Summary Basis of Decision for Trazimera

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 Trazimera is located below.

Post-Authorization Activity Table (PAAT) for Trazimera

Updated: 2024-08-12

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 Trazimera, a product which contains the medicinal ingredient trastuzumab. 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.

Drug Identification Number (DIN):

  • DIN 02483467 - 440 mg/vial, trastuzumab, powder for solution, intravenous administration
  • DIN 02483475 - 150 mg/vial, trastuzumab, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

 

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 249937

2021-02-26

Issued NOC 2021-06-18

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information to align with that of the reference biologic drug, Herceptin, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 242479

2020-07-31

Issued NOC 2021-04-14

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Trazimera (trastuzumab) can be used in combination with Perjeta (pertuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 242739

2020-08-11

Issued NOC 2021-03-11

Submission filed as a Level I – Supplement for the addition of an alternate drug substance manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 245827

2020-10-28

Cancellation Letter Received 2020-11-24

Submission filed as a Level II – Supplement (Safety) to update the PM to align with that of the reference biologic drug, Herceptin. The changes were not in scope of a Labelling Only SNDS and additional information was required. The submission was cancelled administratively by the sponsor to be refiled.

NC # 243303

2020-08-26

Issued NOL 2020-11-02

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 02483467, 02483475) market notification

Not applicable

Date of first sale: 2019-10-22

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NC # 231839

2019-09-20

Issued NOL 2019-12-16

Submission filed as a Level II (90 day) Notifiable Change to update the PM to align with that of the reference biologic drug, Herceptin. As a result of the NC, modifications were made to the Adverse Reactions section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 226793

2019-04-12

Issued NOL

2019-08-15

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 226272

2019-03-28

Issued NOC

2019-08-15

Submission filed as a Level I - Supplement to update the PM, and to update the inner and outer labels, and package insert. The benefit-risk profile for Trazimera remains positive when used for its approved indication. The packaging components were also updated to meet the Plain Language Labelling requirements. The changes to the labelling were reviewed and considered acceptable, and an NOC was issued.

NDS # 212140

2017-12-15

Issued NOC

2019-08-15

Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Trazimera

Date SBD issued: 2020-02-04

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

Trastuzumab

Drug Identification Number (DIN):

  • DIN 02483467 - 440 mg/vial, powder for solution, intravenous administration
  • DIN 02483475 - 150 mg/vial, powder for solution, intravenous administration

Pfizer Canada ULC

New Drug Submission Control Number: 212140

 

On August 15, 2019, Health Canada issued a Notice of Compliance (NOC) to Pfizer Canada ULC for Trazimera, a biosimilar to Herceptin (the reference biologic drug). The terms "biosimilar biologic drug" and "biosimilar" are used by Health Canada to describe subsequent entry versions of a Canadian approved innovator biologic drug with demonstrated similarity to a reference biologic drug. Biosimilars were previously referred to as subsequent entry biologics in Canada. Both Trazimera and Herceptin contain highly similar versions of the medicinal ingredient, trastuzumab.

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. For a biosimilar, the weight of evidence is provided by the structural and functional studies, whereas the non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, pharmacokinetic and pharmacodynamic, and clinical studies.

The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in 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, Herceptin is the reference biologic drug. Similarity between Trazimera and Herceptin 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 Trazimera for all of the indications that are currently authorized for Herceptin.

The market authorization of Trazimera was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. Similarity was established through data derived from comparative structural, functional, non-clinical, and clinical studies. Based on Health Canada's review, the benefit-risk profile of Trazimera is considered to be highly similar to the reference biologic drug for the following indications (which include relevant caveat statements):

  • Early Breast Cancer
     

    For detailed information on the inclusion criteria for the clinical trials of trastuzumab in early breast cancer according to the TNM (Tumour, Node, Metastasis) classification system, see Part II: Clinical Trials - Reference Biologic Drug section of the Trazimera Product Monograph.

    Based on the analysis of the HERA trial, the benefits of the adjuvant treatment with trastuzumab for low risk patients not given adjuvant chemotherapy are unknown.

    The comparative efficacy and safety between different chemotherapy regimens (i.e., concurrent versus sequential, anthracycline containing versus non-anthracycline containing) was not studied.

