Summary Basis of Decision for Renflexis

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 Renflexis is located below.

Recent Activity for Renflexis

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.

Post-Authorization Activity Table (PAAT) for Renflexis

Updated: 2024-02-16

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

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

Drug Identification Number (DIN):

DIN 02470373 – 100 mg/vial, infliximab, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 275221

2023-05-12

Issued NOC 2023-10-04

Submission filed as a Level II – Supplement (Safety) to update the PM to align with that of the reference biologic drug, Remicade. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; and Drug Interactions sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 273124

2023-03-08

Issued NOL 2023-06-07

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug substance and drug product (release and stability). The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 274817

2023-04-27

Cancellation Letter Received 2023-05-10

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update the PM to align with that of the reference biologic drug, Remicade. The proposed revisions exceeded the scope of an NC. The submission was therefore cancelled administratively by the sponsor.

SNDS # 265135

2022-06-16

Issued NOC 2023-02-09

Submission filed as a Level I – Supplement to update the PM to align with that of the reference biologic drug, Remicade, and to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Dosage and Administration sections of the PM, and corresponding changes to the package insert. An NOC was issued.

NC # 263087

2022-04-05

Cancellation Letter Received 2022-04-14

Submission filed as a Level II (90 day) Notifiable Change to update the PM to align with that of the reference biologic drug, Remicade. The proposed revisions exceeded the scope of an NC. The submission was therefore cancelled administratively by the sponsor.

NC # 252580

2021-05-07

Issued NOL 2021-06-15

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in specification for the materials. The submission was considered acceptable, and an NOL was issued.

NC # 252055

2021-04-22

Issued NOL 2021-06-02

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the extension of the reference standard shelf-life or retest period. The submission was considered acceptable, and an NOL was issued.

NC # 245252

2020-10-14

Issued NOL 2021-01-11

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in cell bank/seed bank manufacturing site. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 242515

2020-08-04

Issued NOL 2020-10-21

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls applied during the drug product manufacturing process or on intermediates. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 233430

2019-11-21

Issued NOL 2020-02-25

Submission filed as a Level II (90 day) Notifiable Change to update the PM to align with that of the reference biologic drug, Remicade. As a result of the NC, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 235910

2020-02-07

Cancellation Letter Received 2020-02-17

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the modification of a primary container closure system and a change in the specifications used to release a primary or functional secondary container closure component. The changes were not in scope of an NC but were considered to be Level III changes. The sponsor cancelled the submission administratively.

NC # 232108

2019-09-30

Issued NOL 2020-01-15

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the qualification of a new lot of reference standard against the approved reference standard and a change in the drug substance release or shelf‐life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 227947

2019-05-17

Issued NOC 2019-11-22

Submission filed as a Level I – Supplement for the addition of a drug substance and drug product manufacturing facility.The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 223340

2018-12-28

Issued NOL 2019-04-05

Submission filed as a Level II (90 day) Notifiable Change to update the PM to align with that of the reference biologic drug, Remicade. As a result of the NC, modifications were made to the Warnings and Precautions; Adverse Reactions; and Dosage and Administration sections of the PM, and to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 222233

2018-11-23

Issued NOL 2019-03-05

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the drug substance and drug product release or shelf-life specifications and a change in the controls applied during the drug substance manufacturing process or on intermediates. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 223430

2019-01-04

Issued NOL

2019-01-25

 

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf-life of the primary reference standard. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 215030

2018-04-10

Issued NOC

2018-11-06

Submission filed as a Level I – Supplement for changes to the manufacture of the drug substance and drug product. The data were reviewed and considered acceptable, and an NOC was issued.

NC # 213295

2018-01-31

Issued NOL

2018-05-01

 

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug product, and changes to the drug substance storage and shipping conditions. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02470373) market notification

Not applicable

Date of first sale: 2018-03-22

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

NDS # 188114

2015-09-30

Issued NOC 2017-12-01

Notice of Compliance issued for New Drug Submission.

 
 
Summary Basis of Decision (SBD) for Renflexis

Date SBD issued: 2018-02-02

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

Infliximab
100 mg/vial, powder for solution, intravenous

Drug Identification Number (DIN):

  • 02470373

Samsung Bioepis Co., Ltd.

