Summary Basis of Decision for Ixifi
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Ixifi is located below.
Recent Activity for Ixifi
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.
Summary Basis of Decision (SBD) for Ixifi
Date SBD issued: 2022-04-06
The following information relates to the new drug submission for Ixifi.
Infliximab
Drug Identification Number (DIN):
- DIN 02523191 - 100 mg/vial infliximab, powder for solution, intravenous infusion
Pfizer Canada ULC
New Drug Submission Control Number: 248134
On December 21, 2021, Health Canada issued a Notice of Compliance (NOC) to Pfizer Canada ULC for Ixifi, 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. Ixifi contains the medicinal ingredient infliximab, which has been demonstrated to be highly similar to infliximab contained in the reference biologic drug Remicade.
Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. To be considered a biosimilar, the weight of evidence is provided by the structural and functional studies; the non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, pharmacokinetic and pharmacodynamic, and clinical studies.
The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought.
For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.
In this drug submission, Remicade is the reference biologic drug. Similarity between Ixifi 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 Ixifi for all of the indications that are currently authorized for Remicade.
The market authorization was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. Similarity was established through data derived from comparative structural, functional, non-clinical, and clinical studies. Based on Health Canada’s review, the benefit-risk profile of Ixifi is considered to be similar to the benefit-risk profile of the reference product, and is therefore considered favourable for the (following indications):
- 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 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. Ixifi 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 infliximab for injection are 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 infliximab for injection 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, Ixifi 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.
Ixifi should be used by physicians who have sufficient knowledge of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis, and/or plaque psoriasis and who have fully familiarized themselves with the efficacy/safety profile of Ixifi.
1 What was approved?
Ixifi, a biological response modifier, 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 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. Ixifi 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 infliximab for injection are 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 infliximab for injection 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, Ixifi 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.
Ixifi should be used by physicians who have sufficient knowledge of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis, and/or plaque psoriasis and who have fully familiarized themselves with the efficacy/safety profile of Ixifi.
Indications have been authorized in pediatric patients (<18 years of age) aged 9 years and older with moderate to severely active Crohn’s disease, and in patients aged 6 years and older with moderate to severely active ulcerative colitis. In general, adverse events reported in pediatric patients with Crohn’s disease or ulcerative colitis who received infliximab for injection were similar to those reported in adult patients with Crohn’s disease or ulcerative colitis, respectively. It should be noted that in the Phase III study (REACH), of pediatric patients with Crohn’s disease, all were required to be receiving a stable dose of either 6-mercaptopurine, azathioprine, or methotrexate.
Indications have not been authorized in pediatric populations in which the safety and efficacy of infliximab have not been established. These include pediatric patients with Crohn’s disease less than 9 years of age or with ulcerative colitis less than 6 years of age, and pediatric patients with plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, or juvenile rheumatoid arthritis.
Evidence from clinical studies suggests that the use of infliximab in geriatric patients (≥65 years of age) is not associated with any overall differences in safety and efficacy. In rheumatoid arthritis clinical trials (ATTRACT) and plaque psoriasis trials, no overall differences were observed in the effectiveness or safety of infliximab among 181 patients with rheumatoid arthritis and 5 patients with plaque psoriasis, aged 65 or older compared to younger patients; however, the incidence of serious adverse events in patients aged 65 or older was higher in both infliximab for injection and control groups compared to younger patients. In Crohn’s disease, ulcerative colitis, ankylosing spondylitis and psoriatic arthritis studies, there were insufficient numbers of patients 65 years of age and over to determine whether they respond differently from patients 18 to 64 years of age. As there is generally a higher incidence of infections in geriatric patients, caution should be used in treating patients in this population.
Ixifi is a biosimilar to Remicade, with both drugs containing the medicinal ingredient infliximab. Ixifi is produced in Chinese Hamster Ovary (CHO) cells using recombinant deoxyribonucleic acid (DNA) technology. Infliximab is a human-murine chimeric monoclonal antibody of the immunoglobulin G (IgG) subclass. It binds with high affinity and selectivity to tumour necrosis factor (TNF) α, a cytokine which mediates inflammatory responses.
