Summary Basis of Decision for Amgevita

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

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

Recent Activity for Amgevita

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Amgevita

Updated: 2024-02-05

The following table describes post-authorization activity for Amgevita, a product which contains the medicinal ingredient adalimumab. 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.

  • DIN 02459299 – 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-use prefilled syringe
  • DIN 02459302 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-use prefilled auto-injector
  • DIN 02459310 - 20 mg/0.4 mL adalimumab, solution, subcutaneous injection, single-use prefilled syringe

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 256159 2021-08-26 Issued NOC 2022-09-09 Submission filed as a Level I – Supplement for the expansion of the indication. The indication authorized was: Pediatric Ulcerative Colitis - inducing and maintaining clinical remission in pediatric patients 5 years of age and older with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy including corticosteroids and/or azathioprine or 6-mercaptopurine (6-MP) or who are intolerant to such therapies. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 262484 2022-03-17 Issued NOL 2022-06-07 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an alternative non-rigid needle shield, composed without dry natural rubber for use with the autoinjector presentation. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 254689 2021-07-08 Issued NOL 2021-07-29 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 considered acceptable, and an NOL was issued.
SNDS # 249793 2021-02-23 Issued NOC 2021-07-09 Submission filed as a Level I – Supplement to update the PM as a result of the replacement of the rubber in the prefilled syringe needle cover with synthetic rubber (not containing latex). The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration and Dosage Forms, Strengths, Composition and Packaging sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.
Drug product (DINs 02459299, 02459302, 02459310) market notification Not applicable Date of first sale
2021-02-19

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 234183 2019-12-05 Issued NOC
2020-11-04

Submission filed as a Level I – Supplement to add new indications for Amgevita and revised dosing information. The indications authorized were adolescent hidradenitis suppurativa and pediatric uveitis. Regulatory Decision Summary published.
SNDS # 232586 2019-10-15 Issued NOC
2020-11-04

Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the drug substance and a manufacturing scale-up. The stability profiles of the drug substance and drug product remain unchanged. The information was reviewed and considered acceptable. An NOC was issued.
SNDS # 221310 2018-10-25 Issued NOC
2020-11-04

Submission filed as a Level I – Supplement to add an alternate manufacturing facility for the drug product. There were no changes proposed to the drug substance. The information was reviewed and considered acceptable. An NOC was issued.
SNDS # 219453 2018-08-23 Issued NOC
2020-11-04

Submission filed as a Level I – Supplement to add new indications for Amgevita. The indications authorized were hidradenitis suppurativa, uveitis, and polyarticular juvenile idiopathic arthritis. Regulatory Decision Summary published.
SNDS # 205613 2017-05-15 Issued NOC
2020-11-04

Submission filed as a Level I – Supplement to update the Product Monograph (PM) to align it with the PM for the reference biologic drug. The submission was reviewed and considered acceptable, and an NOC was issued.
NDS # 190433 2015-12-11 Issued NOC
2020-11-04

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Amgevita

Date SBD issued: 2021-07-08

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

Adalimumab

Drug Identification Number (DIN):

  • DIN 02459299 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-use prefilled syringe
  • DIN 02459302 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-use prefilled auto-injector
  • DIN 02459310 - 20 mg/0.4 mL adalimumab, solution, subcutaneous injection, single-use prefilled syringe

Amgen Canada Inc.

New Drug Submission Control Number: 190433

 

On November 4, 2020, Health Canada issued a Notice of Compliance to Amgen Canada Inc. for Amgevita, a biosimilar to Humira (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. Amgevita contains the medicinal ingredient adalimumab, which has been demonstrated to be highly similar to adalimumab contained in the reference product, Humira.

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; 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, Humira is the reference biologic drug. Similarity between Amgevita and Humira 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 Amgevita for all of the indications that were authorized for Humira at the time of the submission, with the exception of polyarticular juvenile idiopathic arthritis.

