Summary Basis of Decision for Eylea
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Eylea is located below.
Recent Activity for Eylea
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Eylea
Updated: 2023-10-03
The following table describes post-authorization activity for Eylea, a product which contains the medicinal ingredient aflibercept. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the 
Management of Drug Submissions and Applications Guidance.
Drug Identification Number (DIN):
- DIN 02415992 - 40 mg/mL, aflibercept, solution, intravitreal injection, single-use vial
- DIN 02505355 – 40 mg/mL, aflibercept, solution, intravitreal injection, single-use pre-filled syringe
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| SNDS # 270257 | 2022-12-05 | Issued NOC 2023-06-29 | Submission filed as a Level I – Supplement for the addition of an alternate drug substance manufacturing facility. The submission was reviewed and considered acceptable, and an NOC was issued. |
| SNDS # 266439 | 2022-07-26 | Issued NOC 2023-06-29 | Submission filed as a Level I – Supplement to update the PM to include the option of a flexible (individualized) treatment regimen in patients with DME. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and package inserts. An NOC was issued. |
| SNDS # 265084 | 2022-06-10 | Issued NOC 2022-11-10 | Submission filed as a Level II – Supplement (Safety) to update the PM handling instructions to include a cautionary statement for the management of the pre-filled syringe should damage occur. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration section of the PM, and corresponding changes were made to the package insert. An NOC was issued. |
| SNDS # 268693 | 2022-10-14 | Cancellation Letter Received 2022-10-30 | Submission filed as a Level I – Supplement for the addition of an alternate drug substance manufacturing site. The submission was cancelled administratively by the sponsor before screening began. |
| SNDS # 264495 | 2022-05-20 | Cancellation Letter Received 2022-06-02 | Submission filed as a Level II – Supplement (Safety) update the PM handling instructions to include a cautionary statement for the management of the pre-filled syringe should damage occur. The sponsor cancelled the submission administratively before screening began. |
| SNDS # 249941 | 2021-02-26 | Issued NOC 2022-02-10 | Submission filed as a Level I – Supplement to update the PM with the addition of a new dosing regimen with a modified length of treatment interval for patients with DME. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration; Clinical Pharmacology; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and package inserts. An NOC was issued. |
| SNDS # 250821 | 2021-03-19 | Issued NOC 2021-09-09 | Submission filed as a Level I – Supplement to update the inner and outer labels and package inserts and to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable, and an NOC was issued. |
| SNDS # 248069 | 2021-02-05 | Issued NOC 2021-05-14 | Submission filed as a Level II – Supplement (Safety) to update the PM with safety information. The changes were in response to an Advisement Letter issued by Health Canada to Bayer Inc., dated January 7, 2021, requesting revisions related to systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM. An NOC was issued. |
| NC # 247140 | 2020-12-02 | Issued NOL 2021-03-17 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for several changes that affect the manufacturing and analytical testing of the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 228646 | 2019-06-19 | Issued NOC 2020-12-22 | Submission filed as a Level I – Supplement to update the PM with data from the ALTAIR study to update the treatment regimen for wAMD. A NON was issued on May 20, 2020, due to several important limitations identified in the submission. In the response filed by the sponsor on July 7, 2020, addition data was provided from the ARIES study. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration; Action and Clinical Pharmacology; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Consumer Information and package insert. An NOC was issued. |
| SNDS # 236083 | 2020-02-13 | Issued NOC 2020-09-25 | Submission filed as a Level I – Supplement for the addition of a new presentation (pre-filled syringe, 40 mg/mL) and manufacturing facility for the drug product. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02505355) was issued for the new presentation. |
