Summary Basis of Decision for Zirabev
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 Zirabev is located below.
Recent Activity for Zirabev
The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.
The following table describes post-authorization activity for Zirabev, a product which contains the medicinal ingredient bevacizumab. 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 found in Post-Authorization Activity Tables (PAATs).
For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.
Updated: 2024-03-08
Drug Identification Number (DIN):
DIN 02489430 - 100 mg/4 mL (25 mg/mL), bevacizumab, solution, intravenous administration
DIN 02489449 - 400 mg/16 mL (25 mg/mL), bevacizumab, solution, intravenous administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
SNDS # 277377 |
2023-07-19 |
Issued NOC 2023-10-19 |
Submission filed as Level II – Supplement (Safety) to update the PM to align with that of the reference biologic, Avastin. 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. An NOC was issued. |
|
SNDS # 269160 |
2022-11-30 |
Issued NOC 2023-03-28 |
Submission filed as a Level II – Supplement (Safety) to update the PM to align with that of the reference biologic, Avastin. The changes were in response to an Advisement Letter issued by Health Canada dated October 31, 2022, related to arterial (including aortic) aneurysms, dissections, and rupture. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM. An NOC was issued. |
|
SNDS # 262607 |
2022-03-21 |
Issued NOC 2022-10-24 |
Submission filed as a Level I – Supplement to establish conditions for the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
NC # 256956 |
2021-09-23 |
Issued NOL 2021-11-30 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the drug product release or shelf-life specifications. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 252359 |
2021-05-04 |
Issued NOL 2021-06-17 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the in-use shelf life of the diluted drug product in infusion bags. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NDS # 217524 |
2018-06-22 |
Issued NOC 2021-01-05 |
The submission was reviewed and considered acceptable, and an NOC was issued for the New Drug Submission. |
|
NC # 241314 |
2020-07-02 |
Issued NOL 2020-10-08 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a new product class to a manufacturing facility. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 235008 |
2020-01-09 |
Cancellation Letter Received 2020-02-21 |
Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. Health Canada did not consider the changes necessary and the sponsor cancelled the submission. |
|
NC # 234975 |
2020-01-08 |
Cancellation Letter Received 2020-02-21 |
Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. Health Canada did not consider the changes necessary and the sponsor cancelled the submission. |
|
Drug product (DINs 02489430, 02489449) market notification |
Not applicable |
Date of first sale: 2019-09-25 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NDS # 218183 |
2018-07-13 |
Issued NOC 2019-06-14 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Zirabev
Date SBD issued: 2019-11-15
The following information relates to the New Drug Submission for Zirabev.
Bevacizumab
Drug Identification Number (DIN):
- DIN 02489430 - 100 mg/4 mL (25 mg/mL), solution, intravenous administration
- DIN 02489449 - 400 mg/16 mL (25 mg/mL), solution, intravenous administration
Pfizer Canada ULC
New Drug Submission Control Number: 218183
On June 14, 2019, Health Canada issued a Notice of Compliance (NOC) to Pfizer Canada ULC for Zirabev, a biosimilar to Avastin (the reference biologic drug). The terms biosimilar biologic drug" and "biosimilar" are used by Health Canada to describe subsequent entry versions of a Canadian approved innovator biologic drug with demonstrated similarity to a reference biologic drug. Biosimilars were previously referred to as subsequent entry biologics in Canada. Both Zirabev and Avastin contain highly similar versions of the medicinal ingredient, bevacizumab.
Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. The weight of evidence is provided by the structural and functional studies, whereas the non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, pharmacokinetic and pharmacodynamic, and clinical studies.
The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in support of the indications being sought.
For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.
In this drug submission, Avastin is the reference biologic drug. Similarity between Zirabev and Avastin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Within this drug submission, the sponsor requested the authorization of Zirabev for four of the indications currently authorized for Avastin.
The market authorization of Zirabev was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. Similarity was established through data derived from comparative structural, functional, non-clinical and clinical studies. Based on Health Canada's review, the benefit-risk profile of Zirabev is considered to be highly similar to the reference biologic drug for the following indications (which include relevant caveat statements):
- Metastatic Colorectal Cancer
Zirabev in combination with fluoropyrimidine-based chemotherapy is indicated for first-line treatment of patients with metastatic carcinoma of the colon or rectum.
Consideration should be given to current standard of care guidelines for colorectal cancer.