New Drug Submission Control Number: 188114

 

On December 1, 2017, Health Canada issued a Notice of Compliance (NOC) to Samsung Bioepis Co., Ltd. for Renflexis, a biosimilar to Remicade (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. Both Renflexis and Remicade contain highly similar versions of the medicinal ingredient, infliximab.

Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. To be considered a biosimilar, the weight of evidence is provided by the structural and functional studies; the non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, pharmacokinetic and pharmacodynamic, and clinical studies.

The demonstration of similarity between the biosimilar and its reference biologic drug enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

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

In this drug submission, Remicade is the reference biologic drug. Similarity between Renflexis and Remicade 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 Renflexis for all of the indications that are currently authorized for Remicade (100 mg/vial).

The market authorization was based on comparative quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology) and clinical (bioavailability, safety and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile profile of Renflexis is considered favourable for:

  • use in combination with methotrexate for the reduction in signs and symptoms, inhibition of the progression of structural damage and improvement in physical function in adult patients with moderately to severely active rheumatoid arthritis.
  • reduction of signs and symptoms and improvement in physical function in patients with active ankylosing spondylitis who have responded inadequately, or are intolerant to, conventional therapies.
  • reduction of signs and symptoms, induction and maintenance of clinical remission and mucosal healing and reduction of corticosteroid use in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to a corticosteroid and/or aminosalicylate. Renflexis can be used alone or in combination with conventional therapy.
  • reduction of signs and symptoms and induction and maintenance of clinical remission in pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy (corticosteroid and/or aminosalicylate and/or an immunosuppressant). The safety and efficacy of Renflexis is not established in patients less than 9 years of age.
  • treatment of fistulising Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with conventional treatment.
  • reduction of signs and symptoms, induction and maintenance of clinical remission and mucosal healing, and reduction or elimination of corticosteroid use in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy (i.e., aminosalicylate and/or corticosteroid and/or an immunosuppressant).
  • reduction of signs and symptoms, induction and maintenance of clinical remission, and induction of mucosal healing in pediatric patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy (i.e., aminosalicylate and/or corticosteroid and/or an immunosuppressant). The safety and efficacy of Renflexis have not been established in patients less than 6 years of age.
  • reduction of signs and symptoms, induction of major clinical response, and inhibition of the progression of structural damage of active arthritis, and improvement in physical function in patients with psoriatic arthritis.
  • treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, Renflexis should be used after phototherapy has been shown to be ineffective or inappropriate. When assessing the severity of psoriasis, the physician should consider the extent of involvement, location of lesions, response to previous treatments, and impact of disease on the patient's quality of life.

Renflexis should be used by physicians who have sufficient knowledge of rheumatoid arthritis and/or ankylosing spondylitis and/or Crohn's disease and/or ulcerative colitis and/or psoriatic arthritis and/or plaque psoriasis and who have fully familiarized themselves with the efficacy/safety profile of Renflexis.

 

1 What was approved?

 

Renflexis, an anti-inflammatory medicine that belongs to the class of drugs called biological response modifiers, was authorized for:

  • use in combination with methotrexate for the reduction in signs and symptoms, inhibition of the progression of structural damage and improvement in physical function in adult patients with moderately to severely active rheumatoid arthritis.
  • reduction of signs and symptoms and improvement in physical function in patients with active ankylosing spondylitis who have responded inadequately, or are intolerant to, conventional therapies.
  • reduction of signs and symptoms, induction and maintenance of clinical remission and mucosal healing and reduction of corticosteroid use in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to a corticosteroid and/or aminosalicylate. Renflexis can be used alone or in combination with conventional therapy.
  • reduction of signs and symptoms and induction and maintenance of clinical remission in pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy (corticosteroid and/or aminosalicylate and/or an immunosuppressant). The safety and efficacy of Renflexis is not established in patients less than 9 years of age.
  • treatment of fistulising Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with conventional treatment.
  • reduction of signs and symptoms, induction and maintenance of clinical remission and mucosal healing, and reduction or elimination of corticosteroid use in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy (i.e., aminosalicylate and/or corticosteroid and/or an immunosuppressant).
  • reduction of signs and symptoms, induction and maintenance of clinical remission, and induction of mucosal healing in pediatric patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy (i.e., aminosalicylate and/or corticosteroid and/or an immunosuppressant). The safety and efficacy of Renflexis have not been established in patients less than 6 years of age.
  • reduction of signs and symptoms, induction of major clinical response, and inhibition of the progression of structural damage of active arthritis, and improvement in physical function in patients with psoriatic arthritis.
  • treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, Renflexis should be used after phototherapy has been shown to be ineffective or inappropriate. When assessing the severity of psoriasis, the physician should consider the extent of involvement, location of lesions, response to previous treatments, and impact of disease on the patient's quality of life.

