Summary Basis of Decision for Ruxience

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 Ruxience is located below.

Recent Activity for Ruxience

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

 

The following table describes post-authorization activity for Ruxience, a product which contains the medicinal ingredient rituximab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

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

 

Updated: 2024-07-26

 

Drug Identification Number (DIN):

DIN 02495724 - 10 mg/mL, rituximab, solution, intravenous administration

 

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 279813

2023-10-10

Issued NOC 2024-03-06

Submission filed as a Level II – Supplement (Safety) to update the PM to align with that of the reference biologic drug, Rituxan, to migrate it to the 2020 format, and to align it with Health Canada’s Policy statement: Content of product monograph for biosimilar biologic drugs – clinical comparative study results. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; Clinical Trials; and Non-Clinical Toxicology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.

SNDS # 276531

2023-06-23

Issued NOC 2024-02-07

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

SNDS # 255404

2021-08-03

Issued NOC 2021-12-10

Submission filed as a Level I – Supplement for changes to the vial label (10 mL vial). The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 241451

2020-07-08

Issued NOC 2020-11-24

Submission filed as a Level I – Supplement for changes to the inner and outer labels (10 mL vial). The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 243564

2020-09-02

Issued NOL 2020-11-05

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to provide the continued process verification protocol for the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 239138

2020-05-01

Issued NOL 2020-07-08

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the labelled storage conditions for the drug product or the diluted or reconstituted product. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02495724) market notification

Not applicable

Date of first sale: 2020-05-26

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

NDS # 224164

2019-02-06

Issued NOC 2020-05-04

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Ruxience

Date SBD issued: 2020-07-30

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

Rituximab

Drug Identification Number (DIN):

  • DIN 02495724 - 10 mg/mL, solution, intravenous administration

Pfizer Canada ULC

New Drug Submission Control Number: 224164

 

On May 4, 2020, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for Ruxience, a biosimilar to Rituxan (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. Ruxience contains the medicinal ingredient rituximab, which has been demonstrated to be highly similar to rituximab contained in the reference product, Rituxan.

Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. For a biosimilar, the weight of evidence is provided by the structural and functional studies. 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, pharmacodynamic and pharmacokinetic, 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.

Within this drug submission, the sponsor requested authorization of Ruxience for all of the indications that are currently authorized for Rituxan, the reference biologic drug. Similarity between Ruxience and Rituxan was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

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 Ruxience is considered to be similar to the benefit-risk profile of the reference product, and is therefore considered favourable for the following indications:

  • Non-Hodgkin's Lymphoma (NHL)
     
  • Ruxience (rituximab for injection) is indicated for:
    • 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 CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
       
    • the treatment of patients with previously untreated stage III/IV follicular, CD20-positive, B-cell non-Hodgkin's lymphoma in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy.
       
    • the maintenance treatment of patients with follicular non-Hodgkin's lymphoma who have responded to induction therapy with either CHOP or CHOP plus Ruxience.
       
    • 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 Ruxience or CVP plus Ruxience.
       
  • Chronic Lymphocytic Leukemia (CLL)
     
  • Ruxience (rituximab for injection) is indicated for 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 rituximab 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 R-FC (rituximab-fludarabine and cyclophosphamide) in CLL patients who were previously treated with rituximab in combination with fludarabine and cyclophosphamide has not been studied.
     
  • Rheumatoid Arthritis (RA)
     
  • Ruxience in combination with methotrexate is indicated in adult patients:
     
    • 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.
       
  • Rituximab in combination with methotrexate has been shown to reduce the rate of progression of joint damage as measured by X-ray.
     
  • Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)
     
  • Ruxience in combination with glucocorticoids is indicated for the induction of remission in adult patients with severely active granulomatosis with polyangiitis (GPA, also known as Wegener's granulomatosis) and microscopic polyangiitis (MPA).
     
  • Consideration should be given to current treatment guidelines for vasculitis.

 

1 What was approved?

 

Ruxience, an antineoplastic agent, was authorized for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis (also known as Wegener's granulomatosis), and microscopic polyangiitis.