    • the treatment of patients with early stage breast cancer with Eastern Cooperative Oncology Group (ECOG) 0-1 status, whose tumours overexpress human epidermal growth factor receptor 2 (HER2)
      • following surgery and after chemotherapy
      • following adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel
      • in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.
         
  • Metastatic Breast Cancer
     

    The benefits of treatment with trastuzumab in patients who do not overexpress HER2 (HER2 overexpression 0 as defined by a validated immunohistochemical [IHC] assay) or who exhibit lower-level overexpression (HER2 overexpression 1+ as defined by a validated immunohistochemical [IHC] assay and the subgroup of patients with HER2 overexpression 2+ as defined by a validated immunohistochemical [IHC] assay that corresponds to 1+ scoring by the investigative clinical trial assay) are unclear (see Warnings and Precautions: Selection of Patients / Diagnostic Tests section of the Trazimera Product Monograph).

    • the treatment of patients with metastatic breast cancer whose tumours overexpress HER2.
       
  • Metastatic Gastric Cancer
     

    Trazimera should only be administered to patients with metastatic gastric cancer whose tumours have HER2 overexpression as defined by IHC2+ confirmed by fluorescent in situ hybridization (FISH+), or IHC3+ as determined by an accurate and validated assay.

    • use in combination with capecitabine or intravenous 5-fluorouracil and cisplatin for the treatment of patients with HER2 positive metastatic adenocarcinoma of the stomach or gastroesophageal junction who have not received prior anticancer treatment for their metastatic disease.
       

 

1 What was approved?

 

Trazimera, an antineoplastic drug, was authorized for the following indications (which include relevant caveat statements):

  • Early Breast Cancer
     

    For detailed information on the inclusion criteria for the clinical trials of trastuzumab in early breast cancer according to the TNM (Tumour, Node, Metastasis) classification system, see Part II: Clinical Trials - Reference Biologic Drug section of the Trazimera Product Monograph.

    Based on the analysis of the HERA trial, the benefits of the adjuvant treatment with trastuzumab for low risk patients not given adjuvant chemotherapy are unknown.

    The comparative efficacy and safety between different chemotherapy regimens (i.e., concurrent versus sequential, anthracycline containing versus non-anthracycline containing) was not studied.

    • the treatment of patients with early stage breast cancer with Eastern Cooperative Oncology Group (ECOG) 0-1 status, whose tumours overexpress human epidermal growth factor receptor 2 (HER2)
      • following surgery and after chemotherapy
      • following adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel
      • in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.
         
  • Metastatic Breast Cancer
     

    The benefits of treatment with trastuzumab in patients who do not overexpress HER2 (HER2 overexpression 0 as defined by a validated immunohistochemical [IHC] assay) or who exhibit lower-level overexpression (HER2 overexpression 1+ as defined by a validated immunohistochemical [IHC] assay and the subgroup of patients with HER2 overexpression 2+ as defined by a validated immunohistochemical [IHC] assay that corresponds to 1+ scoring by the investigative clinical trial assay) are unclear (see Warnings and Precautions: Selection of Patients / Diagnostic Tests section of the Trazimera Product Monograph).

    • the treatment of patients with metastatic breast cancer whose tumours overexpress HER2.
       
  • Metastatic Gastric Cancer
     

    Trazimera should only be administered to patients with metastatic gastric cancer whose tumours have HER2 overexpression as defined by IHC2+ confirmed by fluorescent in situ hybridization (FISH+), or IHC3+ as determined by an accurate and validated assay.

    • use in combination with capecitabine or intravenous 5-fluorouracil and cisplatin for the treatment of patients with HER2 positive metastatic adenocarcinoma of the stomach or gastroesophageal junction who have not received prior anticancer treatment for their metastatic disease.
       

The safety and effectiveness of trastuzumab in pediatric patients have not been established.

The reported clinical experience is not adequate to determine whether older patients (aged 65 years or older) respond differently to trastuzumab treatment than younger patients.

Trazimera is a biosimilar to Herceptin. Both drugs contain the medicinal ingredient trastuzumab, a humanized immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that is directed against the extracellular domain of the HER2. Trastuzumab binds to the HER2 on the surface of cancer cells and inhibits their proliferation and survival.