Renflexis should be used by physicians who have sufficient knowledge of rheumatoid arthritis and/or ankylosing spondylitis and/or Crohn's disease and/or ulcerative colitis and/or psoriatic arthritis and/or plaque psoriasis and who have fully familiarized themselves with the efficacy/safety profile of Renflexis.

Renflexis is a biosimilar to Remicade. Both drugs contain the medicinal ingredient, infliximab. Infliximab is a chimeric human/murine immunoglobulin G1 (IgG1) monoclonal antibody that binds with high affinity to the human tumour necrosis factor alpha (TNFα). Infliximab is produced by recombinant deoxyribonucleic acid (DNA) technology in a Chinese hamster ovary (CHO) mammalian cell expression system.

Similarity between Renflexis and the reference biologic drug, Remicade, has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, and comparative clinical studies (bioavailability, safety and efficacy) in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Renflexis 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. Renflexis is also contraindicated in:

  • patients with severe infections such as sepsis, abscesses, tuberculosis and opportunistic infections.
  • patients with moderate or severe (New York Heart Association Class III/IV) congestive heart failure.
  • patients with a history of hypersensitivity to infliximab for injection, to other murine proteins, or to any of the excipients.

Renflexis 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.

Renflexis (100 mg/vial infliximab) is presented as a powder for solution. In addition to the medicinal ingredient, the powder contains sucrose, polysorbate 80, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate heptahydrate.

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

 

2 Why was Renflexis approved?

 

Health Canada considers that the benefit-risk profile of Renflexis is favourable for:

  • use in combination with methotrexate for the reduction in signs and symptoms, inhibition of the progression of structural damage and improvement in physical function in adult patients with moderately to severely active rheumatoid arthritis.
  • reduction of signs and symptoms and improvement in physical function in patients with active ankylosing spondylitis who have responded inadequately, or are intolerant to, conventional therapies.
  • reduction of signs and symptoms, induction and maintenance of clinical remission and mucosal healing and reduction of corticosteroid use in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to a corticosteroid and/or aminosalicylate. Renflexis can be used alone or in combination with conventional therapy.
  • reduction of signs and symptoms and induction and maintenance of clinical remission in pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy (corticosteroid and/or aminosalicylate and/or an immunosuppressant). The safety and efficacy of Renflexis is not established in patients less than 9 years of age.
  • treatment of fistulising Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with conventional treatment.
  • reduction of signs and symptoms, induction and maintenance of clinical remission and mucosal healing, and reduction or elimination of corticosteroid use in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy (i.e., aminosalicylate and/or corticosteroid and/or an immunosuppressant).
  • reduction of signs and symptoms, induction and maintenance of clinical remission, and induction of mucosal healing in pediatric patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy (i.e., aminosalicylate and/or corticosteroid and/or an immunosuppressant). The safety and efficacy of Renflexis have not been established in patients less than 6 years of age.
  • reduction of signs and symptoms, induction of major clinical response, and inhibition of the progression of structural damage of active arthritis, and improvement in physical function in patients with psoriatic arthritis.
  • treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, Renflexis should be used after phototherapy has been shown to be ineffective or inappropriate. When assessing the severity of psoriasis, the physician should consider the extent of involvement, location of lesions, response to previous treatments, and impact of disease on the patient's quality of life.

Renflexis should be used by physicians who have sufficient knowledge of rheumatoid arthritis and/or ankylosing spondylitis and/or Crohn's disease and/or ulcerative colitis and/or psoriatic arthritis and/or plaque psoriasis and who have fully familiarized themselves with the efficacy/safety profile of Renflexis.

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

Renflexis is considered to be biosimilar to Remicade. Remicade is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Remicade is authorized are adult rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and adult and pediatric ulcerative colitis and Crohn's disease including adult patients with fistulising Crohn's disease.

