Summary Basis of Decision for Truxima

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 Truxima is located below.

Recent Activity for Truxima

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 Truxima

Date SBD issued: 2019-08-14

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

Rituximab

Drug Identification Number (DIN):

  • DIN 02478382 - 100 mg/10 mL solution, intravenous administration
  • DIN 02478390 - 500 mg/50 mL solution, intravenous administration

Celltrion Healthcare Co. Ltd.

New Drug Submission Control Number: 208204

On April 4, 2019, Health Canada issued a Notice of Compliance (NOC) to Celltrion Healthcare Co. Ltd. for Truxima, a biosimilar to Rituxan (the reference biologic drug). The terms "Biosimilar Biologic Drugs" 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 Truxima and Rituxan contain highly similar versions of the medicinal ingredient, rituximab.

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 biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.

In this drug submission, Rituxan is the reference biologic drug. Similarity between Truxima and Rituxan 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 Truxima for the indications that are currently authorized for Rituxan relating to non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and rheumatoid arthritis (RA).

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 Truxima is considered to be highly similar to the reference biologic drug for various indications relating to the following conditions:

Non-Hodgkin's Lymphoma
  • The treatment of patients with relapsed or refractory low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma.
  • The treatment of patients with CD20-positive, diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy.
  • The treatment of patients with previously untreated Stage III/IV follicular, CD20-positive, B-cell non-Hodgkin's lymphoma in combination with cyclophosphamide, vincristine and prednisolone (CVP) chemotherapy.
  • The maintenance treatment of patients with follicular non-Hodgkin's lymphoma who have responded to induction therapy with either CHOP or CHOP plus Truxima.
  • Single-agent maintenance treatment of previously untreated patients with advanced follicular non-Hodgkin's lymphoma with high tumour burden and who have responded to induction therapy with either CHOP plus Truxima or CVP plus Truxima.

Chronic Lymphocytic Leukemia

  • The treatment of patients with previously untreated or previously treated B-cell chronic lymphocytic leukemia (B-CLL), Binet Stage B or C, in combination with fludarabine and cyclophosphamide.

The use of Truxima in CLL is based on an improvement in progression-free survival. Overall survival benefit has not been demonstrated in patients with previous treatment for CLL. The efficacy of treatment with Truxima-fludarabine and cyclophosphamide (R-FC) in CLL patients who were previously treated with Truxima in combination with fludarabine and cyclophosphamide has not been studied.

Rheumatoid Arthritis

  • In combination with methotrexate, to reduce signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more tumour necrosis factor (TNF) inhibitor therapies.

Truxima in combination with methotrexate has been shown to reduce the rate of progression of joint damage as measured by X-ray.

1 What was approved?

Truxima, an antineoplastic agent, was authorized for various indications relating to the following conditions:

Non-Hodgkin's Lymphoma (NHL)

  • The treatment of patients with relapsed or refractory low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma.
  • The treatment of patients with CD20-positive, diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy.
  • The treatment of patients with previously untreated Stage III/IV follicular, CD20-positive, B-cell non-Hodgkin's lymphoma in combination with cyclophosphamide, vincristine and prednisolone (CVP) chemotherapy.
  • The maintenance treatment of patients with follicular non-Hodgkin's lymphoma who have responded to induction therapy with either CHOP or CHOP plus Truxima.
  • Single-agent maintenance treatment of previously untreated patients with advanced follicular non-Hodgkin's lymphoma with high tumour burden and who have responded to induction therapy with either CHOP plus Truxima or CVP plus Truxima.

Chronic Lymphocytic Leukemia (CLL)

  • The treatment of patients with previously untreated or previously treated B-cell chronic lymphocytic leukemia (B-CLL), Binet Stage B or C, in combination with fludarabine and cyclophosphamide.