Similarity between Trazimera and the reference biologic drug, Herceptin, has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, comparative pharmacokinetic studies, and one main comparative clinical trial in patients with HER2 positive metastatic breast cancer, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Trazimera is contraindicated in patients with known hypersensitivity to trastuzumab, Chinese hamster ovary (CHO) cell proteins, or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Trazimera 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.

Trazimera (trastuzumab 440 mg/vial or 150 mg/vial) is presented as a powder for solution. In addition to the medicinal ingredient, the powder contains L-histidine, L-histidine hydrochloride monohydrate, polysorbate 20, and sucrose.

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

 

2 Why was Trazimera approved?

 

Health Canada considers that the benefit-risk profile of Trazimera is highly similar to the reference biologic drug Herceptin for the treatment of HER2-positive early breast cancer, HER2-positive metastatic breast cancer, and HER2-positive metastatic gastric cancer. Similarity between Trazimera and Herceptin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The New Drug Submission (NDS) filed for Trazimera requested authorization for all of the indications and clinical uses that are currently authorized for Herceptin. The indications have been authorized on the basis of demonstrated similarity between Trazimera and the reference biologic drug.

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

To support the clinical comparability of Trazimera and Herceptin, the sponsor provided evidence of pharmacokinetic similarity of Trazimera and Herceptin in healthy male volunteers. Comparable clinical efficacy was demonstrated for Trazimera and Herceptin (each in combination with paclitaxel) in the first-line treatment of patients with HER2-positive metastatic breast cancer (Study B3271002). Based on central radiology assessments, the primary efficacy endpoint of objective response rate was comparable in both treatment groups. The objective response rate in the intent-to-treat population (707 randomized patients) was 62.5% (95% confidence interval [CI]: 57.2%, 67.6%) in the Trazimera group and 66.5% (95% CI: 61.3%, 71.4%) in the Herceptin group. The risk ratio for the objective response rate between the two groups (Trazimera over Herceptin) was 0.940 (95% CI: 0.842, 1.049). The 95% CI of the risk ratio for the objective response rate was fully contained within the prespecified equivalence margins of 0.80 to 1.25. The risk difference of the objective response rate (Trazimera group minus Herceptin group), expressed as a difference in proportions, was -0.04 (95% CI: -0.110, 0.031). The equivalence margin selected and used for the risk difference was ±0.13, and CI was within these margins. No clinically meaningful differences were identified in the results of the comparative safety or immunogenicity assessment.

Supportive data were derived from another comparative clinical trial of Trazimera and Herceptin as neoadjuvant treatment for patients with HER2-positive operable breast cancer (Study B3271004).

Trazimera has demonstrated a comparable safety profile with its reference product, Herceptin. Therefore, the Adverse Reactions section of the Trazimera Product Monograph is based on the clinical experience with the reference biologic drug. Furthermore, as with Herceptin, a Serious Warnings and Precautions box has been included in the Trazimera Product Monograph to highlight the following serious risks: medication errors between Trazimera (trastuzumab) and Kadcyla (trastuzumab emtansine), cardiotoxicity, infusion reactions, pulmonary toxicity, and embryo-fetal toxicity.

A Risk Management Plan (RMP) for Trazimera was submitted by Pfizer Canada ULC to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

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

Overall, the therapeutic benefits of Trazimera are expected to be similar to the known benefits of the reference biologic drug, Herceptin, 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 Trazimera 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 Trazimera?

 

Submission Milestones: Trazimera

Submission Milestone Date
Pre-submission meeting: 2017-09-19
Submission filed: 2017-12-15
Screening  
Screening Acceptance Letter issued: 2018-02-01
Review  
Review of Risk Management Plan complete: 2018-09-06
Clinical Evaluation complete: 2018-11-23
Quality Evaluation complete: 2018-11-26
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-11-26
Patent Hold  
Submission placed on Patent Hold: 2018-11-28
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2019-08-15

 

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

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

The onus is on the Trazimera sponsor to monitor the post-market safety profile of this biosimilar product as well as the Product Monograph of the reference biologic drug for safety signals that could impact the biosimilar, and make safety updates to the Trazimera 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 Trazimera?

 

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 Trazimera 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

 

Trazimera was developed as a biosimilar to the reference biologic drug, Herceptin. 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

Comprehensive side-by-side characterization of the structure, purity, and in vitro biological activity of trastuzumab (also known as PF-05280014), Herceptin licensed in the United States (trastuzumab-US) and Herceptin approved in the European Union (trastuzumab-EU) was presented in the quality data submitted.

