Summary Basis of Decision for Abevmy

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

Contact: Office of Regulatory Affairs, Biologic and Radiopharmaceutical Drugs Directorate

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

Recent Activity for Abevmy

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 Abevmy, 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: 2024-04-02

Drug Identification Number (DIN):

DIN 02522179 - 100 mg/4 mL (25 mg/mL), bevacizumab, solution, intravenous administration

DIN 02522160 - 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 # 281243	2023-11-22	Cancellation Letter Received 2023-12-20	Submission filed as a Level I – Supplement to update the PM to align with the PM of the reference biologic drug (Avastin). A number of issues were identified with the submission and the sponsor cancelled the submission administratively.
NDS # 273572	2023-03-22	Issued NOC 2023-05-15	Submission filed to transfer ownership of the drug product from BGP Pharma ULC to Biosimilar Collaborations Ireland Limited (BCIL). An NOC was issued.
SNDS # 269169	2022-11-30	Issued NOC 2023-04-25	Submission filed as a Level II – Supplement (Safety) to update the PM. The changes were in response to an Advisement Letter issued by Health Canada, dated October 31, 2022, to BGP Pharma ULC 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 # 270447	2022-12-07	Issued NOC 2023-04-05	Submission filed as a Level I – Supplement for a change in scale of the drug product manufacturing process for both the 100 mg/4 mL and 400 mg/16 mL presentations. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 268191	2022-09-27	Issued NOL 2022-12-21	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the specifications used to release a primary or functional secondary container closure component. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 267376	2022-08-26	Issued NOL 2022-12-09	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance and drug product release or shelf‐life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 259936	2021-12-23	Issued NOC 2022-11-23	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Abevmy, 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 Abevmy. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 262888	2022-03-30	Issued NOL 2022-05-02	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the labelled storage conditions for the drug product or the diluted or reconstituted product. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DINs 02522179, 02522160) market notification	Not applicable	Date of first sale: 2022-04-13	The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 237499	2020-06-07	Issued NOC 2021-11-05	NOC issued for New Drug Submission.

Summary Basis of Decision (SBD) for Abevmy

Date SBD issued: 2022-04-21

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

Bevacizumab

Drug Identification Number (DIN):

DIN 02522179 - 100 mg/4 mL (25 mg/mL), solution, intravenous administration
DIN 02522160 - 400 mg/16 mL (25 mg/mL), solution, intravenous administration

BGP Pharma ULC

New Drug Submission Control Number: 237499

On November 5, 2021, Health Canada issued a Notice of Compliance (NOC) to BGP Pharma ULC for Abevmy, 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. Abevmy 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 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. To be considered a biosimilar, the weight of evidence is provided by the structural and functional studies; 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 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 Abevmy 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 Abevmy for four of the five indications currently authorized for Avastin. The indication for treatment of platinum‑sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer was not proposed for Abevmy.

The market authorization of Abevmy was based on the quality (chemistry and manufacturing), non-clinical and clinical 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 Abevmy is considered to be similar to the benefit‑risk profile of the reference product, and is therefore considered favourable for the following indications:

Metastatic Colorectal Cancer

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

Abevmy, 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

Abevmy 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 Abevmy.

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 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

Abevmy, 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?

Abevmy is an antineoplastic drug. It was authorized for the treatment of the following diseases: 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.

The safety and efficacy of Abevmy have not been assessed in pediatric (younger than 18 years of age) patients. 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, grade 3‑4 leukopenia, neutropenia, thrombocytopenia, proteinuria, diarrhea, and fatigue as compared to those 65 years of age and younger when treated with bevacizumab. The risk and benefit of the administration of Abevmy in patients over 65 years of age should be carefully evaluated prior to initiating therapy.

Abevmy is a biosimilar to Avastin. Both drugs contain the medicinal ingredient, bevacizumab. Abevmy (bevacizumab) for injection is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and prevents the interaction of VEGF with its receptors on the surface of endothelial cells. The interaction with VEGF inhibits angiogenesis and tumour growth.