| NC # 230310 | 2019-08-01 | Issued NOL 2019-11-04 | Submission filed as a Level II (90 day) Notifiable Change to update the PM with safety information from the completed VIVID/VISTA DME studies. As a result of the NC, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 215495 | 2018-04-17 | Issued NOC 2019-03-19 | Submission filed as a Level I – Supplement to update the PM with the introduction of an optional treat and extend dosing regimen (2-week adjustment) for the treatment of wAMD. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration; Action and Clinical Pharmacology; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Consumer Information and package insert. An NOC was issued. |
| NC # 223013 | 2018-12-13 | Issued NOL 2019-03-14 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls applied during the drug substance manufacturing process and a change in the drug substance and drug product release or shelf-life specifications. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 222807 | 2018-12-06 | Issued NOL 2019-03-14 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the addition of an alternate quality control testing site for the drug substance (release and stability). The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 216823 | 2018-06-01 | Issued NOC 2019-01-15 |
Submission filed as a Level I - Supplement to add an alternate manufacturing site for the production of the drug product. The information was reviewed and considered acceptable. An NOC was issued. |
| SNDS # 207553 | 2017-07-17 | Issued NOC 2018-06-01 |
Submission filed as a Level I - Supplement to adjust the dosing regimen for Eylea for the treatment of diabetic macular edema (DME) to indicate that dosing every month may be continued after the first 5 months in some patients. The option for continued monthly dosing in some patients after the initial 5 monthly injections of Eylea is supported by results from clinical trials as well as from real world evidence in the form of feedback from Canadian specialists. There was no change to the previously authorized DME indication. With the changes to the PM proposed in this submission, the benefit/risk of Eylea for the treatment of DME continues to be considered favourable. The submission was reviewed and considered acceptable, and an NOC was issued. |
| SNDS # 205200 | 2017-05-01 | Issued NOC 2018-04-12 |
Submission filed as a Level I - Supplement to provide a safety and efficacy update to the PM based on two Phase III studies in patients with diabetic macular edema (DME). As a result of the submission, the following sections of the PM were updated: Warnings and Precautions, Adverse Reactions, Action and Clinical Pharmacology, and Clinical Trials. Corresponding changes were made to the PM Part III: Patient Medication Information. There was no change in the authorized indication or the dosage and administration. The benefit/risk profile for Eylea remains positive when used for the treatment of DME. The submission was reviewed and considered acceptable, and an NOC was issued. |
| SNDS # 204121 | 2017-03-27 | Issued NOC 2018-03-09 |
Submission filed as a Level I - Supplement for an alternate dosing schedule for the treatment of neovascular age-related macular degeneration. The inclusion of this information in the PM does not change the previously established favourable benefit/risk ratio of Eylea for the treatment of neovascular age-related macular degeneration. The submission was reviewed and considered acceptable, and an NOC was issued. |
| SNDS # 186851 | 2015-08-11 | Issued NOC 2017-05-19 |
Submission filed as a Level I - Supplement for the treatment of myopic choroidal neovascularisation. Regulatory Decision Summary published. |
| NC # 203333 | 2017-02-28 | Issued NOL 2017-04-03 |
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to clarify that a vial of Eylea should only be used for the treatment of one eye. As a result of the NC, modifications were made to the Dosage and Administration section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 201426 | 2016-12-21 | Issued NOL 2017-03-27 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to generate a new Working Cell Bank, and to change the cell bank qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 200196 | 2016-11-10 | Issued NOL 2017-02-10 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to implement the new Eylea reference standard program (refile of NC # 196169). The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 199968 | 2016-11-03 | Issued NOL 2016-12-07 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the controls applied on the drug substance intermediate, and to change the specifications used to release the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 198916 | 2016-10-04 | Issued NOL 2016-11-25 |
