Summary Basis of Decision for Avsola
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 Avsola is located below.
Recent Activity for Avsola
The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.
The following table describes post-authorization activity for Avsola, a product which contains the medicinal ingredient infliximab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).
For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.
Updated: 2024-04-23
Drug Identification Number (DIN):
DIN 02496933 - 100 mg/vial infliximab, intravenous administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
NC # 274378 |
2023-04-14 |
Issued NOL 2023-05-15 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an extension of the reference standard shelf‐life or retest period. The submission was considered acceptable, and an NOL was issued. |
|
SNDS # 272100 |
2023-02-03 |
Cancellation Letter Received 2023-03-31 |
Submission filed as a Level I – Supplement to update the PM. The proposed revisions exceeded the scope of a Labelling Only SNDS. The submission was therefore cancelled administratively by the sponsor. |
|
SNDS # 264677 |
2022-05-30 |
Issued NOC 2022-11-18 |
Submission filed as a Level I – Supplement to update the outer label and package insert. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
SNDS # 262502 |
2022-03-16 |
Issued NOC 2022-06-21 |
Submission filed as a Level I – Supplement for the addition of a new drug substance manufacturing site. The submission was reviewed and considered acceptable, and an NOC. |
|
SNDS # 259724 |
2021-12-17 |
Issued NOC 2022-05-17 |
Submission filed as a Level I – Supplement to update the PM to align with that of the reference biologic drug, Remicade, and to migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Drug Interactions; and Dosage and Administration sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued. |
|
SNDS # 252417 |
2021-05-05 |
Issued NOC 2021-10-27 |
Submission filed as a Level I – Supplement for the addition of an alternate drug product manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
NC # 253572 |
2021-06-07 |
Issued NOL 2021-07-02 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls (in‐process tests and/or acceptance criteria) applied during the drug substance manufacturing process or on intermediates. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
Drug product (DIN 02496933) market notification |
Not applicable |
Date of first sale: 2020-06-01 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NDS # 226189 |
2019-03-27 |
Issued NOC 2020-03-12 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Avsola
Date SBD issued: 2020-05-27
The following information relates to the New Drug Submission for Avsola.
Infliximab
Drug Identification Number (DIN):
- DIN 02496933 - 100 mg/vial infliximab, intravenous administration
Amgen Canada Inc.orporated
New Drug Submission Control Number: 226189
On March 12, 2020, Health Canada issued a Notice of Compliance (NOC) to Amgen Canada Incorporated for Avsola, a biosimilar to Remicade (the reference biologic drug). The terms "biosimilar biologic drug" and "biosimilar" are used by Health Canada to describe subsequent entry versions of a Canadian approved innovator biologic drug with demonstrated similarity to a reference biologic drug. Biosimilars were previously referred to as subsequent entry biologics in Canada. Both Avsola and Remicade contain highly similar versions of the medicinal ingredient, infliximab.
Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. For a biosimilar, the weight of evidence is provided by the structural and functional studies, whereas 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 Avsola 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 Avsola 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 Avsola is considered to be highly similar to the reference biologic drug 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. Avsola 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 is not established in patients less than 9 years of age.
- treatment of fistulising Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with conventional treatment.
- reduction of signs and symptoms, induction and maintenance of clinical remission and mucosal healing, and reduction or elimination of corticosteroid use in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy (i.e., aminosalicylate and/or corticosteroid and/or an immunosuppressant).
- reduction of signs and symptoms, induction and maintenance of clinical remission, and induction of mucosal healing in pediatric patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy (i.e., aminosalicylate and/or corticosteroid and/or an immunosuppressant). The safety and efficacy of infliximab 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, Avsola 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.
Avsola should be used by physicians who have sufficient knowledge of rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriatic arthritis or plaque psoriasis, and who have fully familiarized themselves with the efficacy and safety profile of Avsola.
1 What was approved?
Avsola, 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. Avsola 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 is not established in patients less than 9 years of age.
- treatment of fistulising Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with conventional treatment.
- reduction of signs and symptoms, induction and maintenance of clinical remission and mucosal healing, and reduction or elimination of corticosteroid use in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy (i.e., aminosalicylate and/or corticosteroid and/or an immunosuppressant).
- reduction of signs and symptoms, induction and maintenance of clinical remission, and induction of mucosal healing in pediatric patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy (i.e., aminosalicylate and/or corticosteroid and/or an immunosuppressant). The safety and efficacy of infliximab 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, Avsola 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.
Avsola should be used by physicians who have sufficient knowledge of rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriatic arthritis or plaque psoriasis, and who have fully familiarized themselves with the efficacy and safety profile of Avsola.