Ruxience is a biosimilar to Rituxan. Both drugs contain the medicinal ingredient, rituximab, a recombinant chimeric immunoglobulin G1 (IgG1) kappa monoclonal antibody with two identical heavy chains and two identical light chains, covalently linked with four inter-chain disulfide bonds. Rituximab binds to the transmembrane CD20 antigen located on the surface of normal precursor B cells, mature B lymphocytes, and malignant B cells.

Similarity between Ruxience and the reference biologic drug, Rituxan, has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, and comparative clinical studies in patients with rheumatoid arthritis and patients with low tumour burden follicular lymphoma in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Ruxience is contraindicated in:

  • patients who are hypersensitive to this drug 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 cell proteins, or to any component of this product.
  • patients who have or have had progressive multifocal leukoencephalopathy.

In addition, Ruxience is not recommended for use in patients with severe, active infections.

Ruxience 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.

Ruxience (10 mg/mL rituximab) is presented as a solution. In addition to the medicinal ingredient, the solution contains edetate disodium dihydrate, L-histidine, L-histidine monohydrate hydrochloride, polysorbate 80, sucrose, 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 Ruxience Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Ruxience approved?

 

Health Canada considers that the benefit-risk profile of Ruxience is highly similar to that of the reference biologic drug, Rituxan, for use in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis. Similarity between Ruxience and Rituxan was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Ruxience (rituximab) is a chimeric monoclonal IgG1 antibody that binds with high affinity to CD20, a membrane-embedded surface protein expressed primarily by the B-cell lineage throughout B-cell differentiation prior to terminal differentiation into plasma cells. Given that non-Hodgkin's lymphoma and chronic lymphocytic leukemia are malignancies that most often arise from various stages of B-cell development, CD20 is an attractive target that has been exploited in their treatment. B cells have also been demonstrated to play an important role in the development of autoimmune diseases including rheumatoid arthritis.

The reference product, Rituxan, has proven to be invaluable in the treatment of non-Hodgkin's lymphoma and chronic lymphocytic leukemia. It has also demonstrated its usefulness in patients with rheumatoid arthritis whose disease has not responded to other available therapies and among patients with other autoimmune diseases. Based on these findings, the reference product (Rituxan) is authorized for use in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis.

On the basis of an extensive analytical and biological similarity assessment of Ruxience, in combination with comparative non-clinical and clinical data, the sponsor sought authorization for each of the indications held by the Canadian reference product, Rituxan.

As clinical support for authorization, the sponsor provided evidence demonstrating pharmacokinetic similarity between Ruxience and reference rituximab in patients with rheumatoid arthritis. In addition, clinically meaningful differences in safety and efficacy were not detected in a randomized, controlled, clinical equivalence trial comparing Ruxience to reference rituximab in patients with low tumour burden follicular lymphoma. The primary outcome of the study was the overall response rate. The study met the predefined objective of demonstrating that Ruxience is clinically equivalent to reference rituximab in terms of overall response rate in the chosen study population. The results of these studies, in combination with the results of extensive comparative physicochemical and functional assessments, provide sufficient evidence of similarity to support the authorization of Ruxience for use in treating non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis.

The safety profile of Ruxience is considered to be comparable to that which has been established for the reference biologic drug, Rituxan. The Adverse Reactions section of the Ruxience Product Monograph is based on the clinical experience with the reference biologic drug. As found in the Product Monograph for Rituxan, a Serious Warnings and Precautions box has been included in the Product Monograph for Ruxience. This section highlights the risks of infusion reactions, progressive multifocal leukoencephalopathy, tumour lysis syndrome, hepatitis B virus reactivation, mucocutaneous reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome), infections, and cardiovascular events.

Serious adverse reactions reported during post-marketing use of rituximab are also listed in the Ruxience Product Monograph.

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

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

Based on an assessment of the relevant information provided in the submission, including a scientific rationale for the authorization of each indication, Ruxience is considered to have a benefit-risk balance similar to that established for the claimed indications, which are currently held by the reference product, Rituxan. Therefore, the benefit-risk balance for Ruxience is considered favourable for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis, as outlined in the Ruxience Product Monograph.