The use of Truxima in CLL is based on an improvement in progression-free survival. Overall survival benefit has not been demonstrated in patients with previous treatment for CLL. The efficacy of treatment with Truxima-fludarabine and cyclophosphamide (R-FC) in CLL patients who were previously treated with Truxima in combination with fludarabine and cyclophosphamide has not been studied.

Rheumatoid Arthritis (RA)

  • In combination with methotrexate, to reduce signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more tumour necrosis factor (TNF) inhibitor therapies.

Truxima in combination with methotrexate has been shown to reduce the rate of progression of joint damage as measured by X-ray.

Truxima is a biosimilar to Rituxan. Both drugs contain the medicinal ingredient, rituximab, which is produced in Chinese Hamster Ovary (CHO) cells using recombinant deoxyribonucleic acid (DNA) technology. Rituximab is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody, which binds to the CD20 antigen present on the surfaces of malignant and normal B cells. Rituximab is believed to promote the lysis of B cells upon binding to CD20.

Similarity between Truxima and the reference biologic drug, Rituxan, has been established on the basis of comparative studies to evaluate properties including stability, degradation profiles, structure (primary, secondary and tertiary), purity, biological activity, and glycan profiles, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The safety and effectiveness of Truxima have not been studied in the pediatric (<18 years of age) or geriatric (≥65 years of age) populations. Although a formal study has not been carried out in geriatric patients, exploratory subgroup analysis indicates that use in the CLL setting is associated with differences in efficacy and safety in the geriatric population.

Truxima is contraindicated in:

  • Patients who are hypersensitive to rituximab or to any ingredient in the formulation, including any non-medicinal ingredient or component of the container.
  • Patients with known Type I hypersensitivity or anaphylactic reactions to murine proteins, Chinese Hamster Ovary (CHO) cell proteins, or to any component of the product.
  • Patients who have or have had progressive multifocal leukoencephalopathy (PML).

Additionally, Truxima is not recommended for use in patients with severe, active infections.

Truxima 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.

Truxima (100 mg/10 mL and 500 mg/50 mL rituximab) is presented as a solution. In addition to the medicinal ingredient, the solution contains hydrochloric acid, polysorbate 80, sodium chloride, trisodium citrate dihydrate, sodium hydroxide, and water for injection.

For more information, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.

Additional information may be found in the Truxima Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Truxima approved?

Health Canada considers that the benefit-risk profile of Truxima is highly similar to the reference biologic drug Rituxan for various indications relating to the following conditions:

Non-Hodgkin's Lymphoma (NHL)

  • The treatment of patients with relapsed or refractory low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma.
  • The treatment of patients with CD20-positive, diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy.
  • The treatment of patients with previously untreated Stage III/IV follicular, CD20-positive, B-cell non-Hodgkin's lymphoma in combination with cyclophosphamide, vincristine and prednisolone (CVP) chemotherapy.
  • The maintenance treatment of patients with follicular non-Hodgkin's lymphoma who have responded to induction therapy with either CHOP or CHOP plus Truxima.
  • Single-agent maintenance treatment of previously untreated patients with advanced follicular non-Hodgkin's lymphoma with high tumour burden and who have responded to induction therapy with either CHOP plus Truxima or CVP plus Truxima.

Chronic Lymphocytic Leukemia (CLL)

  • The treatment of patients with previously untreated or previously treated B-cell chronic lymphocytic leukemia (B-CLL), Binet Stage B or C, in combination with fludarabine and cyclophosphamide.

The use of Truxima in CLL is based on an improvement in progression-free survival. Overall survival benefit has not been demonstrated in patients with previous treatment for CLL. The efficacy of treatment with Truxima-fludarabine and cyclophosphamide (R-FC) in CLL patients who were previously treated with Truxima in combination with fludarabine and cyclophosphamide has not been studied.

Rheumatoid Arthritis (RA)

  • In combination with methotrexate, to reduce signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more tumour necrosis factor (TNF) inhibitor therapies.