Similarity between Abevmy and the reference biologic drug, Avastin, has been established on the basis of structural and functional studies, comparative non‑clinical studies, a comparative pharmacokinetic study in healthy adult male volunteers, and a comparative efficacy, safety, and immunogenicity study in patients with stage IV non‑squamous non-small cell lung cancer, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Abevmy (25 mg/mL bevacizumab) is presented as a solution, and dosing is based on patient weight. Recommended doses are dependent on the indication. In addition to the medicinal ingredient bevacizumab, the solution also contains α, α ‑ trehalose dihydrate, sodium dihydrogen phosphate dihydrate, sodium phosphate dibasic anhydrous, polysorbate 20, ortho phosphoric acid, sodium hydroxide, and water for injection.

The use of Abevmy 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. Abevmy is also contraindicated in patients with untreated central nervous system metastases.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Abevmy Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.

2 Why was Abevmy approved?

Based on Health Canada's review, the benefit‑risk profile of Abevmy is considered to be similar to that of the reference product, Avastin. Therefore, the benefit‑risk profile of Abevmy 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. Similarity between Abevmy and Avastin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Abevmy is considered to be biosimilar to Avastin. Avastin is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Avastin is authorized are 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 Abevmy requested authorization for four of the five indications currently authorized for Avastin. The indication for the treatment of patients with first recurrence platinum‑sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer, as authorized for Avastin, was not claimed for Abevmy. The remaining four indications for Abevmy have been authorized on the basis of demonstrated similarity between Abevmy and the reference biologic drug, Avastin.

Based on comparative structural and functional studies, Abevmy and Avastin were judged highly similar in terms of quality attributes.

To support the clinical comparability of Abevmy to Avastin, the sponsor provided evidence of the pharmacokinetic similarity between Abevmy and Avastin in healthy male volunteers. The sponsor also provided the results of a Phase III, randomized, double-blind, equivalence trial (Study MYL‑1402O‑3001) of Abevmy plus paclitaxel-carboplatin versus Avastin plus paclitaxel-carboplatin for the first‑line treatment of patients with stage IV 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 41.5% and 43.1% in the Abevmy and Avastin arm, respectively. The 90% confidence interval (CI) for the risk ratio (RR) of the objective response rate for Abevmy versus Avastin (RR = 0.96, 90% CI [0.83, 1.12]) was fully contained within the pre‑specified margin (0.73, 1.36). As Health Canada’s preferred endpoint for establishing similarity is the ratio of the objective response rate using a 95% CI, the Abevmy Product Monograph was revised to state the results of the primary analysis using the 95% CI (0.81, 1.15), which was determined to have met the equivalence margin. No clinically meaningful differences were identified in the results of the comparative safety or immunogenicity assessment.

Abevmy also demonstrated a comparable safety profile with its reference product, Avastin. Therefore, the Adverse Reactions section of the biosimilar Product Monograph is based on clinical experience with the reference biologic drug. Furthermore, as with Avastin, a Serious Warnings and Precautions box has been included in the Abevmy Product Monograph to highlight the reports of serious local and systemic adverse events with unauthorized intravitreal use, gastrointestinal perforations, wound healing complications, and hemorrhage.

To support the authorization of Abevmy in each of the proposed indications, BGP Pharma ULC provided a scientific rationale that was in line with Health Canada’s biosimilar guidance document Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Based on the assessment of all the relevant data provided in the submission, Abevmy is considered to have a benefit‑risk profile that is 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.

A Risk Management Plan (RMP) for Abevmy was submitted by BGP Pharma 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 Abevmy was accepted.

Overall, Abevmy is considered to have a benefit-risk profile comparable to that which has been established for the claimed indications for its reference biologic drug Avastin. The benefits of Abevmy 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 Abevmy 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 Abevmy?