See Drug-Drug Interactions section of the Zirabev Product Monograph for further information on the use of Zirabev in combination with irinotecan.
Please refer to the Product Monographs for irinotecan, 5-fluorouracil and leucovorin for additional information on these products, and specifically the Dosage and Administration sections for guidance on dose adjustments.
- Locally Advanced, Metastatic or Recurrent Non-Small Cell Lung Cancer
Zirabev, in combination with carboplatin/paclitaxel chemotherapy regimen, is indicated for treatment of patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer.
- Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer
Zirabev in combination with paclitaxel, topotecan or pegylated liposomal doxorubicin is indicated for the treatment of patients with recurrent, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens. These patients should not have received prior vascular endothelial growth factor (VEGF)-targeted therapy including Zirabev. The effectiveness of bevacizumab in platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer is based on a study in patients with disease progression within less than six months from the most recent platinum-based chemotherapy, with a minimum of four platinum therapy cycles completed. A statistically significant improvement in progression-free survival was seen. No overall survival benefit was demonstrated with bevacizumab.
- Malignant Glioma (World Health Organization Grade IV) - Glioblastoma
Zirabev, in combination with lomustine, is indicated for the treatment of patients with glioblastoma after relapse or disease progression, following prior therapy.
The efficacy of bevacizumab in relapsed glioblastoma is based on an improvement in progression-free survival, while an improvement in overall survival was not demonstrated in study EORTC 26101.
1 What was approved?
Zirabev is an antineoplastic drug. It was authorized for the treatment of the following diseases (the indications include relevant caveat statements):
- Metastatic Colorectal Cancer
Zirabev in combination with fluoropyrimidine-based chemotherapy is indicated for first-line treatment of patients with metastatic carcinoma of the colon or rectum.
Consideration should be given to current standard of care guidelines for colorectal cancer.
See Drug-Drug Interactions section of the Zirabev product Monograph for further information on the use of Zirabev in combination with irinotecan.
Please refer to the Product Monographs for irinotecan, 5-fluorouracil and leucovorin for additional information on these products, and specifically the Dosage and Administration sections for guidance on dose adjustments.
- Locally Advanced, Metastatic or Recurrent Non-Small Cell Lung Cancer
Zirabev, in combination with carboplatin/paclitaxel chemotherapy regimen, is indicated for treatment of patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer.
- Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer
Zirabev in combination with paclitaxel, topotecan or pegylated liposomal doxorubicin is indicated for the treatment of patients with recurrent, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens. These patients should not have received prior vascular endothelial growth factor (VEGF)-targeted therapy including Zirabev. The effectiveness of bevacizumab in platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer is based on a study in patients with disease progression within less than six months from the most recent platinum-based chemotherapy, with a minimum of four platinum therapy cycles completed. A statistically significant improvement in progression-free survival was seen. No overall survival benefit was demonstrated with bevacizumab.
- Malignant Glioma (World Health Organization Grade IV) - Glioblastoma
Zirabev, in combination with lomustine, is indicated for the treatment of patients with glioblastoma after relapse or disease progression, following prior therapy.
The efficacy of bevacizumab in relapsed glioblastoma is based on an improvement in progression-free survival, while an improvement in overall survival was not demonstrated in study EORTC 26101.
Zirabev is a biosimilar to Avastin. Both drugs contain the medicinal ingredient bevacizumab, a recombinant humanized monoclonal antibody that selectively binds to and neutralizes the biologic activity of human VEGF.
Similarity between Zirabev and the reference biologic drug, Avastin, has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, a comparative pharmacokinetic study in healthy male volunteers, and a comparative efficacy and safety study in patients with advanced non-squamous non-small cell lung cancer, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Zirabev is contraindicated in:
- patients who are hypersensitive to this drug, Chinese hamster ovary cell products or other recombinant human or humanized antibodies or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container;
- patients with untreated central nervous system metastases.
The safety and efficacy of Zirabev in pediatric (younger than 18 years of age) patients have not been assessed. Therefore, Health Canada has not authorized an indication for pediatric use.
In randomized clinical trials, patients over 65 years of age had an increased risk of developing arterial thromboembolic events including cerebrovascular accidents, transient ischemic attacks, myocardial infarction, proteinuria, grade 3-4 leukopenia, neutropenia, thrombocytopenia, diarrhea, and fatigue as compared to those 65 years of age and younger when treated with bevacizumab. The risk and benefit of Zirabev administration in patients over 65 years of age should be carefully evaluated prior to initiating therapy.