Similarity between Ixifi and the reference biologic drug Remicade has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, comparative bioavailability studies, and comparative clinical efficacy, safety and immunogenicity studies in patients with severely active rheumatoid arthritis who have had an inadequate response to methotrexate, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Ixifi (100 mg/vial infliximab) is presented as a powder for solution. In addition to the medicinal ingredient, the powder contains sucrose, disodium succinate hexahydrate, succinic acid, and polysorbate 80. No preservatives are present.
Ixifi is contraindicated in:
- patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
- patients with severe infections such as sepsis, abscesses, tuberculosis and opportunistic infections.
- patients with moderate or severe (New York Heart Association [NYHA] Class III/IV) congestive heart failure.
- patients with a history of hypersensitivity to infliximab, to other murine proteins, or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Ixifi Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.
2 Why was Ixifi approved?
Based on Health Canada's review, the benefit-risk profile of Ixifi is considered to be similar to that of the reference product, and is therefore considered favourable for the (following indications): rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease (in adults and pediatric patients 9 years and older), fistulising Crohn’s disease, ulcerative colitis (in adults and pediatric patients 6 years and older), psoriatic arthritis, and plaque psoriasis.
Ixifi should be used by physicians who have sufficient knowledge of these diseases and who have fully familiarized themselves with the efficacy/safety profile of Ixifi.
Similarity between Ixifi and Remicade was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Ixifi is considered to be biosimilar to Remicade. Remicade is authorized and marketed in Canada for rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease (adult and pediatric), fistulising Crohn’s disease, ulcerative colitis (adult and pediatric), psoriatic arthritis, and plaque psoriasis. The New Drug Submission (NDS) filed for Ixifi 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 Ixifi and the reference biologic drug.
Tumour necrosis factor alpha (TNFα) is a cytokine which mediates immune responses and has central roles in a wide range of biological processes. Uncontrolled production or function of TNFα is associated with the pathogenesis of various autoimmune inflammatory diseases. Infliximab, the medicinal ingredient in both Ixifi and Remicade, neutralizes the biological activity of TNFα by binding with high affinity to the soluble and transmembrane forms of TNFα and inhibits the binding of TNFα with its receptors. At the time of authorization of Ixifi, four other biosimilars to Remicade had been authorized by Health Canada.
The biosimilar and the reference biologic drug were judged highly similar in terms of quality attributes (based on comparative structural and functional studies).
Comparative bioavailability and comparative pharmacokinetic studies demonstrated similarity in healthy volunteers.
The results of Study B5371002 were submitted to provide evidence of comparability between Ixifi and Remicade with respect to clinical efficacy, safety, and immunogenicity. This study is described in detail in the Comparative Clinical Efficacy and Safety section. The comparative clinical study ruled out clinically meaningful differences in efficacy, safety, and immunogenicity between the biosimilar and the reference biologic drug, in patients with severely active rheumatoid arthritis who have had an inadequate response to methotrexate. The demonstration of similarity enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.
Ixifi has demonstrated a comparable safety profile with its reference product, Remicade. Therefore, the Adverse Reactions section of the biosimilar Product Monograph is based on the clinical experience with the reference biologic drug. As with Remicade, the major identified safety concerns include the risk of infection, hepatosplenic T-cell lymphoma, and pediatric malignancy. These issues have been addressed through appropriate labelling in the Serious Warnings and Precautions box in the Product Monograph for Ixifi, as is found in the Product Monograph for Remicade.
Neither the biosimilar nor the reference biologic drug have been studied in patients with severe hepatic or renal impairment. It is not known if gender differences, genetic polymorphism, renal insufficiency or hepatic insufficiency have effects on clearance or volume of distribution of Ixifi.
A Risk Management Plan (RMP) for Ixifi was submitted by Pfizer Canada ULC to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. At the time of Notice of Compliance issuance, there were no RMP-related issues that would preclude the authorization of Ixifi.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Ixifi Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
The sponsor submitted a brand name assessment that included testing for look-alike sound-alike attributes. Upon review, the proposed name Ixifi was accepted.