The New Drug Submission for Abevmy was filed with Health Canada on June 7, 2020. During review of the submission, gaps were identified in the quality (chemistry and manufacturing) component of the file, specifically in reference to the Standard Testing Procedures. Therefore, Health Canada issued a Notice of Deficiency (NOD) to BGP Pharma ULC on May 19, 2021. On July 19, 2021, BGP Pharma ULC submitted a response to the NOD which contained updated Standard Testing Procedures in addition to the provision of adequate responses to all queries contained in the NOD. Upon review of the sponsor's response, Health Canada issued a Notice of Compliance on November 5, 2021.

Submission Milestones: Abevmy

Submission Milestone	Date
New Drug Submission filed	2020-06-07
Screening
Screening Acceptance Letter issued	2020-07-23
Review
Review of Risk Management Plan completed	2021-03-22
Labelling review completed	2021-05-10
Clinical/medical evaluation completed	2021-05-17
Quality evaluation completed	2021-05-19
Biostatistics evaluation completed	2021-05-19
Notice of Deficiency issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate (quality issues)	2021-05-19
Response to Notice of Deficiency filed:	2021-07-19
Screening
Screening Acceptance Letter issued	2021-07-26
Review
Clinical/medical evaluation completed	2021-08-25
Quality evaluation completed	2021-10-26
Labelling review completed	2021-10-29
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate	2021-11-05

The review of the quality (chemistry and manufacturing), non‑clinical, and clinical components of the New Drug Submission for Abevmy was based on a critical assessment of the data package submitted to Health Canada.

The foreign questions and answers provided from the Food and Drug Administration and European Medicines Agency were consulted as added references, in lieu of issuing specific questions to the sponsor, as per Method 3, described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Abevmy New Drug Submission was made independently based on the Canadian review.

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

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 Abevmy 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:

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

As described above, the review of the New Drug Submission for Abevmy was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Quality Basis for Decision

Abevmy 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.

The biological activity of Abevmy is considered to be representative of the mechanism of action and pharmacological effect of Avastin.

Comparative Structural and Functional Studies

Abevmy was developed as a biosimilar to match the strength and product characteristics of the European Union approved Avastin (Avastin-EU) and the United States licensed Avastin (Avastin-US). Avastin sourced from the European Union was declared as the non‑Canadian reference product. Both 100 mg/4mL and 400 mg/16mL strengths of Abevmy and the reference products (Avastin‑EU and Avastin‑US) were represented in the biosimilarity assessment.

The results of the biosimilarity studies demonstrated that Abevmy is identical to Avastin in terms of primary structure and is highly similar with regard to higher order structure, functional activity, and drug product attributes.

Differences were observed with respect to product-related substances and impurities. Abevmy lots had lower levels of high molecular weight proteins (HMWP), charge variants, oxidized species, nonglycosylated heavy chain, and a thioether variant. Differences in glycoforms were also observed. These analytical differences observed in product-related substances and impurities had no impact on the biological activity and are unlikely to be clinically meaningful.

Comparative stability and forced degradation studies using different stress conditions generated similar degradation profiles for Abevmy, Avastin‑US and Avastin‑EU, further supporting the similarity of the three products.

Together, these results indicate that Abevmy is highly similar to Avastin‑EU and support the quality requirements for Abevmy to be considered a biosimilar to Avastin.

Characterization of the Drug Substance

Bevacizumab is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody, composed of two identical heavy and two identical light chains. The molecular mass of bevacizumab is approximately 149,000 Da. The antibody selectively binds to human vascular endothelial growth factor (VEGF) and inhibits the binding of VEGF with its receptors 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 of the Drug Substance and Drug Product and Process Controls

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 and viral inactivation steps. Following purification, the bulk drug substance is filtered into the drug substance containers pending batch disposition.