Suitable methods were used to provide a detailed, multi-faceted similarity analysis of the structure and in vitro biological activity of PF-05280014 compared with trastuzumab-US and trastuzumab-EU. The methods were selected based on their capability of elucidating and comparing primary structure, post-translational modifications, molecular size, charge isoforms, product-related substances and impurities, higher-order structure, aggregation, and biological activity of the materials. Extensive orthogonal analytical approaches were employed to further increase the confidence in structural assignments and the assessment of biological activity. Some minor differences were observed and subsequently characterized. These differences were not considered relevant, as there were no differences in the in vitro biological activity of PF-05280014, trastuzumab-US, and trastuzumab-EU.

The analytical similarity assessment supports the conclusion that PF-05280014 is highly similar to trastuzumab-US and trastuzumab-EU.

Trastuzumab-EU has been identified as the non-Canadian reference biologic drug used for the purposes of demonstrating biosimilarity with PF-05280014. An extensive comparative assessment of trastuzumab-US and trastuzumab-EU showed the two products were indistinguishable from each other.

Characterization of the Drug Substance

Trastuzumab is a humanized immunoglobulin G1 (IgG1) kappa monoclonal antibody with two identical heavy chains and two identical light chains, covalently linked with four inter-chain disulfide bonds. The molecular weight of trastuzumab is approximately 148 kDa. The antibody binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 (HER2).

Detailed characterization studies were performed to provide assurance that trastuzumab 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, trastuzumab (PF-05280014), is produced by recombinant deoxyribonucleic acid (rDNA) technology in a mammalian expression system (Chinese hamster ovary [CHO] line). The final cell culture is harvested and clarified by centrifugation and depth filtration to remove cells and debris. The product is then subjected to protein A chromatography, low pH virus inactivation, anion-exchange chromatography, and cation-exchange chromatography. Subsequently, the product is processed through a virus retaining filter, followed by concentration and buffer exchange in an ultrafiltration/diafiltration step. The excipients are added to the product to achieve the final formulation of the drug substance, followed by final filtration and freezing. The drug substance is filled in stainless steel vessels designed for freeze/thaw (cryovessels) or ethylene vinyl acetate (EVA) bags.

The drug product manufacture starts with controlled thawing of the drug substance (received in cryovessels). The thawed drug substance may be transferred to a manufacturing vessel to continue drug product manufacture. Alternatively, to facilitate the drug substance usage, the thawed drug substance may be dispensed into EVA bags and refrozen for continued storage.

The bulk drug product is sterilized by filtration and aseptically filled into vials. Vials are partially stoppered prior to lyophilization. Upon completion of the lyophilization cycle, the vials are fully stoppered, capped with a crimp seal, and visually inspected.

Trazimera is supplied as a lyophilized powder in two dosage strengths, 440 mg/vial and 150 mg/vial. Each 440 mg vial of Trazimera should be reconstituted with 20 mL of bacteriostatic water for injection (BWFI) to yield a multi-dose solution containing 21 mg/mL trastuzumab. The BWFI is supplied along with the drug product, and contains 1.1% benzyl alcohol as a preservative. Data have been provided to support the compatibility of the diluent with Trazimera, the manufacturing process and controls, process validation, batch analysis, and stability. The reconstituted multi-dose solution of Trazimera should be stored at 2°C to 8°C, and any unused portion should be discarded after 28 days.

The 150 mg vial of Trazimera should be reconstituted with 7.2 mL sterile water for injection (not supplied with the drug product) to yield a single-dose solution containing 21 mg/mL trastuzumab. The reconstituted single-use solution of Trazimera should be used immediately and any remaining portion should be discarded.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the trastuzumab with the excipients and the BWFI is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation guidelines.

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 methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed shelf life of the drug product, Trazimera, is 48 months when stored at the recommended temperature of 2ºC to 8°C. Trazimera may also be stored at a maximum temperature of 30°C for a single period of up to three months, without exceeding the original expiration date.

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

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.

Based on risk assessment scores determined by Health Canada, on-site evaluations of the facilities involved in the manufacture and testing of the drug substance and the drug product were not deem 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 no or minimal risk of transmissible spongiform encephalopathy and are therefore considered suitable for the production of Trazimera.

