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PrREMSIMA

Contact: Office of Regulatory Affairs, Biologics and Genetic Therapies Directorate

Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Remsima is located below.

Recent Activity for Remsima

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 decision was negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Remsima

Updated: 2015/04/08

The following table describes post-authorization activity for Remsima, 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.

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

Drug Identification Number (DIN):
DIN 02419483 - 100 mg/vial infliximab, powder for solution, intraveous

Post-Authorization Activity Table (PAAT)
Activity/Submission Type, Control Number Date Submitted Decision and Date Summary of Activities
NC # 178514 2014/10/01 Issued No Objection Letter 2015/02/11 Submission filed as a Level II (120 day) Notifiable Change (Safety Change) to update the Product Monograph in response to a Health Canada letter dated 2014/03/25. The submission was reviewed and considered acceptable, and a No Objection Letter was issued
Drug product (DIN 02419483) market notification Not applicable Date of first sale: 2014/09/18 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Next link will take you to another Web site Food and Drug Regulations.
NDS # 160195 2012/11/14 Issued NOC 2014/01/15 Notice of Compliance issued for New Drug Submission.
(the most recent activities are listed first)

Summary Basis of Decision (SBD) for Remsima

Date SBD Issued: 2014/04/01

The following information relates to the original authorization of the new drug submission for Remsima.

Infliximab
100 mg/vial, powder for solution, intravenous
Drug Identification Number (DIN): 02419483
Celltrion Healthcare Co. Ltd.
New Drug Submission Control Number: 160195

On January 15, 2014, Health Canada issued a Notice of Compliance to Celltrion Healthcare Co. Ltd. for the drug product, Remsima.

The market authorization was based on the quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Remsima (active ingredient infliximab) was filed as a Subsequent Entry Biologic product to the Canadian authorized product, Remicade (active ingredient infliximab marketed by Janssen Inc.). The term "subsequent entry biologic" is used by Health Canada to describe a biologic drug that enters the market subsequent to a version previously authorized in Canada, with demonstrated similarity to a reference biologic drug. In this drug submission, Remicade is the reference product. Similarity between Remsima and Remicade was established in accordance with the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), for the authorized indications.

Based on Health Canada's review, the benefit/risk profile of Remsima 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.
  • the reduction of signs and symptoms and improvement in physical function in patients with active ankylosing spondylitis who have responded inadequately, or who are intolerant, to conventional therapies.
  • the 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, Remsima 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.
  1. What was approved?
  2. Why was Remsima approved?
  3. What steps led to the approval of Remsima?
  4. What follow-up measures will the company take?
  5. What post-authorization activity has taken place for Remsima?
  6. What other information is available about drugs?
  7. What was the scientific rationale for Health Canada's decision?

1. What was approved?

Remsima (infliximab), 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.
  • the reduction of signs and symptoms and improvement in physical function in patients with active ankylosing spondylitis who have responded inadequately, or who are intolerant, to conventional therapies.
  • the 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, Remsima 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.

Remsima should be used by physicians who have sufficient knowledge of rheumatoid arthritis and/or ankylosing spondylitis and/or psoriatic arthritis and/or plaque psoriasis and who have fully familiarized themselves with the efficacy/safety profile of Remsima.

Evidence from clinical studies suggests that the use in the geriatric population (>65 years of age) is associated with no overall differences in safety and efficacy.

The safety and efficacy of Remsima have not been established in pediatric patients.

Remsima is contraindicated for:

  • 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, to other murine proteins, or to any of the excipients.

Remsima was approved for use under the conditions stated in the Remsima Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

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

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

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

2. Why was Remsima approved?

Health Canada considers that the benefit/risk profile of Remsima 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.
  • the reduction of signs and symptoms and improvement in physical function in patients with active ankylosing spondylitis who have responded inadequately, or who are intolerant, to conventional therapies.
  • the 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, Remsima 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.

Infliximab, the active ingredient of Remsima, is a chimeric immunoglobin G1 (IgG1) monoclonal antibody that binds with high affinity to human tumour necrosis factor alpha (TNFα), a key inflammatory cytokine involved in the pathogenesis of a variety of inflammatory diseases. Remsima is comparable to the Canadian authorized drug product Remicade (active ingredient infliximab, marketed by Janssen Inc.). Remsima was filed as a Subsequent Entry Biologic to Remicade. Similarity between Remsima and Remicade was established in accordance with the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), for the indications stated above.