Truxima in combination with methotrexate has been shown to reduce the rate of progression of joint damage as measured by X-ray.

Similarity between Truxima and Rituxan was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Truxima is considered to be biosimilar to Rituxan. Rituxan is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Rituxan is authorized are NHL, CLL, RA, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The New Drug Submission (NDS) filed for Truxima requested authorization for the indications relating to NHL, CLL, and RA that are currently authorized for Rituxan. Rituxan is also authorized for additional indications, which include treatment of GPA and MPA. However, these indications were not requested in the submission filed for Truxima. The indications have been authorized on the basis of demonstrated similarity between Truxima and the reference biologic drug.

Non-Hodgkin's lymphoma and CLL arise in lymphocytes, with the majority of cases originating in B cells at various stages of development. An estimated 36,175 Canadians are affected by NHL, and an additional 22,510 Canadians live with leukemia or are in disease remission, with CLL as one of the most common types in adult patients. B cells have also been implicated the development of autoimmune diseases, including RA. Approximately 300,000 Canadians (one in 100 adults) are affected by RA.

Rituximab, the medicinal ingredient in Truxima, is a monoclonal immunoglobulin G1 (IgG1) antibody. It binds with high affinity to CD20, a protein expressed on the surface of B cells throughout the differentiation process. This initiates a process that ultimately results in the lysis of B cells.

At the time of authorization, Truxima was the only biosimilar drug to Rituxan in Canada.

The biosimilar and the reference biologic drug were determined to be highly similar in terms of quality attributes (based on comparative structural and functional studies). Comparisons of the pharmacokinetic parameters of the two drugs demonstrated that patients are expected to achieve similar levels of exposure to rituximab from either Truxima or the reference biologic drug. Additionally, comparative clinical trials ruled out clinically meaningful differences in safety and efficacy between the biosimilar and the reference biologic drug in patients with RA or advanced follicular lymphoma (a common type of NHL). The demonstration of similarity enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

Truxima has demonstrated a comparable safety profile with its reference product, Rituxan. Therefore, the Adverse Reactions section of the biosimilar Product Monograph is based on the clinical experience with the reference biologic drug. As with Rituxan, the major identified safety concerns include infusion reactions, progressive multifocal leukoencephalopathy (PML), tumour lysis syndrome, Hepatitis B virus (HBV) reactivation, mucocutaneous reactions, infections, and cardiovascular adverse events. These issues, as well as guidelines and expectations regarding the proper administration of Truxima, have been addressed in the Serious Warnings and Precautions box of the Product Monograph, as is found in the Product Monograph for Rituxan.

A Risk Management Plan (RMP) for Truxima was submitted by Celltrion Healthcare 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.

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

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

Submission Milestones: Truxima

Submission MilestoneDate
Pre-submission meeting:2017-02-28
Submission filed:2017-08-04
Screening
Screening Acceptance Letter issued:2017-09-08
Review
Review of Risk Management Plan complete:2018-04-06
Quality Evaluation complete:2018-05-10
Clinical Evaluation complete:2018-07-04
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2018-07-04
Patent Hold
Submission placed on Patent Hold:2018-07-05
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate:2019-04-04

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 Truxima 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 Truxima 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 Truxima?

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's life cycle.

At this time, no PAAT is available for Truxima. 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:

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

Truxima was developed as a biosimilar to the reference biologic drug, Rituxan. For biosimilars, the weight of evidence is provided by structural and functional studies. 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 Truxima is considered to be representative of the mechanism of action and pharmacological effect of Rituxan.

Comparative Structural and Functional Studies

The reference biologic drug for Truxima is Rituxan (authorized in Canada and the United States), which is also marketed under the brand name MabThera in the European Union. Comparative testing for Truxima involved pairwise analyses between Truxima and Rituxan, Truxima and MabThera, and Rituxan and MabThera. The comparison of Rituxan and MabThera was conducted to demonstrate similarity between the two products, as both Rituxan and MabThera were used in the comparative clinical studies, and MabThera was compared to Truxima in non-clinical studies.