 

7.2 Non-Clinical Basis for Decision

 

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

The non-clinical database submitted for Trazimera 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.

In a number of in vitro binding and functional assays reflective of the mechanism of action of trastuzumab, Trazimera was shown to have similar biological activity to Herceptin licensed in the United States (trastuzumab-US) and Herceptin approved in the European Union (trastuzumab-EU).

A single-dose intravenous toxicokinetic study was conducted in male mice (55 mice/group) to compare the effects of Trazimera, trastuzumab-EU and trastuzumab-US (at doses of 1, 10, or 100 mg/kg). Trazimera was well tolerated, and its toxicokinetic profile, tolerability, and anti-drug antibody response were similar to trastuzumab-US and trastuzumab-EU at all doses tested.

The non-clinical findings are supportive of similarity between Trazimera and Herceptin.

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

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

 

 

7.3 Clinical basis for decision

 

The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in support of the indications being sought, and therefore clinical trials are not required to support each indication.

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 degree of similarity at the quality level determines the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Comparative Pharmacokinetic Studies

The medicinal ingredient in Trazimera, trastuzumab, is a humanized monoclonal antibody that selectively targets an extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. Trastuzumab is a mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, ADCC mediated by trastuzumab has been shown to be preferentially exerted on HER2 overexpressing cancer cells as compared to cancer cells that do not overexpress HER2.

The pharmacokinetic similarity of Trazimera, Herceptin licensed in the United States (Herceptin-US) and Herceptin approved in the European Union (Herceptin-EU) was demonstrated in a single-dose, randomized, double-blind, three-arm, parallel-group study (B3271001) conducted in 105 healthy male subjects, who received a single intravenous infusion of 6 mg/kg of the test and reference drugs. For the purpose of this new drug submission, Herceptin-EU was the reference biologic drug. The 90% confidence interval (CI) for the ratio of geometric least squares mean of Trazimera to Herceptin-EU for the area under the serum-concentration-time from time 0 to the last quantifiable concentration (AUCt) and the point estimate of the maximum concentration Cmax were within the prespecified acceptance margins of 80.0% to 125.0%. The study demonstrated comparable pharmacokinetic results.

A secondary supportive element of pharmacokinetic similarity was provided in the supportive comparative study (Study B3271004, described in Comparative Clinical Efficacy, Safety, and Immunogenicity) conducted in patients with operable HER2-positive breast cancer treated with Trazimera in combination with docetaxel and carboplatin or Herceptin-EU in combination with docetaxel and carboplatin, as neoadjuvant treatment. The study had a pharmacokinetic primary endpoint, the percentage of patients with trough plasma concentration (Ctrough) >20 µg/mL at Cycle 5 (Cycle 6 pre-dose). There were 93 (92.1%) patients with a Ctrough >20 µg/mL at Cycle 5 in the Trazimera group and 83 (93.3%) patients in the Herceptin-EU group. The stratified estimated difference (standard error) between Trazimera and Herceptin-EU was -0.76% (95% CI: -8.02%, 6.49%), and thus the lower limit of the 95% CI of the stratified difference between Trazimera and Herceptin-EU (-8.02%) was above the chosen non-inferiority margin of -12.5%.The primary endpoint met the prespecified non-inferiority criterion.

For further details, please refer to the Trazimera 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 Trazimera and its reference biologic drug were evaluated as first-line treatment for patients with HER2-positive metastatic breast cancer in Study B3271002. Supportive data were derived from another comparative trial of Trazimera and Herceptin-EU as neoadjuvant treatment for patients with HER2-positive operable breast cancer (Study B3271004).

Main Study (Study B3271002)

The comparative clinical trial B3271002 was a randomized, double-blind, parallel-group study in which patients with HER2-positive metastatic breast cancer received, as first-line treatment, either Trazimera in combination with paclitaxel or Herceptin-EU in combination with paclitaxel. The primary objective was to compare the objective response rate in the two treatment groups. The objective response rate was defined as the percentage of patients within each treatment group that achieved response (either complete response or partial response) by Week 25 of the study, subsequently confirmed by Week 33, in accordance with the Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Secondary endpoints included duration of response, one-year progression-free survival rate, one-year survival rate, safety, peak and trough drug concentrations at selected cycles, and incidence of anti-drug antibodies, including neutralizing antibodies.