Avsola is a biosimilar to Remicade. Both drugs contain the medicinal ingredient, infliximab, which 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 Avsola and Remicade has been established on the basis of comparative studies to evaluate properties including stability, degradation profiles, structure, purity, potency, and biological activity, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
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. 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 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.
Avsola 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 of the excipients.
Avsola was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Avsola (100 mg/vial infliximab) is presented as a lyophilised powder for solution. In addition to the medicinal ingredient, the powder contains dibasic sodium phosphate anhydrous, monobasic sodium phosphate monohydrate, polysorbate, and sucrose.
The market authorization was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. For more information, refer to the Quality (Chemistry and Manufacturing), Non‑clinical, and Clinical Basis for Decision sections.
Additional information may be found in the Avsola Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Avsola approved?
Health Canada considers that the benefit‑risk profile of Avsola is highly similar to the reference biologic drug Remicade for the treatment of 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), active arthritis, psoriatic arthritis, and plaque psoriasis.
Avsola should be used by physicians who have sufficient knowledge of these diseases, and who have fully familiarized themselves with the efficacy and safety profile of Avsola.
Similarity between Avsola and Remicade was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Avsola 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), active arthritis, psoriatic arthritis, and plaque psoriasis. The New Drug Submission (NDS) filed for Avsola 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 Avsola and the reference biologic drug.
Tumour necrosis factor (TNF) α 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 Avsola 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 Avsola, three other biosimilars to Remicade had been authorized by Health Canada.
The results of Study 20140111 were submitted to provide evidence of comparability between Avsola and Remicade with respect to clinical efficacy and safety. This study is described in detail in the Comparative Clinical Efficacy and Safety section.
The biosimilar and the reference biologic drug were determined to be highly similar with respect to quality attributes, based on comparative structural and functional studies. Comparisons of the pharmacokinetic parameters of the two drugs demonstrated comparability between Avsola and the reference biologic drug, Remicade. The demonstration of similarity is derived from the comparative structural and functional, non‑clinical, and clinical studies. This enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.
Avsola has demonstrated a comparable safety profile with its reference biologic drug, 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 in the Serious Warnings and Precautions box of the Product Monograph for Avsola, as is found in the Product Monograph for Remicade.
A Risk Management Plan (RMP) for Avsola was submitted by Amgen Canada Incorporated to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Avsola was accepted.
Overall, Avsola is considered to have a benefit/risk profile comparable to that of its reference biologic drug Remicade with respect to the authorized indications. The benefits of Avsola are considered to outweigh the potential risks in its target patient population. The identified safety issues can be managed through labelling and adequate monitoring.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. The market authorization was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. For more information, refer to the Quality (Chemistry and Manufacturing), Non‑clinical, and Clinical Basis for Decision sections.
3 What steps led to the approval of Avsola?
Submission Milestones: Avsola
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2018-12-06 |
| Submission filed: | 2019-03-27 |
| Screening | |
| Screening Acceptance Letter issued: | 2019-05-17 |
| Review | |
| Review of Risk Management Plan complete: | 2019-12-27 |
| Quality Evaluation complete: | 2020-02-27 |
| Clinical Evaluation complete: | 2020-03-09 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2020-03-09 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate: | 2020-03-12 |
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 Food and Drugs Act and Regulations.
The onus is on the Avsola sponsor to monitor the post-market safety profile of this biosimilar product as well as the Product Monograph of the reference biologic drug for safety signals that could impact the biosimilar, and make safety updates to the Avsola 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
Avsola 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 Avsola 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 Avsola and the designated reference product, Remicade sourced from the United States (Remicade [US]). Analytical methods were chosen based on knowledge of the structure, function, and heterogeneity of infliximab, to examine attributes which are critical to the biological activity and stability of the product.
A wide range of characteristics was tested, including physico‑chemical properties, biological activity for the primary and additional mechanisms of action, purity and impurity profiles, and stability profiles including forced degradation conditions.
The outcomes of the biosimilarity assessment demonstrate that Avsola is identical to the reference product with respect to primary structure, and highly similar with respect to higher‑order structures, post‑translational modifications, and biological activity. Minor differences were observed, but do not affect potency and are not expected to be clinically meaningful. Comparative thermal stability and forced degradation studies with the lyophilized powder and the reconstituted drug product generated similar degradation profiles to those of the reference biologic drug. Additionally, these studies revealed no unexpected degradation pathways for Avsola. Collectively, the results demonstrate that Avsola is highly similar to the reference biologic drug.