The physicochemical and biological properties of the drugs were evaluated through orthogonal methods. Collectively, the results of these analyses indicate that Truxima is similar to Rituxan and MabThera with respect to post-translational modifications, including deamidation, oxidation, and C-terminal lysine variants. Similarity was also demonstrated in the number, distribution, and nature of charged variants, glycosylation profiles, and binding affinities to CD20. Some minor differences were noted in biochemical properties, but are not expected to affect the safety or efficacy of Truxima. Additionally, no new impurities were found in Truxima that are not present in Rituxan and MabThera.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that rituximab, the medicinal ingredient in Truxima, consistently exhibits the desired characteristic structure and biological activity. The primary, secondary and tertiary structure, glycosylation pattern, charge variants, purity, potency, and binding activity of rituximab were confirmed through validated methods.

The stability and forced degradation profile of Truxima were also characterized and found to be highly similar to those of Rituxan and MabThera.

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

The drug substance, rituximab, is produced by recombinant deoxyribonucleic acid (DNA) technology using Chinese Hamster Ovary (CHO) cells. The CHO cell culture in which rituximab is expressed is initiated from a single working cell bank (WCB) vial. To prevent nutrient depletion in the culture medium, the cell culture undergoes expansion through a fed-batch process. Cells are initially cultured in flasks, and transferred to successively larger vessels as the culture grows. They are eventually pooled into a single bioreactor, reaching a commercial scale of 15,000 L. The cells are harvested and undergo clarification, in preparation for the purification of rituximab.

Rituximab is purified from the cell culture through several chromatography steps, interspersed with additional procedures to inactivate and remove any viral contaminants present. Appropriate controls have been implemented throughout the process to ensure the consistent production of high-quality rituximab.

The drug product, Truxima, is manufactured at the same site as the drug substance. The formulation buffer is prepared, and used to dilute the purified rituximab. The solution undergoes sterile filtration, and is transferred aseptically into vials. The vials are fully stoppered, capped, inspected, and stored.

During the product development, changes made to the drug substance and drug product manufacturing processes were due to scaling up, as well as to improve the similarity between Truxima and Rituxan. Comparability studies were performed, which demonstrated that the product quality was not affected by these changes.

The drug substance and drug product manufacturing processes have been appropriately validated. All validation batches met the predefined acceptance criteria. Examination of the manufacturing processes demonstrated that they can consistently produce the drug substance and drug product with the desired quality.

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

Control of the Drug Substance and Drug Product

The commercial specifications for the drug substance have been established. The analytical procedures were selected to evaluate quality characteristics of the drug substance with respect to identity, concentration, potency, purity, safety, and structural characteristics. These methods have been appropriately validated, and were considered suitable for controlling the critical quality attributes.

The commercial specifications for the drug product were appropriately justified. The batch analysis data from available clinical and commercial drug product batches support the specifications. The specification methods have been appropriately validated or qualified.

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

Samples from consecutively manufactured batches of final product lots were tested for purity using reduced and non-reduced capillary electrophoresis sodium dodecyl sulfate (CE-SDS). Potency was assessed through a complement-dependent cytotoxicity (CDC) assay. The results of these analyses are reflective of consistency in the manufacturing process. This confirmed that the methods used in-house are acceptable for their intended use, and positively supported the quality review recommendation.

For post-approval monitoring, Truxima is considered a low risk product as rituximab is well-characterized and there are no significant outstanding issues in the submission. The risk level associated with a drug product is determined by factors including the nature of the product, its indication and target patient population, and the manufacturer's production and inspection history.