The sponsor requested authorization for all of the indications and uses currently authorized to Remicade. Remicade is currently authorized for indications and uses in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease, and ulcerative colitis. Comparability between Remsima and the reference product was established based on comparative chemistry and manufacturing studies, and comparative non-clinical studies. Comparative pharmacokinetic studies and clinical studies in patients with rheumatoid arthritis or ankylosing spondylitis patients did not identify clinically meaningful differences. A pivotal comparative efficacy and safety study demonstrated that Remsima provided comparable clinical efficacy with an acceptable safety profile in patients with rheumatoid arthritis. A pivotal comparative pharmacokinetic study satisfactorily demonstrated pharmacokinetic comparability in patients with ankylosing spondylitis. For the remaining indications and uses, extrapolation was required.

The indications for psoriatic arthritis and plaque psoriasis were granted on the basis of similarity and the absence of meaningful differences, between Remsima and the reference product, in product quality, mechanism of action, disease pathophysiology, safety profile, dosage regimen and on clinical experience with the reference product. Scientific rationales submitted by the sponsor were found to be adequate to support extrapolation to the indications and uses pertaining to psoriatic arthritis and plaque psoriasis; however, extrapolation to indications and uses pertaining to Crohn's disease and ulcerative colitis could not be recommended due to differences between Remsima and the reference product, that could have an impact on the clinical safety and efficacy of these products in these indications. As a result, the benefit/risk assessments for Remsima in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis were considered to be positive, while the benefit/risk assessment of Remsima in patients with Crohn's disease or ulcerative colitis could not be completed. Additional information is presented in the Clinical Efficacy and Characterization of the Drug Substance sections.

The known risks of infliximab treatment have been included in the Remsima Product Monograph. The identified safety concerns include risk of infection (tuberculosis, invasive fungal infections, and other opportunistic infections) as well as hepatosplenic T-cell lymphoma which has been observed with the reference product in disease populations for which Remsima has not been authorized. Also, lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including infliximab.All of these conditions are listed in a Serious Warnings and Precautions Box in the Remsima Product Monograph.

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

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

Overall, the studies demonstrated that Remsima was well-tolerated and associated with a manageable safety profile. Based on the safety and efficacy profile, the benefits of Remsima treatment are considered to outweigh the risks. Restrictions to manage risks associated with the identified safety concerns have been incorporated into the Remsima Product Monograph.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Next link will take you to another Web site Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3. What steps led to the approval of Remsima?

The Remsima New Drug Submission (NDS) was filed as a Subsequent Entry Biologic (SEB) product to the Canadian authorized product, Remicade (infliximab, marketed by Janssen Inc.). The term "subsequent entry biologic" is used by Health Canada to describe a biologic drug that enters the market subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug.

Celltrion Healthcare Co. Ltd. developed Remsima/Inflectra as a similar biological medicinal product to the drug product, Remicade. These products contain the active ingredient, infliximab, and have the same formulation.

The Remsima and Inflectra NDSs are the first NDSs to be filed as SEBs to infliximab and are the first monoclonal antibodies to be filed under the SEB regulatory pathway.

Submission Milestones: Remsima
Submission Milestone Date
Pre-submission meeting: 2011/10/14
Submission filed: 2012/11/14
Screening
Screening Deficiency Notice issued: 2013/01/14
Response filed: 2013/02/04
Screening Acceptance Letter issued: 2013/03/21
Review
On-Site Evaluations: 2013/11/25 to 2013/11/29
2013/12/02 to 2013/12/06
2013/12/09 to 2013/12/10
Quality Evaluation complete: 2014/01/15
Clinical Evaluation complete: 2014/01/15
Labelling Review complete: 2014/01/15
Notice of Compliance issued by Director General: 2014/01/15

The Canadian regulatory decision on the quality, non-clinical, and clinical review of Remsima was based on a critical assessment of the Canadian data package. Health Canada used Celltrion Healthcare Co. Ltd.'s responses to the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) Day 120 and Day 180 List of Questions as an added reference, particularly for assessing immunogenicity as more information was provided by the sponsor to address CHMP questions.