Characterization of the Drug Substance
Detailed characterization studies were performed to provide assurance that infliximab, the medicinal ingredient in Avsola, consistently exhibits the desired characteristic structure and biological activity. The primary and higher‑order structures, molecular mass, size and charge variants, purity, potency, and biological activity of infliximab were all confirmed through appropriately qualified methods.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The manufacturing of Avsola 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 infliximab material 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 four 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 (medicinal ingredient in Avsola) is consistent and yields a product of suitable quality.
To produce the drug product, Avsola, the infliximab drug substance is thawed, pooled, mixed, and filtered. The solution then undergoes aseptic filling into vials, which are partially stoppered before the solution is lyophilized. The vials are then completely stoppered, capped, and inspected, and stored at 2‑8°C. The sponsor has demonstrated by formal validation studies that the manufacturing process is capable of consistently manufacturing lots of vials that meet pre‑established specifications.
Examination of the facilities and manufacturing processes has demonstrated that they can consistently produce the drug substance and drug product with suitable quality.
All non‑medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of infliximab with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The proposed control strategy was found to be suitable for controlling the identified critical quality attributes, and for ensuring production of Avsola that meets quality expectations. Samples from final product lots were tested for potency and purity, and the results support the suitability of the methods.
Avsola is a Schedule D (biologic) drug and is therefore subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. As part of this program, final product lots were tested using a subset of release methods. For post‑approval monitoring, Avsola was classified as a product requiring a low level of assessment. The risk level assigned to a drug product is determined by factors including the nature of the product, its indication and target patient population, and the manufacturer's production and inspection history.
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 48 month shelf life at 2‑8°C for Avsola is considered acceptable. Additional storage and special handling instructions are included in the Avsola Product Monograph.
Facilities and Equipment
Although an on‑site evaluation (OSE) was recommended for the drug substance manufacturing facility, it was not feasible to conduct the OSE during the review cycle due to scheduling constraints. The suitability of the facility to manufacture the drug substance was adequately assessed through review of the dossier. No issues were identified, and the results of this assessment indicated that the facility and processes were suitable for the production of the drug substance.
Based on a risk assessment score determined by Health Canada, an OSE was not recommended or conducted for the drug product manufacturing facility.
Adventitious Agents Safety Evaluation
The master and working cell banks were tested using compendial methods and were found to be sterile and free of non‑viral adventitious agents. Unprocessed bulk used in the manufacturing process was also tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated. Under worst‑case conditions, the process has been shown to inactivate and remove viral contaminants. Detected levels are below the acceptable limits.
The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.
7.2 Non-Clinical Basis for Decision
For biosimilars, the degree of similarity at the quality level determines the scope and the breadth of the required non‑clinical data. Non‑clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty.
The non‑clinical database submitted for Avsola was in compliance with the requirements for non‑clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Comparative in vitro and ex vivo studies demonstrated no major differences between Avsola and Remicade.
An in vivo non‑clinical study was conducted in Sprague‑Dawley rats to compare the toxicological profiles of Avsola and Remicade (US). There were no major toxicological findings that differed between Avsola and the reference biologic drug.
The results of the comparative non‑clinical studies and the potential risks to humans have been included in the Avsola Product Monograph. Considering the intended use of Avsola, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Avsola Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Clinical basis for decision
The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in support of the indications being sought. Therefore, clinical trials are not required to support each indication.
For biosimilars, the purpose of the clinical program is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The degree of similarity at the quality level determines the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.
Comparative Pharmacokinetic Studies
Infliximab, the medicinal ingredient in Avsola, binds with high affinity and specificity to tumour necrosis factor (TNF) α, a cytokine which mediates inflammatory responses. Tumour necrosis factor α plays a central role in various biological activities, and 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 20140108 compared the pharmacokinetics of Avsola, Remicade sourced from the United States (Remicade [US], the reference biologic drug), and Remicade sourced from the European Union (Remicade [EU]). This study was conducted in 148 healthy subjects, who were randomized evenly between three treatment groups to receive a 5 mg/kg dose of one of the three investigational drugs. Serum samples were collected up to Day 57 of the study. The results were focused on comparison between Avsola and Remicade (US), the designated Canadian reference product.
A noncompartmental analysis method was used to estimate pharmacokinetic parameters, including the area under the concentration‑time curve from time 0 to the last quantifiable concentration (AUCT; a measure of exposure over time), and the maximum observed serum concentration (Cmax). The results with respect to these parameters were fully contained within pre‑specified margins which met Health Canada's criteria for pharmacokinetic similarity, indicating pharmacokinetic comparability between Avsola and Remicade (US).
For further details, please refer to the Avsola Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Clinical Efficacy and Safety
Study 20140111 compared Avsola to its reference product, Remicade (US) (hereafter referred to as Remicade), with respect to clinical efficacy and safety. This pivotal Phase III study was conducted in 558 patients with moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate. The objective of this study was to rule out any clinically meaningful differences in safety, efficacy, and immunogenicity between Avsola and Remicade. Immunogenicity is addressed in the Comparative Immunogenicity section.
