Summary Basis of Decision for Bambevi

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 Bambevi is located below.

Recent Activity for Bambevi

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.

The following table describes post-authorization activity for Bambevi, 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 that are found in PAATs.

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

Updated: 2023-08-30

Drug Identification Number (DIN):

  • DIN 02520729 - bevacizumab100 mg/4 mL (25 mg/mL), solution, intravenous administration
  • DIN 02520737- bevacizumab 400 mg/16 mL (25 mg/mL), solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 269899 2022-11-22 Issued NOC 2023-06-26 Submission filed as a Level I – Supplement for a change in the drug substance manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 257734 2021-10-22 Issued NOC 2022-10-06 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Bambevi in combination with carboplatin and gemcitabine is indicated for the treatment of patients with first recurrence platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer. These patients should not have received prior VEGF-targeted therapy including Bambevi. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 259220 2021-12-01 Issued NOC 2022-05-11 Submission filed as a Level I – Supplement to update the inner, outer and package insert mock-up labels. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 261071 2022-01-31 Issued NOL 2022-03-24 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for change testing procedure for the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DINs 02520729, 02520737) market notification Not applicable Date of first sale: 2021-11-09 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 244450 2020-09-25 Issued NOC 2021-09-23 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Bambevi

Date SBD issued: 2022-01-11

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

Bevacizumab

Drug Identification Number (DIN):

  • DIN 02520729 - 100 mg/4 mL (25 mg/mL), solution, intravenous administration
  • DIN 02520737- 400 mg/16 mL (25 mg/mL), solution, intravenous administration

Apotex Inc.

New Drug Submission Control Number: 244450

 

On September 23, 2021, Health Canada issued a Notice of Compliance (NOC) to Apotex Inc. for Bambevi, 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. Bambevi 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, the sponsor requested the authorization of Bambevi for four of the five indications currently granted to Avastin, the reference biologic drug. Similarity between Bambevi and Avastin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The market authorization of Bambevi 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 Bambevi 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

    Bambevi 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 Bambevi Product Monograph for further information on the use of Bambevi 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

    Bambevi, 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

    Bambevi 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 Bambevi.

    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

    Bambevi, 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?

 

Bambevi 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-resistant recurrent epithelial ovarian, fallopian tube and primary peritoneal cancer, and malignant glioma (World Health Organization grade IV) - glioblastoma.

Bambevi 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 Bambevi and the reference biologic drug, Avastin, has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, comparative pharmacokinetic studies 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.

Bambevi is contraindicated in:

  • Patients with known hypersensitivity to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
  • Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
  • Patients with untreated central nervous system metastases.

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

The risk and benefit of Bambevi 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.

Bambevi 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.

Bambevi (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 α,α-trehalose dihydrate, sodium phosphate, polysorbate 20, 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 Bambevi Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Bambevi approved?

 

Bambevi is considered to be a biosimilar to the reference biologic drug, Avastin. Similarity between Bambevi 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 filed for Bambevi requested authorization for four of the five indications currently granted to the reference biologic drug. The indication that was not sought by the sponsor, due to intellectual property reasons, refers to the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Based on Health Canada’s review, the benefit-risk profile of Bambevi is considered to be similar to the benefit-risk profile of Avastin. Therefore, the benefit-risk profile of Bambevi is considered favourable 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.

Based on comparative structural and functional studies, Bambevi and Avastin were judged highly similar in terms of quality attributes. To support the clinical comparability of Bambevi to Avastin, the sponsor provided evidence of the pharmacokinetic similarity between Bambevi and Avastin in healthy male volunteers. The sponsor also provided the results of a Phase III, randomized, double-blind, comparative efficacy and safety study of Bambevi plus paclitaxel and carboplatin versus Avastin plus paclitaxel and carboplatin for the treatment of patients with non-squamous non-small cell lung cancer. The study met its primary efficacy endpoint by demonstrating similarity in the objective response rate. The reported objective response rate, as determined by an independent review committee using the Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in the intention-to-treat population, was 40.3% and 44.6% in the Bambevi arm and the Avastin arm, respectively. The 95% confidence interval (CI) of the risk ratio (RR) for Bambevi versus Avastin based on the objective response rates was fully contained within the prespecified similarity margins of 0.73 to 1.36 (RR = 0.91, 95% CI: 0.76, 1.09). No clinically meaningful differences were identified in the results of the comparative safety or immunogenicity assessment.