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 Ruxience?

 

Submission Milestones: Ruxience

Submission Milestone Date
Pre-submission meeting: 2018-08-08
Submission filed: 2019-02-06
Screening  
Screening Acceptance Letter issued: 2019-03-25
Review  
Review of Risk Management Plan complete: 2019-11-07
Clinical Evaluation complete: 2019-12-23
Quality Evaluation complete: 2020-01-09
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2020-01-14
Patent Hold  
Submission placed on Patent Hold: 2020-01-16
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate: 2020-05-04

 

The Canadian regulatory decision on the review of Ruxience was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

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 sponsor to monitor the post-market safety profile of this biosimilar product as well as the Product Monograph of the reference biologic drug, Rituxan, for safety signals that could affect the biosimilar, and make safety updates to the Ruxience 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 Ruxience?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Ruxience is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

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

 

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

 

Ruxience 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.

Comparative Structural and Functional Studies

The reference product chosen for the assessment of biosimilarity was MabThera, authorized in the European Union. MabThera was considered a suitable proxy for the Canadian-sourced Rituxan as it met all of the requirements set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The sponsor provided data to support authorization of two strengths of Ruxience, 100 mg/10 mL and 500 mg/50 mL. While the strengths are the same as those approved for Rituxan and MabThera, the formulations are different. Ruxience is formulated to a pH of 5.8 in L-histidine, EDTA, sucrose, and polysorbate 80, whereas Rituxan and MabThera are formulated to a pH of 6.5 in sodium citrate, sodium chloride, and polysorbate 80.

The bioisimilarity assessment was conducted as a three-way physicochemical and functional similarity assessment using MabThera, Rituxan sourced from the United States (Rituxan-US), and Ruxience. Both strengths were included in the studies.

The biosimilarity assessment included extensive physicochemical and biological characterization as well as comparative forced degradation studies. No new impurities were detected in the Ruxience drug substance or drug product as compared to MabThera. Comparative forced degradation studies of Ruxience and MabThera showed similar degradation pathways and profiles. The data provided support to the sponsor's assertion that Ruxience is highly similar to the reference product MabThera.

Characterization of the Drug Substance

The medicinal ingredient in Ruxience, rituximab, is a genetically engineered chimeric immunoglobulin G1 (IgG1) kappa monoclonal antibody with two identical heavy chains and two identical light chains, covalently linked with four inter-chain disulfide bonds. It has an approximate molecular weight of 145 kDa. The antibody is directed against the transmembrane CD20 antigen, located on the surface of normal precursor B cells, mature B lymphocytes, and malignant B cells.

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

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within the established and acceptable limits.

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

Rituximab (PF-05280586) is produced by recombinant deoxyribonucleic (DNA) technology in Chinese hamster ovary (CHO) cells. Qualification of the master cell bank was done in accordance with relevant International Council for Harmonisation (ICH) guidelines and the results of those studies have confirmed its identity, sequence integrity, purity, and safety. The working cell bank was derived from one cryovial of the master cell bank and met suitable acceptance criteria.

The manufacturing process for rituximab (PF-05280586) is initiated with the thawing of a vial from the working cell bank. Cells from the working cell bank are progressively expanded and the cell culture fluid is harvested, centrifuged, clarified, and further purified using a combination of chromatographic steps and viral inactivation/removal steps. The resulting solution is concentrated and formulated prior to its filtration and dispensing into cryovessels. The drug substance is stored frozen.

All results of the in-process control and release tests met suitable process validation acceptance criteria. The clinical and non-clinical studies were conducted using a drug substance manufactured at a commercial scale at the commercial facility.

The drug product, Ruxience, is available in two strengths, 100 mg/10 mL and 500 mg/50 mL. Both strengths are prepared using the same manufacturing process with differences only in the vial size (15 mL and 50 mL) and the fill volume (10.39 mL and 50.48 mL). The drug substance is shipped in cryovessels to the drug product manufacturing site, where it may be used directly from the cryovessels or dispensed into storage bags for future use. The commercial drug product manufacturing process consists of the manufacture of a formulation buffer that is used to dilute the drug substance to the target protein concentration of 10 mg/mL, followed by redundant sterile filtration. Sterile filtered bulk is subsequently filled into vials that are stoppered, capped, and visually inspected.