Zirabev was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Zirabev (25 mg/mL bevacizumab) is presented as a solution. In addition to the medicinal ingredient, the solution contains edetate disodium dihydrate (EDTA), polysorbate 80, sodium hydroxide, succinic acid, sucrose, and water for injection.
For more information, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.
Additional information may be found in the Zirabev Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Zirabev approved?
Health Canada considers that the benefit-risk profile of Zirabev is highly similar to the reference biologic drug Avastin for the treatment of metastatic colorectal cancer, locally advanced, metastatic or recurrent non-small cell lung cancer, platinum-resistant recurrent epithelial ovarian, fallopian tube and primary peritoneal cancer, and malignant glioma (World Health Organization grade IV) - glioblastoma. Similarity between Zirabev and Avastin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Zirabev is considered to be a biosimilar to Avastin. In Canada, Avastin is authorized for the treatment of metastatic colorectal cancer, locally advanced, metastatic or recurrent non-small cell lung cancer, platinum-sensitive recurrent epithelial ovarian, fallopian tube and primary peritoneal cancer, platinum-resistant recurrent epithelial ovarian, fallopian tube and primary peritoneal cancer, and malignant glioma (World Health Organization grade IV) - glioblastoma.
The New Drug Submission filed for Zirabev requested authorization for four of the five indications and clinical uses currently authorized for Avastin. The indications have been authorized on the basis of demonstrated similarity between Zirabev and the reference biologic drug.
Based on comparative structural and functional studies, the biosimilar and the reference biologic drug were judged highly similar in terms of quality attributes.
To support the clinical comparability of Zirabev to Avastin, the sponsor provided evidence of the pharmacokinetic similarity of Zirabev and Avastin in healthy male volunteers. The sponsor also provided the results of a Phase III, randomized, double-blind, equivalence trial of Zirabev plus paclitaxel-carboplatin versus Avastin plus paclitaxel-carboplatin for the first-line treatment of patients with advanced non-squamous non-small cell lung cancer. The trial met its primary efficacy endpoint by demonstrating similarity in the objective response rate. The reported objective response rate, as determined by local review using the Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in the intent-to-treat population, was 45.3% and 44.6% in the Zirabev and Avastin arm, respectively. The 95% confidence interval (CI) of the risk ratio (RR) for Zirabev versus Avastin in the objective response rate (RR = 1.01, 95% CI [0.863, 1.193]) was fully contained within the prespecified margin (0.729, 1.371). No clinically meaningful differences were identified in the results of the comparative safety or immunogenicity assessment.
Zirabev has demonstrated a comparable safety profile with its reference product, Avastin. Therefore, the Adverse Reactions section of the biosimilar Product Monograph is based on the clinical experience with the reference biologic drug. Furthermore, as with Avastin, a Serious Warnings and Precautions box has been included in the Zirabev Product Monograph to highlight the reports of serious local and systemic adverse events with unauthorized intravitreal use, gastrointestinal perforations, wound healing complications, and hemorrhage.
A Risk Management Plan (RMP) for Zirabev was submitted by Pfizer Canada ULC to Health Canada. Upon review, the RMP was considered to be acceptable. 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.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Zirabev was accepted.
Overall, the therapeutic benefits of Zirabev for the authorized indications are expected to be similar to the known benefits of the reference biologic drug, Avastin, and are considered to outweigh the potential risks. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Zirabev Product Monograph to address the identified safety concerns.
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 Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.
3 What steps led to the approval of Zirabev?
Submission Milestones: Zirabev
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2017-05-31 |
| Submission filed: | 2018-07-13 |
| Screening | |
| Screening Acceptance Letter issued: | 2018-08-17 |
| Review | |
| On-Site Evaluation: | 2019-01-21 - 2019-01-25 |
| Review of Risk Management Plan complete: | 2019-04-23 |
| Quality Evaluation complete: | 2019-06-10 |
| Clinical/Medical Evaluation complete: | 2019-06-10 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2019-06-12 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2019-06-14 |
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?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
The onus is on the sponsor to monitor the post-market safety profile of this biosimilar product as well as the Product Monograph of the reference biologic drug for safety signals that could impact the biosimilar, and make safety updates to the Zirabev Product Monograph as appropriate. New safety issues that are first identified with the biosimilar, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both the biosimilar and the reference biologic drug. For more information, refer to the Fact Sheet: Biosimilars.
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.
