Summary Basis of Decision for Ontruzant

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 Ontruzant is located below.

Recent Activity for Ontruzant

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Summary Basis of Decision (SBD) for Ontruzant

Date SBD issued: 2022-06-23

The following information relates to the new drug submission for Ontruzant.

Trastuzumab

Drug Identification Number (DIN):

  • DIN 02524317 - 150 mg trastuzumab/vial, powder for solution, intravenous infusion
  • DIN 02524325 - 440 mg trastuzumab/vial, powder for solution, intravenous infusion

Samsung Bioepis Co., Ltd.

New Drug Submission Control Number: 235995

On January 28, 2022, Health Canada issued a Notice of Compliance (NOC) to Samsung Bioepis Co., Ltd for Ontruzant, 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. Ontruzant contains the medicinal ingredient trastuzumab, which has been demonstrated to be highly similar to trastuzumab contained in the reference biologic drug, Herceptin.

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, Herceptin is the reference biologic drug. Similarity between Ontruzant 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 Ontruzant for all of the indications that are currently authorized for Herceptin in Canada.

The market authorization 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 Ontruzant is considered to be similar to the benefit-risk profile of the reference biologic drug, and is therefore considered favourable for the following indications:

Early Breast Cancer (EBC)

Ontruzant (trastuzumab) is indicated for 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.

For detailed information on the inclusion criteria for the clinical trials of trastuzumab in EBC according to the TNM (Tumour, Node, Metastasis) classification system, see the Ontruzant Product Monograph.

Based on the analysis of the HERA trial, the benefit 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.

Metastatic Breast Cancer (MBC)

Ontruzant is indicated for the treatment of patients with MBC whose tumours overexpress HER2.

The benefits of treatment with Ontruzant in patients who do not overexpress HER2 (HER2 overexpression 0 as determined by a validated immunohistochemical [IHC] test) or who exhibit lower-level overexpression (HER2 overexpression 1+ as determined by a validated IHC test, and the subgroup of patients with HER2 overexpression 2+ as determined by a validated IHC test that corresponds to 1+ scoring by the investigative clinical trial assay), are unclear.

Ontruzant 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. For information on the use of Ontruzant in combination with Perjeta and docetaxel, consult the Product Monograph for Perjeta.

Metastatic Gastric Cancer (MGC)

Ontruzant in combination with capecitabine or intravenous 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2-positive metastatic adenocarcinoma of the stomach or gastro-esophageal junction who have not received prior anti-cancer treatment for their metastatic disease.

Ontruzant should only be administered to patients with MGC whose tumours have HER2 overexpression as defined by IHC2+ confirmed by fluorescent in situ hybridization (FISH+), or IHC 3+ as determined by an accurate and validated assay.

1 What was approved?

Ontruzant, an antineoplastic agent, was authorized for the following indications:

Early Breast Cancer (EBC)

Ontruzant (trastuzumab) is indicated for the treatment of patients with early stage breast cancer with astern 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.

For detailed information on the inclusion criteria for the clinical trials of trastuzumab in EBC according to the TNM (Tumour, Node, Metastasis) classification system, see the Ontruzant Product Monograph.

Based on the analysis of the HERA trial, the benefit 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.

Metastatic Breast Cancer (MBC)

Ontruzant is indicated for the treatment of patients with MBC whose tumours overexpress HER2.

The benefits of treatment with Ontruzant in patients who do not overexpress HER2 (HER2 overexpression 0 as determined by a validated immunohistochemical [IHC] test) or who exhibit lower-level overexpression (HER2 overexpression 1+ as determined by a validated IHC test, and the subgroup of patients with HER2 overexpression 2+ as determined by a validated IHC test that corresponds to 1+ scoring by the investigative clinical trial assay), are unclear.

Ontruzant 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. For information on the use of Ontruzant in combination with Perjeta and docetaxel, consult the Product Monograph for Perjeta.

Metastatic Gastric Cancer (MGC)

Ontruzant in combination with capecitabine or intravenous 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2-positive metastatic adenocarcinoma of the stomach or gastro-esophageal junction who have not received prior anti-cancer treatment for their metastatic disease.

Ontruzant should only be administered to patients with MGC whose tumours have HER2 overexpression as defined by IHC2+ confirmed by fluorescent in situ hybridization (FISH+), or IHC 3+ as determined by an accurate and validated assay.

Ontruzant is not authorized for use in pediatric patients (<18 years of age), as no clinical safety or efficacy data are available to Health Canada for this population.

The reported clinical experience in older patients is not adequate to determine whether they respond to Ontruzant differently than younger patients.

