cases associated with potential neurodevelopment impairment for the next two annual summary safety reports (PBRERs or PSURs) following the authorization of ROP indication in Canada. Interim data report of the Firefleye Next study 20275 are expected to be provided in a dedicated section of Eylea PBRERs. PBRERs should also include safety reviews of important identified and potential risks, the search criteria used to identify case reports, and interim data of studies as proposed.
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 Eylea (aflibercept) 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 Eylea (aflibercept), 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 Eylea (aflibercept) 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 informationwithin 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