In total, there were 707 patients randomized in a 1:1 ratio to receive Trazimera plus paclitaxel (number of patients [n] = 352 [49.8%]) or Herceptin-EU plus paclitaxel (n = 355 [50.2%]). Randomization was stratified by prior trastuzumab exposure and estrogen receptor status. Overall, the demographic and baseline disease characteristics were comparable between the two treatment groups. The mean age of the patients (±standard deviation) was 54.1 (±10.8) years. The majority of the patients were White (67.3%) and 26.6% were Asian.

Trastuzumab was administered weekly, on Days 1, 8, 15, and 22 of each 28-day cycle. A loading dose of 4 mg/kg was administered by intravenous infusion over 90 minutes at Day 1 of Cycle 1, with subsequent weekly intravenous infusions of 2 mg/kg over 30 to 90 minutes. Dose reductions for trastuzumab were not permitted. Paclitaxel was administered on Days 1, 8, and 15 of each 28-day cycle with a starting dose of 80 mg/m2 by intravenous infusion over 60 minutes, and the dose could be thereafter reduced as per the study protocol. In the absence of disease progression or prohibitive toxicity, patients were to receive treatment with paclitaxel for at least six cycles or until maximal benefit of response was obtained. Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the trastuzumab regimen could be changed at the discretion of the investigator to every three weeks at a dose of 6 mg/kg.

Comparative Clinical Efficacy

Based on central radiology assessments, the primary endpoint of objective response rate was comparable in both treatment groups. The objective response rate in the intent-to-treat (ITT) population (i.e., all randomized patients) was 62.5% (95% confidence interval [CI]: 57.2%, 67.6%) in the Trazimera group and 66.5% (95% CI: 61.3%, 71.4%) in the Herceptin-EU group. The risk ratio for the objective response rate between the two groups (Trazimera over Herceptin-EU) was 0.940 (95% CI: 0.842, 1.049). As the 95% CI of the risk ratio for the objective response rate was within the prespecified equivalence margins of 0.80 to 1.25, it met the prespecified equivalence criterion. The risk difference of the objective response rate (Trazimera group minus Herceptin-EU group), expressed as a difference in proportions, was -0.04 (95% CI: -0.110, 0.031). The equivalence margin selected and used for the risk difference was ±0.13, and the 95% CI was within these margins.

The primary endpoint was also analyzed after all patients had either completed the Week 53 tumour assessment or discontinued study drug earlier than the Week 53 visit. The results were found to be consistent with the Week 33 primary endpoint analysis.

The secondary endpoints of progression-free survival, duration of response, and 1-year survival rate were also found to be similar between the treatment groups.

In the ITT population, there were 144 (40.9%) and 148 (41.7%) patients who had disease progression or had died in the Trazimera group and the Herceptin-EU group, respectively. The median progression-free survival was 12.16 months in the Trazimera group and 12.06 months in the Herceptin-EU group.

Of the 224 (63.6%) patients who had a confirmed response in the Trazimera group, 151 (67.4%) patients were without subsequent progression or death up to Week 53. In the Herceptin-EU group, of the 238 (67.0%) patients who had a confirmed response, 157 (66.0%) patients were without subsequent progression or death up to Week 53. The median duration of response was 11.27 months in the Trazimera group and 10.58 months in the Herceptin-EU group.

Up to Week 53, there were 42 (11.9%) and 43 (12.1%) patients who had died in the Trazimera group and the Herceptin-EU group, respectively. The median time to death could not be estimated in the treatment groups due to the small proportion of deaths observed. The survival probability at Month 12 was 89.31% (95% CI: 85.48%, 92.17%) in the Trazimera group and 87.36% (95% CI: 83.27%, 90.51%) in the Herceptin-EU group.

Comparative Clinical Safety

There were 337 (96.6%) patients in the Trazimera group and 339 (96.0%) patients in the Herceptin-EU group who experienced at least one treatment-emergent adverse event. The most frequently reported (≥20% in either group) treatment-emergent adverse events were alopecia (189 [54.2%] patients in the Trazimera group and 185 [52.4%] patients in the Herceptin-EU group), anemia (120 [34.4%] patients in the Trazimera group and 131 [37.1%] patients in the Herceptin-EU group), neutropenia (99 [28.4%] patients in the Trazimera group and 91 [25.8%] patients in the Herceptin-EU group), and peripheral sensory neuropathy (93 [26.6%] patients in the Trazimera group and 83 [23.5%] patients in the Herceptin-EU group).