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. Truxima for infusion is stable at 2-8ºC for 48 months, protected protected from light. As Truxima for infusion does not contain any antimicrobial preservative, it is essential to ensure that prepared solutions for infusion are not microbiologically compromised. Truxima prepared as a dilution for infusion is stable at 2-8ºC for 24 hours, and at room temperature for an additional 12 hours. The product should be protected from light.

The proposed packaging and components are acceptable. No incompatibilities have been observed between the packaging components and Truxima.

Facilities and Equipment

An on-site evaluation (OSE) was not conducted during the review of the submission for Truxima. The drug substance and drug product are manufactured at the same site, which was previously evaluated in connection with a different drug. The site received a compliant rating, and the OSE previously conducted at this site was considered sufficient in this case.

Adventitious Agents Safety Evaluation

The master, working, and extended production cell banks were tested to confirm that they are free of contaminants. Unprocessed bulk in the drug substance manufacturing was tested to confirm the absence of mycoplasma and viral contaminants. Additionally, the drug substance manufacturing process has shown robust and effective viral clearance for potential viral contaminants. Bioburden and endotoxin levels were regularly monitored as part of the in-process controls. The estimated amount of retrovirus-like particles in the final product is <1.98 × 10-10 particles per dose, or less than one particle per 5.1 × 109 doses.

All raw materials of animal origin used to manufacture rituximab were assessed for the risk of transmitting transmissible spongiform encephalopathy (TSE) in compliance with the Note for Guidance on Minimizing the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMA/410/01, Revision 3). The results of this evaluation indicate that the risk of TSE transmission from these materials is minimal.

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 Truxima was in compliance with the requirements for non-clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The outcomes of non-clinical studies did not reveal any differences in toxicology or toxicokinetics between Truxima and the reference biologic drug.

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

For more information, refer to the Truxima 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 biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized. The reference biologic drug for Truxima is Rituxan (authorized in Canada and the United States), which is also marketed under the brand name MabThera in the European Union. Structural and functional similarity between Rituxan and MabThera was established in the quality review, to support the use of both Rituxan and MabThera in the comparative clinical studies with Truxima.

For biosimilars, the purpose of the clinical program 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 and Pharmacodynamic Studies

Rituximab, the medicinal ingredient in Truxima, is a chimeric monoclonal immunoglobulin G1 (IgG1) antibody. It binds with high affinity to CD20, a protein expressed on the surfaces of B cells throughout development, prior to their differentiation into plasma cells. The interaction of rituximab with CD20 is believed to stimulate B cell lysis, potentially via complement-dependent cytotoxicity or antibody-dependent cell-mediated cytotoxicity.

The submission included results from two clinical studies aiming to demonstrate comparability between the pharmacokinetic parameters of Truxima and those of Rituxan and MabThera. Study CT-P10 3.2 was conducted in rheumatoid arthritis (RA) patients, and Study CT-P10 3.3 was conducted in patients with advanced follicular lymphoma (a type of non-Hodgkin's lymphoma [NHL]). Both studies were randomized, parallel-group, active-controlled, and double-blind. The dosage regimens selected for each study were appropriate for the condition (either RA or NHL) of the patients. In Study CT-P10 3.2 (RA patients), sampling was conducted over a single dosing period. In Study CT-P10 3.3 (NHL patients), sampling occurred in the fourth cycle of a series of infusions extending over eight cycles. The comparative pharmacokinetic analysis therefore included data from single and multiple dosing regimens. Results from both studies were within the accepted limits of 80% to 125%, at a confidence interval (CI) of 90%. The outcomes of both studies indicate that a patient should achieve the same exposure to rituximab from either Truxima or the reference product.

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

Comparative Clinical Efficacy and Safety

The comparative clinical efficacy of Truxima and its reference biologic drug, Rituxan, were evaluated primarily in a pivotal study, CT-P10 3.2, and a supportive study, CT-P10 3.3. Both studies also compared the safety of Truxima and Rituxan.