Overall, Ixifi is considered to have a benefit-risk profile comparable to that which has been established for the claimed indications for its reference biologic drug Remicade. The benefits of Ixifi are considered to outweigh the potential risks. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Ixifi Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.
3 What steps led to the approval of Ixifi?
The review of the quality and clinical components of the New Drug Submission (NDS) for Ixifi was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the United States Food and Drug Administration (FDA) were used as added references, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Ixifi NDS was made independently based on the Canadian review.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Ixifi
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2017-01-17 |
| New Drug Submission filed | 2021-01-08 |
| Screening | |
| Screening Acceptance Letter issued | 2021-02-25 |
| Review | |
| Review of Risk Management Plan completed | 2021-09-03 |
| Quality evaluation completed | 2021-10-22 |
| Non-clinical evaluation completed | 2021-11-18 |
| Clinical/medical evaluation completed | 2021-12-14 |
| Biostatistics evaluation completed | 2021-12-21 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2021-12-21 |
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
The onus is on the Ixifi sponsor to monitor the post-market safety profile of this biosimilar 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 Ixifi 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.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Quality Basis for Decision
As described above, the review of the New Drug Submission for Ixifi was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Ixifi was developed as a biosimilar to the reference biologic drug Remicade. For biosimilars, the weight of evidence is provided by structural and functional studies. Biosimilars are manufactured to the same regulatory standards as other biologic drugs. In addition to a typical chemistry and manufacturing data package that is submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity with the reference biologic drug.
The biological activity of Ixifi is considered to be representative of the mechanism of action and pharmacological effect of Remicade.
Comparative Structural and Functional Studies
The biosimilarity assessment involved comparative testing between Ixifi and the designated reference biologic drug, Remicade sourced from Europe (Remicade-EU). Remicade-EU is a suitable proxy for the version of this product authorized in Canada as it meets all of the requirements set forth in Health Canada’s Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Ixifi has the same dosage form, strength, concentration after reconstitution, and route of administration as the reference biologic drug. The excipient composition of Remicade-EU and Ixifi differ in terms of buffer and pH (phosphate versus succinate, respectively).
The biosimilarity study utilized a comprehensive panel of tests to evaluate a variety of attributes of the drug products including physicochemical properties, biological activity, purity and impurity profiles, and stability profiles including forced degradation conditions. Quality attributes were identified and assessed for their potential to affect efficacy, pharmacokinetics and pharmacodynamics, safety and immunogenicity, as well as their relevance in establishing biosimilarity.
The outcomes of the biosimilarity assessment demonstrated that Ixifi is highly similar to Remicade. Minor differences were observed with regards to the glycan and charge variant profiles, however, these differences did not impact biological activity and are not considered clinically meaningful.
Comparative stability and forced degradation studies using different stress conditions generated similar degradation profiles for Ixifi and Remicade further supporting the similarity of the products. Taken together, these studies demonstrate a high degree of similarity between Ixifi and Remicade.
Characterization of the Drug Substance
Detailed characterization studies were performed to provide assurance that infliximab, the medicinal ingredient in Ixifi, consistently exhibits the desired characteristic structure and biological activity.
Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established and acceptable limits.
Manufacturing Process of the Drug Substance and Drug Product and Process Controls
Ixifi is supplied as a single-use, sterile, preservative-free lyophilized powder for intravenous infusion.
The manufacturing of Ixifi begins with Chinese Hamster Ovary (CHO) cells that have been genetically modified to express its medicinal ingredient, infliximab. A culture is initiated from a single vial of CHO cells, and is transferred to progressively larger vessels until it reaches commercial scale. The cells are harvested from the culture, and infliximab is isolated and purified through a series of chromatography, filtration, and viral inactivation steps. The purified bulk drug substance is further subjected to an ultrafiltration/diafiltration step and then undergoes formulation to add the excipients. The resulting bulk infliximab drug substance is then sterile filtered into storage containers and frozen. Process validation studies were conducted by manufacturing three lots using the commercial scale and process. The results of these studies and of the batch analysis data have shown that the manufacture of infliximab (the medicinal ingredient in Ixifi) is consistent and yields a product of suitable quality.