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 benefits-risk profile of Amgevita is considered to be similar to the benefit-risk profile of the reference product, and is therefore considered favourable for the following indications:

Rheumatoid Arthritis

  • Reducing the signs and symptoms, inducing major clinical response and clinical remission, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. Amgevita can be used alone or in combination with methotrexate or other disease-modifying anti-rheumatic drugs.

  • When used as first-line treatment in recently diagnosed patients who have not been previously treated with methotrexate, Amgevita should be given in combination with methotrexate. Amgevita can be given as monotherapy in case of intolerance to methotrexate or when treatment with methotrexate is contraindicated.

Psoriatic Arthritis

  • Reducing the signs and symptoms of active arthritis and inhibiting the progression of structural damage and improving the physical function in adult psoriatic arthritis patients. Amgevita can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • Reducing signs and symptoms in patients with active ankylosing spondylitis who have had an inadequate response to conventional therapy.

Adult Crohn’s Disease

  • Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy, including corticosteroids and/or immunosuppressants. Amgevita is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Pediatric Crohn’s Disease

  • Reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 13 to 17 years of age weighing ≥40 kg with severely active Crohn’s disease and/or who have had an inadequate response or were intolerant to conventional therapy (a corticosteroid and/or aminosalicylate and/or an immunosuppressant) and/or a tumour necrosis factor alpha antagonist.

Ulcerative Colitis

  • Treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy including corticosteroids, azathioprine and/or 6-mercaptopurine or who are intolerant to such therapies. The efficacy of Amgevita in patients who have lost response to or were intolerant to tumour necrosis factor-blockers has not been established.

Plaque Psoriasis

  • Treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, Amgevita should be used after phototherapy has been shown to be ineffective or inappropriate.

 

1 What was approved?

 

Amgevita, a biologic response modifier, was authorized for the following indications:

Rheumatoid Arthritis

  • Reducing the signs and symptoms, inducing major clinical response and clinical remission, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. Amgevita can be used alone or in combination with methotrexate or other disease-modifying anti-rheumatic drugs.

  • When used as first-line treatment in recently diagnosed patients who have not been previously treated with methotrexate, Amgevita should be given in combination with methotrexate. Amgevita can be given as monotherapy in case of intolerance to methotrexate or when treatment with methotrexate is contraindicated.

Psoriatic Arthritis

  • Reducing the signs and symptoms of active arthritis and inhibiting the progression of structural damage and improving the physical function in adult psoriatic arthritis patients. Amgevita can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • Reducing signs and symptoms in patients with active ankylosing spondylitis who have had an inadequate response to conventional therapy.

Adult Crohn’s Disease

  • Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy, including corticosteroids and/or immunosuppressants. Amgevita is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Pediatric Crohn’s Disease

  • Reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 13 to 17 years of age weighing ≥40 kg with severely active Crohn’s disease and/or who have had an inadequate response or were intolerant to conventional therapy (a corticosteroid and/or aminosalicylate and/or an immunosuppressant) and/or a tumour necrosis factor alpha antagonist.

Ulcerative Colitis

  • Treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy including corticosteroids, azathioprine and/or 6-mercaptopurine or who are intolerant to such therapies. The efficacy of Amgevita in patients who have lost response to or were intolerant to tumour necrosis factor-blockers has not been established.

Plaque Psoriasis

  • Treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, Amgevita should be used after phototherapy has been shown to be ineffective or inappropriate.

The safety and efficacy of adalimumab were investigated in pediatric patients 13 to 17 years of age weighing ≥40 kg with severely active Crohn’s disease and/or who have had an inadequate response or who were intolerant to conventional therapy.

Evidence from clinical studies and experience suggests that use of adalimumab in the geriatric population (65 years of age or older) is not associated with differences in effectiveness.

Amgevita is a biosimilar to Humira. Both drugs contain the medicinal ingredient adalimumab. Adalimumab is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody directed against tumour necrosis factor alpha (TNF-α), a key inflammatory cytokine involved in the pathogenesis of a variety of inflammatory diseases.