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

4. What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Next link will take you to another Web site Food and Drugs Act and Next link will take you to another Web site Regulations.

5. What post-authorization activity has taken place for Remsima?

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 decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Remsima 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?

Clinical Basis for Decision

The Remsima New Drug Submission (NDS) was filed as a Subsequent Entry Biologic (SEB) product to the Canadian authorized product, Remicade (active ingredient infliximab, marketed by Janssen Inc.). An SEB product is a biologic drug that enters the market subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug. In consideration of supporting information generated using the reference biologic drug, an SEB approval may be granted based on a reduced amount of original non-clinical and clinical information tailored to a particular class of products or a specific case.

In this NDS, Remsima (active ingredient infliximab) was submitted as a similar biological medicinal product to the reference biologic drug, Remicade. Remicade is authorized for use in nine indications and uses in patients with inflammatory diseases. The specific diseases for which Remicade is authorized include rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease, and ulcerative colitis. Remicade is also authorized for pediatric use in Crohn's disease and ulcerative colitis. On the basis of a reduced non-clinical and clinical data package, the sponsor requested market authorization, for Remsima, for all of the indications and uses currently authorized for the reference product, Remicade.

Clinical Pharmacology

Remsima was developed as a Subsequent Entry Biologic to the infliximab product, Remicade. Therefore, the biological activity of Remicade is considered to be representative of the mechanism of action and pharmacological effect of Remsima.

A comparative pharmacokinetic (PK) analysis was conducted between Remsima and the reference drug, Remicade, in a pivotal, parallel group study (CT-P13 1.1) in 250 patients with ankylosing spondylitis. Patients were randomized 1:1 to receive either Remsima or Remicade. The PK parameters, area under the concentration-time curve over the dosing interval (AUCtau) and maximum serum concentration (Cmax) at steady state were the primary endpoints, but in the context of an intravenous infusion, their conventional interpretation as surrogates to estimate relative bioavailability was considered to be insufficient. Multiple discriminant analyses resulted in classification accuracy that was less than 14% over what would be expected if the observations were randomly assigned to the test or reference categories. This level of accuracy suggested that Remsima could not be distinguished from the reference product, Remicade, based on the seven PK parameters (estimated at steady-state using a non-compartmental analysis) that were incorporated into the discriminant analysis.

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

Clinical Efficacy

The NDS for Remsima was filed with a reduced clinical package, based on the sponsor's claimed comparability in quality and manufacturing data between Remsima and the Canadian authorized product, Remicade. The sponsor submitted one pivotal clinical safety and efficacy study (Study CT-P13 3.1) and one pivotal PK study (Study CT-P13 1.1) to support a conclusion of no meaningful clinical difference between Remsima and Remicade. The pivotal efficacy and safety study was conducted in patients with active rheumatoid arthritis. The pivotal PK study was conducted in patients with active ankylosing spondylitis. No clinical studies were conducted in patients with psoriatic arthritis, plaque psoriasis, Crohn's disease, or ulcerative colitis. Therefore, authorization of these remaining indications and uses would require extrapolation from the submitted clinical studies.

Rheumatoid Arthritis

Study CT-P13 3.1 was a pivotal trial designed as a randomized, double-blind, multicentre, parallel-group, clinical equivalence study that compared the efficacy and safety of Remsima with the reference product, Remicade, in adult patients with active rheumatoid arthritis who did not respond adequately to methotrexate (MTX) alone. A total of 606 patients were randomized to receive Remsima or Remicade (3 mg/kg body weight) administered as 2-hour intravenous infusions at Weeks 0, 2, 6, then every 8 weeks up to 54 weeks, co-administered with MTX and folic acid.

Treatment with Remsima or Remicade resulted in comparable rates of response. The improvement in rheumatoid arthritis patients was determined according to American College of Rheumatology (ACR) criteria, with ACR20 indicating an improvement of at least 20%. The primary endpoint compared the proportions of ACR20 responders at Week 30 using the all-randomized population. Patients with missing data were considered non-responders. The analysis found that 60.9% and 58.6% of the patients in the Remsima and Remicade groups, respectively, achieved an ACR20 response. These percentages resulted in an estimated treatment difference of 2% [95% confidence interval (CI): -6%, 10%]. The result was entirely contained within the pre-defined comparability margins of -15% to 15%. Analysis of the ACR20 endpoint using the per-protocol population also indicated that the two treatments were comparable. Additional analyses of the ACR20 at Weeks 14 and 54, and of the ACR50/70 at Weeks 14, 30 and 54, supported the ACR20 findings of comparable efficacy. All ACR comparisons resulted in minimal treatment differences with 95% CIs falling within the pre-defined ACR20 (Week 30) comparability margins of -15% to 15%.