Process validation studies demonstrated that a drug product of acceptable quality is consistently manufactured at the proposed manufacturing site.

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

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of rituximab 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 a suitable reference standard to verify that they meet approved specifications. Analytical procedures are validated and in compliance with ICH guidelines.

Ruxience 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. As part of this program, final product lots were tested using a subset of release methods and shown to be fit for purpose.

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 satisfactory.

The stability data support the proposed shelf life of 24 months for the Ruxience drug product, when stored at a temperature of 2°C to 8°C.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment involved in production 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.

Both sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

Adequate control measures are incorporated in the manufacturing process of rituximab (PF-05280586) to prevent contamination and maintain microbial control. Purification process steps designed to remove and inactivate any potential viral contaminants from the cell culture process are adequately validated. Endotoxin and bioburden testing are integrated in the control strategy and meet relevant guidelines and requirements.

No raw materials or excipients of biological origin were used in the development of the recombinant cell line, establishment of the master and working cell banks, or in the drug substance and drug product manufacturing process.

 

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 Ruxience 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.

One comparative single-dose study and one comparative 4-week repeat-dose study were conducted in cynomolgus monkeys. The non-clinical studies did not identify any notable differences in toxicology or toxicokinetics between the Ruxience and the reference product.

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

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

 

 

7.3 Clinical basis for decision

 

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 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. Accordingly, the clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Comparative Pharmacokinetics

The sponsor submitted one pivotal comparative pharmacokinetic study (B3281001) to establish equivalence in the pharmacokinetic parameters between Ruxience and the reference product, MabThera (rituximab sourced from the European Union [EU]). Mabthera (hereafter referred to as rituximab-EU) was considered a suitable proxy for Rituxan authorized in Canada as it met all of the requirements set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Study B3281001 was a randomized, double-blind, 3-arm, parallel-group study in patients with active rheumatoid arthritis on a background of methotrexate who had an inadequate response to one or more tumour necrosis factor (TNF) antagonist therapies. Patients continued with receiving stable doses of methotrexate (10 mg/week to 25 mg/week) and were required to receive supplementary folate. The study was designed to compare the pharmacokinetics of Ruxience to rituximab-EU and rituximab sourced from the United States, rituximab-US.

The study enrolled 220 subjects who were randomized in a ratio of 1:1:1 to Ruxience, rituximab-EU or rituximab-US. Patients received their assigned treatment, which included two doses of 1,000 mg administered two weeks apart (on days 1 and 15). Sampling occurred over a period of 168 days (covering both doses). The sampling time was sufficient to characterize an adequate portion of the concentration versus time curve.

The sponsor's primary analysis of comparative pharmacokinetics was conducted on the per-protocol population, defined as all subjects who were randomized to and received the full dose of the planned study treatment and who had no major protocol violations that would affect the analysis. The analysis included 63, 67, and 68 subjects who received Ruxience, rituximab-EU, and rituximab-US, respectively. Similarity in pharmacokinetics was demonstrated by the 90% confidence intervals (CI) of the ratios of the geometric means of the area under the serum concentration versus time curve from time 0 to the last measured concentration at time T (AUCT) and the maximum observed serum concentration (Cmax) (point estimate) falling entirely within the predefined similarity margins of 80.0% to 125.0%.

The per-protocol population analysis excluded the data for 22 subjects. Although the sponsor purposefully overpowered the study to account for loss of subjects, there remained concern that the assessment could be biased due to imbalances that might have arisen through exclusions. Another concern arose due to the exclusion of 9 subjects, enrolled at a single site, who were excluded because of unexplained inconsistencies in their pharmacokinetic data. Given that Health Canada's Guidance Document: Conduct and Analysis of Comparative Bioavailability Studies clearly states that all subjects who have evaluable data should be included in the analyses, the reviewer of the submission performed an analysis on the intention-to-treat (ITT) population (all randomized subjects) using nominal sampling times. This analysis demonstrated pharmacokinetic similarity, as the ratios of the geometric means of AUCT and Cmax and their 90% CIs fell entirely within the predefined similarity margins of 80.0% to 125.0%. Finally, the sponsor was asked to recalculate the ratios after including all evaluable subjects and considering actual sampling times. The results of these analyses were also demonstrative of pharmacokinetic similarity. Therefore, pharmacokinetic similarity has been adequately demonstrated in compliance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document and the Guidance Document: Conduct and Analysis of Comparative Bioavailability Studies.