Similarity between Amgevita and the reference biologic drug, Humira, has been established on the basis of comparative structural and functional, non-clinical, pharmacokinetic, safety, tolerability, bioavailability, and immunogenicity studies, and in clinical studies in patients with moderate to severe rheumatoid arthritis or moderate to severe plaque psoriasis, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Amgevita is contraindicated in:

  • Patients with known hypersensitivity to Amgevita (adalimumab) or any of its components.
  • Patients with severe infections such as sepsis, tuberculosis, and opportunistic infections.
  • Patients with moderate to severe heart failure (New York Heart Association [NYHA] class III/IV).

Amgevita 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.

Amgevita (20 mg/0.4 mL adalimumab) is presented as a solution in a single-dose prefilled syringe. Amgevita (40 mg/0.8 mL adalimumab) is presented as a solution in a single-dose prefilled syringe and as a single-dose prefilled auto-injector. In addition to the medicinal ingredient, the solution contains 10 mM glacial acetic acid, 0.10% (w/v) polysorbate 80, sodium hydroxide for pH adjustment, 9.0% (w/v) sucrose, and water for injection.

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

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

 

2 Why was Amgevita approved?

 

Based on Health Canada's review, the benefit-risk profile of Amgevita is considered to be similar to the benefit-risk profile of the reference product, and is therefore considered favourable for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn's disease, ulcerative colitis, and plaque psoriasis. Similarity between Amgevita and Humira was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Amgevita is considered to be biosimilar to Humira. In Canada, Humira is authorized and marketed for several indications and clinical uses. The specific diseases for which Humira is authorized are rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, and plaque psoriasis. The New Drug Submission filed for Amgevita requested authorization for all of the indications and clinical uses that were authorized for Humira at the time of the submission, with the exception of polyarticular juvenile idiopathic arthritis. The indications have been authorized on the basis of demonstrated similarity between Amgevita and the reference biologic drug.

The target diseases for Amgevita include a host of immune-mediated conditions with shared inflammatory pathways involving tumour necrosis factor alpha (TNF-α). Tumour necrosis factor alpha is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF-α are found in the synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an important role in both pathologic inflammation and joint destruction. Increased levels of TNF-α are also found in psoriasis plaques and contribute to the inflammatory response, proliferation and decreased maturation of keratinocytes, and associated vascular damages, all of which are characteristics of the disease.

Adalimumab, the medicinal ingredient in Amgevita, is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody that binds with high affinity and specificity to soluble and membrane-bound TNF-α. Tumour necrosis factor alpha is a key inflammatory cytokine involved in the pathogenesis of a variety of inflammatory diseases. By binding to TNF-α, adalimumab has been shown to decrease the inflammation process of these diseases.

Amgevita and Humira were judged to be highly similar in terms of quality attributes based on comparative structural and functional studies. Comparable pharmacokinetics, safety, tolerability, and immunogenicity between Amgevita and Humira were established in a comparative pharmacokinetic study conducted in healthy adult volunteers. In addition, clinically meaningful differences in safety, efficacy, and immunogenicity were not demonstrated in two randomized, controlled, clinical studies comparing Amgevita and Humira in patients with moderate to severe rheumatoid arthritis or moderate to severe plaque psoriasis. The results of these studies, in combination with the results of comparative physicochemical and biological assays, provide sufficient evidence of similarity to Amgevita. As additional support for the authorization of Amgevita, in each of the noted indications, the sponsor provided scientific rationales that adequately address the principles of extrapolation as outlined in Health Canada’s Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics.

This demonstration of similarity 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. Therefore, the Adverse Reactions section of the Amgevita Product Monograph is based on the clinical experience with the reference biologic drug, Humira.

As with Humira, a Serious Warnings and Precautions box describing reports of hepatosplenic T-cell lymphoma, infections, and pediatric malignancies in patients treated with TNF-blockers has been included in the Amgevita Product Monograph.

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

A Look-alike Sound-alike brand name assessment was performed and the proposed name, Amgevita, was accepted

Overall, the benefits of Amgevita therapy are expected to be similar to the known benefits of the reference biologic drug, Humira, and are considered to outweigh the potential risks. Appropriate warnings and precautions are in place in the Amgevita 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 and Basis for Decision sections.