The drug product, Abevmy, is manufactured using common methodologies for the production of aseptic protein products. The drug substance is thawed, pooled, mixed, pre‑filtered, and sterile filtered. The sterile solution is aseptically filled into 6 mL or 20 mL glass vials using an automated filling machine. All filling processes are performed in a Grade A environment. The vials are then stoppered, sealed with aluminum seals, and 100% visually inspected. Labelling and packaging is then performed.

Process validation batches/lots were manufactured at the intended commercial scales and manufacturing sites. Process performance qualification data demonstrated that the manufacturing processes are capable of consistently manufacturing bevacizumab drug substance and drug product of acceptable quality. All process parameters, in-process controls, process attributes, release testing results, and stability results met pre-defined criteria, acceptance limits, and specifications for all validation lots.

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 manufacturing processes are controlled by process parameters, in‑process controls, and in‑process tests with defined operating ranges, actions, limits, and acceptance criteria. Criticality of each of these was appropriately defined, and were based on risk assessments, process characterization studies, and previous experience gained during development. If any results are outside of specified ranges/limits, a deviation is opened and an investigation is performed.

While the overall approach to the analytical method validation of the analytical methods was found acceptable, deficiencies were identified during review of Standard Testing Procedures (STPs) used for release and stability testing of the drug substance and drug product. The STPs lacked certain details (e.g., necessary steps and aids) to assure consistent performance of each assay. Due to this issue, a Notice of Deficiency (NOD) was issued by Health Canada to BGP Pharma ULC on May 19, 2021. On July 19, 2021, Health Canada received a reply from BGP Pharma ULC in response to the NOD. In their response, BGP Pharma ULC provided updated STPs and adequate responses to all queries contained in the NOD. Since all deficiencies were satisfactorily addressed, Health Canada resumed the quality (chemistry and manufacturing) review of the Abevmy submission.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the updated STPs 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 24‑month shelf life for Abevmy is considered acceptable, when stored at a temperature of 5 ºC ± 3 ºC.

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 manufacturing of the Abevmy drug substance was waived due to a recent successful rating on an OSE for another product with a similar manufacturing process, in addition to a travel ban due to the coronavirus disease (COVID‑19).

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 are therefore considered suitable for use in the production of Abevmy.

7.2 Non-Clinical Basis for Decision

For biosimilars, the degree of similarity at the quality level determines the scope and breadth of the required non‑clinical data. Non‑clinical studies serve to complement the structural and functional studies and to address potential areas of residual uncertainty.

The non‑clinical database submitted for Abevmy 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.

A series of in vivo acute and repeat‑dose toxicity studies were conducted in mice, rabbits and monkeys to characterize the toxicological effects of Abevmy and to compare them to those of Avastin. Comparative toxicokinetic parameters were investigated in two of the repeat‑dose toxicity studies, showing a long half‑life and accumulation with repeated administration. Overall, no overt off‑target toxicity was observed at up to 133.5 mg/kg in rabbits, or 445 mg/kg in mice. However, gender specific adverse effects were observed at 50 mg/kg in cynomolgus monkeys, including effects on female reproductive organs and male skeletal growth and development. These effects were similar to those previously reported with the reference product, Avastin.

The results of the comparative non-clinical studies have been included in the Abevmy Product Monograph. In view of the intended use of Abevmy, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Abevmy 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 and Pharmacodynamic Studies

The medicinal ingredient in Abevmy, bevacizumab, is a recombinant humanized monoclonal antibody that selectively binds to human vascular endothelial growth factor (VEGF), thereby neutralizing its biologic activity. Bevacizumab inhibits the binding of VEGF with its receptors (Fms-related tyrosine kinase 1 [Flt-1] and kinase insert domain receptor [KDR]) on the surface of endothelial cells. Neutralizing the biologic activity of VEGF reduces the vascularisation of tumours, thereby inhibiting tumour growth.

