Summary Basis of Decision for Avtozma

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 (ORA-BRDD)

Summary Basis of Decision (SBD)

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

Recent Activity for Avtozma

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. At this time, no PAAT is available for Avtozma. When the PAAT for Avtozma becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Avtozma

Date SBD Issued: 2025-12-16

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

Tocilizumab

Drug Identification Number (DIN):

DIN 02562022 – tocilizumab 80 mg/4 mL, solution, intravenous administration, single-use vial
DIN 02562030 – tocilizumab 200 mg/10 mL, solution, intravenous administration, single-use vial
DIN 02562049 – tocilizumab 400 mg/20 mL, solution, intravenous administration, single-use vial
DIN 02562057 – tocilizumab 162 mg/0.9 mL, solution, subcutaneous administration, single-use pre-filled syringe
DIN 02562065 – tocilizumab 162 mg/0.9 mL, solution, subcutaneous administration, single-use pre-filled autoinjector

Celltrion Inc.

New Drug Submission Control Number: 283028

Submission Type: New Drug Submission

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): L04 Immunosuppressants

Date Filed: 2024-03-08

Authorization Date: 2025-10-16

On October 16, 2025, Health Canada issued a Notice of Compliance (NOC) to Celltrion Inc. for Avtozma, a biosimilar of Actemra (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. Avtozma contains the medicinal ingredient tocilizumab, which has been demonstrated to be highly similar to tocilizumab contained in the reference biologic drug, Actemra.

Authorization of a drug as 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. The weight of evidence of similarity to the reference biologic drug is provided by the structural and functional studies, whereas the non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, and clinical studies. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought. For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.

In this drug submission, Actemra is the reference biologic drug. Similarity between Avtozma and Actemra was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. The sponsor requested the authorization of Avtozma for all of the indications that are currently authorized for Actemra.

The market authorization of Avtozma 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, and clinical studies. Based on Health Canada’s review, the benefit-risk profile of Avtozma is considered to be similar to the benefit-risk profile of the reference biologic drug, and is therefore considered favourable for the following indications:

Rheumatoid Arthritis (intravenous or subcutaneous formulations)

Avtozma (tocilizumab) is indicated for:

reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis.

Tocilizumab (intravenous only) in combination with methotrexate has been shown to reduce the rate of progression of radiographic joint damage at Week 52.

Avtozma is to be given in combination with methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs); however, in cases of intolerance to methotrexate or where treatment with methotrexate is not appropriate Avtozma may also be given as monotherapy.

Giant Cell Arteritis (subcutaneous formulation only)

Avtozma is indicated for the treatment of giant cell arteritis in adult patients.

Polyarticular Juvenile Idiopathic Arthritis (intravenous or subcutaneous formulations)

Avtozma is indicated for the treatment of signs and symptoms of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older who have responded inadequately to previous therapy with DMARDs.

Systemic Juvenile Idiopathic Arthritis (intravenous or subcutaneous formulations)

Avtozma is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older, who have responded inadequately to previous therapy with one or more non-steroidal anti-inflammatory drugs and systemic corticosteroids.

Cytokine release syndrome (intravenous formulation only)

Avtozma is indicated for the treatment of patients with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome, in accordance with patient populations specified for authorized CAR T cell products.

Coronavirus disease 2019 (intravenous formulation only)

Avtozma is indicated for the treatment of hospitalized adult patients with coronavirus disease 2019 (COVID-19) who are receiving systemic corticosteroids, and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation.

1 What was approved?

Avtozma, an interleukin inhibitor, was authorized as a biosimilar of the reference biologic drug Actemra for reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis; the treatment of giant cell arteritis in adult patients; the treatment of signs and symptoms of active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older who have responded inadequately to previous therapy with disease-modifying anti-rheumatic drugs; the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients 2 years of age and older, who have responded inadequately to previous therapy with one or more non-steroidal anti-inflammatory drugs and systemic corticosteroids; the treatment of patients with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS), in accordance with patient populations specified for authorized CAR T cell products; and the treatment of hospitalized adult patients with coronavirus disease 2019 (COVID-19) who are receiving systemic corticosteroids, and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation.