 

3 What steps led to the approval of Amgevita?

 

Submission Milestones: Amgevita

Submission Milestone Date
Pre-submission meeting 2015-10-28
Submission filed 2015-12-10
Screening  
Screening Acceptance Letter issued 2016-01-29
Review  
Labelling Review complete 2016-06-27
Quality Evaluation complete 2016-11-21
Review of Risk Management Plan complete 2016-11-22
Non-clinical Evaluation complete 2016-11-23
Clinical/Medical Evaluation complete 2016-11-24
Intellectual Property Hold  
Submission placed on Intellectual Property Hold 2016-11-24
Notice of Compliance issued by Director General, Biologics and Radiopharmaceutical Drugs Directorate 2020-11-04

 

The Canadian regulatory decision on the review of Amgevita was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency and the United States Food and Drug Administration were used as added references.

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

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

The onus is on the Amgevita 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 Amgevita Product Monograph as appropriate. New safety issues that are first identified with the biosimilar, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both the biosimilar and the reference biologic drug. For more information, refer to the Fact Sheet: Biosimilars.

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

  • Submitting to Health Canada a Periodic Benefit-Risk Evaluation Report for Amgevita on an annual basis.
  • Reviewing the Amgevita Product Monograph once per year at a minimum. Changes to the product monograph related to safety should be submitted to Health Canada as a Notifiable Change, together with a rationale explaining the change.

 

5 What post-authorization activity has taken place for Amgevita?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Amgevita is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up-to-date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Quality Basis for Decision

 

Amgevita was developed as a biosimilar to the reference biologic drug, Humira. 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 Amgevita is considered to be representative of the mechanism of action and pharmacological effect of Humira.

Comparative Structural and Functional Studies

The sponsor performed a comprehensive analytical similarity assessment between Amgevita and Humira sourced from the United States (Humira-US) and the European Union (Humira-EU).

The assessment included comparative evaluations of biological activity, primary structure, higher order structure, particles and aggregates, product-related substances and impurities, thermal stability and degradation studies, general properties, and process-related impurities. The methods used were appropriately validated or qualified and deemed suitable for their intended use.

The similarity assessment demonstrated that Amgevita is highly similar to Humira-US and Humira-EU, and by extension, to Humira authorized in Canada.

Characterization of the Drug Substance

The drug substance, adalimumab, is a recombinant, fully human immunoglobulin G1 (IgG1) type monoclonal antibody that consists of 1,330 amino acids and has a molecular weight of approximately 148 kDa. Adalimumab binds and neutralizes human tumour necrosis factor alpha (TNF-α), a cytokine that mediates the inflammatory response, and prevents its interaction with its receptors, p55 and p75. Additionally, adalimumab binds neonatal Fc receptor (FcRn) and Fc gamma receptors (FcγR) and mediates effector functions such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity in vitro.

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

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

The drug substance is expressed in Chinese hamster ovary cells. The manufacturing process consists of a series of cell expansions followed by the production of cell culture using a fed-batch process. The cell culture fluid is chilled and acid precipitated prior to harvest by disk-stack centrifugation. The downstream processes consist of a protein A column followed by a series of chromatography and viral inactivation steps. The pooled eluent is then passed through a virus reduction nanofilter, concentrated, and buffer exchanged using tangential flow ultrafiltration. The formulated drug substance pool is then filtered into polycarbonate containers, which are sealed, labelled, and stored at -40 °C to -20 °C.

Both the master and working cell banks have been tested and characterized in accordance with International Council for Harmonisation (ICH) guidelines. Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. Minor changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review. The sponsor has adequately demonstrated that the drug substance manufacturing facility is capable of consistently manufacturing drug substance of acceptable quality.

The Amgevita drug product is a single-use, preservative-free, ready-to-use solution for subcutaneous injection at a concentration of 40 mg/0.8 mL or 20 mg/0.4 mL (both 50 mg/mL). The primary container closure system is a sterile prefilled syringe barrel. The final drug product is available as a prefilled syringe or a prefilled auto-injector.