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

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

A Risk Management Plan (RMP) for Bambevi was submitted by Apotex Inc. 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 Bambevi 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 Bambevi was accepted.

Overall, the therapeutic benefits of Bambevi 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 Bambevi 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 Bambevi?

 

The Canadian regulatory decision regarding Bambevi was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the European Medicines Agency was used as an added reference.

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

 

Submission Milestones: Bambevi

Submission Milestone Date
New Drug Submission filed 2020-09-25
Screening  
Screening Acceptance Letter issued 2020-11-19
Review  
Review of Risk Management Plan completed 2021-08-12
Quality evaluation completed 2021-09-16
Non-clinical evaluation completed 2021-09-16
Labelling review completed 2021-09-23
Clinical/medical evaluation completed 2021-09-23
Notice of Compliance issued by Director General, Biologics and Radiopharmaceutical Drugs Directorate 2021-09-23

 

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 Bambevi 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 Bambevi 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 Bambevi?

 

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 Bambevi 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

 

Bambevi was developed as a biosimilar to the reference biologic drug, Avastin. For biosimilars, the weight of evidence 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 similarity assessment was performed using lots of European Union (EU)-sourced Avastin and lots of Bambevi. EU-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 comprehensive panel of tests was conducted to evaluate the physicochemical, biological, purity and impurity, and stability profiles of the drug products. Statistical quality ranges for similarity assessment were defined using a tiered approach. The overall approach applied was acceptable and the results of the studies demonstrated that Bambevi is highly similar to Avastin with respect to amino acid sequence, higher-order structure, biological activity, protein concentration, and stability profiles.

Minor differences were observed in the glycan profiles. These differences are not considered meaningful, since both Avastin and Bambevi displayed similar binding to the macrophage mannose receptor and to the complement component C1q, and both products lacked antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activity.

Analyses of Bambevi batches indicated the presence of an amino acid sequence variant with a relative abundance of 1.3% at position 226 in the heavy chain of the antibody (HC226), corresponding to a cysteine to tyrosine substitution. Studies demonstrated that the quaternary structure of the antibody was maintained in the native state and the potency of the Bambevi batches was similar to that of Avastin. The presence of low levels of this variant in Bambevi does not impact the mechanism of action (i.e., potency) or structure of the molecule and this minor difference is not likely to be clinically meaningful.

Taken together, the biosimilarity assessment results support the conclusion that Bambevi is highly similar to Avastin.

Characterization of the Drug Substance

Bevacizumab is a recombinant humanized monoclonal antibody (immunoglobulin G1) designed to bind soluble forms of human vascular endothelial growth factor (VEGF) with high affinity and specificity. It inhibits VEGF binding to receptors on endothelial cells, thereby neutralizing the biological activity of VEGF in angiogenesis within tumours. The antibody has a molecular weight of approximately 149,000 Da.

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 MB02).

In the upstream manufacturing process, a cell culture is initiated with the use of one thawed vial of cells from MB02 working cell bank and the cells are expanded in multiple steps until sufficient cells are obtained to inoculate the fed-batch production bioreactors. In the downstream manufacturing process, the harvested cell culture fluid is purified through capture, viral inactivation, chromatography steps, and nanofiltration. Subsequently, the purified bulk drug substance undergoes an ultrafiltration/diafiltration step along with polysorbate addition. The formulated MB02 drug substance is filtered, filled into bottles, and stored frozen until it is shipped to the drug product manufacturing site.

The entire drug substance commercial manufacturing process was validated with the manufacture of three process performance qualification batches, as well as ancillary studies to establish hold times, maximum column and filter re-use, and shipping conditions. The process validation studies have demonstrated that the manufacturing facility is capable of consistently manufacturing Bambevi drug substance that meets all quality attributes.