There were 70 (20.1%) patients in the Trazimera group and 73 (20.7%) patients in the Herceptin-EU group who experienced at least one serious adverse event. The most frequently reported serious adverse events in the study were disease progression (32 [9.2%] and 27 [7.6%] patients), pulmonary embolism (5 [1.4%] and 3 [0.8%] patients), and pneumonia (4 [1.1%] and 3 [0.8%] patients) in the Trazimera group and the Herceptin-EU group, respectively.

Treatment-related treatment-emergent adverse events were adverse events considered by the investigator as related to trastuzumab and/or paclitaxel. There were 315 (90.3%) patients in the Trazimera group and 314 (89.0%) patients in the Herceptin-EU group who experienced at least one treatment-related treatment-emergent adverse event. The most frequently reported (≥20% in either group) treatment-related treatment-emergent adverse events were alopecia (185 [53.0%] and 184 [52.1%] patients), anemia (98 [28.1%] and 112 [31.7%] patients), neutropenia (97 [27.8%] and 89 [25.2%] patients), and peripheral sensory neuropathy (91 [26.1%] and 81 [22.9%] patients) in the Trazimera group and the Herceptin-EU group, respectively. Such treatment-emergent adverse events can be expected in patients receiving paclitaxel chemotherapy. Trastuzumab-related treatment-emergent adverse events were considered by the investigator as related to trastuzumab only. There were 104 (29.8%) patients in the Trazimera group and 101 (28.6%) patients in the Herceptin-EU group who experienced at least one trastuzumab-related treatment-emergent adverse event.

Comparative Immunogenicity

Prior to initiation of treatment, 30 (8.6%) patients and 14 (4.0%) patients from the Trazimera group and the Herceptin-EU group, respectively, tested positive for anti-drug antibodies. Neutralizing antibodies were found in 20 (5.7%) patients and 9 (2.6%) patients in the Trazimera group and the Herceptin-EU group, respectively. The baseline observation of anti-drug antibodies prior to study treatment may be related to a false positive rate of approximately 1% for the anti-drug antibodies assay. Overall, at the end of the study, two patients (1 [0.3%] in the Trazimera group and 1 [0.3%] in the Herceptin-EU group) tested positive for anti-drug antibodies from Cycle 1, Day 1 post-treatment through 378 days post-randomization. The results reflect a low immunogenicity for both products and are consistent with data reported in literature from other studies of trastuzumab/Herceptin.

Supportive study (Study B3271004)

Study B3271004 was a randomized, double-blind clinical trial that evaluated the pharmacokinetics, efficacy, safety, and immunogenicity of Trazimera in combination with docetaxel and carboplatin (Trazimera group) versus Herceptin-EU in combination with docetaxel and carboplatin (Herceptin-EU group) in patients with operable HER2-positive breast cancer in the neoadjuvant setting. Of note, this supportive trial includes an indication that has not been authorized for the reference product in Canada, as well as a secondary endpoint of pathological complete response that has not been used to demonstrate clinical benefit for authorization purposes of other drugs or indications.

There were 226 patients randomized in a ratio of 1:1 to the Trazimera group (114 patients) or the Herceptin-EU group (112 patients). Randomization was stratified by primary tumour size, estrogen receptor status, and progesterone receptor status. Patients were to receive trastuzumab for six cycles (approximately 18 weeks). Two hundred and fifteen patients completed the study: 109 (95.6%) in the Trazimera group and 106 (94.6%) in the Herceptin-EU group.

The study had a pharmacokinetic primary endpoint, defined as the percentage of patients with trough plasma concentration over 20 µg/mL at Cycle 5 (Cycle 6 pre-dose) (see Comparative Pharmacokinetic Studies). Secondary efficacy endpoints included pathological complete response, objective response rate, safety, and immunogenicity. The study was not powered to detect differences in the secondary endpoints. Consequently, the results have to be interpreted with caution and can only be viewed as supportive.