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

Comparative Clinical Efficacy, Safety, and Immunogenicity

The efficacy, safety, and immunogenicity of Ruxience in comparison to the innovator version of rituximab were assessed in patients with low tumour burden follicular lymphoma (study B3281006) and patients with rheumatoid arthritis (study B3281001 and its extension, study B3281004).

Comparative Clinical Efficacy

Patients with low tumour burden follicular lymphoma (study B3281006)

One pivotal comparative study was submitted to support the sponsor's assertion that no clinically meaningful differences exist between the biosimilar (Ruxience) and the innovator version of rituximab. The study, B3281006, was a multicentre, randomized, double-blind study of Ruxience versus innovator rituximab sourced from the EU (rituximab-EU), for the first-line treatment of patients with CD20-positive, low tumour burden follicular lymphoma. The study population was considered a suitable test population for a comparison of response rates to support a demonstration of biosimilarity. While treatment options for patients with low tumour burden follicular lymphoma often include a watch-and-wait approach, the use of rituximab as a first-line monotherapy is also considered a reasonable option and is associated with a high overall response rate (ORR) of approximately 77%. Based on these previous findings and on discussions with international regulators, the sponsor predefined margins for equivalence in ORR of -16% to 16%.

The study randomized 198 patients to rituximab-EU and 196 patients to Ruxience, 197 and 196 of whom, respectively, received at least one dose of study treatment. Randomization was stratified by the Follicular Lymphoma International Prognostic Index 2 (FLIPI2) classification (low, medium and high risk). A review of the baseline patient demographics and disease characteristics demonstrated that the treatment arms were well balanced.

Patients were to receive the study drug to which they were randomized once weekly for 4 weeks at a dose of 375 mg/m2, the usual dose of rituximab administered to adult patients with non-Hodgkin's lymphoma.

The primary outcome was the ORR by treatment arm, based on blinded central review, among the ITT population at study week 26. The primary objective was to demonstrate equivalence in the ORR within the predefined margins. The blinded central review applied the 2007 International Working Group response criteria in the assessment of response. The estimated ORRs were 70.7% (95% CI: 63.8%, 76.9%) and 75.5% (95% CI: 68.9%, 81.4%) in the rituximab-EU and Ruxience treatment arms. The risk difference was 4.66% (95% CI: -4.16%, 13.47%). As the 95% CI of the risk difference was entirely contained within the predefined equivalence margins (-16%, 16%), the trial was determined to have met its primary objective.

Subgroup analyses of the ORR demonstrated consistency across patients with various baseline demographic and disease characteristics.

Rheumatoid arthritis (study B3281001)

Supportive comparative efficacy data stem from the pivotal comparative pharmacokinetic study B3281001 (see Comparative Pharmacokinetics) conducted in patients with active rheumatoid arthritis and inadequate response to anti-TNF treatment. In this study, efficacy was compared descriptively and included assessments of the American College of Rheumatology (ACR) response endpoints (ACR20/50/70) and the 28-joint disease activity score with C-reactive protein (DAS28-CRP) at various time points. The assessments were supportive of biosimilarity, considering that the study was not designed to make any definitive conclusions regarding similarity beyond pharmacokinetic similarity.

Comparative Clinical Safety

Patients with low tumour burden follicular lymphoma (study B3281006)

In the pivotal study B3281006 (described in Comparative Clinical Efficacy), the safety population included all patients with low tumour burden follicular lymphoma who received at least one dose of study medication (n = 393). One patient randomized to the rituximab-EU arm did not receive any study medication and was therefore not included in the safety population.