The drug product manufacturing process consists of drug substance pooling, mixing, bioburden reduction, sterile filtration, aseptic vial filling, and finishing operations. Process validation studies were conducted by manufacturing three consecutive drug product batches at the commercial scales proposed for each of the two presentations. The studies have demonstrated that the process is able to consistently manufacture Bambevi drug product that meets all quality attributes.

An appropriate control strategy, including in-process controls and parameters, control of raw materials, and specifications, has been established which should ensure the consistent production of a high-quality drug substance and drug product.

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 drug substance and drug product specifications were harmonized with those agreed on by the European Medicines Agency and include validated assays for identity, quantity, purity, potency, impurities, and safety. The non-compendial analytical methods were validated according to relevant International Council for Harmonisation (ICH) guidelines at the appropriate testing facilities, and the compendial methods were qualified in compliance with the respective pharmacopeia (Pharmacopoeia Europaea and the United States Pharmacopeia). A two-tiered reference standard program has been established.

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 30 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

An on-site evaluation of the drug substance manufacturing facility could not be conducted by Health Canada, due to the coronavirus disease 2019 (COVID-19) pandemic and travel restrictions at the time of the submission review. To mitigate the risk of not conducting an on-site evaluation, a thorough review of the documentation associated with critical activities at this site was undertaken. Extensive additional information on the facility, quality systems, and standard operating procedures was reviewed.

Based on a risk assessment performed by Health Canada, an on-site evaluation for the drug product manufacturing site was not deemed necessary.

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.

The biologic raw materials originate from sources with no or minimal risk of contamination with transmissible spongiform encephalopathy agents or other human pathogens.

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

 

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 sponsor submitted results from comparative in vitro functional assays that support similar biological activity of Bambevi and EU-Avastin (sourced from the European Union and considered a suitable proxy for Avastin authorized in Canada). In addition, results from one 28-day comparative repeat-dose toxicity study in cynomolgus monkeys showed no biologically significant differences between Bambevi and EU-Avastin in terms of toxicological effects and toxicokinetic parameters. The non-clinical portion of the Bambevi 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 Bambevi Product Monograph. In view of the intended use of Bambevi, no pharmacological or toxicological issues were identified within this submission to preclude authorization of the product.

For more information, refer to the Bambevi 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 Pharmacokinetic Studies

The test drug, Bambevi, was compared with Avastin sourced from the European Union (EU-Avastin) and Avastin sourced from the United States (US-Avastin) as the primary and secondary reference formulations, respectively. 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.

The pharmacokinetic parameters of the three formulations were examined in a randomized, double-blind, three-arm, parallel-group study, MB02-A-05-18, in which healthy male subjects received a single dose of 3 mg/kg of the assigned drug as an intravenous infusion. When Bambevi was compared to the primary reference (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 within the acceptable limits of 80% to 125% at the confidence level of 90%. An analogous two-way parallel-group study, MB02-A-04-18, investigating Bambevi and EU-Avastin in Japanese subjects, demonstrated similar outcomes.

For further details, please refer to the Bambevi 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 Bambevi and its reference biologic drug Avastin were evaluated in one pivotal comparative Phase III clinical study in patients with stage IIIB/IV (unresectable, locally advanced, recurrent or metastatic) non-squamous non-small cell lung cancer (NSCLC). Three supportive Phase I studies, conducted in healthy male subjects, provided additional safety and immunogenicity data.