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Adverse Reactions, Dosage and Administration, and Overdosage sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 196139 | 2016-06-20 | Cancellation Letter Received 2016-09-27 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to implement the new Eylea reference standard program. A number of issues were identified with the submission during review, and the sponsor was therefore recommended to withdraw and refile. The submission was cancelled by the sponsor. |
| NC # 193901 | 2016-04-01 | Issued NOL 2016-07-13 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the vial stopper specifications. The submission was reviewed and considered acceptable, and an NOL was issued. |
| Summary Safety Review | Not applicable | Posted 2016-05-10 |
Summary Safety Review for Eylea (aflibercept) - Assessing the Risk of Side Effects Outside the Eye (systemic side effects). |
| SNDS # 180861 | 2014-12-22 | Issued NOC 2015-12-10 |
Regulatory Decision Summary published. |
| SNDS # 177418 | 2014-08-22 | Issued NOC 2015-08-12 |
Submission filed as a Level I - Supplement to update the Product Monograph with second year data obtained from the Phase III studies that support theage-related macular degeneration (AMD) indication. In the second year, the visual acuity achieved at Week 52 was maintained at Week 96.No new safety signals were identified in the second year compared to the first year. As labelled, Health Canada considers that the benefit/risk of Eylea for the treatment of AMD continues to be favourable. |
| New safety review | Not applicable | Started between 2015-01-01 and 2015-03-31 |
Health Canada started a safety review for Eylea. |
| NC # 178024 | 2014-09-16 | Issued No Objection Letter 2014-12-29 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to provide several changes to the quality information submitted for the drug substance and drug product. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| SNDS # 170564 | 2013-12-06 | Issued NOC 2014-11-28 |
Submission filed as a Level I – Supplement for an expanded indication for Eylea, for the treatment of diabetic macular edema (DME). The submission included data from two randomized, 3-year, multicentre, double-masked, active (laser)-controlled Phase III pivotal clinical studies (VISTA and VIVID). The evidence supporting the new indication was based on 1-year data from the ongoing studies. The efficacy in the improvement of best corrected visual acuity (BCVA) was supported in the two clinical studies. Eylea was generally well-tolerated in DME patients based on the safety data pooled from VISTA and VIVID through 12 months. The benefit/risk profile for the administration of Eylea for the expanded indication was considered positive. The data were reviewed and considered acceptable, and a Notice of Compliance was issued. |
| NDS # 168770 | 2013-10-21 | Issued NOC 2014-10-16 |
This New Drug Submission was submitted, prior to the initial approval of Eylea, to propose an additional new indication. The submission included data from two randomized, multicentre, double-masked, sham-controlled Phase III clinical trials (COPERNICUS and GALILEO). The efficacy in the improvement of best corrected visual acuity (BCVA) was supported in the two clinical trials. No new safety concerns were identified. The benefit/risk profile for the administration of Eylea for the expanded indication was considered positive as labelled. The Notice of Compliance was issued for the expanded indication of 'the treatment of visual impairment due to macular edema secondary to central retinal vein occlusion'. |
| Drug product (DIN 02415992) market notification | Not applicable | Date of first sale: 2013-12-23 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 149321 | 2011-08-17 | Issued NOC 2013-11-08 |
Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Eylea
Date SBD issued: 2014-01-09
The following information relates to the New Drug Submission for Eylea.
Aflibercept, 40 mg/mL, solution, intravitreal injection
Drug Identification Number (DIN):
- 02415992
Bayer Inc.
New Drug Submission Control Number: 149321
On November 8, 2013, Health Canada issued a Notice of Compliance to Bayer Inc. for the drug product, Eylea.
The market authorization was based on quality (chemistry and manufacturing), non clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Eylea administered every 2 months following 3 initial monthly doses is favourable for the treatment of neovascular (wet) age-related macular degeneration.
1 What was approved?
Eylea, an ophthalmological/antineovascularization agent, was authorized for the treatment of neovascular (wet) age-related macular degeneration (AMD). Eylea is a recombinant fusion protein consisting of portions of human Vascular Endothelial Growth Factor (VEGF) receptor 1 and 2 extracellular domains fused to the Fc portion of human immunoglobulin G1 (IgG1) and formulated as an iso osmotic solution for intravitreal injection.