The extent of exposure was similar in the treatment arms as 390 out of 393 subjects received all four doses of study medication.

Adverse events were observed in most subjects. There were 79.6% and 73.6% of patients in the Ruxience and rituximab-EU treatment arms, respectively, who had an adverse event regardless of relationship to treatment. Serious adverse events were experienced by 8.7% of patients receiving Ruxience and 7.6% of patients receiving rituximab-EU. Adverse events that were considered grade 3 or higher occurred in 14.3% of patients who received Ruxience and 13.2% of those who received rituximab-EU. Treatment discontinuation, due to an adverse event, was required for 1.5% and 1.0% of patients in the Ruxience and rituximab-EU treatment arms, respectively. Temporary treatment discontinuation due to an adverse event was required for 25.9% of patients treated with rituximab-EU compared to 18.9% of patients treated with Ruxience.

Infusion-related reactions were slightly more common among patients who received rituximab-EU in comparison to those who received Ruxience (29.9% vs. 25.0%).

Overall, the adverse event profile was similar for the two treatments and did not suggest a difference that could be attributable to product-related differences.

Patients with rheumatoid arthritis (study B3281001 and its extension, study B3281004)

Supportive comparative safety data were derived from the pivotal pharmacokinetic study B3281001 (described in the Comparative Pharmacokinetics). The extent of exposure was similar in the three arms of the study (Ruxience, rituximab-EU, rituximab-US). Of the 220 treated subjects, 217 received the full course of rituximab (1,000 mg administered on days 1 and 15).

Adverse events were reported for 68.5%, 61.6%, and 55.4% of patients receiving Ruxience, rituximab-US, and rituximab-EU, respectively. Serious adverse events were experienced by 6.8% of patients in the Ruxience treatment arm, compared to 1.4% of patients in the rituximab-EU treatment arm, and 5.5% of patients in the rituximab-US treatment arm. Grade 3 and higher adverse events occurred in 21 patients. The reported rates were 13.7%, 13.7%, and 1.4% in the Ruxience, rituximab-US, and rituximab-EU treatment arms, respectively. The sponsor was asked to provide any available information to explain the discrepancy in the rates of grade 3 or higher adverse events observed between the rituximab-EU arm and the remaining treatment arms. In the response, the sponsor acknowledged the differences, but pointed out that there was no common adverse reaction that accounted for the differences, with each grade 3 or higher adverse event preferred term occurring in 1 or 2 patients. The sponsor also provided information demonstrating that 7 out of 10 subjects in the Ruxience arm and 5 out of 10 subjects in the rituximab-US arm had medical histories that would suggest a predisposition to the adverse events that were observed. Importantly, no grade 4 events occurred in any of the three treatment arms.

The rate of withdrawal from treatment due to adverse events was low and similar between treatment arms (2.7% in the Ruxience arm, 1.4% in the rituximab-EU arm, and 1.4% in the rituximab-US arm).

Infusion-related reactions were reported for 13.7% of patients in each of the Ruxience and rituximab-US arms, while the rate of infusion-related reactions was 6.8% in the rituximab-EU arm.

Overall, the safety profile of Ruxience observed in study B3281001 is consistent with the known safety profile for Rituxan when used to treat patients with rheumatoid arthritis who have had inadequate response to anti-TNF therapies.

Study B3281004 was an extension study for subjects with active rheumatoid arthritis who had participated for at least 16 weeks in study B3281001 and had not received intervening treatment with investigational agents or other biologics (including rituximab-US and rituximab-EU) in the period between completing study B3281001 and entering study B3281004. This study evaluated the safety (including immunogenicity) of treatment with Ruxience, as well as the safety and immunogenicity occurring after transitioning from rituximab-US or rituximab-EU to Ruxience. Fifty-nine patients who received Ruxience in B3281001 continued to be treated with Ruxience in B3281004. Of the subjects who were randomized to rituximab-EU in B3281001, 33 were randomized to receive one course of rituximab-EU followed by two courses of Ruxience and 33 were randomized to receive three courses of Ruxience. Similarly, of the subjects randomized to rituximab-US in B3281001, 30 were randomized to receive one course of rituximab-US followed by two courses of Ruxience, while 30 were randomized to receive three courses or Ruxience.