The New Drug Submission (NDS) filed for Renflexis requested authorization for all of the indications and clinical uses that are currently authorized for Remicade. The indications have been authorized on the basis of demonstrated similarity between Renflexis and the reference biologic drug Remicade.

Infliximab, the active ingredient of Renflexis and the reference biologic drug Remicade, is a chimeric human/murine immunoglobulin G1 (IgG1) monoclonal antibody that binds with high affinity to human tumour necrosis factor alpha (TNFα), a key inflammatory cytokine that possesses a variety of biological functions (e.g., mediation of inflammatory responses), and that contributes to the pathology of several inflammatory diseases including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, ulcerative colitis and Crohn's disease.

The biosimilar Renflexis and the reference biologic drug Remicade were considered to be highly similar in terms of quality attributes (based on comparative structural and functional studies), non-clinical and clinical data. Pharmacokinetic (PK) similarity between Renflexis and Remicade was established in a PK study conducted in healthy volunteers. Comparable efficacy and safety between the two products were also demonstrated in a comparative clinical study conducted in rheumatoid arthritis patients. Numerical differences in some adverse events were reported between Renflexis and Remicade in the clinical studies, but they are not considered to be clinically meaningful. A numerically higher immunogenicity was observed in patients treated with Renflexis compared with those treated with Remicade in the Phase III study up to Week 54. Given that the implication of the difference in the occurrence of immunogenicity between the treatment arms was unknown, clinical similarity between Renflexis and Remicade could not be confirmed, and thus a risk-benefit assessment of Renflexis could not be completed. Consequently, a Notice of Deficiency (NOD) was issued to request additional long-term data pertaining to the transition-extension period (Weeks 54-78) of the Phase III study to further understand the clinical significance of these immunogenicity results. Based on this new set of data, it was found that the immunogenicity profile of Renflexis was consistent with that observed up to Week 54. The small difference in immunogenicity up to Week 78 did not translate into clinically meaningful differences in efficacy or safety. Therefore, the deficiencies raised in the NOD were considered addressed.

A Serious Warnings and Precautions box describing serious warnings and precautions has been included in the Product Monograph for Renflexis, as is found in the Product Monograph for Remicade. The identified safety concerns include the risk of infections (e.g. tuberculosis), hepatosplenic T-cell lymphoma, and pediatric malignancy (lymphoma and other malignancies in children and adolescents treated with TNF-blockers).

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

A Look-alike Sound-alike brand name assessment was performed and the proposed name Renflexis was accepted. The submission was also accepted from a labelling perspective.

Overall, based on the totality of evidence derived from the comparative structural, analytical and functional, non-clinical and clinical data, similarity between Renflexis and Remicade has been demonstrated. Furthermore, the scientific rationale provided by the sponsor to support the authorization of Renflexis in each indication held by the reference biologic drug is considered adequate and is in line with Health Canada's Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Therefore, the benefit-risk profile of Renflex is considered favourable for the treatment of adult rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and adult and pediatric ulcerative colitis and Crohn's disease including adult patients with fistulising Crohn's disease.

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 for Decision sections.

 

3 What steps led to the approval of Renflexis?

 

A New Drug Submission (NDS) for Renflexis was filed in 2015. Upon review of this NDS, a Notice of Deficiency (NOD) was issued to the sponsor on October 6, 2016 as it was determined that a benefit-risk profile for Renflexis could not be thoroughly assessed. Additional long-term data from the transition-extension period of the comparative clinical study in patients with rheumatoid arthritis (Weeks 54 to 78) were requested to further understand the clinical significance of the immunogenicity results. A Notice of Deficiency (NOD) Response was received on January 17, 2017 which contained the requested information. Upon review, Health Canada considered that the issues identified in the NOD were adequately addressed, and a Notice of Compliance (NOC) was issued on December 1, 2017.

