Summary Basis of Decision for Aybintio

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Aybintio is located below.

Recent Activity for Aybintio

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 Aybintio, 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: 2024-07-15

Drug Identification Number (DIN):

  • DIN 02522829 – 100 mg/4 mL (25 mg/mL) bevacizumab, solution, intravenous administration
  • DIN 02522837 – 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 # 283594 2024-02-16 Issued NOC 2024-06-27 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information, and to delete the clinical comparative study results of Aybintio from the PM. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications; Contraindications; Warnings and Precautions; Adverse Reactions; Drug Interactions; Clinical Pharmacology; Clinical Trials; Non-Clinical Toxicology, sections of the PM, and corresponding changes were made to Patient Medication Information and to the package insert. An NOC was issued.
NC # 270720 2022-12-15 Issued NOL 2023-02-10 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance release or shelf-life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 267861 2022-09-20 Issued NOC 2023-01-30 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration and Adverse Reactions sections of the PM, and corresponding changes were made to Patient Medication Information and to the package insert. An NOC was issued.
SNDS # 265037 2022-06-15 Issued NOC 2023-01-13 Submission filed as a Level I – Supplement to add a manufacturing site for the production of the drug product. The submission was reviewed and considered acceptable, and an NOC was issued.
Drug product (DINs 02522829, 02522837) market notification Not applicable Date of first sale: 2022-06-27 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 247724 2020-12-18 Issued NOC 2021-11-30 NOC issued for New Drug Submission.
NDS # 247369 2020-12-11 Issued NOC 2021-11-30 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Aybintio

Date SBD issued: 2022-02-04

The following information relates to the New Drug Submission for Aybintio.

Bevacizumab

Drug Identification Number (DIN):

  • DIN 02522829 - 100 mg/4 mL (25 mg/mL), solution, intravenous administration
  • DIN 02522837 - 400 mg/16 mL (25 mg/mL), solution, intravenous administration

Samsung Bioepis Co., Ltd.

New Drug Submission Control Number: 247369, 247724

 

On November 30, 2021, Health Canada issued a Notice of Compliance (NOC) to Samsung Bioepis Co., Ltd. for Aybintio, 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. Aybintio contains the medicinal ingredient bevacizumab, which has been demonstrated to be highly similar to bevacizumab contained in the reference product, Avastin.

Authorization of a biosimilar means that the product 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 for similarity 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, 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 the indications being sought and therefore clinical trials are not required to support each indication. For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.

Within this submission (Control Number 247369), the sponsor requested the authorization of Aybintio for all of the indications currently granted to Avastin, the reference biologic drug (see What steps led to the approval of Aybintio?). Similarity between Aybintio and Avastin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The market authorization of Aybintio was based on the quality (chemistry and manufacturing) package submitted and 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 Aybintio is considered to be similar to the benefit-risk profile of the reference product, and is therefore considered favourable for the following indications (the indications include relevant caveat statements):

  • Metastatic Colorectal Cancer

    Aybintio, 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 the Drug-Drug Interactions section of the Aybintio Product Monograph for further information on the use of Aybintio 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

    Aybintio, in combination with a carboplatin/paclitaxel chemotherapy regimen, is indicated for the treatment of patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer.
     
  • Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer

    Aybintio, in combination with carboplatin and gemcitabine, is indicated for the treatment of patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer. These patients should not have received prior vascular endothelial growth factor (VEGF)-targeted therapy including Aybintio.
     

    The effectiveness of bevacizumab in platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer is based on an improvement of progression-free survival in patients who had first recurrence after six months of platinum-based chemotherapy. No overall survival benefit was demonstrated with bevacizumab.
     

  • Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer

    Aybintio, 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 VEGF-targeted therapy including Aybintio.

    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

    Aybintio, 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?

 

Aybintio is an antineoplastic agent. It was 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.

Aybintio 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 vascular endothelial growth factor.

Similarity between Aybintio 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 metastatic or recurrrent non-squamous non-small cell lung cancer, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Aybintio is contraindicated in:

  • Patients with known hypersensitivity to any components of the product, Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
  • Patients with untreated central nervous system metastases.

The safety and efficacy of Aybintio in pediatric (younger than 18 years of age) patients have not been established. Therefore, Health Canada has not authorized an indication for pediatric use.

The risk and benefit of Aybintio administration in patients over 65 years of age should be carefully evaluated prior to initiating therapy. In randomized clinical trials, patients older than 65 years of age had an increased risk of developing arterial thromboembolic events (including cerebrovascular accidents, transient ischemic attacks, myocardial infarction), grades 3-4 leukopenia, neutropenia, thrombocytopenia, proteinuria, diarrhea, and fatigue, as compared to those 65 years of age and younger when treated with bevacizumab.