Patients were randomized in a 1:1 ratio to receive either Avsola or Remicade, with 279 patients in each treatment group. Patients received a 3 mg/kg intravenous infusion of their assigned investigational drug on Day 1 of Week 0, at Weeks 2 and 6, and every 8 weeks thereafter until Week 22. At Week 22, patients initially randomized to receive Remicade were randomized again in a 1:1 ratio to either continue treatment with Remicade or switch to treatment with Avsola. Patients received a 3 mg/kg intravenous infusion of their assigned investigational drug every 8 weeks through Week 46.
The primary efficacy endpoint was the response difference of 20% improvement in the American College of Rheumatology (ACR) core set measurements at Week 22. The ACR 20 response is defined as a 20% improvement in swollen joint count, tender joint count, and three of the following five parameters: the subject's global health assessment, the investigator's global health assessment, the subject's assessment of disease‑related pain, the Health Assessment Questionnaire ‑ Disability Index (HAQ‑DI), and serum level of C‑reactive protein (CRP).
The analysis of the primary efficacy endpoint was performed on the intent‑to‑treat (ITT) analysis set, with non‑responder imputation (NRI) for patients with a missing ACR 20 response at Week 22. Initial calculations showed that the upper bound of the two‑sided 95% confidence interval (CI) did not fall within the predefined equivalence margin of ±15%. The sponsor evaluated this result and proposed that random baseline imbalances could have contributed to the differences observed between the Avsola and Remicade treatment groups. This was confirmed through additional sensitivity analyses, in which the response difference was estimated following adjustments for ACR components, patients' ages, body mass index (BMI) category, and use of oral corticosteroids, nonsteroidal anti‑inflammatory drugs (NSAIDs), and methotrexate. Based on this model, the estimated response difference of ACR 20 at Week 22 was 7.18%, with a two‑-sided 95% CI of (-0.49%, 14.85%). This result was found to be more robust than the initial outcome, and falls entirely within the predefined equivalence margins for the primary analysis.
The results of the 28‑joint Disease Activity Score based on CRP (DAS28‑CRP) for rheumatoid arthritis and ACR components, a key secondary endpoint, were consistent with the results of the primary analysis. This provides further support of comparability between Avsola and the reference biologic drug.
The safety analysis set consisted of 556 patients (99.6%) who received investigational drug (Avsola and/or Remicade) at least once, in any amount. The incidence and severity of adverse events were comparable between treatment groups. Through Week 22, Grade 1 or 2 adverse events were reported in 256 patients (46%). Grade 3 or higher adverse events were reported in 12 patients in the Avsola treatment group (4.3%) and in 14 patients in the Remicade treatment group (5%). The most frequent adverse events, upper respiratory tract infections and rheumatoid arthritis, were reported in 5% or more of patients and were balanced in both treatment groups. No new safety signals were identified during the study.
Two deaths were reported during the course of the study: one patient in the Avsola group due to pneumococcal pneumonia, and one patient in the Remicade group due to a road traffic accident.
Overall, the safety profile for Avsola is considered to be comparable to that of the reference biologic drug, Remicade. The risk of infections, hepatosplenic T‑cell lymphoma, and pediatric malignancy are highlighted in a Serious Warnings and Precautions box in the Avsola Product Monograph, as they are in the Remicade Product Monograph.
For more information, refer to the Avsola Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Immunogenicity
Treatment with any therapeutic protein is naturally accompanied by the risk of immunogenicity (the development of anti‑drug antibodies [ADAs], which have the potential to neutralize the drug's biological activity). Immunogenicity was evaluated by the measurement of ADAs and neutralizing antibodies (NAbs), and Avsola 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
Avsola is considered to be biosimilar to Remicade, the reference biologic drug. 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), active arthritis, psoriatic arthritis, and plaque psoriasis.
Within this drug submission, the sponsor requested the authorization of Avsola for all of the indications that are currently authorized for Remicade.
Similarity between Avsola 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. Therefore, clinical trials are not required to support each indication.
The indications have been authorized on the basis of demonstrated similarity between Avsola and the reference biologic drug with respect to structural and functional, non-clinical and clinical studies. In addition, a scientific rationale taking into consideration the mechanism of action, pharmacological effect, pathophysiological mechanisms of the diseases involved, safety profile, dosage regimen, and clinical experience with the reference biologic drug Remicade, was provided and was considered in line with Health Canada's biosimilar guidance document.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| AVSOLA | 02496933 | AMGEN CANADA INC | INFLIXIMAB 100 MG / VIAL |