Ontruzant is a biosimilar to Herceptin. Both drugs contain the medicinal ingredient trastuzumab. Trastuzumab is a recombinant deoxyribonucleic acid (DNA)-derived humanised monoclonal antibody (immunoglobulin G1 [IgG1] kappa) that binds to HER2. Trastuzumab binding inhibits ligand-independent HER2 signalling, resulting in inhibition of proliferation of human tumour cells that overexpress HER2. Additionally, trastuzumab is a potent mediator of antibody-dependent cell-mediated cytotoxicity.

Similarity between Ontruzant and the reference biologic drug, Herceptin, has been established on the basis of comparative structural, functional, non-clinical, and clinical studies in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Ontruzant (440 mg trastuzumab/vial and 150 mg trastuzumab/vial) is presented as a lyophilized powder for solution for intravenous infusion. The sponsor provided chemistry and manufacturing data to support both presentations although the150 mg/vial presentation is not available for Herceptin. In addition to the medicinal ingredient, the lyophilized powder contains L-histidine, L-histidine hydrochloride monohydrate, polysorbate 20, and α,α-trehalose dihydrate.

The use of Ontruzant is contraindicated in patients with known hypersensitivity to trastuzumab, Chinese hamster ovary cell proteins, or any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. When using in combination with Perjeta (pertuzumab) and docetaxel, consult the Perjeta and docetaxel Product Monographs for further information on these drugs.

Ontruzant was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Ontruzant 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 Ontruzant approved?

Based on Health Canada's review, the benefit-risk profile of Ontruzant is considered to be similar to that of the reference biologic drug, and is therefore considered favourable for the treatment of human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, metastatic breast cancer, and metastatic gastric cancer. Similarity between Ontruzant 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 Ontruzant 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 Ontruzant and the reference biologic drug. Additionally, the sponsor provided chemistry and manufacturing data to support a presentation of 150 mg/vial, which is not available for Herceptin.

Ontruzant and the reference biologic drug were judged highly similar in terms of quality attributes, based on comparative structural and functional studies.

No major issues were identified from the comparative non-clinical studies and the comparative pharmacokinetic study in healthy male subjects. In the comparative clinical efficacy and safety study (Study SB3-G31-BC) in women with HER2-positive early breast cancer or locally advanced breast cancer, equivalence in breast pathologic complete response (bpCR) based on the risk difference was not demonstrated between Ontruzant and the reference Herceptin (sourced from the European Union [EU-Herceptin]). A Notice of Deficiency (NOD) was issued by Health Canada.

In response to the NOD, the sponsor provided follow-up cardiotoxicity and survival information from an extension study (Study SB3-G31-BC-E). The results indicate that the difference in the bpCR rates observed between Ontruzant and the reference biologic drug did not translate to a clinically meaningful difference in survival after 5 years of survival follow-up. In addition, further analysis of the ratio in bpCR rates between the two treatment arms of Study SB3-G31-BC revealed that the 95% confidence interval was fully contained within the pre-specified equivalence margins. Finally, cardiotoxicity information collected during the follow-up in a cohort of patients who had completed Study SB3-G31-BC did not show a clinically meaningful difference between treatment arms. Taken together with all the discussions and supportive data provided, the difference observed in bpCR rates is not expected to have a meaningful clinical impact on long-term efficacy and safety.

Based on the totality of evidence derived from the comparative structural, functional, non-clinical and clinical data, similarity between Ontruzant and Herceptin has been demonstrated. Furthermore, in accordance with Health Canada’s biosimilar guidance document, a scientific rationale was provided to support the authorization of Ontruzant in the proposed indications held by the reference product Herceptin, which was found satisfactory in the context of the demonstration of biosimilarity from a quality and clinical perspective. Taken together, the benefit-risk profile of Ontruzant is considered favourable for the treatment of patients with early breast cancer, metastatic breast cancer, and metastatic gastric cancer.

Ontruzant has demonstrated a comparable safety profile to its reference biologic drug, Herceptin. Therefore, the Adverse Reactions section of the biosimilar Product Monograph is based on the clinical experience with the reference biologic drug. As with Herceptin, the major identified safety concerns include the risk of medication error (possible confusion with trastuzumab emtansine), cardiotoxicity, infusion reactions, pulmonary toxicity, and embryo-fetal toxicity. These issues have been addressed in a Serious Warnings and Precautions box included in the Product Monograph for Ontruzant, as is found in the Product Monograph for Herceptin.