The safety and efficacy of Avtozma in patients less than 2 years of age with sJIA and pJIA have not been established. The safety and efficacy of Avtozma for treating CAR T cell-induced CRS in children under the age of 3 have not been established.

Of the 2,644 patients who received tocilizumab in studies, 435 patients with rheumatoid arthritis were 65 years of age and older, including 50 patients who were 75 years of age and older. The frequency of serious infection among tocilizumab-treated subjects 65 years of age and older was higher than those under the age of 65. There is a higher incidence of infections in the elderly population in general; therefore, caution should be used when treating the elderly with Avtozma.

Avtozma should not be administered to patients with known hypersensitivity to tocilizumab or any of its components, or patients with active infections, with the exception of COVID-19, as indicated.

Avtozma is a biosimilar of Actemra. Both drugs contain the medicinal ingredient tocilizumab. Tocilizumab is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody that binds to both soluble- and membrane-bound interleukin-6 receptors (sIL-6R and mIL-6R). It has been shown to inhibit sIL-6R- and mIL-6R-mediated signaling through these receptors, thereby hindering the pro-inflammatory effects of IL-6.

Similarity between Avtozma and the reference biologic drug, Actemra, has been established on the basis of comparative structural and functional studies, comparative bioavailability studies, and clinical studies in patients with moderately to severely active rheumatoid arthritis, in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

Avtozma (tocilizumab 80 mg/4 mL, 200 mg/10 mL, 400 mg/20 mL, and 162 mg/0.9 mL) is presented as a solution. In addition to the medicinal ingredient, the solution contains L-histidine, L-histidine-hydrochloride monohydrate, L-methionine, L-threonine, polysorbate 80 and water for injection.

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 Product Monograph for Avtozma 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 Avtozma approved?

Avtozma is considered a biosimilar of Actemra, the reference biologic drug. Similarity between Avtozma and Actemra was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

Comprehensive biosimilarity assessment studies demonstrated analytical and functional biosimilarity between Avtozma and the reference biologic product authorized in the European Union (herein referred to as EU-RoActemra). EU-RoActemra was considered a suitable proxy for the Canadian reference product, as it met the requirements for a non-Canadian reference biologic drug set forth in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. No clinically meaningful differences between Avtozma and EU-RoActemra with respect to pharmacokinetics and immunogenicity were identified in two Phase I studies (CT-P47 1.1 and CT-P47 1.2) in healthy subjects. Further evidence of the clinical comparability of Avtozma and EU-RoActemra included the pharmacokinetic, efficacy, safety, and immunogenicity results of a Phase III study (CT-P47 3.1) in patients with moderately to severely active rheumatoid arthritis.

In Canada, Actemra is authorized for reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis; the treatment of giant cell arteritis in adult patients; the treatment of signs and symptoms of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older who have responded inadequately to previous therapy with disease-modifying anti-rheumatic drugs; the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older, who have responded inadequately to previous therapy with one or more non-steroidal anti-inflammatory drugs and systemic corticosteroids; the treatment of patients with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome, in accordance with patient populations specified for authorized CAR T cell products; and the treatment of hospitalized adult patients with coronavirus disease 2019 (COVID-19) who are receiving systemic corticosteroids, and require supplemental oxygen, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation.

The New Drug Submission (NDS) for Avtozma requested authorization for all of the indications granted to Actemra on the basis of demonstrated similarity between Avtozma and the reference biologic drug in structural, functional, and clinical studies, the common mechanism of action of tocilizumab across all indications, and clinical experience with the reference biologic drug.

Based on Health Canada's review, the benefit-risk profile of Avtozma is considered to be similar to that of the reference biologic drug, Actemra. Therefore, the benefit-risk profile of Avtozma is considered favourable for the indications sought.

A Risk Management Plan (RMP) for Avtozma was submitted by Celltrion Inc. to Health Canada. 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. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Product Monograph for Avtozma met 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 Avtozma was accepted.