Additional secondary endpoints were investigated using the all-randomized and per protocol populations. These included the Hybrid ACR, Disease Activity Score in 28 joints (DAS28), European League Against Rheumatism (EULAR) response, Clinical Disease Activity Index (CDAI) score, Simplified Disease Activity Index (SDAI) score and assessments using Health Assessment Questionnaires and Short Form 36 (SF-36) questionnaires. Review of these endpoints did not identify any clinically concerning differences between the two products, Remsima and Remicade.

Joint damage progression (JDP) was assessed by X-rays taken at baseline and Week 54. Radiographs were scored using the van der Heijde modified Sharp scoring method. Although, the analysis of JDP excluded a large number of patients, the complete case analysis did not identify clinically meaningful differences between the two products. To provide further reassurance that the two products were comparable in this respect, a subset of 20 patients was selected and their radiographs were requested by the reviewer. In-house scoring of these radiographs indicated that this subset of patients, who received either Remsima or Remicade, achieved comparable JDP scores and that these scores were consistent with what has been observed historically in patients receiving Remicade or other anti-tumour necrosis factor agents.

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

Ankylosing Spondylitis

Study CT-P13 1.1, a randomized, double-blind, multicentre, parallel-group, comparative PK study also compared the efficacy and safety of Remsima with the reference product, Remicade, in patients with active ankylosing spondylitis. A total of 250 patients were randomized 1:1 to receive Remsima or Remicade (5 mg/kg body weight) administered as a 2-hour intravenous infusion at Weeks 0, 2, 6, then every 8 weeks up to 54 weeks.

Although the assessment of efficacy was secondary to the assessment of pharmacokinetics, no clinically meaningful differences were identified in the assessment of efficacy. The all-randomized population was assessed for clinical response according to the Assessment of SpondyloArthritis International Society (ASAS) criteria. Patients with missing data were considered non-responders. The proportions of patients achieving an ASAS20 response (an improvement of ≥20%) at Week 30 in the Remsima and Remicade treatment groups were 63% and 67%, respectively. This resulted in an estimated treatment difference of 4% (95% CI: -16%, 8%), which was considered to support the clinical comparability of the two products. Analyses of the treatment difference at Weeks 14 and 54 provided results similar to that obtained at Week 30. Evaluation of ASAS40 responses also indicated that the products elicited comparable levels of response. Importantly, the level of response elicited by both Remicade and Remsima were in line with what has been reported previously for ankylosing spondylitis patients receiving Remicade. The results of the all-randomized analyses of ASAS20/40 were supported by results obtained for the per protocol population.

Other secondary endpoints that were investigated included Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), chest expansion, and an assessment using the SF-36 questionnaire. These assessments were supportive of product comparability with both products eliciting improvements in clinical response.

Crohn's Disease, Ulcerative Colitis, Psoriatic Arthritis, and Plaque Psoriasis

As noted in the document Guidance for Industry: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), extrapolation may be possible where rationales are sufficiently persuasive. The decision to extrapolate should be based on:

  • the demonstration of product similarity through a detailed and comprehensive comparative product characterization.
  • A thorough understanding of the mechanism(s) of action and the similarities and differences in the mechanism(s) of action that play a role in each of the indicated conditions for which a sponsor applies.
  • an understanding of the pathophysiological mechanism(s) of the indicated diseases and the differences and similarities between them.
  • the safety profile in the respective conditions and/or populations.
  • clinical experience with the reference drug.

In addition to these principles, comparative clinical studies should be performed in a population that is sensitive to product changes using a clinical endpoint that is capable of detecting such changes. This sensitivity may depend on a number of factors such as the magnitude of clinical effect over placebo, the use of concomitant therapies, the immmunocompetence of study participants, and the nature of the clinical endpoint under study. Furthermore, differences in other aspects such as route of administration, posology and pharmacokinetic/pharmacodynamic (PK/PD) profile of the therapeutic in each of the proposed indications, should be considered.