 

Submission Milestones: Renflexis

Submission Milestone Date
Pre-submission meeting: 2015-07-07
Submission filed: 2015-09-30
Screening 1  
Screening Acceptance Letter issued: 2015-12-11
Review 1  
Review of Risk Management Plan complete: 2016-04-25
Initial Labelling Review complete: 2016-06-21
Clinical Evaluation complete: 2016-09-06
Biostatistics Evaluation complete: 2016-09-06
Notice of Deficiency (NOD) issued by Director General, Biologics and Genetic Therapies Directorate (safety issues): 2016-10-06
NOD Response filed: 2017-01-17
Screening 2  
Screening Acceptance Letter issued: 2017-02-06
Review 2  
Clinical Evaluation complete: 2017-11-10
Biostatistics Evaluation complete: 2017-11-10
Quality Evaluation complete: 2017-11-30
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2017-11-30
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2017-12-01

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Renflexis was based on a critical assessment of the data package submitted to Health Canada. Foreign review documentation from the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) was used as an added reference.

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 Renflexis 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 Renflexis 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.

As part of the marketing authorization for Renflexis, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):

  • Submitting the same additional long-term data (e.g. observational study in patients with ankylosing spondylitis and Crohn's disease) that will be provided to the European Medicines Agency (EMA), when they become available.
  • Submitting the same data from post-authorization registry programmes (e.g. adverse events in hepatobiliary system and further characterization of alanine aminotransferase elevation in Renflexis-treated population) that will be provided to the EMA, when they become available.
  • Submitting a revised Renflexis Product Monograph to align the Part II section with other product monographs of infliximab products according to the most updated Health Canada Product Monograph template.

 

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

 

Renflexis was developed as a biosimilar to the reference biologic drug, Remicade. For biosimilars, the weight of evidence is provided by structural and functional studies. In addition to a typical chemistry and manufacturing data package that is submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity with the reference biologic drug.

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

Renflexis was shown to be similar to the EU-sourced Remicade in terms of its mechanism of action. Both products had similar binding activities for soluble and membrane bound TNF-α, and lack of binding to TNF-β. As infliximab is an IgG1, Fc-related functions were also investigated with several binding and apoptosis assays and were found to show similar activities.

Comparative Structural and Functional Studies

The sponsor performed head-to-head characterization, stability (long-term, accelerated, stressed conditions), forced degradation and photostability studies to compare the Renflexis drug substance (infliximab) and drug product to Remicade. Renflexis was found to be highly similar to Remicade with regard to its structure, physicochemical and biophysical properties, biological activities (antigen-binding [Fab] fragment and Fc-related functions) and stability and forced degradation profiles. Renflexis and Remicade were considered highly similar. Although differences were observed between the Renflexis and Remicade charged variant and glycosylation profiles, these still maintain functional similarity, do not compromise safety and efficacy or pose any immunogenic risk and are unlikely to translate into clinically meaningful differences.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that the Renflexis drug substance, infliximab, consistently exhibits the desired characteristic structure and biological activity.

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

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

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

The drug substance, infliximab, is produced by recombinant deoxyribonucleic acid (rDNA) technology. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The manufacturing process of the drug substance consists of a series of stages which include vial thaw, inoculation, cell expansion, harvest and detergent inactivation. Downstream operations include a series of chromatographic steps, a low pH hold, a viral filtration step and an ultrafiltration/diafiltration step. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.

Results of all release tests, in-process testing and characterization tests were comparable to historical batches. The results of these studies and of the batch analysis data have shown that the manufacture of the drug substance is consistent and yields a product of suitable quality.

The drug product, Renflexis, is sterile filtered, aseptically filled into vials, lyophilized, capped, and labelled using conventional pharmaceutical equipment and facilities.

In-process controls and lot release tests for the drug product were established and validated. The materials used in the manufacture of the drug product are considered suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

Drug substance and drug product specifications include assays for appearance, identity, quantity, biological activity, purity and impurities, and safety. The control strategy is suitable to monitor the control of the drug substance and drug product. Established test specifications and validated analytical test methods are considered acceptable.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

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 36-month shelf life at 2° to 8°C for Renflexis is considered acceptable.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

On-site evaluations of the facilities involved in the manufacture and testing of the drug substance, infliximab, and the drug product, Renflexis, were not warranted as the facilities were recently evaluated and obtained a satisfactory rating.

Adventitious Agents Safety Evaluation

The infliximab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated. Finally, the excipients used in the drug product formulation are not of animal or human origin.

 

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 Renflexis 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. Comparative in vitro and in vivo studies demonstrated no major differences between Renflexis and Remicade. Toxicity studies were not performed.