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

The submitted inner and outer labels, package insert and Patient Medication Information section of the Ontruzant Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements. The sponsor submitted a brand name assessment that included testing for look-alike sound-alike attributes. Upon review, the proposed name Ontruzant was accepted.

Overall, the benefits of Ontruzant therapy are expected to be similar to the known benefits of the reference biologic drug, Herceptin, and are considered to outweigh the potential risks.

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 Ontruzant?

Based on an evaluation of the data submitted as part of the New Drug Submission (NDS) for Ontruzant, Health Canada issued a Notice of Deficiency (NOD) due to deficiencies related to the comparative clinical efficacy and safety study. In response to the NOD, the sponsor provided follow-up cardiotoxicity and survival information from an extension study. Upon review, a Notice of Compliance was recommended.

The review of the quality and clinical components of the NDS for Ontruzant was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the United States Food and Drug Administration and the European Medicines Agency were used as added references, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Ontruzant NDS 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.

Submission Milestones: Ontruzant

Submission MilestoneDate
Pre-submission meeting2019-10-22
New Drug Submission filed2020-02-27
Screening 1
Screening Acceptance Letter issued2020-04-17
Review 1
Review of Risk Management Plan completed2021-01-04
Quality evaluation completed2021-02-04
Non-clinical evaluation completed2021-02-05
Clinical/medical evaluation completed2021-02-09
Notice of Deficiency issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate (safety and effectiveness issues)2021-02-09
Response to Notice of Deficiency filed:2021-03-19
Screening 1
Screening Acceptance Letter issued2021-04-01
Review 1
Review of Risk Management Plan completed2021-11-28
Quality evaluation completed2022-01-05
Clinical/medical evaluation completed2022-01-14
Labelling review completed2022-01-17
Submission placed on Intellectual Property Hold2022-01-21
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate2022-01-28

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 Ontruzant 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 Ontruzant Product Monograph as appropriate. New safety issues that are first identified with the biosimilar, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both the biosimilar and the reference biologic drug. For more information, refer to the Fact Sheet: Biosimilars.

6 What other information is available about drugs?

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

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

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

Ontruzant was developed as a biosimilar to the reference biologic drug, Herceptin. 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 Ontruzant is considered to be representative of the mechanism of action and pharmacological effect of Herceptin.

Comparative Structural and Functional Studies

To establish similarity between Ontruzant and the reference biologic drug, Ontruzant was compared to Herceptin reference biologic drug sourced from the European Union (EU-Herceptin; 150 mg/vial) and the United States (US-Herceptin; 420 mg/vial), with EU-Herceptin being the main reference biologic drug. A combination of extensive structure/function characterization and forced degradation studies were performed to compare Ontruzant to Herceptin. These studies have established a high degree of similarity in the primary, secondary and tertiary structure, as well as the purity, biological activity, and stability and forced degradation profiles of Ontruzant and Herceptin. Although some minor differences were identified, these are unlikely to result in any clinically meaningful differences. Taken together, these studies suggest a high degree of similarity between Ontruzant and Herceptin.

Characterization of the Drug Substance

Detailed characterization studies were performed on early development, clinical batches, and process validation batches to provide assurance that the drug substance, trastuzumab, consistently exhibits the desired characteristic structure and biological activity. The characterization studies evaluated structure (primary, secondary, and higher-order), glycosylation, charge variants, purity/impurities, and biological activities.  

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The drug substance, trastuzumab, is manufactured using recombinant deoxyribonucleic acid (DNA) technology in Chinese hamster ovary (CHO) cells. The CHO cell culture is expanded until it reaches commercial scale production. The clarified harvest is processed through a series of chromatography steps, viral inactivation, and filtration steps. The trastuzumab material undergoes formulation to achieve the target concentration, and the resulting bulk trastuzumab drug substance is filtered into sterile bags and frozen.

The sponsor has demonstrated that the proposed drug substance manufacturing facility is capable of consistently manufacturing trastuzumab drug substance of acceptable quality with the proposed commercial batch size. Additional batch and comparability information was provided and supports a post-validation change in the compendial grade of ferric chloride to ensure glycosylation consistency.

The manufacturing process for the drug product, Ontruzant (available as a single-dose vial containing 150 mg trastuzumab and as a multi-dose vial containing 440 mg trastuzumab), includes drug substance thawing and pooling, sterile filtration, filling and partial stoppering, lyophilization and crimping, visual inspections, labelling, and final packaging. The 440 mg presentation is supplied with 20 mL of Bacteriostatic Water for Injection for reconstitution. The 150 mg presentation is reconstituted with Sterile Water for Injection that is not supplied with the drug product.