Eylea is contraindicated for patients who are hypersensitive to this drug, to any ingredient in the formulation, or to any component of the container. Eylea is also contraindicated for patients with ocular or periocular infection, or active intraocular inflammation. Eylea was approved for use under the conditions stated in the Eylea Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Eylea (40 mg/mL, aflibercept) is presented as solution for intravitreal injection, single use vials for the treatment of a single eye. In addition to the medicinal ingredient, the solution contains sodium phosphate monobasic monohydrate, disodium phosphate dibasic heptahydrate, sodium chloride, sucrose, polysorbate 20, and water for injection.
For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Eylea Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Eylea approved?
Health Canada considers that the benefit/risk profile of Eylea administered every 2 months following 3 initial monthly doses is favourable for the treatment of neovascular (wet) age-related macular degeneration (AMD).
Neovascular AMD is the most common cause of legal blindness, affecting ~10% of individuals aged 65 to 74 years, and ~30% aged 75 to 85 years, and the current standard of care is anti-vascular epithelial growth factor (VEGF) therapy. Ranibizumab, a monoclonal antibody, was the first biologic treatment for AMD, authorised by Health Canada in June 2007, and is administered by monthly intravitreal injection. It has a high affinity to VEGF-A, which prevents it from binding to receptors and thereby inhibits abnormal growth of new blood vessels (retinal neovascularisation) and AMD. Eylea (aflibercept) is a recombinant protein which binds with high affinity VEGF-A and placental growth factor (PIGF), but can be injected every two months for the same purpose.
Eylea has been shown to be efficacious in patients with neovascular AMD. The market authorization was based on two randomized, multicentre, double blind, active controlled studies. Eylea 2 mg administered every 8 weeks following 3 initial monthly doses was shown to be non-inferior to ranibizumab 0.5 mg administered every 4 weeks, for the primary endpoint of vision maintenance (loss of <15 letters).
No clinically significant differences in safety were observed between the Eylea treatment groups compared to the ranibizumab treatment groups, except, as expected, fewer injection-related serious adverse events (SAEs) were reported in patients treated with Eylea 2 mg every 8 weeks versus the monthly regimens. The most common ocular SAEs were reduced visual acuity, retinal hemorrhage, retinal pigment epithelial tear, and endophthalmitis. The most common SAEs related to the injection procedure included endophthalmitis, traumatic cataract, increased intraocular pressure, and vitreous detachment. A potential risk of arterial thromboembolic events (ATEs) exists following intravitreal use of VEGF inhibitors, including Eylea. Appropriate warnings and precautions are in place in the Eylea Product Monograph to address the identified safety concerns.
A Risk Management Plan (RMP) for Eylea was submitted by Bayer Inc. to Health Canada. An updated RMP with Health Canada-target questionnaires for the AMD indication has been recently submitted. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
Overall, the therapeutic benefits seen in the pivotal studies are considered positive. Eylea has an acceptable safety profile with appropriate risk minimization measures based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and adequate monitoring as required in the RMP. Eylea is considered non-inferior to the comparator drug, ranibizumab, administered monthly. Fewer injection-related adverse events were reported and fewer injections and patient-visits are required with the bimonthly dose of Eylea, compared to monthly dosing. Therefore, the benefit/risk of Eylea for the treatment of neovascular AMD is considered positive, and the regimen of intravitreal injections every two months following 3 initial monthly doses is recommended.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Eylea?
A New Drug Submission (NDS) for Eylea was filed with Health Canada on August 17, 2011. Due to issues identified in the review of the chemistry and manufacturing information, a Notice of Deficiency (NOD) was issued for Eylea on June 4, 2012. The sponsor submitted a response to the NOD and all of the concerns that led to the NOD were satisfactorily addressed. The NOD response for Eylea entered the clinical and the chemistry and manufacturing review streams on January 14, 2013. The reviews were completed and the submission was found to be in compliance with the Food and Drugs Act and Regulations. A Notice of Compliance was issued on November 8, 2013.