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

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

 

 

7.3 Clinical basis for decision

 

The demonstration of similarity between the biosimilar and its reference biologic drug enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

For biosimilars, the purpose of the clinical program is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The degree of similarity at the quality level determines the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Comparative Pharmacokinetic and Pharmacodynamic Studies

Renflexis (infliximab) is a chimeric human-murine immunoglobulin gamma subclass (IgG1) monoclonal antibody that binds with high affinity to both soluble and transmembrane forms of human tumour necrosis factor alpha (TNF-α). The protein TNF-α is a key inflammatory cytokine that possesses a variety of biological functions (e.g., mediation of inflammatory responses), and that contributes to the pathology of several inflammatory diseases including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, ulcerative colitis, and Crohn's disease. Biological activities attributed to TNF-α include: induction of pro-inflammatory cytokines such as interleukins 1 and 6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, and induction of acute phase reactants and other liver proteins.

Study SB2-G11-NHV was a Phase I, randomized, three-arm, single-dose study with the primary objective to demonstrate pharmacokinetic (PK) comparability between Renflexis and Remicade sourced from Europe (EU) or Remicade sourced from the United States in healthy volunteers. Because the EU-sourced Remicade was designated as the official reference biologic product in Canada, the results described below focus on the PK comparison between Renflexis and the EU-sourced Remicade (also referred to as Remicade).

Each subject received a single-dose of 5 mg/kg of Renflexis or Remicade. Blood samples were collected up to Day 71. A non-compartmental analysis method using actual sampling times was used to calculate the PK parameters. The PK results showed that the 90% confidence interval (CI) for the ratio of geometric least squares (LS) mean (expressed as percentages) of Renflexis to Remicade for the area under the curve calculated to the last measured concentration (AUClast) [99.4%; 90% CI: 91.5%-107.9%], and the point estimate of the maximum serum concentration (Cmax) [100.7%] were within the acceptance margins of 80% to 125%.

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

Comparative Clinical Efficacy, Safety and Immunogenicity

A comparative clinical study (SB2-G31-RA) was submitted to support the comparability of Renflexis and Remicade with respect to the efficacy, safety, and immunogenicity. Supportive comparative safety data from the PK study (SB2-G11-NHV) were also included.

Study SB2-G31-RA was a Phase III, randomized, double-blind, multicentre study comparing the efficacy, safety, and immunogenicity of Renflexis and EU-sourced Remicade in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate (MTX) therapy. A total of 584 patients were randomized 1:1 to receive either 3 mg/kg of Renflexis (n = 291) or Remicade (n = 293) intravenously at Weeks 0, 2 and 6, followed by an administration every 8 weeks until Week 46. The study protocol also allowed a step-wise dose increase by 1.5 mg/kg, up to a maximum of 7.5 mg/kg, after Week 30 until Week 46 if the patient's RA symptoms were not well controlled by the existing dose. Each patient received oral or parenteral MTX (10-25 mg weekly) and folic acid (5-10 mg weekly) during the study period. The study duration was 54 weeks.

The primary objective was to demonstrate the comparability in the American College of Rheumatology (ACR) twenty-percent improvement (ACR20) response rate at Week 30 between Renflexis and Remicade using an equivalence margin of ±15% on the risk difference in response rate. The key secondary objectives were to evaluate the safety and immunogenicity of Renflexis compared with Remicade.

During the clinical review of this drug submission, a numerical increase in the incidence of anti-drug antibodies (ADAs) was observed in patients treated with Renflexis compared with those treated with Remicade up to Week 54. As a result, Health Canada issued a Notice of Deficiency (NOD) and requested additional long-term data from the transition-extension period (Week 54 to Week 78) of the study (SB2-G31-RA) to provide further insights into the potential immunogenic profile of Renflexis and its significance on the clinical outcomes. During this transition-extension period, patients who originally received Remicade were re-randomized 1:1 to a) continue to receive Remicade (Remicade/Remicade arm) or b) switch to Renflexis (Remicade/Renflexis arm). Patients who were originally receiving Renflexis continued to receive Renflexis (Renflexis/Renflexis arm). The immunogenicity, safety, and efficacy were assessed up to Week 78.