Overall, the therapeutic benefits of Avtozma for the authorized indications are expected to be similar to the known benefits of the reference biologic drug, Actemra, and are considered to outweigh the potential risks. The identified safety concerns can be managed through labelling and monitoring. Appropriate warnings and precautions are in place in the Product Monograph for Avtozma to address the identified safety concerns. A Serious Warnings and Precautions box highlights the risk of serious infections and hepatoxicity, which has been reported in patients receiving tocilizumab. The Adverse Reactions section of the Product Monograph for Avtozma is based on the clinical experience with Actemra.

The NDS 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 Avtozma?

The review of the New Drug Submission (NDS) for Avtozma was based on a critical assessment of the data package submitted to Health Canada. As per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, the review of the clinical safety and efficacy components of the NDS for Avtozma was based on a critical assessment of the clinical safety and efficacy review conducted by the European Medicines Agency (EMA). As per Method 3 of the aforementioned document, the review completed by the EMA was used as an added reference for the review of the clinical pharmacology component of the NDS, while the reviews completed by the EMA and United States Food and Drug Administration were used as added references for the review of the Quality component of the NDS.

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

Submission Milestones: Avtozma

Submission Milestone	Date
New Drug Submission filed	2024-03-08
Screening
Screening Deficiency Notice issued	2024-05-02
Response to Screening Deficiency Notice filed	2024-05-24
Screening Acceptance Letter issued	2024-07-08
Review
Review of Risk Management Plan completed	2025-03-26
Quality evaluation completed	2025-04-29
Clinical/medical evaluation completed	2025-09-12
Labelling review completed	2025-10-07
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate	2025-10-16

4 What follow-up measures will the company take?

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

The onus is on the sponsor to monitor the post-market safety information for Avtozma as well as the Product Monograph of the reference biologic drug for safety signals that could impact the safety profile of Avtozma, and make safety updates to its Product Monograph as appropriate. New safety issues that are first identified with Avtozma, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both Avtozma and the reference biologic drug. For more information, refer to the Biosimilar Biologic Drugs in Canada: Fact Sheet.

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

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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.

At this time, no PAAT is available for Avtozma. When available, the PAAT will be incorporated into this SBD.

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 Guidance Document: Notice of Compliance with Conditions (NOC/c), 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?

Refer to the What steps led to the approval of Avtozma? section for more information about the review process for this submission.

7.1 Quality Basis for Decision

Avtozma (tocilizumab) was developed as a biosimilar of the reference biologic drug, Actemra. The weight of evidence of similarity between a biosimilar and the reference biologic drug 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 to the reference biologic drug.

Comparative Structural and Functional Studies

Avtozma has been developed as a biosimilar of the reference tocilizumab, Actemra. The biosimilarity evaluation was conducted as a pairwise analytical assessment using Avtozma and the reference biologic product authorized in the European Union (herein referred to as EU-RoActemra). For the purpose of this drug submission, Health Canada considers EU-RoActemra a suitable proxy for Actemra authorized in Canada, as it meets all of the requirements for a non-Canadian reference biologic drug set forth in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

The results of the biosimilarity assessment demonstrate that Avtozma is identical to EU-RoActemra with respect to primary structure and highly similar in terms of higher order structure, purity, and biological activities. Some differences were observed in post-translational modifications, size and charge variants, and degradation pathways. The differences were appropriately justified and are not expected to impact clinically relevant attributes.

Characterization of the Drug Substance

The drug substance, tocilizumab, is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody composed of two identical heavy chains and two identical light chains. Tocilizumab is a glycoprotein with one N-linked glycosylation site in the CH2 domain of each heavy chain. It has a theoretical molecular weight of approximately 145 kDa, based on the amino acid sequence. The observed molecular weight of tocilizumab is approximately 148 kDa due to glycosylation. Tocilizumab binds to both soluble- and membrane-bound interleukin-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit sIL-6R- and mIL-6R-mediated signaling through these receptors, thereby hindering the pro-inflammatory effects of IL-6.