- 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 Quality Basis for Decision
Zirabev was developed as a biosimilar to the reference biologic drug, Avastin. For biosimilars, the weight of evidence is provided by structural and functional studies. In addition to a typical chemistry and manufacturing data package that is submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity with the reference biologic drug.
Comparative Structural and Functional Studies
A three-way similarity assessment was conducted using lots of Avastin sourced from the European Union (Avastin-EU), lots of Avastin sourced from the United States (Avastin-US), and lots of Zirabev.
The biosimilarity study evaluated a variety of attributes including physicochemical properties, biological activity, purity and impurity profiles, and stability profiles including forced degradation conditions. Quality attributes were identified and assessed for their potential to affect activity, pharmacokinetics/pharmacodynamics, safety and immunogenicity, as well as for their relevance in establishing biosimilarity.
The results of the biosimilarity studies demonstrate that Zirabev is identical to Avastin concerning the primary structure and highly similar with regard to higher order structure, post-translational modifications, and potency.
Differences were observed with respect to charge variants and purity. The lots of Zirabev have lower levels of high molecular mass species, fragments and higher levels of basic species. However, it was determined that these differences do not affect the potency of Zirabev and are unlikely to be clinically meaningful.
Comparative stability and forced degradation studies using different stress conditions generated similar degradation profiles for Zirabev, Avastin-US, and Avastin-EU, further supporting similarity of the three products.
Together, these results indicate that Zirabev is highly similar to Avastin-EU, and support the quality requirements for Zirabev to be considered a biosimilar to Avastin.
Characterization of the Drug Substance
Bevacizumab is a recombinant humanized monoclonal immunoglobulin G of the subclass 1 kappa (IgG1κ), composed of two identical heavy and two identical light chains. The molecular mass is approximately 149,000 Da. The antibody selectively binds to human vascular endothelial growth factor (VEGF) and inhibits the binding of VEGF to its receptors, Flt-1 and KDR, on the surface of endothelial cells. Neutralizing the biologic activity of VEGF reduces the vascularization of tumours, thereby inhibiting tumour growth.
Detailed characterization studies were performed to provide assurance that bevacizumab consistently exhibits the desired characteristic structure and biological activity.
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 and acceptable limits.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The drug substance, bevacizumab, is produced by recombinant deoxyribonucleic acid (rDNA) technology in a mammalian cell expression system (Chinese hamster ovary [CHO] cell line). The final cell culture is harvested, clarified, and subsequently purified using a series of chromatographic steps. Viral inactivation and clearance are achieved by low pH, anion-exchange chromatography and nanofiltration. Following purification, the bulk drug substance is filtered into the drug substance containers pending batch disposition.
The drug product, Zirabev, is manufactured using common methodologies for the production of aseptic protein products including sterilization by filtration of the bulk solution, aseptic filling into sterile glass vials, and closing with sterile rubber closures. Zirabev is a single-use, preservative-free, liquid concentrate for infusion containing 25 mg/mL bevacizumab. The presentations of Zirabev, 400 mg/16 mL and 100 mg/4 mL (both with concentration of 25 mg/mL bevacizumab), are manufactured using the same process steps and controls. The only differences between the presentations are the fill volume and the container closure size. All other manufacturing steps and process parameters are the same.
The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of bevacizumab with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.
Through Health Canada's lot release testing and evaluation program, final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.
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 proposed 36-month shelf life for Zirabev is considered acceptable, when stored at a temperature of 2ºC to 8ºC and protected from light.
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 (OSE) of the facility involved in the manufacture and testing of the drug substance has been conducted by Health Canada, with a satisfactory rating.
Based on the OSE risk assessment score, an OSE for the drug product manufacturing site was not deemed necessary.
Both sites involved in production are compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
The drug substance 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) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.
The biologic raw materials originate from sources with minimal risk of transmissible spongiform encephalopathy and therefore are considered suitable for the production of Zirabev.
7.2 Non-Clinical Basis for Decision
For biosimilars, the degree of similarity at the quality level determines the scope and the breadth of the required non-clinical data. Non-clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty.
The non-clinical database submitted for Zirabev was in compliance with the requirements for non-clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
No biologically significant functional differences between Zirabev and Avastin sourced from the United States (Avastin-US) or Zirabev and Avastin sourced from the European Union (Avastin-EU) were observed in the pharmacological studies that compared vascular endothelial growth factor (VEGF) binding, inhibition of cell growth, and the absence of Fc-mediated effector functions. A four-week comparative repeat-dose toxicity study in young cynomolgus monkeys demonstrated comparable toxicokinetic and toxicology profiles for Zirabev and Avastin. The non-clinical findings are supportive of similarity between Zirabev and Avastin.
