Summary Basis of Decision for Riximyo

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 Riximyo is located below.

Recent Activity for Riximyo

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.

The following table describes post-authorization activity for Riximyo, 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 that are found in PAATs.

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

Updated: 2023-08-04

Drug Identification Number (DIN):

DIN 02498316 – 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
NC # 272636 2023-02-24 Issued NOL 2023-05-24 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to a drug substance manufacturing facility. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 261906 2022-03-02 Issued NOL 2022-04-19 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the controls applied during the drug substance manufacturing process. The submission was considered acceptable, and an NOL was issued.
NC # 259381 2021-12-09 Issued NOL 2022-03-04 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the drug product manufacturing process and a change in the labelled storage conditions for the drug product. The submission was reviewed and considered acceptable. As a result of the NC, modifications were made to the Storage, Stability and Disposal section of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOL was issued.
NC # 257604 2021-10-15 Issued NOL 2022-01-26 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the drug substance purification process. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 252269 2021-04-30 Issued NOC 2021-10-05 Submission filed as a Level I – Supplement to update the mock-up label. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 242572 2020-08-07 Issued NOC 2021-06-30 Submission filed as a Level I – Supplement to add an indication for Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 249727 2021-03-02 Issued NOL 2021-06-08 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 239713 2020-05-26 Issued NOL 2020-08-13 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to transfer quality control testing activities to a new facility. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02498316) market notification Not applicable Date of first sale: 2020-05-22 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 214058 2018-03-06 Issued NOC 2020-04-28 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Riximyo

Date SBD issued: 2020-09-02

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

Rituximab

Drug Identification Number (DIN):

  • DIN 02498316 - 10 mg/mL, solution, intravenous administration

Sandoz Canada Inc.orporated

New Drug Submission Control Number: 214058

On April 28, 2020, Health Canada issued a Notice of Compliance (NOC) to Sandoz Canada Incorporated for Riximyo, a biosimilar to Rituxan. 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. Riximyo contains the medicinal ingredient rituximab, which has been demonstrated to be highly similar to the 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. To be considered a biosimilar, the weight of evidence is provided by the structural and functional studies. The non‑clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non‑clinical, pharmacokinetic and pharmacodynamic, and clinical studies.

The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought.

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

In this drug submission, Rituxan is the reference biologic drug. Similarity between Riximyo 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 Riximyo for a subset of the indications that are currently authorized for Rituxan: 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 Riximyo is considered to be highly similar to the reference biologic drug for 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 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 rituximab.
    • 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 rituximab or CVP plus rituximab.
       
  • 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 Riximyo 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)
    • 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.
  • Rituximab 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?

 

Riximyo, an antineoplastic agent, was authorized for the treatment of certain types of non‑Hodgkin's lymphomas, chronic lymphocytic leukemia, and rheumatoid arthritis.

Riximyo is a biosimilar to the reference biologic drug, Rituxan. Both drugs contain the medicinal ingredient, rituximab, which is a genetically engineered chimeric murine/human monoclonal antibody produced by mammalian cell (Chinese hamster ovary) suspension culture in a nutrient medium. The chimeric anti‑CD20 antibody is directed against the CD20 antigen found on the surface of normal and malignant B cells. After binding to the CD20 antigen, rituximab is believed to exert its therapeutic effect by promoting B‑cell lysis.

Similarity between Riximyo and the reference biologic drug, Rituxan, has been established on the basis of comparative structural and functional studies, comparative non‑clinical studies, one comparative pharmacokinetic/pharmacodynamic, safety, efficacy, and immunogenicity study in patients with rheumatoid arthritis, and one comparative efficacy, safety, and pharmacokinetic study in patients with follicular lymphoma in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The safety and effectiveness of Riximyo 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.

Riximyo is contraindicated in:

  • 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.
  • Patients with known hypersensitivity to any component of the product, including any non‑medicinal ingredient, or component of the container.

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

Riximyo 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.

Riximyo (10 mg/mL rituximab) is presented as a solution. In addition to the medicinal ingredient, the solution contains polysorbate 80, sodium chloride, sodium citrate, and water for injection.