The rates of adverse events and the rates of serious adverse events in study B3281004 were comparable between each of the treatment sequences.

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

Comparative Immunogenicity

Immunogenicity of Ruxience was evaluated in patients with low tumour burden follicular lymphoma (study B3281006) and patients with rheumatoid arthritis (study B3281001 and its extension, study B3281004). The patients with low tumour burden follicular lymphoma were considered a suitable population for immunogenicity assessment. These patients had not received prior chemotherapy regimens and received rituximab as monotherapy, whereas the rheumatoid arthritis patients in study B3281001 could have had prior treatment with a variety of products including disease-modifying antirheumatic drugs and TNF antagonists. In addition, rheumatoid arthritis patients in study B3281001 received concomitant methotrexate, which may affect the immune response.

In study B3281006, patients were followed for up to 52 weeks. The overall rate of anti-drug antibody positivity observed at any time post-baseline was 19.8% for patients who received rituximab-EU and 22.1% for patients who received Ruxience. Anti-drug antibodies against Ruxience were cross-reactive with rituximab-EU in 93% of cases suggesting that the former were elicited by epitopes common to both products. The majority of anti-drug antibodies against rituximab-EU were also cross-reactive with Ruxience (76.9%).

The rates of anti-drug antibody positivity in study B3281001 (or later) were 12.3%, 13.5%, and 9.6% for rituximab-US, rituximab-EU, and Ruxience, respectively. Of note, the follow-up could be variable for patients in this study due to the extension study enrollment that was available, but not required, beginning at week 16. In the extension study, B3281004, the overall results of immunogenicity testing gave no clear indication that continuing with a single treatment (Ruxience) or switching between Ruxience and the reference product (rituximab-EU or rituximab-US) was associated with an impact on the rate of immunogenicity.

Overall, the assessments of immunogenicity are considered adequate and supportive of biosimilarity.

Indications

Similarity between Ruxience and the reference biologic drug, 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 sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug and therefore clinical trials are not required to support each indication.

Within this drug submission, the sponsor provided a rationale for requesting the authorization of indications that were not specifically studied in the clinical development program for Ruxience. The sponsor addressed each of the critical points including the mechanism of action in each indication, pharmacokinetic and biodistribution differences between populations, immunogenicity, and potential toxicity differences between indications. The primary focus of the scientific justification was on the similarity demonstrated through comparative physicochemical and functional assessments, non-clinical comparisons and clinical pharmacokinetic, safety, and efficacy comparisons.

Based on the evidence submitted, Ruxience was authorized for the same indications currently held by the reference drug Rituxan, as follows:

  • Non-Hodgkin's Lymphoma (NHL)
     
  • Ruxience (rituximab for injection) is indicated for:
     
    • 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 CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
       
    • the treatment of patients with previously untreated stage III/IV follicular, CD20-positive, B-cell non-Hodgkin's lymphoma in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy.
       
    • the maintenance treatment of patients with follicular non-Hodgkin's lymphoma who have responded to induction therapy with either CHOP or CHOP plus Ruxience.
       
    • 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 Ruxience or CVP plus Ruxience.
       
  • Chronic Lymphocytic Leukemia (CLL)
     
  • Ruxience (rituximab for injection) is indicated for 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 rituximab 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 R-FC (rituximab-fludarabine and cyclophosphamide) in CLL patients who were previously treated with rituximab in combination with fludarabine and cyclophosphamide has not been studied.
     
  • Rheumatoid Arthritis (RA)
     
  • Ruxience in combination with methotrexate is indicated in adult patients:
     
    • 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.
       
  • Rituximab in combination with methotrexate has been shown to reduce the rate of progression of joint damage as measured by X-ray.
     
  • Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)
     
  • Ruxience in combination with glucocorticoids is indicated for the induction of remission in adult patients with severely active granulomatosis with polyangiitis (GPA, also known as Wegener's granulomatosis) and microscopic polyangiitis (MPA).
     
  • Consideration should be given to current treatment guidelines for vasculitis.

 

 

 

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