The drug product manufacturing process consists of the thawing, filtrating, and aseptic filling of the drug substance into syringe barrels to form prefilled syringes. Once filled, the prefilled syringes are immediately seated with a sterile plunger stopper. The prefilled syringes are labelled and undergo final assembly, where the plunger rod is added and the backstop manually clipped over the syringe flange, or the prefilled syringe is inserted into auto-injector subassemblies.

In-process controls and lot release tests for the drug product were established and validated. The sponsor has adequately demonstrated that the drug product manufacturing facility is capable of consistently manufacturing drug product of acceptable 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 the medicinal ingredient 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, and analytical procedures are validated in compliance with ICH guidelines.

Amgevita is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 30-month shelf life at 2 to 8 ºC for Amgevita, including an in-use storage period of up to 14 days at 25 ºC, is considered acceptable.

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

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance was not conducted as it was determined that the manufacturing schedule did not provide the opportunity for Health Canada to observe the manufacturing process. In addition, Health Canada’s familiarity with the facility and the lack of risk signals in the submission did not warrant a regulatory hold. It is recommended that an OSE be considered at the next opportunity.

An OSE of the facility involved in the manufacture and testing of the drug product was not warranted since the facility was recently evaluated and obtained a satisfactory rating.

Adventitious Agents Safety Evaluation

Raw materials of animal and recombinant deoxyribonucleic acid origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. A letter of attestation has been provided, confirming that the material is not from a country or area affected by bovine spongiform encephalopathy or transmissible spongiform encephalopathy, indicating that the product is considered to be safe for human use.The excipients used in the final product formulation are not of animal or human origin.

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Preharvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses) and that appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

 

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 structural and functional studies and address potential areas of residual uncertainty.

The non-clinical database submitted for Amgevita 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.

Two comparative in vivo repeat-dose studies were conducted in cynomolgus monkeys to demonstrate similarity between Amgevita and Humira.

In Study 114832, a two-week non-terminal comparative study in male cynomolgus monkeys, Amgevita and Humira were well tolerated at 32 mg/kg. Consistent with data available for historical non-clinical studies using adalimumab, there were no adalimumab-related effects observed on clinical signs, body weight, hematology, serum chemistry, or coagulation parameters.

Study 115674, a one-month terminal comparative repeat-dose study in male and female cynomolgus monkeys, used higher doses of adalimumab and included a vehicle control and special endpoints to assess effects on tissue lymphoid cells. Toxicokinetic profiles were comparable between Amgevita and Humira with no sex differences. There was a moderate accumulation in exposure after the fourth dose of Amgevita and Humira. No anti-drug antibodies were detected and there were no adalimumab-related effects observed on clinical signs, body weight, food consumption, physiologic measurements, ophthalmic or electrocardiogram examinations, serum chemistry, urinalysis, or macroscopic necropsy findings in the Amgevita or Humira groups. A transient increase in neutrophil count and fibrinogen concentration was observed on Day 4 in some animals administered Amgevita and Humira. Levels were normal on Day 29. Consistent with historical microscopic findings after adalimumab administration, the histological changes for Amgevita and Humira were limited to the lymphoid tissues. Changes were similar for Amgevita and Humira, and included a mild to moderate decrease in size and the number of germinal centers in axillary lymph nodes, mesenteric lymph nodes, and tonsils. In the spleen, a similar decrease in CD21+ B lymphocytes for Amgevita and Humira was observed by immunohistochemical staining and by flow cytometry.

The non-clinical studies did not identify any differences in toxicology or toxicokinetics between Amgevita and Humira.

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

For more information, refer to the Amgevita 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, and 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 structural complexity of the reference 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.

Amgevita is a biosimilar to Humira. Both drugs contain the medicinal ingredient adalimumab. Adalimumab is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody directed against tumour necrosis factor alpha (TNF-α). Amgevita binds specifically to TNF-α and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF-expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an important role in both pathologic inflammation and joint destruction. Increased levels of TNF are also found in psoriasis plaques, which contribute to the inflammatory response, proliferation and decreased maturation of keratinocytes, and associated vascular damage, all of which are characteristics of the disease.