In the per-protocol population analysis, the percentage of patients achieving pathological complete response was 46.5% (n = 47) in the Trazimera group and 48.3% (n = 43) in the Herceptin-EU group. The estimated stratified difference between Trazimera and Herceptin-EU was -2.81% (95% CI: -16.58%, 10.96%). Based on central radiology assessments for the per-protocol population, the objective response rate for Trazimera and Herceptin-EU were 88.1% (95% CI: 80.2%, 93.7%) and 82.0% (95% CI: 72.5%, 89.4%), respectively. The estimated stratified difference was 5.96% (95% CI: -4.01%, 15.94%).

The safety population (patients who received at least one dose of study drug) included 113 patients from the Trazimera group and 112 patients from the Herceptin-EU group. The percentage of patients reporting at least one treatment-emergent adverse event in the Trazimera group was 96.5% (109 patients) and 94.6% (106 patients) in the Herceptin-EU group. The safety results were comparable for the two treatment groups. Of the 225 patients, none tested positive for anti-drug antibodies during the study.

Conclusion

The clinical data have shown no clinically meaningful differences between Trazimera and Herceptin in terms of efficacy, safety, and immunogenicity.

The safety profile of Trazimera is considered to be comparable to that which has been established for the reference biologic drug Herceptin. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warnings and Precautions section of the Trazimera Product Monograph, as they are in the Product Monograph for Herceptin.

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

Indications

Trazimera is considered to be a biosimilar to Herceptin, the reference biologic drug. Herceptin is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Herceptin is authorized in Canada are HER2-positive early stage breast cancer, HER2-positive metastatic breast cancer, and HER2-positive metastatic gastric cancer.

Within this drug submission, the sponsor requested the authorization of Trazimera for all of the indications that are currently authorized for Herceptin. Upon Health Canada's review, Trazimera was authorized for the treatment of the following diseases (the indications include relevant caveat statements):

  • Early Breast Cancer
     

    For detailed information on the inclusion criteria for the clinical trials of trastuzumab in early breast cancer according to the TNM (Tumour, Node, Metastasis) classification system, see Part II: Clinical Trials - Reference Biologic Drug section of the Trazimera Product Monograph.

    Based on the analysis of the HERA trial, the benefits of the adjuvant treatment with trastuzumab for low risk patients not given adjuvant chemotherapy are unknown.

    The comparative efficacy and safety between different chemotherapy regimens (i.e., concurrent versus sequential, anthracycline containing versus non-anthracycline containing) was not studied.

    • the treatment of patients with early stage breast cancer with Eastern Cooperative Oncology Group (ECOG) 0-1 status, whose tumours overexpress human epidermal growth factor receptor 2 (HER2)
      • following surgery and after chemotherapy
      • following adjuvant chemotherapy consisting of doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel
      • in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.
         
  • Metastatic Breast Cancer
     

    The benefits of treatment with trastuzumab in patients who do not overexpress HER2 (HER2 overexpression 0 as defined by a validated immunohistochemical [IHC] assay) or who exhibit lower-level overexpression (HER2 overexpression 1+ as defined by a validated immunohistochemical [IHC] assay and the subgroup of patients with HER2 overexpression 2+ as defined by a validated immunohistochemical [IHC] assay that corresponds to 1+ scoring by the investigative clinical trial assay) are unclear (see Warnings and Precautions: Selection of Patients / Diagnostic Tests section of the Trazimera Product Monograph).

    • the treatment of patients with metastatic breast cancer whose tumours overexpress HER2.
       
  • Metastatic Gastric Cancer
     

    Trazimera should only be administered to patients with metastatic gastric cancer whose tumours have HER2 overexpression as defined by IHC2+ confirmed by fluorescent in situ hybridization (FISH+), or IHC3+ as determined by an accurate and validated assay.

    • use in combination with capecitabine or intravenous 5-fluorouracil and cisplatin for the treatment of patients with HER2 positive metastatic adenocarcinoma of the stomach or gastroesophageal junction who have not received prior anticancer treatment for their metastatic disease.
       

Similarity between Trazimera and Herceptin was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug, and therefore clinical trials are not required to support each indication. The indications have been authorized on the basis of demonstrated similarity between Trazimera and the reference biologic drug in structural, functional, non-clinical, and clinical studies.

 

 

 

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