Process validation studies demonstrated that the proposed drug product manufacturing facilities were capable of manufacturing Ontruzant drug product of consistent quality within their proposed batch ranges.

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.

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 trastuzumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

Control of critical steps of the drug substance and drug product manufacturing processes were appropriately defined throughout development based on risk assessments and current process understanding. All in-house analytical methods were appropriately validated, and compendial methods complied with appropriate pharmacopeia. The proposed release and stability specifications are based on International Council for Harmonisation guidelines, manufacturing process history, batch release and stability data at the commercial scale, and relevant development studies.

The potential for N-nitrosamine impurities from the rubber stoppers was identified. However, based on the low risk of N-nitrosamines leaching into the final product and the proposed oncological indications, the benefits of the drug product outweigh the potential risk of N-nitrosamine exposure.

Ontruzant is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

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 48-month shelf life at 2 to 8 °C for Ontruzant is considered acceptable. Bacteriostatic Water for Injection is used as a diluent for the multi-dose 440 mg trastuzumab presentation of Ontruzant. The proposed 36-month shelf life for Bacteriostatic Water for Injection is considered acceptable when stored at 2 to 8 °C. When Ontruzant is co-packaged with Bacteriostatic Water for Injection, the shortest of the expiration dates will be used on the label.

Container closure integrity testing was performed as part of the stability program. Testing outcomes support integrity over the proposed 48-month shelf life of Ontruzant. The provided comprehensive safety assessment supports the suitability of the container closure systems for their intended purposes.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production of Ontruzant are considered suitable for the activities and products manufactured.

Based on risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary. Additionally, these facilities were recently evaluated and had obtained satisfactory ratings from Health Canada.

All 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. Raw material sourcing and testing, viral clearance process validation, and facility controls are in place to ensure that the drug substance, and the resulting drug product, are free of adventitious agents.

No materials of animal or human origin are used in the production of the drug substance, drug product, or Bacteriostatic Water for Injection. There is no risk of transmissible spongiform encephalopathy/bovine spongiform encephalopathy associated with this product, as per the statements and certificates provided by the sponsor.

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 Ontruzant 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.

An in vivo pharmacology assessment utilizing a human breast tumour xenograft murine model suggested that tumour growth inhibition was comparable between Ontruzant and Herceptin sourced from the European Union (EU-Herceptin) and Herceptin sourced from the United States (US-Herceptin).

The toxicologic profile of Ontruzant was considered comparable to that of EU-Herceptin and US-Herceptin in a 4-week repeat-dose toxicology study performed in cynomolgus monkeys. There were no new or unexpected toxicities observed, and the toxicokinetic profiles were similar. There were no anti-drug antibodies detected in any animals.

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

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

7.3 Clinical basis for decision

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

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

A bioequivalence analysis was conducted between the biosimilar, Ontruzant, and the reference products of Herceptin sourced from the European Union (EU-Herceptin) and the United States (US-Herceptin). All subjects received a common dose of 6 mg/kg, administered by an intravenous infusion. The required ratios and confidence intervals (CIs) were estimated through a parallel, three-way design and demonstrated compliance with the standards for bioequivalence, in as much as the administration of the drug by intravenous infusion would likely ensure absolute bioavailability of all formulations, regardless of any inherent properties of the drug itself. In this context, the results would suggest that the net amounts of drug delivered to the recipient from either formulation would fall within the limits associated with the concept of bioequivalence.

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

Comparative Clinical Efficacy and Safety

The comparative clinical efficacy and safety of Ontruzant and its reference biologic drug, EU-Herceptin, were evaluated in Study SB3-G31-BC, a randomized, double-blind, parallel-group, multicentre study in women with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer or locally advanced breast cancer. Patients were randomized in a 1:1 ratio to receive an 8 mg/kg loading dose of either Ontruzant (number of patients [n] = 437) or EU-Herceptin (n = 438) by intravenous infusion, followed by a 6 mg/kg maintenance dose every 3 weeks for 8 cycles concurrently with 8 cycles of chemotherapy in a neoadjuvant setting. Chemotherapy consisted of 75 mg/m2 docetaxel given every 3 weeks for 4 cycles followed by 4 cycles of FEC (5-fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2) given every 3 weeks. Randomization was stratified by disease stage and hormone receptor status.

Patients then underwent surgery and subsequently received an additional 10 cycles of intravenous Ontruzant or EU-Herceptin as per randomization to complete 1 year of treatment. After completion of adjuvant therapy, the patients were followed for 30 days after the last dose of Ontruzant or EU-Herceptin to the end of study visit.