Submission Milestones: Eylea
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2011-03-30 |
| Submission filed: | 2011-08-17 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2011-10-07 |
| Review 1 | |
| Quality Evaluation complete: | 2012-06-04 |
| Notice of Deficiency (NOD) issued by Director General (quality issues): | 2012-06-04 |
| Response filed: | 2012-12-02 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2013-01-14 |
| Review 2 | |
| On-Site Evaluation: | 2013-10-21 - 2013-10-25 |
| Quality Evaluation complete: | 2013-11-08 |
| Clinical Evaluation complete: | 2013-11-08 |
| Labelling Review complete: | 2013-11-08 |
| Notice of Compliance issued by Director General: | 2013-11-08 |
The Canadian regulatory decision on the non-clinical and clinical review of Eylea was based on a critical assessment of the Canadian data package. The foreign reviews completed by the United States Food and Drug Administration (FDA) were used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
As part of the marketing authorization for Eylea, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):
- Providing to Health Canada all post-marketing studies/ commitments for Eylea made to the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) when they become available.
- Before Eylea becomes commercially available, educational materials for this indication should be reviewed by Health Canada and distributed to ophthalmologists.
- Inform Health Canada about any safety signals, that is, increased incidence of any serious adverse events (SAEs), injection-related SAEs, etc. compared to clinical studies with Eylea and/or post-marketing data for the drug, ranibizumab.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are members of the VEGF family of pro-angiogenic factors that can act as potent mitogenic, chemotactic, and vascular permeability factors for endothelial cells. Vascular endothelial growth factor acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2. Excessive activation of these receptors by VEGF-A can result in pathological neovascularization and excessive vascular permeability which is believed to contribute to vision loss in a variety of ocular diseases, including neovascular (wet) age-related macular degeneration (AMD). Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF and thereby can inhibit the binding and activation of these cognate VEGF receptors.
The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Eylea for the specified indication.
For further details, please refer to the Eylea Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The safety and efficacy of Eylea (aflibercept) were assessed in two randomized, multicentre, double blind, active controlled studies (VIEW1 and VIEW2) in patients with neovascular (wet) AMD. Study VIEW1 was conducted in Canada and the United States of America. Study VIEW2 was conducted in Europe, Latin America and Asia. A total of 2,412 patients (ages 49 to 99 years, mean 76 years) were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens for 52 weeks. The four treatment groups were:
- Eylea administered at 2 mg every 8 weeks following 3 initial monthly doses (Eylea 2Q8);
- Eylea administered at 2 mg every 4 weeks (Eylea 2Q4);
- Eylea administered at 0.5 mg every 4 weeks (Eylea 0.5Q4); and
- Ranibizumab administered at 0.5 mg every 4 weeks (ranibizumab 0.5Q4).
Following the 52 weeks of treatment, the patients received the study drugs at intervals determined by visual and anatomic outcomes, for example, Best Corrected Visual Acuity (BCVA) letter score and retinal thickness.
The primary efficacy endpoint was the proportion of patients who maintained vision, defined as a loss of <15 letters using the BCVA letter score compared to Baseline at Week 52. The non-inferiority margin was 10%. The secondary efficacy variables included mean changes from Baseline to Week 52 in BCVA [the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score]; the proportion of patients who gained 15 or more letters; the total National Eye Institute 25-itemVisual Function Questionnaire score; and the evaluation of the choroidal neovascularisation area as assessed by fluorescein angiography.
The primary endpoint analysis [Per Protocol Set, Last Observation Carried Forward (LOCF)] tested the non-inferiority of Eylea to ranibizumab 0.5Q4 (non-inferiority margin of 10%). The proportion of patients who maintained vision at Week 52 were 95%, 96%, 95%, and 94% in Study VIEW1 and 96%, 96%, 96%, and 94% in Study VIEW2 in the Eylea 2Q4, 0.5Q4, 2Q8 and ranibizumab 0.5Q4 groups, respectively.