Aybintio 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.

Aybintio (25 mg/mL bevacizumab) is presented as a solution, supplied in a single-use vial as either 100 mg bevacizumab in 4 mL or 400 mg bevacizumab in 16 mL. In addition to the medicinal ingredient, the solution contains acetic acid, polysorbate 20, sodium acetate trihydrate, trehalose dihydrate, 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 Aybintio Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Aybintio approved?

 

Aybintio is considered to be a biosimilar to the reference biologic drug, Avastin. Similarity between Aybintio and Avastin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

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 (Control Number 247369) filed for Aybintio requested authorization for all five indications currently granted to Avastin. Based on Health Canada’s review, the benefit‑risk profile of Aybintio is considered to be similar to the benefit-risk profile of Avastin. Therefore, the benefit-risk profile of Aybintio is considered favourable 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.

Based on comparative structural and functional studies, Aybintio and Avastin were judged highly similar in terms of quality attributes. To support the clinical comparability of Aybintio with Avastin, the sponsor provided evidence of the pharmacokinetic similarity between Aybintio and Avastin in healthy male volunteers. The sponsor also provided the efficacy and safety results of a Phase III, randomized, double-blind study of Aybintio plus paclitaxel and carboplatin chemotherapy versus Avastin plus paclitaxel and carboplatin chemotherapy in patients with metastatic or recurrent non-squamous non-small cell lung cancer. The study demonstrated similarity in the primary efficacy endpoint, defined as the proportion of patients whose best overall response was either complete response or partial response according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 during the induction treatment period by 24 weeks. In the randomized population (i.e., intention-to-treat population), the proportion of patients achieving the best overall response rate by 24 weeks was 47.6% (181/379) in the Aybintio group and 42.8% (164/384) in the Avastin group. The risk ratio of best overall response rate between Aybintio and Avastin was 1.11, with a 95% confidence interval of 0.952 to 1.302, which was contained within the predefined equivalence margins of 0.737 to 1.357. No clinically meaningful differences were identified in the results of the comparative safety or immunogenicity assessment.

Aybintio 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 Aybintio Product Monograph to highlight the reports of serious local and systemic adverse events with unauthorized intravitreal use, development of gastrointestinal perforations, wound healing complications, and hemorrhage.

Serious adverse reactions reported during post-marketing use of bevacizumab are also listed in the Aybintio Product Monograph.

A Risk Management Plan (RMP) for Aybintio was submitted by Samsung Bioepis Co., Ltd. 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.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Aybintio Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Aybintio was accepted.

Overall, the therapeutic benefits of Aybintio 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 Aybintio 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 Aybintio?

 

The sponsor submitted in parallel two drug submissions for Aybintio. Their contents differed solely in relation to the number of indications sought for the biosimilar drug:

  • The New Drug Submission (NDS) Control Number 247369 requested authorization of Aybintio for use in all of the five indications currently held by the reference biologic drug Avastin:
    • 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 NDS Control Number 247724 requested authorization for use of Aybintio in three of the five indications currently held by the reference drug Avastin:
    • metastatic colorectal cancer,
    • locally advanced, metastatic or recurrent non-small cell lung cancer, and
    • malignant glioma (World Health Organization grade IV) - glioblastoma.

With this approach, agreed upon by Health Canada, the sponsor sought to avoid the potential of a delay in the authorization process of Aybintio because of two patent-restricted indications of Avastin (as per the Patent Register) at the time of filing the Aybintio submissions.

Upon finalization of the review, Health Canada issued a Notice of Compliance for each of the submissions on November 30, 2021.

The Canadian regulatory decision regarding Aybintio was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the European Medicines Agency and sponsor’s correspondence with the United States Food and Drug Administration were used as added references.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

 

Submission Milestones: Aybintio

Submission Milestone Date
New Drug Submission Control Number 247369 filed 2020-12-11
New Drug Submission Control Number 247724 filed 2020-12-18
Screening  
Screening Acceptance Letter issued 2021-02-03
Review  
Review of Risk Management Plan completed 2021-09-30
Biostatistics evaluation completed 2021-10-30
Quality evaluation completed 2021-11-10
Non-clinical evaluation completed 2021-11-15
Clinical/medical evaluation completed 2021-11-15
Labelling review completed 2021-11-24
Notice of Compliance issued by Director General, Biologics and Radiopharmaceutical Drugs Directorate 2021-11-30

 

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 Aybintio sponsor to monitor the post-market safety profile of this biosimilar 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 Aybintio 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.