Clinical Pharmacology

Study MYL‑1402O‑1002

A single‑dose, three‑arm, parallel Phase I study conducted in 111 healthy adult male volunteers to investigate the comparative bioavailability of Abevmy, EU‑Avastin and US‑Avastin following a single 1 mg/kg dose administered by intravenous infusion. The study design, sample size, study subject, dosage regimen, and blood sampling scheme are considered appropriate. The area under the plasma concentration‑time curve (AUC_0-t) (90% confidence interval) and maximum serum concentration (C_max) ratios of geometric means for test versus (vs.) reference products fell within Health Canada's bioequivalence standard range of 80.0%-125.0%, indicating comparative bioavailability between the proposed biosimilar and reference products.

Population Pharmacokinetic Model of MYL‑1402O

The primary objective of the population pharmacokinetic analysis was to evaluate the comparative bioavailability of Abevmy and Avastin based on model‑derived parameters. The model was developed using pooled data from the single‑dose Phase I Study MYL‑1402O‑1002 and the multiple‑dose Phase III Study MYL‑1402O‑3001 conducted in healthy subjects and patients with non‑squamous non‑small cell lung cancer, respectively. The final model was a mammillary, two‑compartment model with zero‑order input and interindividual variability terms on clearance, central volume of distribution, peripheral volume of distribution, and intercompartmental clearance. Body surface area, albumin, sum of tumour diameters, and platelet count, race, lean body mass, and study were found to be significant covariates on the pharmacokinetic parameters. The final model is considered validated for the intended purpose of providing supportive evidence in the assessment of the comparative bioavailability of Abevmy and Avastin. Using the final model, exposure metrics following the two treatments were shown to be comparable and treatment was not shown to be a significant covariate.

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

Comparative Clinical Efficacy and Safety

The comparative clinical efficacy, safety, and immunogenicity of Abevmy and its reference biologic drug Avastin were evaluated in one comparative clinical trial (Study MYL‑1402O‑3001).

Study MYL‑1402O‑3001 was a randomized, double-blind, multicentre, study conducted to evaluate the efficacy and safety of Abevmy compared with Avastin, in the first‑line treatment of patients with stage IV non‑squamous non‑small cell lung cancer. The study enrolled 671 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 a combination therapy of either 15 mg/kg of Abevmy or Avastin with paclitaxel (200 mg/m²) and carboplatin (target area under the concentration‑time curve [AUC]) on Day 0 of a 21 day cycle, for up to 6 cycles of therapy with tumor assessments performed every 6 weeks in accordance with the Response Evaluation Criteria in Solid Tumours (RECIST version 1.1). Eligible patients then continued to receive either Abevmy or Avastin every three weeks as monotherapy, and tumor assessments were performed every 12 weeks during this period. The primary efficacy endpoint was the objective response rate as assessed by an independent review during the first 18 weeks. The analyses of the secondary efficacy endpoints, safety, and immunogenicity were based on data collected up to 42 weeks.

Efficacy Results

The reported objective response rate, as determined by local review using RECIST (version 1.1) in the intent‑to‑treat population, was 41.5% and 43.1% in the Abevmy and Avastin arm, respectively. The 90% confidence interval (CI) of the risk ratio (RR) for Abevmy versus Avastin in the objective response rate (RR = 0.96, 90% CI [0.83, 1.12]) was fully contained within the pre‑specified margin (0.73, 1.36); therefore, the MYL‑1402O‑3001 study met its primary efficacy endpoint. Although the primary analysis was planned in consultation with other regulatory agencies, Health Canada’s preferred endpoint for establishing similarity is the ratio of objective response rate using a 95% confidence interval. Therefore, in the Abevmy Product Monograph, the primary analysis of efficacy was revised to state the efficacy results using a 95% CI from 0.81 to 1.15, which still meets the equivalence margin.