Efficacy

Based on the full analysis set (FAS), using the non-responder approach, the ACR20 response rate at Week 30 achieved by patients in the Renflexis arm was 55.5%; and in the Remicade arm, 59.0%. The adjusted difference rate was -2.95 with a 95% CI of -10.88% to 4.97%, which was contained within the pre-specified equivalence margin of ±15%.

Safety

The safety assessment was based on 290 patients in the Renflexis arm and 293 patients in the Remicade arm. A total of 179 patients (61.7%) in the Renflexis arm and 191 patients (65.2%) in the Remicade arm experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs observed in either arm (≥3%) were RA, latent tuberculosis, nasopharyngitis, upper respiratory tract infection, bronchitis, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), back pain, headache, and hypertension. Treatment-related adverse events were reported in 24.1% of the patients in the Renflexis arm and 23.5% of the patients in the Remicade arm.

A total of 10.0% in the Renflexis arm vs. 10.6% in the Remicade arm experienced serious adverse events (SAEs). The most frequently reported SAEs were pneumonia and RA. Appropriate warnings and precautions are in place in the approved Renflexis Product Monograph to address the identified safety concerns, as is found in the Product Monograph for Remicade.

The frequency of some TEAEs was numerically different in the Renflexis arm compared with the Remicade arm (e.g. increased ALT and infections). However, with a longer follow-up time (transition-extension period; Weeks 54-78), the incidences of these TEAEs were comparable between the two treatment arms. Combined together, these numerical differences are considered negligible and not clinically important, and they do not raise concern with respect to the biosimilarity between the two products.

The safety between Renflexis and Remicade during the transition-extension period was consistent with that observed up to Week 54. In the PK study, differences in some TEAEs between Renflexis and Remicade were observed, but they are not considered to be clinically meaningful. The safety profile of Renflexis is consistent with the known safety profile of infliximab. No new safety signals were identified.

Immunogenicity

The overall incidence of anti-drug antibodies (ADAs) at Week 54 was greater in the Renflexis arm (62.4%) compared with the Remicade arm (57.5%). Based on the analysis of the immunogenicity at each timepoint, the difference between the two treatment arms reached 12.8% at Week 54. Most of these patients had neutralizing antibodies (NAbs) (92.7% in the Renflexis arm and 87.5% in the Remicade arm). Despite the numerically higher immunogenicity reported in the Renflexis arm, the incidences of ADAs and NAbs during the transition-extension period (Weeks 54-78) did not increase and were consistent with those observed up to Week 54. The overall incidence of ADAs at Week 78 was 66.2% in the Renflexis/Renflexis arm and 60.4% in the Remicade/Remicade arm. This difference did not translate into clinically meaningful differences in efficacy and/or safety. The deficiencies that were raised in the NOD were considered addressed.

Conclusion

Overall, the safety profile of Renflexis is considered to be comparable to that established for the reference biologic drug Remicade. Comparable efficacy and safety between the two products, Renflexis and Remicade, were demonstrated in the comparative clinical study conducted in RA patients. Numerical differences in some adverse events were reported between Renflexis and Remicade but they were not considered to be clinically meaningful. A numerically higher immunogenicity was observed in patients treated with Renflexis compared with those treated with Remicade up to Week 54 in the comparative clinical study. However, the review of the new set of data from the transition-extension period of the comparative clinical study alleviated the uncertainty pertaining to the difference in immunogenicity between Renflexis and Remicade. Based on the available evidence, no clinically meaningful differences in efficacy, safety and immunogenicity were detected up to Week 78 in the comparative clinical study. These results, in combination with the comparative PK and quality results support the demonstration of similarity between Renflexis and Remicade.

Indications

Renflexis is considered to be biosimilar to Remicade, the reference biologic drug. Remicade is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Remicade is authorized are adult rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and adult and pediatric ulcerative colitis and Crohn's disease including adult patients with fistulising Crohn's disease.

Within this drug submission, the sponsor requested the authorization of Renflexis for all of the indications that are currently authorized for Remicade.

Similarity between Renflexis and Remicade was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized, and therefore clinical trials are not required to support each indication.

The aforementioned indications have been authorized for Renflexis on the basis of comparative structural, analytical and functional, non-clinical and clinical data between Renflexis and the reference biologic drug Remicade.

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