 

5 What post-authorization activity has taken place for Aybintio?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (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 PAAT will continue to be updated during the product life cycle.

The PAAT for Aybintio is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up-to-date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Quality Basis for Decision

 

Aybintio was developed as a biosimilar to the reference biologic drug Avastin. For biosimilars, the weight of evidence for similarity is provided by structural and functional studies. Biosimilars are manufactured to the same regulatory standards as other biologic drugs. 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 biosimilarity assessment was performed using lots of European Union (EU)-sourced Avastin and lots of Aybintio. European Union (EU)-sourced Avastin is considered a suitable proxy for Avastin authorized in Canada as it meets all of the requirements set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

A variety of attributes were evaluated: physicochemical properties, biological activity, purity and impurity profiles, and stability profiles including forced degradation conditions. Quality attributes were identified and assessed in terms of their potential to affect activity, pharmacokinetics and pharmacodynamics, safety and immunogenicity, and in terms of their relevance in establishing biosimilarity.

Some differences were detected in the physicochemical attributes. Additional C- and N-terminal sequence variants were present at low levels only in Aybintio. These sequence variants are extensions at the ends of the amino acid chain and do not represent amino acid insertions within the protein. Therefore, they are considered as product-related substances. The low levels of these sequence variants in Aybintio are not likely to be clinically meaningful, as no adverse effects on the safety and efficacy of the drug product have been observed. The sponsor committed to validate the dedicated method for detection of the relative content of C-terminal sequence variants and submit the relevant documents to Health Canada as a post-Notice of Compliance change.

A characterization study clearly demonstrated that both Aybintio and Avastin lacked antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activity.

Minor differences observed in impurity profiles showed no impact on potency, and are unlikely to be clinically meaningful. Comparative stability and forced degradation studies demonstrated similar degradation pathways.

Overall, the biosimilarity assessment results support the conclusion that Aybintio is highly similar to Avastin.

Characterization of the Drug Substance

Bevacizumab is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to human vascular endothelial growth factor (VEGF) and inhibits the binding of VEGF to its receptors, vascular endothelial growth factor receptor 1 (VEGFR1, also known as fms-like tyrosine kinase‑1 [Flt‑1]) and VEGFR2 (also known as kinase insert domain receptor [KDR]), on the surface of endothelial cells. Neutralizing the biologic activity of VEGF reduces the vascularization of tumours, thereby inhibiting tumour growth. The antibody has a molecular weight of 149 kDa and is composed of two identical heavy chains and two identical light chains.

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 is produced using Chinese hamster ovary cells, which have been genetically engineered to express bevacizumab (also referred to as SB8).

The cell culture process is initiated with the use of one thawed vial of cells from the SB8 working cell bank and the cells are expanded in multiple steps until a sufficient cell density is obtained to inoculate the fed-batch production bioreactor. At harvest, the cell culture fluid is clarified by centrifugation and depth filtration, followed by a virus inactivation step. After harvest, SB8 (the drug substance) is captured and purified by a series of chromatography steps, viral inactivation and removal, ultrafiltration and diafiltration, followed by formulation, final filtration, and filling into storage bags. All drug substance batches were manufactured at the commercial site using the commercial process.

Controls of critical steps of the drug substance manufacturing process were established during manufacturing development, based on a risk assessment and the results of process characterization. Process validation was conducted on four drug substance lots manufactured at the commercial scale. The process validation study has demonstrated that the manufacturing process is capable of consistently manufacturing Aybintio drug substance that meets the desired quality attributes.

The drug product manufacturing process consists of thawing and mixing of the drug substance, dilution with formulation buffer to the target protein concentration, bioburden reduction, sterilization by filtration, filling, stoppering, and capping prior to labelling and packaging. The two SB8 drug product presentations, 100 mg/4 mL (25 mg/mL) and 400 mg/16 mL (25 mg/mL), are manufactured using the same process.

Controls of critical steps of the drug product manufacturing process were established during manufacturing development, based on a risk assessment and the results of process characterization. Process validation was conducted on six consecutive lots of drug product manufactured at the minimum and maximum commercial batch sizes for each of the two presentations. The process validation study demonstrated that the drug product manufacturing process is capable of consistently manufacturing Aybintio drug product that meets the desired quality attributes.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by 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 proposed release and stability specifications for the drug substance and drug product were suitably justified. In-house analytical methods were validated according to relevant International Council for Harmonisation guidelines and compendial methods were in compliance with pharmacopeia standards. All drug substance and drug product batches met the release and stability acceptance criteria.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The results support the consistency of the manufacturing process.