The primary objective of Study SB3-G31-BC was to support clinical comparability of Ontruzant and EU-Herceptin in breast pathologic complete response (bpCR) rate utilizing an equivalence trial. Equivalence in the bpCR rates could be declared if the 90% CI of the ratio in bpCR rates between the two treatment groups was entirely contained within the prespecified equivalence margins of 0.785 to 1.546, or if the 95% CI of the difference in bpCR rates between the two treatment groups was entirely contained within the prespecified equivalence margins of -13% to 13%.

The upper bound of the two-sided 95% CI of the risk difference between the Ontruzant and EU-Herceptin treatment groups was 15.91%. This exceeded the pre-specified upper margin of 13% based on the Full Analysis Set with non-responder imputation (FAS-NRI) population, which is aligned with the intention-to-treat population. Therefore, equivalence in bpCR rates was not met. Supportive data based on other endpoints such as event-free survival and overall survival could not sufficiently address the uncertainties. Based on the evaluation of the data submitted, Health Canada issued a Notice of Deficiency (NOD).

In the response to the NOD, the sponsor provided Study SB3-G31-BC-E, a long-term follow-up study to Study SB3-G31-BC. The primary objective of Study SB3-G31-BC-E was to observe the incidence of symptomatic congestive heart failure (New York Heart Association Class II, III, and IV) and asymptomatic significant left ventricular ejection fraction decrease in participants from Study SB3-G31-BC who were treated with Ontruzant (n = 186) or EU-Herceptin (n = 181) as neoadjuvant and adjuvant treatment. An additional 171 patients from Study SB3-G31-BC were also enrolled for a total of 538 patients (267 patients from the Ontruzant arm and 271 patients from the EU-Herceptin arm) from which information on the long-term efficacy outcomes were analyzed. Although there are various limitations associated with the follow-up study, the results suggest that overall, there are no clinically meaningful differences in overall survival rates over the 5-year follow-up period between the two treatment arms.

Further analysis of the ratio in bpCR rates between the two treatment arms of Study SB3-G31-BC revealed that the 95% CI of the ratio in bpCR rates of 1.070 to 1.444 was entirely contained within the prespecified equivalence margins based on the FAS-NRI population. With additional considerations, the analysis based on the ratio in bpCR rates between the two treatment arms was considered more suitable for this endpoint given the heterogeneity in bpCR rates that has been historically shown in the literature.

The safety profiles of Ontruzant and EU-Herceptin were characterized from the patients who received at least one dose of Ontruzant or EU-Herceptin in Study SB3-G31-BC. The safety profiles observed in the two treatment arms were comparable. No apparent clinically meaningful differences in treatment-emergent adverse events or treatment-emergent adverse events of special interest were observed in either the neoadjuvant phase or the adjuvant phase.

The results from Study SB3-G31-BC-E, which focused on cardiac safety, indicate that no clinically meaningful differences in cardiac safety between the treatment arms were reported after a 5-year follow-up.

As with Herceptin, the major identified safety concerns identified for Ontruzant include the risk of medication error (possible confusion with trastuzumab emtansine), cardiotoxicity, infusion reactions, pulmonary toxicity, and embryo-fetal toxicity. These issues have been addressed in the Serious Warnings and Precautions box of the Product Monograph for Ontruzant, as is found in the Product Monograph for Herceptin.

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

Comparative Immunogenicity

The immunogenicity profiles of Ontruzant and EU-Herceptin were characterized from the patients who received at least one dose of Ontruzant or EU-Herceptin in Study SB3-G31-BC.

The number of patients who had positive result of anti-drug antibodies was low and balanced, with 3 patients (0.7%) in each treatment arm. No patient who was positive for anti-drug antibodies had an infusion-related reaction. Neutralizing antibodies were reported in only 2 patients from each treatment arm.

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

Conclusion

Overall, no apparent differences were observed based on the clinical efficacy, safety, and immunogenicity profiles of Ontruzant and EU-Herceptin, the reference biologic drug.

Indications

Ontruzant is considered to be 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 are HER2-positive early breast cancer, metastatic breast cancer, and metastatic gastric cancer.

Within this drug submission, the sponsor requested the authorization of Ontruzant for all of the indications that are currently authorized for Herceptin.

Similarity between Ontruzant 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 Ontruzant and the reference biologic drug, in comparative structural, functional, non-clinical, and clinical studies. In accordance with Health Canada's biosimilar guidance document, a written scientific rationale was provided to support the authorization of Ontruzant in all the indications held by Herceptin, which was found satisfactory in the context of the demonstration of biosimilarity from a quality and clinical perspective.