To produce the drug product, Ixifi, the infliximab drug substance is thawed, mixed, and sterile filtered. The solution is then aseptically filled into vials, which are partially stoppered prior to lyophilization. The vials are then completely stoppered, capped, visually inspected, and stored at 2-8 °C. The sponsor has demonstrated by formal validation studies that the manufacturing process is capable of consistently manufacturing Ixifi drug product that meet pre-established specifications.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of infliximab with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines. Each lot of Ixifi drug substance and drug product is tested for appearance, identity, quantity, potency, purity, impurities, and safety.
Ixifi is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. 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 60-month shelf life when stored at 5 °C ± 3 °C for Ixifi drug product is considered acceptable. Additionally, at the location of reconstitution, unopened Ixifi may be stored in the original carton at temperatures up to a maximum of 30 °C for a single period of up to 6 months not exceeding the refrigerated expiration date printed on the carton. Once removed from refrigerated storage, Ixifi cannot be returned to refrigerated storage. Additional storage and special handling instructions are listed in the Ixifi Product Monograph.
The proposed in-use stability conditions are supported by data from physiochemical studies and microbial in-use hold-time studies.
With respect to microbiological stability, as the drug product does not contain a preservative, it is recommended that the administration of the infusion solution begin within 3 hours of reconstitution and dilution.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug substance and drug product manufacturing facilities was not recommended.
Both sites involved in production are compliant with good manufacturing practices.
Adventitious Agents Safety Evaluation
The manufacturing process involves master and working cell banks, which have been thoroughly characterized and tested for adventitious agents in accordance with International Council for Harmonisation (ICH) guidelines.
The manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Viral clearance/inactivation is accomplished by a low pH inactivation step, an anion exchange chromatography step, and a virus retaining filtration step. Endotoxin and bioburden are controlled throughout the process.
The raw material of biological origin used in the manufacturing process is adequately tested to ensure freedom from adventitious agents and originates from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens. 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 Ixifi was in compliance with the requirements for non-clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. In order to assess the similarity of the pharmacologic response for Ixifi as compared with reference infliximab (Remicade-EU) and Remicade sourced from the United States (Remicade-US), Ixifi was tested in an extensive panel of comparative in vitro studies that included functional and binding assays reflective of the multiple potential mechanisms of action of Remicade. Overall, the biological activity and functionality of Ixifi was demonstrated to be similar to Remicade-EU and Remicade-US. The similarity assessment, using the full panel of functional and binding assays, also demonstrated that infliximab licensed product lots sourced from the United States and Europe were similar to each other.
The results of the comparative in vitro studies have been included in the Ixifi Product Monograph. In view of the intended use of Ixifi, there are no non-clinical issues within this submission which preclude authorization of the product.
For more information, refer to the Ixifi Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Clinical basis for decision
The purpose of the clinical program for a biosimilar is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The structural complexity of the biologic drug and availability of a relevant and sensitive pharmacodynamic endpoint determine the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.
Comparative Pharmacokinetic Study
Infliximab, the medicinal ingredient in Ixifi, binds with high affinity and specificity to tumour necrosis factor alpha (TNFα), a cytokine which mediates inflammatory responses. Tumour necrosis factor α plays a central role in various biological activities, and the uncontrolled production or function of TNFα has been associated with the pathogenesis of many autoimmune inflammatory diseases. The binding of infliximab to TNFα inhibits the ability of TNFα to bind to its receptors, thereby neutralizing its biological activity.
Infliximab does not neutralise TNFβ (lymphotoxin α), a related cytokine that utilises the same receptors as TNFα.
Study B5371001 compared the pharmacokinetics of Ixifi, Remicade-EU, and Remicade-US. The study was a randomized, double-blind, parallel-group, single-dose study in healthy adult subjects (total number [n] = 151). The primary objective was to compare the pharmacokinetic profiles of the three versions of infliximab. Each subject received a single intravenous dose of 10 mg/kg of Ixifi, Remicade-EU or Remicade-US. Serum pharmacokinetic samples were collected at a suitable frequency up to Day 57. As this was the pivotal pharmacokinetic comparability study in the Ixifi development program, the results focused on the pharmacokinetic comparison of Ixifi and Remicade-EU, which was the designated proxy for the Canadian reference product.