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 stability data support the proposed shelf life of 36 months for the drug product, when stored at 2 °C to 8 °C and protected from light. The product should not be frozen or shaken.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

Based on risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

Overall, the design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured. Both production sites 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. Purification process steps designed to inactivate and remove any potential viral contaminants from the cell culture process are adequately validated. Endotoxin levels and bioburden are adequately controlled throughout the manufacturing process.

Materials of biological origin are properly sourced and tested. Accordingly, the risk of contamination of the drug product with bovine spongiform encephalopathy and transmissible spongiform encephalopathy agents is considered negligible.

No excipients of human or animal origin and no novel excipients are used in the formulation of Aybintio.

 

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 data package submitted in support of demonstrating biosimilarity between Aybintio and the reference biologic drug, Avastin, included studies examining and comparing pharmacodynamic, pharmacokinetic, and toxicological parameters. Results from comparative in vitro functional assays showed similar biological activities of Aybintio and the reference bevacizumab. The sponsor also compared Aybintio and the reference bevacizumab in two in vivo pharmacodynamic studies in mice: one conducted in a human non-small cell lung cancer xenograft model and one that used a human colorectal carcinoma xenograft model. These studies were inconclusive in assessing potential differences between Aybintio and the reference bevacizumab. In a 4-week comparative repeat-dose toxicology study performed in male and female cynomolgus monkeys, no notable differences were observed in the pharmacokinetic and toxicologic profiles of Aybintio and the reference bevacizumab. The non-clinical portion of the Aybintio submission 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.

The results of the comparative non-clinical studies as well as the potential risks to humans have been included in the Aybintio Product Monograph. In view of the intended use of Aybintio, no pharmacological or toxicological issues were identified within this submission to preclude authorization of the product.

For more information, refer to the Aybintio Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Clinical Basis for Decision

 

The purpose of the clinical program for a biosimilar is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The structural complexity of the biologic drug and availability of a relevant and sensitive pharmacodynamic endpoint determine 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 pharmacokinetic profiles of Aybintio and two reference bevacizumab formulations, Avastin sourced from the European Union (EU‑Avastin) and Avastin sourced from the United States (US‑Avastin), were investigated and compared in the comparative pharmacokinetic study SB8‑G11‑NHV. Health Canada considers EU‑Avastin as a suitable proxy for Avastin authorized in Canada, as it meets all of the requirements set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Study SB8‑G11‑NHV was a randomized, double-blind, three-arm, parallel-group study conducted in healthy male subjects, who received a single dose of 3 mg/kg of the assigned drug as an intravenous infusion. When the test drug, Aybintio, was compared to the primary reference drug, EU‑Avastin, all ratios of test/reference of the pharmacokinetic parameters, area under the concentration-time curve (AUC) and maximum serum concentration observed (Cmax), were found to be within the acceptable limits of 80% to 125% at the confidence level of 90%. These results indicate pharmacokinetic similarity between Aybintio and the reference drug product.

In patients with metastatic or recurrent non-squamous non-small cell lung cancer, pharmacokinetic parameters assessed were comparable in the Aybintio treatment group and the EU‑Avastin treatment group (study SB8‑G31‑NSCLC, described in the Comparative Clinical Efficacy, Safety, and Immunogenicity section).

For further details, please refer to the Aybintio Product Monograph, approved by Health Canada and available through the Drug Product Database.

Comparative Clinical Efficacy, Safety, and Immunogenicity

The efficacy, safety, and immunogenicity of Aybintio in comparison to EU‑Avastin (considered a suitable proxy for Avastin authorized in Canada) were assessed in a randomized, double-blind, parallel-group, multicentre, Phase III clinical study (SB8‑G31‑NSCLC) in patients with metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC).

The inclusion and exclusion criteria for enrollment in study SB8‑G31‑NSCLC were consistent with other clinical trials of Avastin in patients with NSCLC. Demographic and baseline disease characteristics were well balanced between the Aybintio group and the EU‑Avastin group. The study consisted of a period of induction treatment with paclitaxel and carboplatin chemotherapy in combination with bevacizumab and a period of maintenance treatment with bevacizumab monotherapy. Randomization was stratified by age group (younger than 70 years or 70 years of age and older) and gender. In total, 763 eligible patients were randomized in a 1:1 ratio to receive, by intravenous infusion, Aybintio (number of patients [n] = 379) or EU‑Avastin (n = 384) 15 mg/kg concurrently with paclitaxel plus carboplatin chemotherapy on Day 1 of every 3-week cycle, for at least 4 cycles and up to 6 cycles of the induction treatment period. Paclitaxel was administered at a dose of 200 mg/m2 and the carboplatin dose was based on the target area under the plasma concentration-time curve (AUC) of 6. Patients with complete response, partial response or stable disease at the end of induction treatment continued to receive maintenance monotherapy with Aybintio or EU‑Avastin every 3 weeks until disease progression, unacceptable toxicity, death, or 12 months from randomization of the last patient, whichever occurred first.