Extensive rationales were provided to support the extrapolation of clinical data from the settings of active rheumatoid arthritis and active ankylosing spondylitis to the remaining indications and uses that are authorized for the reference drug. The principles for extrapolation discussed above, and outlined in the SEB guidance document, were taken into account in the review of this submission, and extrapolation of data from the settings of rheumatoid arthritis and AS to adult and pediatric inflammatory bowel diseases (Crohn's disease, ulcerative colitis) was not recommended. This arose from the observed differences in the level of afucosylation, FcγRIIIa receptor binding, and some in vitro Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) assays. The Chemistry and Manufacturing review team concluded that differences in the ability of the two products to induce ADCC could not be ruled out. The sponsor provided rationale to support their position that ADCC is not an important mediator of the efficacy of their product (or of Remicade); however, after review of the sponsor's rationale for extrapolation and of literature regarding this mechanism of action, it was concluded that ADCC cannot be ruled out as a mechanism of action in the inflammatory bowel diseases (IBD). This position is supported by the observation that certolizumab pegol, another anti-TNF that lacks the ability to induce ADCC, displays only marginal efficacy in Crohn's patients compared to other anti-TNFs, namely infliximab. Therefore, since differences in ADCC have been observed between the two products and because ADCC may be an active mechanism of action for infliximab in the setting of IBD, but not in the setting of rheumatic disease (the studied populations), extrapolation from the settings of rheumatoid arthritis and ankylosing spondylitis to IBD cannot be recommended due to the absence of clinical studies in IBD.

The differences observed in the FcγRIIIa binding and, subsequently, ADCC, do not preclude extrapolation from the settings of rheumatoid arthritis and AS to the other requested indications of psoriatic arthritis and plaque psoriasis. In these diseases, it is likely that ADCC is not an important mechanism for generating a response to infliximab. This is supported by the observation that certolizumab pegol is capable of producing clinical responses of the same order as infliximab in patients with psoriatic arthritis and plaque psoriasis despite its inability to induce ADCC. Further, the extrapolation to psoriatic arthritis and plaque psoriasis is supported by pathophysiology, PK profiles, dosage administered and routes of administration that are similar to those found in patients with rheumatoid arthritis and/or ankylosing spondylitis.

In addition to quality differences that may impact on the safety and efficacy of Remsima in comparison to Remicade, it is also noted that pathophysiological differences exist between the rheumatic diseases and the IBDs making a direct extrapolation between the two groups challenging without clinical or PK/PD bridging data.

The safety profile of infliximab is also different between the rheumatic and inflammatory bowel diseases. In particular, the risk of hepatosplenic T-cell lymphoma appears to be uniquely associated with the inflammatory bowel diseases occurring in adolescents and young adults. It is unclear how physical, chemical and/or biological differences between the SEB and the reference product may affect this risk. Currently, no clinical study has been conducted in the setting of Crohn's disease or ulcerative colitis to show that the differences discussed above will not have an impact on the safety and efficacy in these conditions.

Clinical Safety

The safety database for Remsima included 302 patients with rheumatoid arthritis (Study CT-P13 3.1) and 128 patients with ankylosing spondylitis (Study CT-P13 1.1). Both studies are described in the Clinical Efficacy section. An additional 9 patients with rheumatoid arthritis (Study CT-P13 1.2) were exposed as part of a pilot study to investigate the initial PK, safety, and efficacy of Remsima in comparison to Remicade. Furthermore, the safety database of the reference product, Remicade, is considered relevant to the assessment of safety for Remsima due to the similarity of the products. All three clinical studies were comparative studies to the reference product, Remicade. Patients who were administered Remsima in Study CT-P13 3.1 received a mean of 8.0 doses [Standard Deviation (SD) 2.07] while patients who were administered Remicade received a mean of 7.9 doses (SD 2.08); with 77% and 73% of patients in the Remsima group and Remicade group completing treatment, respectively. Exposure was similar in Study CT-P13 1.1. Patients with ankylosing spondylitis received a mean of 8.4 doses (SD 1.69) and 8.5 doses (SD 1.51) in the Remsima and Remicade groups, respectively. Eighty-five (85%) percent of ankylosing spondylitis patients completed treatment with Remsima while 83% of ankylosing spondylitis patients completed treatment with Remicade. Overall, the extent of exposure was similar between the two treatment groups in both the rheumatoid arthritis and ankylosing spondylitis studies.