Pivotal study (MB02-C-02-17)

The pivotal Phase III comparative safety and efficacy study, MB02-C-02-17, was a multicentre, multinational, double-blind, randomized (1:1), parallel-group, Phase III study with a primary objective of comparing the efficacy and safety of Bambevi plus chemotherapy (carboplatin and paclitaxel) to EU-Avastin plus chemotherapy (carboplatin and paclitaxel). The study enrolled 627 patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC) (number of patients [n] = 315, Bambevi arm; n = 312, EU-Avastin arm). Bevacizumab (Bambevi or EU-Avastin, 15 mg/kg) plus paclitaxel and carboplatin were administered once every three weeks, for six cycles, after which the primary endpoint was assessed (Week 18). Following completion of the six cycles, patients could receive bevacizumab monotherapy, every three weeks. Subjects could continue on monotherapy until disease progression or unacceptable toxicity. The study duration was 52 weeks. Patients were stratified by gender (male/female), smoking status (smoker/non-smoker), disease at diagnosis (newly diagnosed/recurrent disease), and stage of disease (IIIB/IV).

The primary efficacy endpoint of the study was the objective response rate as determined by an independent radiological review committee according to the Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) at Week 18 in the intention-to-treat population. The objective response rate observed was 40.3% for patients in the Bambevi arm and 44.6% for patients in the EU-Avastin arm. The primary comparative efficacy analysis showed a risk ratio of objective response rate of 0.91 (95% confidence interval [CI]: 0.76, 1.09). The two-sided 95% CI for the risk ratio was contained entirely within the prespecified similarity margins of 0.73 to 1.36. An analysis of risk difference was also performed and the observed difference in objective response rate was -4.02 (95% CI: -11.76, +3.71). The 95% CI for the risk difference was within the prespecified margins of -12% to +12%. These results demonstrated that there were no clinically meaningful differences in objective response rate between Bambevi and EU-Avastin. The analyses of secondary efficacy endpoints and comparative analyses were supportive of the results of the primary comparative efficacy analysis.

A trend toward a higher efficacy in the EU-Avastin arm compared to the Bambevi arm was observed, as evidenced by the results of the risk ratio of objective response rate being shifted toward the lower similarity margin, 0.73. A similar observation was made in the analyses of risk difference and other secondary efficacy endpoints. Notably, a high number of patients in the study discontinued treatment early, and the majority of those patients were classified as “missing”, with no objective response rate assessment at Week 18. The proportion of patients who discontinued treatment early was 36.2% (114 patients) in the Bambevi arm and 31.1% (97 patients) in the EU-Avastin arm. In addition, the median duration of exposure to bevacizumab was lower for patients in the Bambevi arm compared to the EU-Avastin arm. To address the impact of the missing data on the biosimilarity comparison, the sponsor performed two sensitivity analyses of objective response rate using multiple imputation approaches. The results of these sensitivity analyses supported the primary analysis results, showing risk ratios of objective response rate of 0.962 (95% CI: 0.813, 1.110) and 0.958 (95% CI: 0.811, 1.104). These analyses were deemed by Health Canada to have adequately addressed the impact of the early treatment discontinuations. The results of these additional analyses demonstrated that the slight imbalances in early treatment discontinuations and in the duration of exposure likely contributed to the shift in efficacy observed in the pivotal study. As the 95% CI of the risk ratio (Bambevi to EU-Avastin) of objective response rate was contained within the prespecified margins, the differences are not considered clinically meaningful.

The safety population was comprised of 621 patients who received at least one dose of Bambevi (n = 311) or the reference drug (EU-Avastin, n = 310). The proportion of patients who experienced at least one treatment-emergent adverse event (TEAE) was similar between the treatment arms, 92.6% in the Bambevi arm and 92.9% in the EU-Avastin arm. The most commonly occurring TEAEs in either treatment arm (reported in at least 10% of patients) were alopecia, anemia, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, asthenia, and nausea. The incidence of grades 3-4 TEAEs was also comparable between the treatment arms, 42.1% in the Bambevi arm and 40.3% in the EU-Avastin arm. Serious TEAEs were experienced by 18.6% of patients in the Bambevi arm and 17.4% of patients in the EU-Avastin arm. Death due to a TEAE occurred in 7.4% of patients in the Bambevi arm and 7.7% of patients in the EU-Avastin arm. Treatment discontinuation due to a TEAE was required for 23.2% of patients in the Bambevi arm versus 20.3% of patients in the EU-Avastin arm. The incidences of any TEAEs, grades 3-4 TEAEs, serious TEAEs, TEAEs leading to discontinuation and fatal TEAEs considered to be drug-related were comparable between the treatment arms. Numerical differences in the incidences of nervous system, gastrointestinal, and cardiac events were noted; however, these were not considered clinically meaningful. Overall, the safety profile of Bambevi 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 Bambevi Product Monograph, as found in the Product Monograph for Avastin.