The results of the comparative non-clinical studies have been included in the Zirabev Product Monograph. In view of the intended use of Zirabev, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Zirabev Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Clinical basis for decision
The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in support of the indications being sought, and therefore clinical trials are not required to support each indication.
For biosimilars, the purpose of the clinical program is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The degree of similarity at the quality level determines the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.
Comparative Pharmacokinetics
The medicinal ingredient in Zirabev, bevacizumab, is a recombinant humanized monoclonal antibody that selectively binds to and neutralizes the biologic activity of human vascular endothelial growth factor (VEGF). Bevacizumab inhibits the binding of VEGF to its receptors, Flt-1 and KDR, on the surface of endothelial cells. Neutralizing the biologic activity of VEGF reduces the vascularization of tumours, thereby inhibiting tumour growth.
The sponsor submitted data from a comparative pharmacokinetic Phase I study (B7391001) of a parallel three-arm design, conducted in 97 healthy male subjects. The study provided three sets of complete pharmacokinetic profiles over time for a single dose of 5 mg/kg, administered by intravenous infusion of the test and reference drugs (Zirabev and bevacizumab products sourced from the European Union [bevacizumab-EU] and the United States [bevacizumab-US]). In all comparisons, the estimated ratios of the area under the serum concentration-time from time 0 to the last quantifiable concentration (AUCt) and the maximum observed serum concentration (Cmax) were within the accepted prespecified criteria for pharmacokinetic similarity of 80.0%-125.0%.
For further details, please refer to the Zirabev Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Clinical Efficacy, Safety, and Immunogenicity
The comparative clinical efficacy, safety, and immunogenicity of Zirabev and its reference biologic drug Avastin were evaluated in one comparative clinical trial (Study B7391003).
Study B7391003 was a randomized, double-blind, multicentre, equivalence trial of Zirabev versus Avastin for the first-line treatment of patients with advanced (unresectable, locally advanced, recurrent or metastatic) non-squamous non-small cell lung cancer. The study enrolled 719 patients. Patients with non-small cell lung cancer are considered a sensitive population to detect clinically meaningful differences between treatment groups in the analysis of the objective response rate.
Patients were randomized (1:1) to receive either 15 mg/kg of Zirabev or Avastin in combination with paclitaxel (200 mg/m2) and carboplatin (target area under the concentration-time curve [AUC] 6) once every three weeks for at least four cycles and no more than six cycles, followed by blinded bevacizumab monotherapy until disease progression, unacceptable toxicity or withdrawal from the study. The primary efficacy endpoint was the objective response rate (assessed by the investigator) based on evaluating the best overall response achieved by week 19 and subsequently confirmed six weeks later, in accordance with the Response Evaluation Criteria in Solid Tumours (RECIST version 1.1). The results of the safety and immunogenicity endpoints were based on data analyzed at 55 weeks.
The objective response rate was 45.3% and 44.6% in the Zirabev and Avastin arm, respectively. The trial met its primary efficacy endpoint by demonstrating that the 95% confidence interval (CI) of the risk ratio (RR) for Zirabev versus Avastin in the objective response rate (RR = 1.01, 95% CI [0.863, 1.193]) was fully contained within the prespecified margin (0.729, 1.371).
The safety analysis population included 356 patients who received Zirabev and 358 patients who received Avastin. The proportions of patients who experienced treatment-emergent adverse events (96.6% versus 96.9%), Grade 3-5 (48% versus 48%), Grade 5 (5.9% versus 6.7%) and serious treatment-emergent adverse events (22.8% versus 22.3%) were comparable in the Zirabev and Avastin treatment arms. Similar proportions of patients died in each treatment group (40.2% in the Zirabev arm and 41.3% in the Avastin arm).
The proportions of patients who discontinued any treatment due to treatment-emergent adverse events were also similar in the two treatment arms (23.9% in the Zirabev arm and 24.0% in the Avastin arm). While the proportion of patients who discontinued bevacizumab treatment due to treatment-emergent adverse events was higher in the Zirabev arm (17.7%) compared to the Avastin arm (13.7%), the difference was not considered clinically meaningful.