The primary endpoint of the study was best overall response rate, defined as the proportion of patients whose best overall response was either complete response or partial response according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 during the induction treatment period by 24 weeks.

In the randomized population (i.e., intention-to-treat population), the proportion of patients achieving the best overall response by 24 weeks was 47.6% (181/379) in the Aybintio group and 42.8% (164/384) in the EU‑Avastin group. The risk ratio of best overall response rate between Aybintio and EU‑Avastin was 1.11, with a 95% confidence interval of 0.952 to 1.302, which fell within the predefined equivalence margins of 0.737 to 1.357.

Secondary endpoints of the study included progression-free survival, overall survival, and duration of response. The best overall response rate by 11 weeks and by 17 weeks of chemotherapy were exploratory endpoints. The results were supportive of the primary comparative efficacy analysis.

The safety evaluation was based on data from 378 (99.7%) patients in the Aybintio group and 380 (99.0%) patients in the EU‑Avastin group who received at least one dose of bevacizumab. The proportions of patients who experienced treatment-emergent adverse events (TEAEs), TEAEs of special interest (hypertension, proteinuria), serious TEAEs, and fatal TEAEs were comparable between the treatment groups. There were 462 (60.6%) patients who discontinued treatment during the maintenance treatment period: 223 (58.8%) patients in the Aybintio group and 239 (62.2%) patients in the EU‑Avastin group. The most commonly reported reason for treatment discontinuation was progressive disease. No new safety concerns were identified in the Aybintio group. Overall, the safety profile of Aybintio 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 Aybintio Product Monograph, as they are in the Product Monograph for Avastin.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity, i.e., the development of anti-drug antibodies (ADAs), which have the potential to neutralize the biological activity of the drug. The proportions of patients with ADAs were found to be comparable between the Aybintio and EU‑Avastin groups. At Cycle 7, 13.5% of patients (46/341) had an overall ADA-positive result in the Aybintio group as compared to 10.1% (34/337) of patients in the EU‑Avastin group. At the end of treatment, these numbers were 16.1% (55/341) and 11.0% (37/337) in the Aybintio group and the EU‑Avastin group, respectively. Overall, the data submitted show no clinically meaningful differences in immunogenicity between the biosimilar and the reference biologic drug.

For more information, refer to the Aybintio Product Monograph, approved by Health Canada and available through the Drug Product Database.

Indications

Similarity between Aybintio and the reference biologic drug, 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 claimed.

Within this drug submission, the sponsor requested the authorization of Aybintio for all of the indications granted for Avastin. The sponsor provided an acceptable scientific rationale for requesting the authorization of indications that were not directly studied in the clinical development program for Aybintio. The rationale addressed each of the critical points for extrapolation of data including the mechanism of action of bevacizumab across all indications, pharmacokinetics, pharmacodynamics and biodistribution of the product in different patient populations, and safety and immunogenicity profiles of bevacizumab across indications. The primary focus of the scientific justification was on the similarity demonstrated through comparative physicochemical and functional assessments, non-clinical comparisons, and clinical pharmacokinetic, safety, and efficacy comparisons.

Based on the evidence submitted, Aybintio has been authorized for the same indications currently held by the reference drug, Avastin, as follows (the indications include relevant caveat statements):

  • Metastatic Colorectal Cancer

    Aybintio, 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 the Drug-Drug Interactions section of the Aybintio Product Monograph for further information on the use of Aybintio 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

    Aybintio, in combination with a carboplatin/paclitaxel chemotherapy regimen, is indicated for the treatment of patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer.
     
  • Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer

    Aybintio, in combination with carboplatin and gemcitabine, is indicated for the treatment of patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer. These patients should not have received prior vascular endothelial growth factor (VEGF)-targeted therapy including Aybintio.
     

    The effectiveness of bevacizumab in platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer is based on an improvement of progression-free survival in patients who had first recurrence after six months of platinum-based chemotherapy. No overall survival benefit was demonstrated with bevacizumab.
     

  • Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer

    Aybintio, 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 VEGF-targeted therapy including Aybintio.

    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

    Aybintio, 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.

 

 

 

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