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

 

2 Why was Riximyo approved?

 

Health Canada considers that the benefit‑risk profile of Riximyo is highly similar to that of the reference biologic drug, Rituxan (rituximab), for the treatment of certain types of non‑Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and rheumatoid arthritis (RA). Similarity between Riximyo and Rituxan was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The reference biologic drug, Rituxan, is authorized and marketed in Canada for the treatment of NHL, CLL, RA, granulomatosis with polyangiitis (GPA, also known as Wegener's granulomatosis) and microscopic polyangiitis (MPA). The New Drug Submission filed for Riximyo requested authorization for a subset of the indications currently authorized for Rituxan: NHL, CLL, and RA. Authorization for the indications relating to GPA and MPA were not requested for Riximyo.

Similarity to Rituxan, the Canadian reference product, was assessed by comparing Riximyo to the European Union‑authorized rutiximab (MabThera‑EU), which was considered a suitable proxy.

The medicinal ingredient in Riximyo, rituximab, is a chimeric monoclonal immunoglobulin G1 (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. Most types of NHL and CLL are malignancies that arise from B cells at various stages of development, therefore, CD20 is an attractive target that can be exploited in their treatment. B cells have also been demonstrated to play an important role in the development of autoimmune diseases, including RA. The reference product, Rituxan, has proven to be invaluable in the treatment of NHL and CLL, and has demonstrated its usefulness in patients with RA who have not responded to other available therapies.

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

As clinical support for authorization, the sponsor provided evidence demonstrating pharmacokinetic similarity between Riximyo and MabThera‑EU in patients with RA. One pivotal study investigated similarity in safety and efficacy in the advanced follicular lymphoma (FL) setting. The FL study met its pre‑defined efficacy endpoint (i.e., demonstration of similarity in overall response rate during the combination treatment phase).

On the basis of clinical studies carried out among patients with RA and patients with advanced FL, Riximyo has demonstrated a comparable safety profile with the reference biologic drug, Rituxan. As with Rituxan, the major identified safety concerns with Riximyo include infusion reactions, progressive multifocal leukoencephalopathy, tumor lysis syndrome, hepatitis B virus reactivation, mucocutaneous reactions including toxic epidermal necrolysis and Stevens‑Johnson syndrome, infections, and cardiovascular events. These issues and relevant recommendations have been addressed in the Serious Warnings and Precautions box of the Riximyo Product Monograph, as is found in the Product Monograph for Rituxan. The Adverse Reactions section of the Riximyo Product Monograph is based on the clinical experience with the reference biologic drug.

A Risk Management Plan (RMP) for Riximyo was submitted by Sandoz Canada Incorporated 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, Riximyo, was accepted.

Overall, Riximyo 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 Riximyo are considered to outweigh the potential risks in the intended patient populations.

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. 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. 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 Riximyo?

 

During the first review cycle, the submission was determined to be incomplete from a clinical perspective, which led to the issuance of a Notice of Deficiency (NOD). (See Clinical Basis for Decision).

The sponsor filed a response to the NOD to address the outstanding concerns. Taking into consideration the sponsor's response to the NOD, the totality of evidence provided in the submission established that Riximyo has a benefit‑risk balance similar to that of the reference product, Rituxan, for the claimed indications. Accordingly, a Notice of Compliance (NOC) was issued for Riximyo.

 

Submission Milestones: Riximyo

Submission Milestone Date
Pre-submission meeting: 2011-12-07
Submission filed: 2018-03-06
Screening 1  
Screening Acceptance Letter issued: 2018-04-20
Review 1  
Review of Risk Management Plan complete: 2018-11-19
Clinical Evaluation complete: 2018-12-17
Quality Evaluation complete: 2018-12-24
Notice of Deficiency (NOD) issued by Director General, Biologics and Genetic Therapies Directorate (safety and effectiveness issues): 2018-12-28
Response filed: 2019-06-28
Screening 2  
Screening Acceptance Letter issued: 2019-07-05
Review 2  
Review of Risk Management Plan complete: 2020-03-04
Clinical Evaluation complete: 2020-04-07
Quality Evaluation complete: 2020-04-24
Notice of Compliance (NOC) issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate: 2020-04-28

 

The Canadian regulatory decision on the review of Riximyo was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency, the Therapeutic Goods Administration (the regulatory body for therapeutic goods in Australia), the United States Food and Drug Administration, the Swiss Agency for Therapeutic Products, Swissmedic, and the Pharmaceuticals and Medical Devices Agency of Japan 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?

 

The onus is on the Riximyo 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 Riximyo 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.

In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments refer to (but are not limited to):

  • Riximyo will be included in registries similar to the ones included for Rituxan in Canada
  • Submitting to Health Canada, as part of routine pharmacovigilance activities, Periodic Benefit‑Risk Evaluation Reports every 6 months for the first year after marketing in Canada, and annually thereafter.
  • Submitting to Health Canada for review, a copy of the educational materials (e.g., healthcare professional educational materials and healthcare professional and patient alert cards) proposed in the Canadian RMP for non‑oncology indications (e.g., rheumatoid arthritis).

 

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

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 Riximyo 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

 

Riximyo (rituximab) was developed as a biosimilar to the reference drug, Rituxan. For biosimilars, the weight of evidence is provided by structural and functional studies. Biosimilars are manufactured to the same regulatory standards as other biologic drugs. In addition to a typical chemistry and manufacturing data package that is submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity with the reference biologic drug.

The biological activity of Riximyo is considered to be representative of the mechanism of action and pharmacological effect of Rituxan.

Comparative Structural and Functional Studies

The reference biologic drug used to establish similarity with Riximyo was MabThera, authorized in the European Union (MabThera‑EU). MabThera‑EU is marketed under the brand name Rituxan in the United States (Rituxan‑US). Of note, both MabThera‑EU and Rituxan‑US were used as reference products in the Riximyo clinical program. Additionally, the nonclinical toxicology study used MabThera‑EU as a reference product.

A scientific bridge was established between MabThera‑EU and Rituxan‑US, based on three pairwise analytical and pharmacokinetic comparisons. To complete the analytical comparisons, Riximyo, MabThera‑EU, and Rituxan‑US were subjected to the same testing plan. Comparability was assessed using a combination of characterization, stability, accelerated stability, and forced degradation studies to assess similarity of Riximyo to the chosen comparator, MabThera‑EU/Rituxan‑US. These studies have established a high degree of similarity in the primary, secondary, and tertiary structure, as well as the purity, biological activity, and the stability and forced degradation profiles of Riximyo and MabThera‑EU/Rituxan‑US.

The non‑Canadian reference product is considered a suitable proxy for the version of this product authorized in Canada as it met all of the requirements set forth in Health Canada's Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Characterization of the Drug Substance

The medicinal ingredient in Riximyo, rituximab, is a chimeric (murine and human) immunoglobulin G1 (IgG1) monoclonal antibody comprised of two heavy chains and two light chains. Rituximab binds to the CD20 antigen expressed on the surface of normal and malignant B cells, and elicits its mechanism of action through antibody‑dependent cellular cytotoxicity, complement‑dependent cytotoxicity, and apoptosis.

Detailed characterization studies were performed to provide assurance that rituximab consistently exhibits the desired characteristic structure and biological activity. These studies involved determination of primary and higher‑order structures, glycosylation, charge heterogeneity, size variants, binding activity, functional bioactivity, and purity/impurities.

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

The Riximyo drug substance is produced in Chinese hamster ovary cells. The manufacturing process begins with thawing one vial of a working cell bank. Subsequent operations can be separated into upstream and downstream processes. The upstream cell culture process is comprised of inoculum preparation, pre‑stage cultivation (expansion batches in bioreactors), and main‑stage cultivation. The downstream purification process consists of separation, capture chromatography, viral inactivation, multimodal chromatography, cation‑exchange chromatography, viral filtration, ultrafiltration/diafiltration, and final filtration, filling, and freezing.

Appropriate in‑process controls and process parameters were implemented throughout the process to ensure consistent production of a high‑quality drug substance. Overall, process validation was successfully performed, demonstrating that the proposed commercial process is capable of reproducibly and consistently producing the Riximyo drug substance of satisfactory purity and desired product quality. 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.

The Riximyo drug product is a sterile concentrate for solution for infusion (for intravenous use after dilution), supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single‑use vials. The manufacture of the Riximyo drug product involves thawing of the required amount of drug substance, dissolving of excipients, compounding, sterile filtration, and aseptic vial filling. In‑process controls for the drug product manufacturing have been appropriately established.

Batch analysis and process validation studies demonstrated that the process scale‑up and optimizations made to the proposed commercial process did not affect the desired product quality. These validation studies covered the manufacturing process validation, aseptic processing (media fill validation), washing, sterilization and depyrogenation of the containers/closures, a hold time study, mechanical stress studies (stirring and pumping), sterile filter validation, and shipping validation. Batch analysis results were comparable and within acceptance criteria. Overall, the process was shown to be capable of reproducibly producing a drug product that meets 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 the medicinal ingredient with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The control strategy includes analytical methods selected to evaluate quality characteristics of Riximyo drug substance for identity, structure, physicochemical characteristics, concentration, potency, purity, and safety. Methods were appropriately verified or validated according to relevant International Council for Harmonisation (ICH) guidelines and are suitable to control the critical quality attributes of Riximyo.

The Canadian release and stability specifications for the drug substance and drug product are appropriate and acceptable, and were harmonized with those approved by the European Medicines Agency. Importantly, the Canadian specifications include additional specification parameters as agreed upon with Health Canada.

Riximyo 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 to be satisfactory.

The proposed shelf life for the Riximyo drug product is 36 months when stored at 2°C to 8°C, and protected from light. The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

An On‑Site Evaluation (OSE) of the facilities involved in the manufacture and testing of Riximyo was not conducted. It was determined that an OSE of the drug substance manufacturing site was not warranted. An OSE of the drug product manufacturing site was recommended, however, it was cancelled due to the coronavirus disease (COVID‑19) pandemic. It was recommended that an OSE be considered at the next opportunity.

Adventitious Agents Safety Evaluation

Based on the review of the comprehensive strategy in place to monitor and assess non‑viral and viral adventitious agents, Health Canada has determined that the manufacturing process of Riximyo incorporates adequate control measures to prevent contamination and maintain microbial control.

In addition, the biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy or other human pathogens.

 

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 Riximyo 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 non‑clinical studies did not identify any differences in toxicology or toxicokinetics between Riximyo and the reference product, Rituxan. One comparative, single‑dose study, and one comparative 4‑week repeat‑dose study, conducted in cynomolgus monkeys investigated B‑cell depletion and recovery as a pharmacodynamic endpoint. B‑cell recovery appeared to occur more rapidly among animals that received repeated administrations of Riximyo (20 mg/kg) in comparison to those that received MabThera‑EU at the same dose. However, due to the limitations associated with animal toxicology studies in general, no definitive conclusions regarding the existence or absence of differences can be drawn.

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

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

 

 

7.3 Clinical basis for decision

 

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

The reference biologic drug for Riximyo is marketed as Rituxan in Canada and the United States (Rituxan‑US), and under the brand name MabThera in the European Union (MabThera‑EU). The submission relied on comparisons made to demonstrate similarity to the Canadian‑authorized product, Rituxan (rituximab). Similarity was assessed by comparing Riximyo to MabThera‑EU, which was considered a suitable proxy for the Canadian reference product, Rituxan, as it met all of the requirements set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

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

Comparative Pharmacokinetics

The pharmacokinetic properties of Riximyo were compared to MabThera‑EU in part I of a pivotal comparative bioavailability study known as study GP13‑201. This randomized, double‑blind, parallel‑group, clinical study included 173 adult patients with rheumatoid arthritis (RA) refractory or intolerant to standard disease‑modifying antirheumatic drugs and anti‑tumour necrosis factor alpha therapies. Patients were randomized in a ratio of 1:1 to receive 1000 mg of either Riximyo or MabThera‑EU as two single intravenous infusions, two weeks apart, in combination with methotrexate.

The study successfully met pre‑defined criteria to establish pharmacokinetic similarity. The primary pharmacokinetic endpoint was the area under the concentration‑time curve (AUC) from time zero to infinity. As per Health Canada's Guidance Document: Conduct and Analysis of Comparative Bioavailability Studies, the sponsor also provided comparisons for the AUC from time zero to the last measurable concentration (AUCT) and maximum blood concentration after first infusion (Cmax,1). The point estimate and 90% confidence interval of the geometric mean ratio (GMR) of AUCT of Riximyo/MabThera‑EU were within the acceptance margins of 80.0% to 125.0%. The GMR for Cmax,1 was 113.3%, which falls within the acceptance margins of 80.0% to 125.0%. 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, please refer to the Riximyo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Comparative Clinical Efficacy and Safety

The efficacy and safety of Riximyo was compared to MabThera‑EU in study GP13‑301. This randomized, double‑blind Phase III clinical study included patients aged 18 years or older with previously untreated, advanced stage (Ann Arbor stage III/IV), CD20 positive follicular lymphoma (FL) with World Health Organization histological grades 1 to 3a. In this study, 618 patients were randomized in a ratio of 1:1 to receive 8 cycles (every 21 days) of either Riximyo in combination with cyclophosphamide, vincristine, and prednisolone (CVP) or MabThera‑EU in combination with CVP. Patients were stratified by the Follicular Lymphoma International Prognostic Index (FLIPI) score risk group (FLIPI score 0 to 2 [low/intermediate risk] vs FLIPI score 3 to 5 [high risk]) and by geographic region (Asia Pacific, Latin America, or Europe).

Patients who achieved a complete response (CR) or partial response (PR) at the end of the combination treatment period were offered single‑agent Riximyo or MabThera‑EU maintenance treatment, according to original treatment assignment, for a period of 2 years. Data provided to Health Canada were based on the first interim analysis, which included data from the completed combination phase, and on‑going maintenance and follow‑up phases. All patients were to be followed for progressive disease and overall survival for a maximum period of 3 years from the date of randomization.

The study met its primary objective, which was to demonstrate the absence of a clinically meaningful difference in the overall response rate (ORR: CR+PR) between Riximyo and MabThera‑EU at the end of the combination treatment period. Response to treatment was assessed using the Modified Response Criteria for Malignant Lymphoma through central blinded review of the radiological response. Comparability between Riximyo and MabThera‑EU was demonstrated since the two‑sided 95% confidence interval of the risk difference in ORR after 8 cycles of combination treatment was entirely contained within the predefined equivalence interval of -12% to 12%.

Of note, a Notice of Deficiency (NOD) was issued in the first review cycle of this submission. One of the deficiencies, related to an unexplained difference in a secondary endpoint, progression free survival (PFS), was observed in study GP13‑301. Upon review of the sponsor's response to the NOD, it was determined that the design of study GP13‑301 did not allow for a meaningful comparison of the secondary time‑to‑event endpoints and that certain design features, rather than differences between the biosimilar and the reference product, could have contributed to the difference. Therefore, the PFS data obtained from the study were considered unreliable. However, the totality of evidence supported biosimilarity and, therefore, the authorization of Riximyo for the requested subset of the indications that are currently authorized for the reference product, Rituxan.

The extent of exposure to the investigational treatment was comparable between the treatment groups for both the combination phase and the maintenance phase. During the combination phase, similar proportions of patients in each treatment group reported adverse events (Riximyo: 92.6%; MabThera‑EU: 91.4%), severe adverse events (Riximyo: 22.8%; MabThera‑EU: 20.0%), adverse events suspected to be related to study drug (Riximyo: 73.7%; MabThera‑EU: 70.8%), and adverse events leading to treatment discontinuation (Riximyo: 7.4%; MabThera‑EU: 7.0%).

The rates of infusion‑related reactions were comparable between the treatment groups (Riximyo: 49.4%; MabThera‑EU: 48.3%). A higher incidence of cardiac disorders was observed in the Riximyo group compared to the MabThera‑EU group (Riximyo: 28 [9.0%]; MabThera‑EU: 15 [4.8%]). This appeared to be at least partially related to the distribution of patients with pre‑existing medical conditions at study randomization. Comparable incidences of deaths were reported during the combination phase (Riximyo: 4 [1.3%]; MabThera‑EU: 7 [2.2%]), maintenance phase (Riximyo: 2 [0.8%], MabThera‑EU: 2 [0.8%]), and post‑treatment phase (Riximyo: 14 [4.5%]; MabThera‑EU: 16 [5.1%]). Underlying non‑Hodgkin's lymphoma (NHL) was the most common cause of death and the incidence was balanced between the treatment groups (Riximyo: 8 [2.6%]; MabThera‑EU: 9 [2.9%]).

As with Rituxan, the major identified safety concerns with Riximyo include infusion reactions, progressive multifocal leukoencephalopathy, tumor lysis syndrome, hepatitis B virus reactivation, mucocutaneous reactions including toxic epidermal necrolysis and Stevens‑Johnson syndrome, infections, and cardiovascular events. These risks are listed in a Serious Warnings and Precautions box in the Riximyo and Rituxan Product Monographs. Statements are also included to highlight that Riximyo should only be administered by health professionals experienced in treating the conditions for which the drug is indicated: NHL, chronic lymphocytic leukemia (CLL), RA. Additionally, patients should be treated in a setting where full resuscitation facilities, medications, and supportive care measures for the treatment of hypersensitivity reactions are immediately available.

In both the FL and RA studies, no new or unexpected safety signals were reported. Also, discontinuation rates and the incidences of adverse events were similar between Riximyo and MabThera‑EU. The treatment‑emergent adverse events are expected to be manageable by following current practices in place for rituximab, and do not raise concerns with respect to the biosimilarity of the two products.

Overall, the safety profile of Riximyo is considered to be comparable to that which has been established for the reference biologic drug, Rituxan.

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

Comparative Immunogenicity

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity, i.e., the development of anti‑drug antibodies (ADAs), which may have the potential to neutralize the biological activity of the drug. Immunogenicity of Riximyo was assessed in RA and FL patients.

In the RA study (study GP13‑201), 22.2% of patients were confirmed positive for binding ADAs in Riximyo‑treated patients while 13.9% and 32.1% of Rituxan‑ and MabThera‑EU‑treated patients developed ADAs, respectively.

In the FL study (study GP13‑301), immunogenicity was detected in 1.8% of patients in the Riximyo group and 1.1% in the MabThera‑EU group.

Of note, one of the major deficiencies listed in the NOD issued in the first review cycle of this submission was related to the immunogenicity method used in study GP13‑201. In response to the NOD, the sponsor developed a more sensitive assay for the detection of ADAs. Upon review, the assay was determined to be acceptable.

Overall, the immunogenicity profile of Riximyo was similar to the reference biologic drugs, Rituxan and MabThera‑EU. While the majority of patients in both studies did not develop ADAs, the detected ADA responses were mainly transient, of low titer, and did not exhibit neutralizing activity.

Indications

Similarity between Riximyo 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 requested the authorization of Riximyo for a subset of the indications that are currently authorized for Rituxan, namely non‑Hodgkin's lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. Authorization for the indications relating to granulomatosis with polyangiitis (also known as Wegener's Granulomatosis) and microscopic polyangiitis was not requested for Riximyo. The indications have been authorized on the basis of demonstrated similarity between the Riximyo and Rituxan in structural and functional studies, mechanisms of action, pharmacological effect, pathophysiological mechanisms of the diseases involved, safety profile, dosage regimen, and clinical experience with the reference biologic drug.

Based on the evidence submitted, Riximyo was authorized for the following indications:

  • 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 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 rituximab.
    • 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 rituximab or CVP plus rituximab.
       
  • 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 Riximyo 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)
    • 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.
  • Rituximab in combination with methotrexate has been shown to reduce the rate of progression of joint damage as measured by X‑ray.

 

 

 

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