No new significant safety signals, which had not been observed previously with Remicade, were observed in Study CT-P13 3.1 and Study CT-P13 1.1. Safety findings from both studies have been included in the Remsima Product Monograph and reflect all treatment emergent adverse events (TEAEs) observed in at least 1% of patients in each of the treatment groups. A summary of the safety findings for each of these studies follows.

Study CT-P13 3.1 - Rheumatoid Arthritis Patients

In Study CT-P13 3.1, TEAEs were experienced by 70.2% of patients treated with Remsima and 70.3% of patients treated with Remicade. The most commonly observed adverse events (AEs) in patients receiving Remsima were latent tuberculosis and upper respiratory tract infection [27 (8.9%) patients each], nasopharyngitis [24 (7.9%) patients), and urinary tract infection [18 (6.0%) patients]. The TEAEs most frequently reported for patients in the Remicade treatment group were latent tuberculosis [25 (8.3%) patients]; urinary tract infection [21 (7.0%) patients]; bronchitis, increased alanine transaminase (ALT), and nasopharyngitis [17 (5.7%) patients each]; and upper respiratory tract infection and headache [16 (5.3%) patients each). Serious adverse events (SAEs) occurred in 42 (13.9%) Remsima patients and 30 (10.0%) Remicade patients. The only SAEs occurring in more than one patient in either group were uveitis (2 Remsima patients; 0 Remicade patients) and deep vein thrombosis (DVT) (2 Remsima patients; 0 Remicade patients). Of the two DVTs, one was considered to be due to contraceptive medication and therefore was likely not related to treatment with Remsima. All other SAEs occurred in 1 patient only. Uveitis is a common occurrence in patients with systemic inflammatory disease and, therefore, the relationship to study drug is uncertain.

Study CT-P13-1.1- Ankylosing Spondylitis Patients

In Study CT-P13 1.1, TEAEs were experienced by 72.7% of patients treated with Remsima patients and 67.2% of patients treated with Remicade. The most commonly reported AEs in patients receiving either Remsima or Remicade were increased ALT [14.8% of Remsima patients versus (vs.) 15.6% Remicade patients], increased aspartate aminotransferase (AST) (12.5% vs. 10.7%), increased gamma-glutamyltransferase (GGT) (3.1% vs. 5.7%), neutropenia (3.1% vs. 4.1%), diarrhea (4.7% vs. 0.8%), headache (7.8% vs. 5.7%), rash (0.8% vs. 4.1%), nasopharyngitis (9.4% vs. 8.2%), increased blood creatine phosphokinase (CPK) (6.3% vs. 4.1%), urinary tract infection (6.3% vs. 0.8%), upper respiratory tract infection (7.8% vs. 10.7%), and influenza (1.6% vs. 4.9%). Serious adverse events occurred in 8 patients in each treatment group (6.3% Remsima; 6.6% Remicade). The most frequently reported SAEs in the Remicade group were infusion-related reactions [3 patients (2.5%)]. No SAEs occurred in more than one patient in the Remsima group.

The overall safety profiles obtained for Remsima in studies performed in patients with rheumatoid arthritis and ankylosing spondylitis are considered acceptable and are consistent with the known safety profile of Remicade and with the safety profile observed for Remicade in these comparative safety and efficacy studies. The known risks of infliximab treatment are conveyed in the Warnings and Precautions section of the approved Remsima Product Monograph.

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

Non-Clinical Basis for Decision

The non-clinical database submitted for Remsima was in compliance with the Subsequent Entry Biologic data requirements for non-clinical studies, as presented in the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs). Two comparative repeat-dose rat toxicity studies revealed that Remsima and Remicade had comparable pharmacological, toxicological, and toxicokinetic effects in animals.

The results of the non-clinical studies, as well as the potential risks to humans, have been included in the Remsima Product Monograph. Appropriate warnings and precautionary measures are in place in the Remsima Product Monograph to address the identified safety concerns.