Study CT-P10 3.2 assessed the efficacy of Truxima in treating rheumatoid arthritis (RA) patients, relative to that of Rituxan and MabThera. This study was conducted in 372 patients who previously had an inadequate response to anti-tumour necrosis factor (TNF) treatment. Patients were randomized to receive 1,000 mg infusions of either Truxima (number of patients [n] = 161), or Rituxan/MabThera (n = 211) at Week 0 and Week 2 of the treatment period. Methotrexate and folic acid were administered concomitantly to all patients during the first 24 weeks of the study. At Week 24, patients were examined to determine whether there was a need for re-treatment, and a second course of the assigned treatment was administered if needed. The main study period was 48 weeks long. Afterwards, patients had the option to enroll in the extension phase, which involved a one-time switch for patients who received Rituxan or MabThera to receive Truxima. As the clinical data from the extension phase is supportive, it is not considered critical to the similarity assessment.

The primary efficacy endpoint was the change in the Disease Activity Score 28-joint count C-reactive protein (DAS28-CRP) from baseline to Week 24. Truxima and the reference biologic drug would be considered comparable if the 95% confidence interval (CI) for the difference in scores between the two treatment groups was contained entirely within the predetermined equivalence margin of -0.6 to +0.6. The difference in scores from baseline to week 24 was determined to be -0.06 with a 95% CI (-0.22, 0.11), and the treatments were therefore considered comparable with respect to efficacy in treating RA.

In the main study period, the extent of exposure to rituximab was similar between the two treatment groups. A higher incidence of treatment-emergent adverse events (TEAEs) was reported among patients treated with Truxima (77.6%) than in patients treated with Rituxan/MabThera (64.5%). This was determined to result from an increase in Grade 1 or 2 infusion-related reactions (IRRs) observed in patients treated with Truxima (20.5%) compared to Rituxan/MabThera (11.8%). However, it should be noted that the IRRs reported for Rituxan in this study are lower than expected based on IRR rates previously reported for Rituxan.

No meaningful differences were observed between the two treatment groups with respect to serious adverse events, including those classified as Grade 3 or higher. Additionally, the rates of TEAEs leading to discontinuation were low in both treatment groups.

Study CT-P10 3.3 evaluated the efficacy of Truxima in treating patients with advanced CD20-positive (CD20+) follicular lymphoma (one of the most common forms of NHL) relative to the efficacy of Rituxan. This was a Phase III non-inferiority study, conducted in 140 patients who had not received any previous treatment. Patients were randomized in a 1:1 ratio (n = 70 in each group) to receive 375 mg/m2 of either Truxima or Rituxan, along with cyclophosphamide, vincristine, and prednisone. Treatment continued for eight cycles, each lasting 21 days.

The primary efficacy endpoint was the overall response rate (ORR) as per the 1999 International Working Group (IWG) criteria, an internationally recognized standard. The ORR was defined as the sum of the complete response, unconfirmed complete response, and partial response rates, over the eight cycles of the study. The predefined non-inferiority margin was -7%. The ORR was 95.7% for Truxima (67 out of 70 patients), and 90.0% for Rituxan (63 out of 70 patients). As the difference in ORR between the two treatment groups was 5.7%, Truxima can be considered non-inferior to Rituxan for the treatment of advanced CD20+ follicular lymphoma.

It is important to note that the analysis of the study results did not include formal statistical significance testing. Only exploratory or descriptive evaluations of the results are permissible due to the number of patients involved. Additionally, there were some imbalances between the two treatment groups in terms of patient demographics and disease characteristics at baseline, which may have biased the results of the study. Although study CT-P10 3.3 had a descriptive analysis of efficacy, the outcomes suggest that the efficacy of Truxima in treating advanced follicular lymphoma is expected to maintain the observed efficacy of Rituxan.