For the mean change from Baseline to Week 52 in BCVA (ETDRS letter score), the mean changes (Full Analysis Set, Last Observation Carried Forward) were 10.9, 6.9, 7.9 and 8.1 letters in Study VIEW1, and 7.6, 9.7, 8.9 and 9.4 letters in Study VIEW2 in the Eylea 2Q4, 0.5Q4, 2Q8 and ranibizumab 0.5Q4 groups, respectively.
For the proportion of patients who gained 15 or more letters, the results were 38%, 25%, 31% and 31% in Study VIEW1, and 29%, 35%, 31% and 34% in Study VIEW2, in the Eylea 2Q4, 0.5Q4, 2Q8, and ranibizumab 0.5Q4 groups, respectively.
In both pivotal studies, all three doses of Eylea were considered non-inferior to ranibizumab for the primary endpoint of vision maintenance (loss of <15 letters). However, based on the pre-defined conditional testing sequence used to control for multiple testing across the secondary endpoints, the statistical superiority of Eylea to ranibizumab across both studies was not demonstrated at any dose.
For more information, refer to the Eylea Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Eylea was evaluated primarily in the two pivotal studies described in the Clinical Efficacy section. A total of 1,824 patients with 12 months exposure to Eylea constituted the safety population in the two double blind active controlled clinical studies (VIEW1 and VIEW2). In both of these studies, 1,223 patients were treated with the Eylea 2 mg dose.
The most common (≥5%) adverse events (AEs) through Week 52 in patients treated with Eylea (all doses) were conjunctival hemorrhage (25%), eye pain (9%), cataract (7%), vitreous detachment (6%), vitreous floaters (6%), and increased intraocular pressure (5%). The most common ocular serious adverse events (SAEs) through Week 52 in patients treated with Eylea 2Q8 and ranibizumab 0.5Q4 included: reduced visual acuity [5 (0.8%) versus (vs.) 3 (0.5%)]; retinal hemorrhage [3 (0.5%) vs. 3 (0.5%)]; retinal tear [2 (0.3%) vs. 1 (0.2%)]; and endophthalmitis [0 (0.0%) vs. 3 (0.5%)], respectively. Non-ocular SAEs in patients treated with Eylea 2Q8 and ranibizumab 0.5Q4 included pneumonia [7 (1.1%) vs. 7 (1.2%)]; fall (6 (1.0%) vs. 7 (1.2%)]; and arteriothrombolic events [20 (3.3%) vs. 11 (1.8%)]; respectively.
Serious adverse reactions related to the injection procedure occurred in 16 of 2,419 patients (0.66%) and in 16 of 26,780 injections with either Eylea or ranibizumab, and included endophthalmitis, traumatic cataract, increased intraocular pressure, and vitreous detachment. Appropriate warnings and precautions are in the Eylea Product Monograph.
There are risks with arteriothrombolic events (ATEs) following intravitreal use of VEGF inhibitors, including Eylea. The ATEs, as defined by Antiplatelet Trialists' Collaboration (APTC) criteria, include nonfatal myocardial infarction, nonfatal stroke, or vascular death (including deaths of unknown cause). During the first year in both pivotal studies, the incidence of APTC events was 1.8% (32 out of 1,824) in the combined group of patients treated with Eylea compared with 1.5% (9 out of 595) in patients treated with ranibizumab.
No new safety signals were noted with Eylea compared to ranibizumab. In the pivotal studies, no clinically significant differences in SAEs across the three Eylea doses were noted, except fewer injection-related SAEs in patients treated with Eylea 2 mg every 8 weeks vs. ranibizumab 0.5 mg every 4 weeks [1(0.2%) vs. 8 (1.3%)]. The AEs and SAEs that were numerically more common with Eylea vs. ranibizumab, including ATEs, are appropriately captured in the Eylea Product Monograph.
A total of 157 patients were treated for up to 44 months in a long-term extension of Phase I and Phase II studies. The safety profile of Eylea was consistent with that seen in the Phase III studies.