Detailed characterization studies were performed to provide assurance that tocilizumab consistently exhibits the desired characteristic structure and biological activity.

The drug substance manufacturing process has been optimized and scaled up during development. Changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

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. A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or low.

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

The drug substance is manufactured using a Chinese hamster ovary cell line. The upstream manufacturing process involves thawing a single vial of the working cell bank which is expanded and used to inoculate the fed-batch production bioreactor. The clarified harvest is purified by affinity chromatography, and the eluates are held at a low pH for viral inactivation. The product is further purified through mixed mode chromatography and viral filtration, followed by concentration and diafiltration into the final formulation buffer. The bulk drug substance is filled into polycarbonate bottles and stored frozen.

Avtozma is supplied for intravenous administration in a vial or for subcutaneous administration in a pre-filled syringe with safety guard or autoinjector. The drug product manufacturing process for the vial presentation involves compounding, sterile filtration, aseptic filling, stoppering, inspection, and storage. The drug product manufacturing process for the pre-filled syringe with safety guard and autoinjector consists of drug substance pooling, sterile filtration, aseptic filling, stoppering, inspection, and storage prior to being assembled with a finger flange, plunger rod, and safety guard or into an autoinjector.

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.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients 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 of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, compendial methods comply with pharmacopeial standards, and device functionality tests comply with International Organization for Standardization (ISO) standards.

Avtozma 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 24-month shelf life at 5±3 °C for the vial presentation is considered acceptable when protected from light. The prepared infusion solution is physically and chemically stable in 0.9% or 0.45% sodium chloride solution at 5±3 °C for up to 1 month and at room temperature up to 30 °C for up to 48 hours. From a microbiological point of view, the prepared infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 5±3 °C unless dilution has taken place in controlled and validated aseptic conditions. The proposed 36-month shelf life at 5±3 °C for the pre-filled syringe with safety guard and autoinjector presentations is considered acceptable when protected from light, including an intermediate storage period of up to 3 weeks at 30 °C when protected from light.

The compatibility of the drug product with the container closure system was demonstrated through stability studies and extractables and leachable studies.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of all facilities and equipment involved in the production are considered suitable.

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug substance manufacturing facility was deemed necessary. However, foreign reviews completed by the United States Food and Drug Administration and the European Medicines Agency were leveraged to support the suitability of the drug substance manufacturing facility, and an on-site evaluation was no longer warranted.

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug product manufacturing facility was not deemed necessary.

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 absence of adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

Materials of animal origin used during the drug substance manufacturing process were subject to a transmissible spongiform encephalopathy risk assessment in accordance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3). The excipients used in the drug product formulation are not of animal or human origin. Accordingly, the risk of contamination of the drug product with bovine spongiform encephalopathy or transmissible spongiform encephalopathy agents is considered negligible.

7.2 Non-Clinical Basis for Decision

For biosimilars, the degree of similarity to the reference biologic drug 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. According to the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs, where similarity is well established by structural and functional studies, and where extensive in vitro mechanistic studies are indicative of similarity, non-clinical in vivo studies may not be necessary.

The results from the analytical similarity assessment (see the Comparative Structural and Functional Studies section) demonstrated a high degree of similarity between Avtozma and Actemra. There were no residual uncertainties identified that needed to be resolved by additional comparative non-clinical in vivo pharmacodynamic, pharmacokinetic, and toxicology studies.

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.

For the purpose of this drug submission, Health Canada considers the reference biologic product authorized in the European Union (herein referred to as EU-RoActemra) a suitable proxy for Actemra authorized in Canada, as it meets all of the requirements for a non-Canadian reference biologic drug set forth in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

Comparative Pharmacokinetics and Pharmacodynamics

Two Phase I comparative bioavailability studies (CT-P47 1.1 and CT-P47 1.2) were performed in healthy subjects to evaluate the pharmacokinetics of Avtozma and EU-RoActemra.