Safety

The majority of patients (92.8% in the Abevmy arm and 92.4% in the Avastin arm) reported at least one treatment‑emergent adverse event. Treatment‑emergent adverse events related to gastrointestinal disorders in all grades were reported in a higher proportion of patients in the Abevmy arm compared to the Avastin arm (38.5% vs. 31%, respectively). The most commonly reported events included nausea, vomiting, diarrhea, and stomatitis. Treatment‑emergent adverse events that were reported with a greater 5% difference between arms and were noted higher in the Abevmy arm were thrombocytopenia, asthenia, and vomiting.

Adverse events of interest overall and those of grade 3 or higher were comparable between the treatment arms. The adverse events of interest that were numerically higher in the Abevmy arm were hypersensitivity, cardiac failure, and embolic and thrombotic events. Epistaxis and hemoptysis events were reported less in the Abevmy arm. Most of these reported adverse events of interest were grade 1 and 2.

Treatment‑emergent adverse events leading to death were notably higher in the Abevmy arm (number [n] = 25; 7.5%) vs. the Avastin arm (n = 14; 4.3%). The number of deaths within 30 days of the first administered dose was also higher in the Abevmy arm (n = 13) compared to the Avastin arm (n = 3). The number of deaths of unknown reason that occurred during the treatment period were higher in Abevmy arm (n = 7) than in the Avastin arm (n = 4). Most of the deaths that were due to treatment‑emergent adverse events occurred during the combination therapy period. Treatment‑emergent adverse events leading to death considered to be related to drug therapy were reported in eight patients in the Abevmy arm. These events included pulmonary embolism, pulmonary hemorrhage, cardiorespiratory arrest, acute coronary syndrome, gastric perforation, and cerebrovascular accident. In comparison, in the Avastin treatment arm, there were five treatment‑emergent adverse events leading to death that were considered to be related to drug therapy. These events included febrile neutropenia, acute respiratory distress syndrome, pulmonary hemorrhage, and sepsis. Most of the reported grade 5 treatment‑emergent adverse events are known to occur in the setting of advanced non‑small cell lung cancer and treatment with chemotherapy and bevacizumab.

Further assessment of the imbalance in deaths due to treatment‑emergent adverse events, identified several confounding factors, including background cardiac and medical history, other comorbidities and clinical progression of the disease. The Abevmy arm, in comparison to the Avastin arm, had a higher number of patients with the following baseline characteristics: subjects aged 65 years or older, lower mean body weight, Eastern Cooperative Oncology Group (ECOG) score level 1, smokers, M1c disease sub‑stage, and cardiac medical history. Based on the clinical evaluation recorded in the case narratives, the imbalance between the treatment arms in the treatment‑emergent adverse events leading to death and unknown causes leading to death was likely associated with the imbalance in baseline characteristics of older age, significant underlying disease, and comorbid conditions, and was less likely attributed to the study drug.

The overall incidence of treatment‑emergent anti‑drug antibodies was similar between the treatment arms (6.5% in the Abevmy arm vs. 4.8% in the Avastin arm). These incidences were typically transient in nature, with the majority occurring at one or two time points. The incidence of neutralizing antibodies was lower in the Abevmy arm (0.6%) compared to the Avastin arm (2.5%). Analyses of the objective response rate and treatment‑emergent adverse events in the sub‑group of anti‑drug antibody positive patients showed no clear effect of anti‑drug antibody status on safety or efficacy.

Overall, the safety profile of Abevmy 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 Warning and Precautions section of the Abevmy Product Monograph, as they are in the Product Monograph for Avastin.

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

Indications

Abevmy is considered to be biosimilar to Avastin, the reference biologic drug. Avastin is authorized and marketed in Canada for several indications and clinical uses. Similarity between Abevmy 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.

Within this drug submission, the sponsor requested the authorization of Abevmy for four of the five indications currently authorized for Avastin. The indication for treatment of platinum‑sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer was not proposed for Abevmy.

Upon review of the submitted information, Abevmy has been authorized for the treatment of the following diseases:

Metastatic Colorectal Cancer