Adverse events of special interest were also comparable between the Zirabev and Avastin arms. These events included arterial thromboembolic events (2.2% versus 2.0%), cardiac disorders (8.1% versus 8.1%), congestive heart failure (1.1% versus 2.5%), hypertension (grade ≥3) (9.6% versus 8.9%), proteinuria/nephrotic syndrome (7.9% versus 9.5%), venous thromboembolic events (3.7% versus 3.1%), gastrointestinal perforation (0% versus 0.8%) and wound healing complications (0.3% versus 0%). Although the percentage of patients with hemorrhagic (bleeding) events was slightly higher with Zirabev (23.3% versus 19.3% with Avastin), this was not considered clinically meaningful as the difference was small and driven by grade 1 and 2 events.
Overall, six patients (1.7%) in the Zirabev arm and seven patients (2.0%) in the Avastin arm tested positive for anti-drug antibodies during the trial. Neutralizing antibodies were detected in one patient in the Zirabev arm and in three patients in the Avastin arm. No clear effect of the anti-drug antibody status on safety or efficacy could be established based on the limited number of patients who developed anti-drug antibodies to bevacizumab. The low proportion of patients with anti-drug antibodies is consistent with historical data, which indicates that bevacizumab has a low immunogenic potential.
Overall, the safety profile of Zirabev is considered to be comparable to that which has been established for the reference biologic drug Avastin. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warnings and Precautions section of the Zirabev Product Monograph, as they are in the Product Monograph for Avastin.
For more information, refer to the Zirabev Product Monograph, approved by Health Canada and available through the Drug Product Database.
Indications
Zirabev is considered to be a biosimilar to Avastin, the reference biologic drug. Avastin is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Avastin is authorized are metastatic colorectal cancer, locally advanced, metastatic or recurrent non-small cell lung cancer, platinum-sensitive recurrent epithelial ovarian, fallopian tube and primary peritoneal cancer, platinum-resistant recurrent epithelial ovarian, fallopian tube and primary peritoneal cancer, and malignant glioma (World Health Organization grade IV) - glioblastoma.
Within this drug submission, the sponsor requested the authorization of Zirabev for four of the indications currently authorized for Avastin.
Zirabev has been authorized for the treatment of the following diseases (the indications include relevant caveat statements):
- Metastatic Colorectal Cancer
Zirabev in combination with fluoropyrimidine-based chemotherapy is indicated for first-line treatment of patients with metastatic carcinoma of the colon or rectum.
Consideration should be given to current standard of care guidelines for colorectal cancer.
See Drug-Drug Interactions section of the Zirabev product Monograph for further information on the use of Zirabev in combination with irinotecan.
Please refer to the Product Monographs for irinotecan, 5-fluorouracil and leucovorin for additional information on these products, and specifically the Dosage and Administration sections for guidance on dose adjustments.
- Locally Advanced, Metastatic or Recurrent Non-Small Cell Lung Cancer
Zirabev, in combination with carboplatin/paclitaxel chemotherapy regimen, is indicated for treatment of patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer.
- Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer
Zirabev in combination with paclitaxel, topotecan or pegylated liposomal doxorubicin is indicated for the treatment of patients with recurrent, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens. These patients should not have received prior vascular endothelial growth factor (VEGF)-targeted therapy including Zirabev. The effectiveness of bevacizumab in platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer is based on a study in patients with disease progression within less than six months from the most recent platinum-based chemotherapy, with a minimum of four platinum therapy cycles completed. A statistically significant improvement in progression-free survival was seen. No overall survival benefit was demonstrated with bevacizumab.
- Malignant Glioma (World Health Organization Grade IV) - Glioblastoma
Zirabev, in combination with lomustine, is indicated for the treatment of patients with glioblastoma after relapse or disease progression, following prior therapy.
The efficacy of bevacizumab in relapsed glioblastoma is based on an improvement in progression-free survival, while an improvement in overall survival was not demonstrated in study EORTC 26101.
Similarity between Zirabev and Avastin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug, and therefore clinical trials are not required to support each indication. The indications have been authorized on the basis of demonstrated similarity between Zirabev and the reference biologic drug, in structural and functional studies, non-clinical and clinical studies.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ZIRABEV | 02489430 | PFIZER CANADA ULC | BEVACIZUMAB 100 MG / 4 ML |
| ZIRABEV | 02489449 | PFIZER CANADA ULC | BEVACIZUMAB 400 MG / 16 ML |