In Study CT-P47 1.1 (Part 2), 284 subjects received a single 162 mg subcutaneous dose of either Avtozma (144 subjects) or EU-RoActemra (140 subjects). In Study CT-P47 1.2, 88 subjects received a single 8 mg/kg intravenous dose of either Avtozma (45 subjects) or EU-RoActemra (43 subjects). The area under the concentration-time curve to the last quantifiable concentration (AUC_0-last) and maximum concentration (C_max)were the primary pharmacokinetic parameters reviewed.

Both studies demonstrated that Avtozma and EU-RoActemra were comparable, as the calculated 90% confidence intervals (CIs) of the ratios of the geometric least square means for AUC_0-lastand C_max were within the comparability margins of 80.0% to 125.0%. In each study, the secondary pharmacokinetic parameters were generally comparable, with no notable differences between treatment groups.

In addition, across the Phase I studies conducted (CT-P47 1.1 and CT-P47 1.2), the immunogenicity profiles of Avtozma and EU-RoActemra were similar and did not raise any safety concerns.

Taken together, the clinical pharmacology data derived from these studies support the pharmacokinetic similarity between Avtozma and EU-RoActemra in healthy subjects.

Comparative Clinical Efficacy and Safety

There were no clinically meaningful differences between Avtozma and EU-RoActemra in terms of pharmacokinetics, efficacy, safety, and immunogenicity in a comparative, randomized, active-controlled, double-blind, multicentre, Phase III study (CT-P47 3.1) conducted in patients with moderately to severely active rheumatoid arthritis.

Four hundred and seventy-one patients were randomized 1:1 to receive an 8 mg/kg intravenous dose of either Avtozma (234 patients) or EU-RoActemra (237 patients) every 4 weeks in combination with a stable dose of methotrexate (10 to 25 mg/week) and folic acid (5 mg or more/week). The primary efficacy endpoint of this study was the mean change from baseline in Disease Activity Score-28 (erythrocyte sedimentation rate) at Week 12, with a predefined criteria for equivalence of -0.6 to +0.6. The data show that the 95% CI of the treatment difference between Avtozma and EU-RoActemra was wholly contained within this equivalence margin (-0.26 to 0.24 in the intention-to-treat analysis set and -0.20 to 0.29 in the per-protocol analysis set).

The safety profile of Avtozma in Study CT-P47 3.1 appeared to be consistent with that of EU-RoActemra. There were no clinically meaningful differences in the overall incidence and severity of adverse events, serious adverse events, or adverse events of special interest, nor in the incidence and reason for discontinuation due to adverse events. A single death occurred in a patient randomized to Avtozma, which was not deemed related to the study drug by the investigator.

No consistent imbalance in immunogenicity was observed between Avtozma and EU-RoActemra and, based on limited data, the presence of anti-drug antibodies had no clinically meaningful impact on the pharmacokinetics, efficacy, and safety of either Avtozma or EU-RoActemra.

Taken together, the data derived from Study CT-P47 3.1 indicate that there are no clinically meaningful differences between Avtozma and EU-RoActemra in patients with rheumatoid arthritis. The safety profile of Avtozma is considered to be comparable to that which has been established for the reference biologic drug Actemra. The known risks of tocilizumab have been appropriately addressed in a Serious Warnings and Precautions Box and the Warnings and Precautions section of the Product Monograph for Avtozma, as they are in the Product Monograph for Actemra.

Indications

Avtozma is considered to be biosimilar to Actemra, the reference biologic drug. Actemra is authorized and marketed in Canada for several indications and clinical uses.

Similarity between Avtozma and Actemra was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. The demonstration of similarity between a proposed biosimilar and its reference biologic drug enables the sponsor's submission for the proposed biosimilar to rely on the safety and efficacy information already generated for the reference biologic drug, and therefore clinical studies are not required to support each of the submitted indications. The indications have been authorized on the basis of demonstrated similarity between Avtozma and the reference biologic drug in structural, functional, and clinical studies, the common mechanism of action of tocilizumab across all indications, and clinical experience with the reference biologic drug.

Upon review of the evidence submitted, Avtozma was authorized for all of the indications currently held by Actemra, as follows: