Summary Basis of Decision for Riabni

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 Riabni is located below.

Recent Activity for Riabni

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 Riabni, 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 AnchorAnchorManagement of Drug Submissions and Applications Guidance.

Updated: 2023-07-13

Drug Identification Number (DIN):

DIN 02513447 – 10 mg/mL rituximab, solution, intravenous injection

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02513447) market notification Not applicable Date of first sale: 2021-04-21 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 237814 2020-03-30 Issued NOC 2021-03-11 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Riabni

Date SBD issued: 2021-11-22

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

Rituximab

Drug Identification Number (DIN):

  • DIN 02513447 - 10 mg/mL rituximab, solution, intravenous injection

Amgen Canada Inc.

New Drug Submission Control Number: 237814

On March 11, 2021, Health Canada issued a Notice of Compliance to Amgen Canada Inc. for Riabni, 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. Riabni 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 product 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 Riabni 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 Riabni for all of the indications that are currently authorized for Rituxan.

The market authorization of Riabni 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 Riabni 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)

  • The treatment of patients with relapsed or refractory low-grade or follicular, CD20-positive, B-cell NHL.
  • The treatment of patients with CD20-positive, diffuse large B-cell NHL (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 NHL in combination with CVP (cyclophosphamide, vincristine, and prednisolone) chemotherapy.
  • The maintenance treatment of patients with follicular NHL who have responded to induction therapy with either CHOP or CHOP plus rituximab.
  • Single-agent maintenance treatment of previously untreated patients with advanced follicular NHL 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 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)

Riabni in combination with methotrexate is indicated in adult patients:

  • To reduce signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more tumour necrosis factor 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)

Riabni in combination with glucocorticoids is indicated for:

  • The induction of remission in adult patients with severely active GPA and MPA.

Consideration should be given to current treatment guidelines for vasculitis.

1 What was approved?

Riabni, an antineoplastic agent, was authorized for the treatment of certain types of non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), and granulomatosis with polyangiitis (GPA, also known as Wegener's granulomatosis), and microscopic polyangiitis (MPA).

Riabni is a biosimilar to the reference biologic drug, Rituxan. Both drugs contain the medicinal ingredient rituximab, which is a genetically engineered chimeric mouse/human immunoglobulin G1 (IgG1) monoclonal antibody. It binds with high affinity to the CD20 antigen, a membrane-embedded surface protein expressed primarily by the B-cell lineage throughout B-cell differentiation and prior to terminal differentiation into plasma cells. After binding to the CD20 antigen expressed on B cells, rituximab promotes B-cell depletion through multiple mechanisms of action. The biological functions that contribute to clinical efficacy are primarily mediated through the induction of effector functions. Complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity effector functions are critical to the mechanism of action.

Similarity between Riabni and Rituxan has been established on the basis of comparative structural, analytical and functional, non-clinical, immunogenicity, pharmacokinetic, pharmacodynamic, and clinical efficacy and safety studies in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

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

Riabni (rituximab) 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.

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

The safety and efficacy of rituximab, and therefore Riabni, have not been established in pediatric (<18 years of age) patients. In the CLL setting, exploratory subgroup analysis indicates that use in the geriatric (≥65 years of age) population is associated with differences in efficacy and safety.

Riabni 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.

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

2 Why was Riabni approved?

Based on Health Canada’s review, the benefit-risk profile of Riabni is considered to be similar to that of the reference product, Rituxan, and is therefore considered favourable for the treatment of certain types of non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), and granulomatosis with polyangiitis (GPA, also known as Wegener's granulomatosis), and microscopic polyangiitis (MPA). Similarity between Riabni and Rituxan was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The medicinal ingredient in Riabni, rituximab, has proven to be invaluable in the treatment of NHLs and CLLs and has demonstrated its usefulness in patients with RA that have not responded to other available therapies. Based on these findings, the reference product, Rituxan, is authorized and marketed in Canada for several indications and clinical uses, including several NHL indications, CLL, RA, GPA, and MPA. The New Drug Submission filed for Riabni requested authorization for all of the indications and clinical uses that are currently authorized for Rituxan. The indications have been authorized on the basis of demonstrated similarity between Riabni and the reference product. Similarity was established on the basis of comparative structural and functional studies.

Rituximab, is a genetically engineered chimeric mouse/human monoclonal immunoglobulin G1 (IgG1) antibody that binds with high affinity to the CD20 antigen, a membrane-embedded surface protein expressed primarily by the B-cell lineage throughout B-cell differentiation and prior to terminal differentiation into plasma cells. Given that the majority of NHLs, and CLLs, are malignancies that arise from various stages of B-cell development, 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. After binding to the CD20 antigen expressed on B cells, rituximab promotes B-cell depletion through multiple mechanisms of action. The biological functions that contribute to clinical efficacy are primarily mediated through the induction of effector functions. Complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity effector functions are critical to the mechanism of action of rituximab.

In support of the biosimilarity of Riabni and Rituxan, the sponsor submitted a non-clinical data package that included pharmacokinetic, pharmacology, and toxicology program elements.

As clinical support for authorization, the sponsor provided evidence demonstrating pharmacokinetic similarity between Riabni and Rituxan in patients with rheumatoid arthritis. A comparative study in patients with low tumor burden follicular lymphoma did not identify any clinically meaningful difference in efficacy between Riabni and Rituxan. The study met its primary objective to establish similarity in efficacy based on the overall response rate. The safety profile of Riabni was determined to be consistent with reference rituximab, based on assessments in studies of patients with follicular lymphoma and rheumatoid arthritis.

Riabni has demonstrated a comparable safety profile with its reference product, Rituxan. Therefore, the Adverse Reactions section of the biosimilar Product Monograph is based on the clinical experience with the reference biologic drug. As with Rituxan, a Serious Warnings and Precautions box has been included in the Riabni Product Monograph, describing reports of severe and life-threatening adverse reactions, infusion reactions, progressive multifocal leukoencephalopathy, tumour lysis syndrome, hepatitis B virus reactivation, mucocutaneous reactions, infections, and cardiovascular events.

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

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Riabni Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.

A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Riabni was accepted.

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 Riabni?

Submission Milestones: Riabni

Submission Milestone Date
Pre-submission meeting 2020-02-11
Submission filed 2020-03-30
Screening  
Screening Acceptance Letter issued 2020-05-15
Review  
Quality Evaluation completed 2021-01-26
Review of Risk Management Plan completed 2021-02-22
Clinical/Medical Evaluation completed 2021-02-24
Non-clinical Evaluation completed 2021-02-24
Labelling Review completed 2021-03-09
Notice of Compliance issued by Director General, Biologics and Radiopharmaceutical Drugs Directorate 2021-03-11

The Canadian regulatory decision on the review of Riabni was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration was used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications 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 Riabni 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 Riabni 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 Riabni?

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 Riabni 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

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

A three pairwise comparison of similarity assessment was conducted using rituximab sourced from the United States (rituximab-US; declared reference product), rituximab sourced from the European Union (rituximab-EU), and Riabni. Although both US- and EU-sourced products were used in similarity assessments with Riabni, rituximab-US is the primary reference product and is in accordance with the requirements as per Health Canada’s Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs (2016).

Comparative Structural and Functional Studies

To assess the comparability of Riabni to the reference biologic drug, rituximab-US, a combination of side-by-side, independent, and age-dependent testing designs was applied. Quantitative, expectation, and quality range assessment criteria were used to determine the similarity for each quality attribute.

Data from these studies demonstrated that Riabni has the same primary and higher order structure as rituximab-US and rituximab-EU, and highly similar post-translational modifications, purity, and potency. Minor differences were observed in biochemical attributes between Riabni, rituximab-US, and rituximab-EU. However, these differences did not impact the potency of Riabni, and are not expected to be clinically meaningful. Stability and forced degradation studies assessing different stressed conditions generated similar degradation profiles for Riabni, rituximab-US, and rituximab-EU.

The in vitro pharmacology data supported a comprehensive analysis of functional similarity of Riabni to rituximab-US and rituximab-EU.

Collectively, the data demonstrate that Riabni is highly similar to both rituximab-US (the reference product) and rituximab-EU, and support the assertion that Riabni is biosimilar to the reference biologic drug.

Characterization of the Drug Substance

The drug substance, rituximab, is a genetically engineered chimeric mouse/human immunoglobulin G1 (IgG1) monoclonal antibody consisting of two heavy chains and two light chains of the kappa subclass.

Detailed characterization studies were performed using orthogonal methods to provide assurance that rituximab consistently exhibits the desired biochemical, biophysical, and biological attributes. Stability studies at the recommended storage condition, accelerated and stressed conditions, and forced degradation condition were performed to evaluate the degradation pathways and molecular stability of rituximab.

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

The manufacturing process for the drug substance, rituximab, consists of a series of process steps: cell culture, harvest, purification, formulation, filtration, and filling into drug substance containers for storage.

Drug substance manufacturing process validation studies were successfully conducted for the commercial manufacturing process at the commercial site and scale. The results of these studies, as well as batch analysis data demonstrate that the manufacture of the drug substance is consistent, reproducible and delivers product of suitable quality. 

The manufacturing process for the drug product, Riabni, includes preparation of the formulation dilution buffer, drug substance thaw, formulation, bioburden reduction filtration, sterile filtration, aseptic vial filling, stoppering, capping, and visual inspection.

Drug product process validation studies were successfully conducted for the commercial manufacturing process at the commercial site and scale for the 100 mg/10 mL and 500 mg/50 mL single dose vial product presentations. The results of these studies, as well as the batch analysis data demonstrate that the manufacture of the drug products is consistent, reproducible, and delivers drug product of suitable quality. The sponsor also provided information regarding a continuous process verification program for drug substance and drug product that will monitor the manufacturing process and product quality.

Overall, the method of manufacturing and the controls used during the manufacturing processes 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 the medicinal ingredient with the excipients is supported by the stability data provided

Control of the Drug Substance and Drug Product

The sponsor has developed an integrated control strategy for the drug substance and drug product. The integrated control strategy was defined after gaining comprehensive knowledge of the process and the product quality attributes, along with an understanding of how these attributes are controlled during manufacturing. The strategy incorporated a number of control elements including process parameters, in-process controls, release specifications, and periodic testing controls (e.g., validation, comparability, and stability) of the drug substance and drug product. The goal of the integrated control strategy was to establish appropriate controls for the manufacturing process, such that the process will consistently deliver the required drug substance and drug product quality.

The drug substance and drug product specifications were established using data from release and stability testing. Both compendial and non-compendial analytical methods are used during in-process steps, release, and stability testing of the drug substance and drug product. For several of the in-process steps, in-process control tests with acceptance criteria are used rather than testing the final drug substance or drug product.All non-compendial methods were validated according to International Council for Harmonisation guidelines and were deemed suitable to control the critical quality attributes of the drug substance and drug product lots.

Riabni 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.

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. The proposed 36 month shelf life when stored at 2 ºC to 8 ºC and protected from light is considered acceptable for both presentations of Riabni (100 mg and 500 mg vials).

Acceptable data were provided to support that, if prepared in an aseptic manner, Ribani diluted in 0.9% sodium chloride may be stored refrigerated at 2 ºC to 8 °C for up to 7 days and that Riabni diluted in 5% dextrose may be stored refrigerated at 2 ºC to 8 °C for up to 24 hours prior to use.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

On-site evaluations of the facilities involved in the manufacture and testing of the drug substance and drug product were not conducted, as they were not deemed necessary based on risk assessment determined by Health Canada.

Adventitious Agents Safety Evaluation

Complementary approaches of raw material risk assessments, the adventitious agent testing of cell banks and unprocessed bulks, and the demonstration of viral clearance by the purification process were used.

The Chinese hamster ovary-derived rituximab cell line is the only animal-derived raw material used in the manufacture of Riabni. This cell line has been tested and shown to be free of adventitious agents and has been assessed as a negligible risk for transmissible spongiform encephalopathy transmission. Therefore, the risk for the transmission of adventitious agents by Riabni is negligible.

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, analytical and functional studies and address potential areas of residual uncertainty.

The non-clinical database submitted for Riabni 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.

In addition to the biological characterization results, supplementary in vitro characterization studies were conducted to provide information relevant to functionality in primary cells and evaluating additional activities related to CD20 engagement involved in the clearance of rituximab.

Non-clinical animal studies consisted of in vivo pharmacology and toxicology assessments. A comparative in vivo pharmacology study in a non-Hodgkin’s lymphoma mouse xenograft tumour model was conducted. Mice were administered 3 mg/kg or 30 mg/kg of either Riabni or sourced from the United States (rituximab-US) by intravenous injection twice weekly for three weeks. The results showed Riabni and rituximab-US had a similar effect on tumour growth inhibition.

A comparative four-week repeat-dose toxicology study was conducted to evaluate the toxicity of Riabni and to qualitatively compare it to the toxicity of rituximab-US. Cynomolgus monkeys were administered 20 mg/kg of either Riabni or rituximab-US by intravenous bolus injection once weekly for four weeks. The results of this study did not identify any notable difference in the toxicological profile between the biosimilar and reference biologic drug.

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

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

7.3 Clinical Basis for Decision

The purpose of the clinical program for a biosimilar is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The structural complexity of the biologic drug and availability of a relevant and sensitive pharmacodynamic endpoint determine the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural, analytical and functional studies and address potential areas of residual uncertainty.

Riabni is a biosimilar to Rituxan. Both drugs contain the medicinal ingredient rituximab. Rituximab is a genetically engineered chimeric mouse/human immunoglobulin G1 (IgG1) monoclonal antibody that binds with high affinity to the CD20 antigen, a membrane-embedded surface protein expressed primarily by the B-cell lineage throughout B-cell differentiation and prior to terminal differentiation into plasma cells. After binding to the CD20 antigen expressed on B cells, rituximab promotes B-cell depletion through multiple mechanisms of action. The biological functions that contribute to clinical efficacy are primarily mediated through the induction of effector functions. Complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity effector functions are critical to the mechanism of action of rituximab.

Comparative Pharmacokinetic Studies

The pharmacokinetic (PK) similarity between Riabni and the reference product, Rituxan sourced from the United States (rituximab-US), was established in a pivotal, comparative, randomized, double-blind, three-arm, parallel group study known as Study 20130108 (see Comparative Clinical Efficacy and Safety section). This study was designed to compare the PK of Riabni to rituximab-US and rituximab sourced from the European Union (rituximab-EU). Importantly, rituximab-US was considered a suitable proxy for Canadian authorized Rituxan and serves as the reference product for this submission. The analytical methodology for the detection of rituximab in human serum was validated and fit-for-purpose.

Pharmacokinetic sampling occurred over a period of 12 weeks. The sponsor provided evidence that sampling over a period of 12 weeks generated sufficient characterization of the area under the serum concentration-time curve (AUC), with AUC from time 0 extrapolated to infinity (AUCinf) requiring less than 10% extrapolation. Additionally, the 12-week sampling period exceeded the recommendations set out in Health Canada’s Conduct and Analysis of Comparative Bioavailability Studies Guidance Document.

Of the 311 patients, 305 were included in the PK parameter analysis set. Pharmacokinetic similarity was demonstrated between Riabni and rituximab-US with a geometric mean ratio of the AUC from time 0 to 12 weeks (AUCT) of 96.03% (90% confidence interval [CI]: 89.50%, 103.03%). The geometric mean ratios for the maximum observed serum concentration, calculated after each of the first two infusions, fell within the pre-defined margins of 80% to 125%. Notably, the sponsor’s analysis for AUCT included 295 patients. During review, the sponsor provided detailed rationales for each exclusion. Per Canadian guidance, several exclusions were not considered acceptable; however, analyses that included these patients did not change the conclusions of the study, which were supportive of PK similarity. Therefore, PK similarity has been adequately demonstrated.

Additional analyses included descriptive comparisons of the CD19+ B cell counts over time, as well as comparisons of trough concentrations of Riabni versus rituximab-US among patients with non-Hodgkin’s lymphoma. These comparisons did not suggest any clinically meaningful differences between Riabni and the reference product.

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

Comparative Clinical Efficacy and Safety

Comparative Clinical Efficacy

20130109 - Non-Hodgkin’s Lymphoma

Study 20130109 was a Phase III, randomized, double-blind, active-controlled, two-arm study comparing Riabni with rituximab-US for the first-line treatment of adult patients with CD20-positive, Grade 1, 2, or 3a low tumor burden follicular lymphoma. Similar patient populations have been used to support the authorization of other rituximab biosimilars and are considered suitable for the purposes of comparing response rates to support a demonstration of biosimilarity.

A total of 256 patients were randomized in a 1:1 ratio to receive 375 mg/m2 of either Riabni or rituximab-US by intravenous infusion once weekly for 4 weeks, and then at Week 12 and Week 20. Randomization was stratified by geographic region and age group (>60 years of age, ≤60 years of age). Demographics and baseline disease characteristics were similar between the treatment groups.

The primary objective of this study was to evaluate the efficacy of Riabni compared to rituximab-US. The primary endpoint was the overall response rate (ORR) by Week 28 and was compared between the two groups based on the risk difference (RD). The modified full analysis set was used for the primary efficacy analysis of the RD and was based on a central, independent, blinded assessment. Based on international regulatory consultation and on historical evidence of high response rates in the defined patient population of up to 85%, the sponsor pre-defined a non-inferiority margin of -15.0% and a non-superiority margin of +35.5% to demonstrate clinical comparability. The larger bound for the non-superiority margin relative to the non-inferiority margin permitted the conduct of a smaller trial for a very effective therapy, and was deemed acceptable given the high response rates expected in this patient population. The selected sample size also provided approximately 83% power for an analysis with a significance level of 0.025, assuming that the ORR is 85% and a symmetrical margin of 15% for non-inferiority and non-superiority.

The ORR was 78.0% (95% CI: 70.7, 85.4) in the Riabni treatment group and 70.2% (95% CI: 62.1, 78.2) in the rituximab-US treatment group (RD = 7.7%; 95% CI: -3.2, 18.6). Thus, the 95% confidence limits were contained within the pre-specified margins, and the trial was considered to have met its primary objective. A supplementary analysis of the primary endpoint by investigator assessment, based on the full analysis set, was supportive of the results based on the primary analysis (RD = 0.5%; 95% CI: -9.3, 10.4). The analysis of the secondary efficacy endpoint of ORR at Week 12 was also supportive of the results, based on the primary analysis by both central (RD = 0.9%; 95% CI: -11.3, 13.2) and investigator (RD = -3.8; 95% CI: -15.6, 8.1) assessments of disease.

Study 20130108 – Rheumatoid Arthritis

Study 20130108 was a Phase I/III randomized, double-blind, active-controlled, three-arm study primarily designed to demonstrate pharmacokinetic similarity between Riabni, rituximab-US, and rituximab-EU in adult patients with moderate to severe rheumatoid arthritis who have an inadequate response or intolerance to one or more anti-tumour necrosis factor therapies. Similar patient populations have been used to support the authorization of other rituximab biosimilars and are considered suitable to support a demonstration of biosimilarity.

Patients (number of patients [n] = 311) were randomized in a 1:1:1 ratio to receive 1,000 mg of either Riabni, rituximab-US, or rituximab-EU by intravenous infusion on Day 1 and Day 15 (dose 1) and at Week 24 and Week 26 (dose 2). Patients who received rituximab-US for their first dose received Riabni for their second dose. Randomization was stratified by geographic region (North America vs. Eastern Europe vs. Western Europe), seropositivity (rheumatoid factor [RF]-positive and/or cyclic citrullinated peptide [CCP]-positive vs. RF-negative and CCP-negative), and number of prior biologic therapies used for rheumatoid arthritis (1 vs. >1).

A secondary objective of the study was the assessment of efficacy using the change in Disease Activity Score 28 using C-reactive protein (DAS28-CRP) from baseline to Week 24. The pre-defined comparability margin was -0.6 to +0.6. The difference between means in DAS28-CRP change from baseline at Week 24 for Riabni versus rituximab-US was -0.070 (95% CI: -0.408, 0.268). Additional efficacy assessments of American College of Rheumatology (ACR) response endpoints (ACR20/50/70) are supportive of the comparable efficacy between Riabni and rituximab-US.  

Comparative Clinical Safety

Study 20130109 – Non-Hodgkin’s Lymphoma

Study 20130109 also comprised a safety analysis set involving 254 patients treated with at least one dose of Riabni (n = 128) or rituximab-US (n = 126). Of the 254 patients in the safety analysis set, 252 received the first four doses, while 93.0% in the Riabni treatment group and 97.6% in the rituximab-US treatment group received all six planned study doses.

Adverse events were reported by 83.6% of patients in the Riabni treatment group and in 75.4% of patients in the rituximab-US treatment group. Most adverse events were Grade 1 or 2 in severity. Adverse events considered to be Grade ≥3 were reported by 10.9% of patients in the Riabni treatment group and by 10.3% of patients in the rituximab-US treatment group. Serious adverse events occurred in 3.9% of patients in the Riabni treatment group and 4.0% of patients in the rituximab-US treatment group. A total of 4 (3.1%) patients in the Riabni treatment group and 1 (0.8%) patient in the rituximab-US treatment group discontinued treatment or discontinued the study due to an adverse event. Nine (7.0%) patients in the Riabni treatment group and 9 (7.1%) patients in the rituximab-US treatment group had a dose delayed or withheld due to an adverse event.

Infusion reactions were reported at similar frequencies in the two treatment groups, occurring in 43.0% of patients in the Riabni treatment group and 42.9% of patients in the rituximab-US treatment group.

Overall, the safety profile of Riabni was similar to that of rituximab-US. No differences were observed that were considered to represent more than the expected variability in the incidence of events consistent with the known safety profile of rituximab.

Study 20130108 – Rheumatoid Arthritis

In Study 20130108, all randomized patients (n = 311) received at least one infusion of Riabni, rituximab-US, or rituximab-EU and were thus included in the safety analysis set. Patients who received rituximab-US for their first dose were to receive Riabni for their second dose; therefore, comparisons of safety between Riabni and rituximab-US were possible from Day 1 until the first infusion of the second dose. Longer-term comparisons of safety between Riabni and rituximab-EU were possible up to the end of the study at Week 48.

In the Riabni treatment group, 98.1% of patients received the two planned infusions of dose 1, compared with 96.1% of patients in the rituximab-US treatment group and 99.0% of patients in the rituximab-EU treatment group.

In the Riabni, rituximab-US, and rituximab-EU treatment groups, from Day 1 until the first infusion of the second dose, adverse events were reported in 50.0%, 42.7%, and 42.3% of patients, adverse events of Grade ≥3 were reported in 4 (3.8%), 4 (3.9%), and 6 (5.8%) patients, serious adverse events were reported by 4 (3.8%), 5 (4.9%), and 5 (4.8%) patients, discontinuation of investigational product or study occurred for 3 (2.9%), 4 (3.9%), and 1 (1.0%) patient, and adverse events leading to a delay of infusion or the withholding of an infusion occurred in 6 (5.8%), 7 (6.8%), and 6 (5.8%) patients, respectively.

Infusion reactions occurring from Day 1 until the first infusion of the second dose were reported at similar frequencies in the Riabni (n = 12; 11.5%) and rituximab-US (n = 12; 11.7%) treatment groups and at a slightly higher frequency than in the rituximab-EU treatment group (n = 7; 6.7%). Consistent with what was observed from Day 1 until the first infusion of the second dose, infusion reactions reported from Day 1 through the end of study were reported at a slightly higher incidence in the Riabni treatment group (n = 16; 15.4%) compared with the rituximab-EU treatment group (n = 9; 8.7%).

Despite some numerical differences between treatment groups, the safety profile of Riabni was shown to be similar to that of rituximab-US and rituximab-EU, and results from the study were consistent with the known safety profile of rituximab in the defined rheumatoid arthritis patient population.

Overall, the safety profile of Riabni is considered to be comparable to that which has been established for the reference biologic drug, Rituxan. Appropriate warnings and precautions are in place in the approved Riabni Product Monograph to address the identified safety concerns, as is found in the Product Monograph for Rituxan. A Serious Warnings and Precautions Box has been included which describes reports of severe and life-threatening adverse reactions, infusion reactions, progressive multifocal leukoencephalopathy, tumour lysis syndrome, hepatitis B virus reactivation, mucocutaneous reactions, infections, and cardiovascular events.

For more information, refer to the Riabni 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. The immunogenicity of Riabni was evaluated in patients with low tumour burden follicular lymphoma (Study 20130109) and in patients with moderate to severe rheumatoid arthritis (Study 20130108).

In Study 20130108, post baseline from Day 1 until the first infusion of the second dose, 13 (13.4%) patients in the Riabni treatment group, 19 (19.6%) patients in the rituximab-US treatment group, and 10 (10.6%) patients in the rituximab-EU treatment group tested positive for the development of binding ADAs. Post baseline, from Day 1 through to the end of study at Week 48, 14 (14.4%) patients in the Riabni treatment group and 13 (13.8%) patients in the rituximab-EU treatment group tested positive for the development of binding ADAs. Eight (8.2%) patients in the Riabni treatment group and 4 (4.3%) patients in the rituximab-EU treatment group tested positive for the development of neutralizing ADAs. The frequency of ADAs are consistent with results observed in prior studies of other rituximab biosimilars in similar patient populations.

In Study 20130109, post baseline through Week 28, 3 (2.4%) patients in the Riabni treatment group and 1 (0.8%) patient in the rituximab-US treatment group tested positive for the development of binding ADAs. One (0.8%) patient in the Riabni treatment group and 1 (0.8%) patient in the rituximab-US treatment group tested positive for the development of neutralizing ADAs. Although the incidence of ADAs is low, it is consistent with similarly low incidence rates observed in prior studies of other rituximab biosimilars in patients with low tumour burden follicular lymphoma.

Overall, the assessments of immunogenicity are supportive of biosimilarity between Riabni, rituximab-US, and rituximab-EU.

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

Indications

Riabni is considered to be biosimilar to Rituxan, the reference biologic drug. Rituxan is authorized and marketed in Canada for several indications and clinical uses, including several non-Hodgkin’s lymphoma (NHL) indications, chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). Within this drug submission, the sponsor requested the authorization of Riabni for all of the indications that are currently authorized for Rituxan.

Similarity between Riabni and Rituxan was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor’s submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug, and therefore clinical trials are not required to support each indication. The indications have been authorized on the basis of demonstrated similarity between Riabni and the reference biologic drug, in structural, analytical and functional, non-clinical, immunogenicity, pharmacokinetic, pharmacodynamic, and clinical efficacy and safety comparisons.

Based on the evidence submitted, Riabni 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 NHL.
  • The treatment of patients with CD20-positive, diffuse large B-cell NHL (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 NHL in combination with CVP (cyclophosphamide, vincristine, and prednisolone) chemotherapy.
  • The maintenance treatment of patients with follicular NHL who have responded to induction therapy with either CHOP or CHOP plus rituximab.
  • Single-agent maintenance treatment of previously untreated patients with advanced follicular NHL 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 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)

Riabni in combination with methotrexate is indicated in adult patients:

  • To reduce signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more tumour necrosis factor 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)

Riabni in combination with glucocorticoids is indicated for:

  • The induction of remission in adult patients with severely active GPA and MPA.

Consideration should be given to current treatment guidelines for vasculitis.

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