The outcomes are indicative of similar safety profiles between the two treatment groups. Treatment-emergent adverse events were reported in 82.9% of patients treated with Truxima, and in 80.0% of patients treated with Rituxan. These were predominantly Grade 1 or 2 TEAEs, with Grade ≥3 TEAEs and TEAEs leading to discontinuation reported more frequently in patients treated with Truxima.

A higher incidence of neutropenia was reported in patients receiving Truxima than in patients receiving Rituxan (34.3% and 22.9%, respectively). However, bone marrow involvement makes patients more susceptible to developing neutropenia. At baseline, bone marrow involvement was more common in patients assigned to the Truxima group (64.3%) than in patients assigned to the Rituxan group. No discontinuations were due to neutropenia, and most cases were resolved without sequelae. Additionally, the incidence of febrile neutropenia was the same in both treatment groups, with two cases in each group.

Three deaths occurred during this study, and these patients were in the group treated with Truxima. Two deaths were due to disease progression, and one death was due to tumour lysis syndrome.

As with Rituxan, the major safety concerns identified for Truxima are infusion reactions, progressive multifocal leukoencephalopathy, tumour lysis syndrome, Hepatitis B virus reactivation, severe mucocutaneous reactions, infections, and cardiovascular adverse events. These risks are listed in a Serious Warnings and Precautions box in the Truxima and Rituxan Product Monographs. Instructions are also included to ensure that Truxima is only administered by healthcare professionals experienced in treating the conditions for which the drug is indicated. Additionally, the treatment site must have full resuscitation facilities, medications, and supportive care measures immediately available.

There were no new or unexpected safety concerns identified for Truxima. The TEAEs are expected to be manageable by following current practices in place for Rituxan, and do not raise concerns with respect to the biosimilarity of the two products.

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

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

Comparative Immunogenicity

The immunogenicity of Truxima and Rituxan were assessed in both studies CT-P10 3.2 (pivotal, in patients with RA) and CT-P10 3.3 (supportive, in patients with advanced follicular lymphoma), using the same validated detection methods.

In Study CT-P10 3.2, the proportion of patients with anti-drug antibodies (ADAs) was lower among patients receiving Truxima than in those receiving Rituxan or MabThera at Weeks 24 and 48. At Week 24, ADAs were detected in 14.9% of patients treated with Truxima, 21.9% of patients treated with Rituxan, and 26.7% of patients treated with MabThera. At Week 48, ADAs were detected in 4.9% of patients treated with Truxima, 9.4% of patients treated with Rituxan, and 8.6% of patients treated with MabThera. Median ADA titers were similar between treatment arms at each observation.

In Study CT-P10 3.3, ADAs were measured at baseline, as well as after Weeks 12 and 24 (which correspond to cycles 4 and 8, respectively). At Week 12, ADAs were detected in 2.9% of patients treated with Truxima and 1.4% of patients treated with Rituxan. At Week 24, ADAs were detected in 1.4% of patients treated with Truxima, and 1.4% of patients treated with Rituxan. There were no concerning differences in antibody concentrations detected during the study, and the results indicate that Truxima and Rituxan are similar in terms of immunogenicity.

Indications

Truxima is considered to be biosimilar to Rituxan, the reference biologic drug. Rituxan is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Rituxan is authorized are NHL, chronic lymphocytic leukemia (CLL), RA, granulomatosis with polyangiitis (GPA, also known as Wegener's Granulomatosis) and microscopic polyangiitis (MPA).

Within this drug submission, the sponsor requested the authorization of Truxima for the indications that are currently authorized for Rituxan relating to NHL, CLL, and RA. Authorization for the indication relating to GPA and MPA was not requested for Truxima.

Similarity between Truxima and Rituxan 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 biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized, and therefore clinical trials are not required to support each indication.

The indications have been authorized on the basis of demonstrated similarity between Truxima and the reference biologic drug, in structural and functional attributes, pharmacological effect, pathophysiological mechanisms of the diseases involved, safety profile, dosage regimen, and clinical experience with the reference biologic drug.

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