Supportive studies (MB02-A-02-17, MB02-A-05-18, and MB02-A-04-18)

Three supportive safety studies (MB02-A-02-17, MB02-A-05-18, and MB02-A-04-18) were included in the submission. All three studies were Phase I, double-blind, randomized, parallel-group, single-dose studies designed to compare the pharmacokinetics, safety, and immunogenicity of Bambevi and Avastin in healthy male subjects.

Studies MB02-A-02-17 and MB02-A-05-18 were three-arm studies comparing Bambevi to EU-Avastin and US-Avastin. Study MB02-A-04-18 was a two-arm study comparing Bambevi to EU-Avastin. Subjects were treated with a single dose of 3 mg/kg of the assigned drug product.

Across these studies, the majority of TEAEs were mild to moderate (grades 1-2) in intensity. There were no subjects who discontinued treatment due to a TEAE and no deaths were reported. The safety data derived from these studies demonstrated comparability between Bambevi and EU-Avastin in healthy subjects, with no meaningful clinical differences observed.

Comparative immunogenicity

Anti-drug antibody (ADA) and neutralizing antibody development was comparatively assessed in both the healthy subject population and the NSCLC population. The studies employed the same validated immunogenicity assays.

In the pivotal NSCLC study (MB02-C-02-17), the proportions of patients with ADAs were comparable between patients treated with Bambevi and patients treated with EU-Avastin. Most patients had low antibody titers, and the median titer was found to be similar in both treatment arms. At baseline (i.e., cycle 1 prior to treatment) the incidence of ADAs was 5.1% in the Bambevi arm and 7.1% in the EU-Avastin arm. The overall post-baseline incidence of ADAs was 18.2% in the Bambevi arm and 16.8% in the EU-Avastin arm. In both treatment arms, the majority of treatment-induced ADAs were transient. There were 3 (1.0%) patients in the Bambevi arm and 10 (3.2%) patients in the EU-Avastin arm with persistent treatment-induced ADAs. The efficacy and safety data from ADA-positive patients were comparable between the treatment arms.

The incidences of treatment-induced ADAs observed in the supportive studies in healthy males (MB02-A-02-17, MB02-A-05-18, and MB02-A-04-18) were comparable between treatment arms. All treatment-induced ADAs were transient.

The incidences of neutralizing antibodies in the pivotal study were comparable between treatment arms (3.4% in the Bambevi arm versus 4.4% in the EU-Avastin arm). The majority of occurrences were transient. One occurrence of persistent treatment-induced neutralizing antibodies was reported for a patient in the EU-Avastin arm. The incidences of neutralizing antibodies observed in the supportive studies in healthy males were low and comparable between treatment arms. No occurrences of persistent neutralizing antibodies were reported in these studies.

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 Bambevi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Indications

Similarity between Bambevi 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.

Within this drug submission, the sponsor requested the authorization of Bambevi for all but one of the indications granted for Avastin. The indication that was not sought by the sponsor, due to intellectual property reasons, refers to the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube and primary peritoneal cancer.

The sponsor provided an acceptable scientific rationale to support the request for authorization of each of the proposed indications. This rationale accounted for the mechanism of action of bevacizumab, pathophysiology of the diseases, dosage regimens for the proposed indications, pharmacokinetics, safety profile, and immunogenicity.

Upon review of the submitted information, Bambevi has been authorized for the treatment of the following diseases (the indications include relevant caveat statements):

  • Metastatic Colorectal Cancer

    Bambevi 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 Bambevi Product Monograph for further information on the use of Bambevi 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

    Bambevi, 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

    Bambevi 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 Bambevi.

    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

    Bambevi, 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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