Study B5371001 demonstrated pharmacokinetic comparability between Ixifi and Remicade-EU as the ratio of their geometric means of the maximum concentration (Cmax) and the 90% confidence intervals (CIs) of their relative geometric means of the area under the concentration-time curve from time 0 to the last quantifiable concentration (AUCT; a measure of exposure over time) were within the comparability margins of 80.0% to 125.0%.
The comparative bioavailability study indicated there are no clinically meaningful differences between the biosimilar and the reference biologic drug.
For further details, please refer to the Ixifi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Clinical Efficacy and Safety
Study B5371002 was a Phase III, randomized, double-blind, two-arm, parallel-group, multicentre study comparing the efficacy, safety, and immunogenicity of Ixifi and Remicade-EU in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate.
Study B5371002 had three treatment periods. In treatment period 1 (TP1), patients were randomized in a 1:1 ratio to receive either 3 mg/kg of Ixifi (n = 324) or Remicade-EU (n = 326) intravenously at Weeks 0, 2 and 6, followed by administration every 8 weeks. Treatment period 2 (TP2) began with dosing at Week 30 when patients initially assigned to Remicade-EU were re-randomized in a 1:1 ratio to switch to Ixifi or to remain on Remicade-EU. Treatment Period 3 (TP3) began with dosing at Week 54 when all remaining patients on Remicade-EU were switched to Ixifi and received open-label Ixifi for an additional 24 weeks. The last administration of the study drug was at Week 70 and the end of treatment visit was at Week 78.
Baseline demographics in Study B5371002 were well balanced across treatment groups and generally representative of the rheumatoid arthritis patient population. The majority of the patients in the intention-to-treat (ITT) population were female (80.3%) and White (77.5%), with a mean age (± standard deviation) of 52.8 (± 13.1) years.
Comparative Efficacy
The primary efficacy endpoint for Study B5371002 was the proportion of patients who achieved an American College of Rheumatology (ACR) 20 response (ACR20; 20% or greater improvement in ACR criteria) at Week 14. In the ITT population, 203 patients (62.7%) in the Ixifi arm and 209 patients (64.1%) in the Remicade-EU arm achieved an ACR20 response at Week 14 with a treatment difference of -1.46%. In the per-protocol population (PP), ACR20 response rates were similar for both treatments as compared to those for the ITT population, with a treatment difference of -0.57%. At Week 14, ACR20 response for both the ITT and PP populations was within Health Canada’s similarity margin criteria of 95% CI ± 12%.
Study B5371002 met its primary objective of demonstrating that the proportion of patients achieving ACR20 response at Week 14 was similar between the Ixifi and Remicade-EU treatment arms. During the transition-extension period (Week 30 onwards), the ACR20 responses were similar between treatment arms (for TP2 - Remicade/Remicade, Remicade/Ixifi and Ixifi/Ixifi arms and for TP3 - Remicade/Remicade/Ixifi, Remicade/Ixifi/Ixifi and Ixifi/Ixifi/Ixifi).
Secondary endpoints including ACR20, ACR50 and ACR70 (50% or greater and 70% or greater improvement in ACR clinical response) responses, and disease activity score-28 for rheumatoid arthritis with C-reactive protein (DAS28-CRP) at various time points up to Week 78 showed similar results based on descriptive statistics across treatment groups.
The clinical efficacy study indicated there are no clinically meaningful differences between the biosimilar and the reference biologic drug.