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

Quality Basis for Decision

Remsima was developed as a Subsequent Entry Biologic to the infliximab drug product, Remicade. Therefore, the biological activity of Remicade is considered to be representative of the mechanism of action and pharmacological effect of Remsima. The Quality review pertained to the Remsima drug substance and drug product. In addition, comparability of Remsima to the reference medicinal product, Remicade, was reviewed in order to evaluate Remsima as a Subsequent Entry Biologic.

Characterization of the Drug Substance

Infliximab, the drug substance of Remsima, is a chimeric human-murine immunoglobulin G1 (IgG1) monoclonal antibody that binds with high affinity to both soluble and transmembrane forms of human tumour necrosis factor alpha (TNFα) but not to lymphotoxin (TNFβ). In this way, infliximab inhibits binding of TNFα with its receptors and neutralises the biological activity of TNFα. Infliximab bears the Fc portion of complement-activating IgG1 and binds to Fc receptors with different patterns of expression on immune cells including monocytes, macrophages, granulocytes, natural killer (NK) cells, B cells, and platelets.

The sponsor used a range of orthogonal methodologies to compare the primary and higher order structure, as well as the charged variants and glycan structures of Remsima and Remicade. In addition, biological assays were used to compare the biological activity of Remsima and Remicade in vitro. Remsima was demonstrated to be comparable to Remicade in a battery of assays evaluating primary and higher order structure and biological activity with respect to TNF binding and neutralization. However, there was an observed quantitative and qualitative difference in the glycosylation pattern. Specifically, Remsima contains a lower level of afucosylated species as compared to Remicade. The degree of afucosylation is known to have a potential impact on Fcγ receptor binding.

With respect to biological activity, no differences were observed in the TNFα binding/ neutralization activity of Remsima and Remicade. Comparable results were demonstrated in cell-based neutralization assay, binding Enzyme-Linked Immuno-Sorbent Assay (ELISA), and receptor binding by Surface Plasmon Resonance. Additionally, no measureable differences were observed in Complement-Dependant Cytotoxicity and Apoptosis assays. In assays to evaluate Fc-mediated activity, no differences were observed with respect to binding of the receptors FCRn, FCγRI, and FCγRIIa.

The data has shown that there is a difference in the NK cell-mediated Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) activity between Remsima and Remicade, but that the difference in activity seems to disappear in the presence of other leukocytes. The sponsor stated that the NK cell assays are less physiologically relevant and that it is likely that in vivo there would be no difference. However, the nature of these cell-based assays and the manipulations required to perform standardized assays of this sort make it difficult to conclusively exclude the potential for a difference in ADCC activity, though the binding differences suggest that only NK cell-mediated ADCC would be affected.

Therefore, Remsima is comparable to Remicade in situations where the mechanism of action is exclusively binding to TNFα. Where the mechanism of action is not clearly defined or where there is a role for ADCC in the mechanism of action, it cannot be conclusively determined that the molecules are comparable.

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

Infliximab, the drug substance of Remsima, is produced as a secreted protein in a large scale cell culture employing a cell line that was transfected with an expression vector containing the coding sequences for both heavy and light chains of infliximab. The purification process includes protein A chromatography, low pH treatment, cation exchange chromatography, anion exchange chromatography followed by nanofiltration, ultrafiltration/diafiltration, and final filtration.

The manufacturing process of the drug product consists of preparation of formulation buffer, formulation of final bulk, sterile filtration, aseptic filling into 20 mL glass vials, freeze-drying, vial stoppering, and sealing with an aluminium flip-off seal.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and the drug product are valid and considered to be adequately controlled within justified limits. The sponsor has demonstrated that the commercial drug substance manufacturing process is able to consistently produce drug substance of acceptable quality. Suitable controls are in place for the drug product, particularly for verification of sterile filtration via filter integrity testing, in-process weight-check during aseptic filling, and freezing rate during lyophilisation.

Control of the Drug Substance and Drug Product

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.

Three lots of consecutively manufactured drug product vials (100 mg/vial) were provided by the sponsor for in-house potency and purity consistency testing. The test results met the established release specification, and therefore are considered acceptable.

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 42-month shelf-life at 2-8°C for Remsima is considered acceptable.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in 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 and the drug product have been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.

Adventitious Agents Safety Evaluation

Not applicable. The excipients used in the drug product formulation are not of animal or human origin.