Overall, Eylea was considered non-inferior to ranibizumab administered monthly for the treatment of neovascular (wet) AMD: however, fewer injection-related SAEs were reported in patients treated with Eylea 2 mg every two months vs. the monthly regimens. Therefore the regimen of administering intravitreal injections of Eylea 2 mg every two months following 3 initial monthly doses is recommended.
For more information, refer to the Eylea Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The results of the non-clinical studies as well as the potential risks to humans have been included in the Eylea Product Monograph.
Aflibercept produced embryo-fetal toxicity and teratogenicity when administered every three days during organogenesis to pregnant rabbits at all doses levels. Dose-related increases in fetal resorptions, abortions, and numerous fetal malformations were observed. The maternal no-observed adverse-effect-level (NOAEL) in these studies was 3 mg/kg. Administration of the lowest dose assessed in rabbits (0.1 mg/kg) resulted in a systemic exposure of approximately 10 times the systemic exposure observed in humans after an intravitreal dose of 2 mg.
Male and female fertility were evaluated as part of the 6-month intravenous toxicity study in monkeys. Absent or irregular menses, changes in female reproductive hormone levels, decreases in mean ovarian and uterus weights, ovarian and uterine microscopic alterations, reduced sperm motility, and sperm morphological abnormalities were observed at all dose levels. All changes were reversible.
Overall, the reproductive and developmental toxicity were well-characterised. Appropriate warnings and precautionary measures are in place in the Eylea Product Monograph to address the identified safety concerns. In view of the intended use of Eylea, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Eylea Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
A Notice of Deficiency (NOD) was issued on June 4, 2012 due mainly to deficiencies related to potency testing of Eylea drug substance and drug product. The sponsor submitted a response to the NOD and the issues outlined in the NOD were reviewed and considered acceptable. All recommendations were addressed by the sponsor in an acceptable manner.
Characterization of the Drug Substance
Aflibercept, the drug substance of Eylea, is a recombinant fusion protein consisting of portions of human VEGF receptor 1 and 2 extracellular domains fused to the Fc portion of human immunoglobulin G1 (IgG1).
Detailed characterization studies were performed to provide assurance that aflibercept consistently exhibits the desired characteristic structure. Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Aflibercept is produced in Chinese hamster ovary K1 cells by recombinant deoxyribonucleic acid (DNA) technology. The aflibercept drug substance manufacturing process consists of a series of steps which include cell culture, harvest, purification stages, including viral inactivation/removal steps, and formulation.
The manufacturing of the Eylea drug product consists of formulating aflibercept drug substance to produce aflibercept Formulated Bulk (FB), filling of FB into single-use vials, and labelling and packaging the vials for distribution.
Process consistency as well as adherence to product quality and safety requirements is monitored during manufacturing with in-process controls.
Process validation data demonstrate that the Eylea manufacturing process operates in a consistent manner, yielding product of acceptable quality.
The Eylea manufacturing process underwent several process changes during development. Data from product quality assessments demonstrate that Eylea produced by different manufacturing process versions is comparable and that there has been no significant impact on quality observed due to the associated process changes.
Control of the Drug Substance and Drug Product
The identity, quality and purity of drug product are assured by employing a similar battery of release tests used for testing of drug substance.
Copies of the analytical method protocols and, where appropriate, validation reports were provided for all analytical procedures used for release and stability of Eylea drug substance and drug product, and are considered satisfactory.
Batch analysis results were also reviewed and were found to comply with specifications demonstrating consistent quality of the batches produced.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The long-term drug product stability data support a 24-month shelf life when the product is stored refrigerated (2°-8°C) and protected from light and freezing.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.
An On-Site Evaluation of the facility involved in the manufacture and testing of aflibercept has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada. The facility was assigned a compliant rating with 2 minor observations that were resolved on site.
Adventitious Agents Safety Evaluation
The manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.
Raw materials of animal and recombinant DNA origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.