Comparative Safety
The clinical safety of Ixifi was evaluated in comparison to its reference biologic drug, Remicade-EU, in Study B5371002. The safety population for TP1 included a total of 649 patients; 323 patients were randomized to the Ixifi arm and treated with Ixifi, and 326 patients were randomized to the Remicade-EU arm and treated with Remicade-EU. Of the 649 patients included in the TP1 safety population, 566 patients were re-randomized to TP2 and constituted the safety population for TP2. Of these 566 patients, 280 patients continued to Ixifi/Ixifi, 143 patients were randomized to Remicade-EU/Remicade-EU, and 143 patients were randomized to Remicade-EU/Ixifi. In TP3, the safety population included 505 patients who continued in the study, all of whom received Ixifi. Overall, there were 253, 126, and 126 patients who received Ixifi/Ixifi/Ixifi, Remicade-EU/Remicade-EU/Ixifi, and Remicade-EU/Ixifi/Ixifi, respectively.
Safety assessments included adverse events, physical examinations, vital signs, electrocardiograms, clinical laboratory testing, and immunogenicity assessments. In the main treatment period, the most common adverse events reported in at least 3% of patients were not clinically meaningfully different to those reported with the reference product. These included infusion-related reactions, increased alanine aminotransferase, and nasopharyngitis. Up to Week 78, five patients died (three in the Ixifi treatment arm and two in the Remicade-EU treatment arm). None of the deaths were considered to be related to study treatment as the patients had multiple comorbidities.
Results up to Week 78 support the safety of Ixifi in patients with moderately to severely active rheumatoid arthritis who were treated in combination with methotrexate. Furthermore, safety assessments up to Week 78 suggested no clinically meaningful difference in immunogenicity and safety among the treatment groups, independent of single treatment transition from Remicade-EU to Ixifi at Week 30 or Week 54. The safety findings for Ixifi were consistent with previous observations for other authorized infliximabs.
The safety database from the single-dose comparative pharmacokinetic Study B5371001 included 49 healthy volunteers randomized to and treated with Ixifi, 48 patients randomized to and treated with Remicade-EU and 49 patients randomized to and treated with Remicade-US. No new safety concerns were identified in this study.
Neither the biosimilar nor the reference biologic drug have been studied in patients with severe hepatic or renal impairment. It is not known if gender differences, genetic polymorphism, renal insufficiency or hepatic insufficiency have effects on clearance or volume of distribution of Ixifi.
With respect to clinical safety, there are no clinically meaningful differences between the biosimilar and the reference biologic drug. As with Remicade, the major identified safety concerns include the risk of infection, hepatosplenic T-cell lymphoma, and pediatric malignancy. These issues have been addressed through appropriate labelling in the Serious Warnings and Precautions box in the Product Monograph for Ixifi, as is found in the Product Monograph for Remicade. Appropriate warnings and precautions are in place in the approved Ixifi Product Monograph to address the identified safety concerns, as is found in the Product Monograph for Remicade. Overall, the safety profile of Ixifi is considered to be comparable to that which has been established for the reference biologic drug Remicade.
For more information, refer to the Ixifi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Immunogenicity
Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). Immunogenicity was evaluated by the measurement of ADAs and neutralizing antibodies (NAbs), and Ixifi and the reference biologic drug were comparable in this respect. Additionally, the impact of ADAs and NAbs on efficacy and safety did not result in any clinically meaningful differences between the two treatment groups.
Indications
Ixifi 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 rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease (adult and pediatric), fistulising Crohn’s disease, ulcerative colitis (adult and pediatric), psoriatic arthritis, and plaque psoriasis.
Within this drug submission, the sponsor requested the authorization of Ixifi for all of the indications that are currently authorized for Remicade.
Similarity between Ixifi 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 sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug, and therefore clinical trials are not required to support each indication. The indications have been authorized on the basis of demonstrated similarity between Ixifi and the reference biologic drug, in structural and functional studies, mechanism of action, pharmacological effect, pathophysiological mechanisms of the diseases involved, safety profile, dosage regimen, and clinical experience with the reference biologic drug.
Based on the evidence submitted, Ixifi was authorized for the following indications:
- 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 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. Ixifi 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 infliximab for injection are 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 infliximab for injection 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, Ixifi 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.
Ixifi should be used by physicians who have sufficient knowledge of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis, and/or plaque psoriasis and who have fully familiarized themselves with the efficacy/safety profile of Ixifi.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| IXIFI | 02523191 | PFIZER CANADA ULC | INFLIXIMAB 100 MG / VIAL |