Amgevita also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (endothelial leukocyte adhesion molecule-1 [ELAM-1], vascular cell adhesion molecule-1 [VCAM-1], and intercellular adhesion molecule-1 [ICAM-1] with a half-maximal inhibitory concentration of 1 to 2 x 10-10 M.

Comparative Pharmacokinetic and Pharmacodynamic Studies

The comparability in the pharmacokinetics between Amgevita and Humira was established in Study 20110217, a randomized, single-blind, single-dose, three-arm, parallel-group study in healthy adult subjects. The study was conducted at a site in the European Union (EU) and at a site in the United States (US).

The study was conducted in 203 healthy adult males and females 18 to 45 years of age. At the EU site, subjects were randomized in a 1:2 ratio to Amgevita and Humira sourced from the EU (Humira-EU), while subjects at the US site were randomized in a 1:2 ratio to Amgevita and Humira sourced from the US (Humira-US). The subjects randomized to Amgevita from the two sites were combined in the analyses of comparative bioavailability. Subjects were administered a single 40 mg subcutaneous dose of Amgevita, Humira-US, or Humira-EU by subcutaneous injection. Serum samples were taken for up to 57 days and an end-of-study visit was to occur at Day 63.

The study demonstrated pharmacokinetic comparability between Amgevita and Humira (Humira-US, and Humira-EU), as evidenced by the 90% confidence intervals (CI) of the geometric mean ratios (expressed as percentages) for the area under the serum concentration-time curve from time 0 to the last quantifiable concentration (AUClast) and for the maximum serum concentration (Cmax), which were fully contained within the predefined margins of 80% to 125%. The AUClast and Cmax were 107% (90% CI: 96.4, 118) and 104%, respectively, for Amgevita versus Humira-US and 99% (90% CI: 89.2, 110) and 96%, respectively, for Amgevita versus Humira-EU.

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

Comparative Clinical Efficacy and Safety

The comparative clinical efficacy and safety of Amgevita and its reference biologic drug, Humira, were evaluated in two Phase III studies, Study 20120262 and Study 20120263.

Study 20120262 was a double blind, randomized (1:1), multicentre, parallel-group study that enrolled 526 patients (number of patients [n] = 264, Amgevita; n = 262, Humira-US). Patients were 18 to 80 years of age and were diagnosed with moderate to severe rheumatoid arthritis as per the 2010 American College of Rheumatology (ACR) or European League Against Rheumatism classification criteria. The study included a 4-week screening and randomization period, a 22-week treatment period, and a 2-week follow-up period, after which the primary endpoint was to be assessed at Week 24. All patients received a stable dose of methotrexate in combination with either Amgevita or Humira-US throughout the study. The treatment arms were well balanced with respect to demographic and baseline disease characteristics.

The primary objective was to demonstrate the absence of clinically meaningful differences between Amgevita and Humira-US. The primary endpoint for comparison between arms was the ACR20 (a 20% improvement in ACR core set measurements) response rate at Week 24. The results of this analysis met predefined equivalence criteria that specified a risk ratio equivalence margin of 0.738 to 1/0.738 (representing an approximate +/-14% absolute treatment difference). The ACR20 response rates, based on the full analysis set (FAS) with non-responder imputation, were 71.2% and 72.1%, respectively, for Amgevita and Humira. The risk ratio for ACR20 was 1.000 (95% CI: 0.899, 1.113) and the risk difference for ACR20 was -0.371 (95% CI: -8.030, 7.289). Based on these results, the study met its primary endpoint of demonstrating equivalence in ACR20 at Week 24 between treatment arms. Secondary efficacy comparisons were supportive of the ACR20 endpoint results. In particular, the study compared Disease Activity Score-28 for Rheumatoid Arthritis with C-reactive Protein (DAS28-CRP) scores between treatment arms. At Week 24, there was no difference in the mean change from baseline between treatment arms (-2.32 versus -2.32). The point estimate and 95% CI for the difference between means was -0.01 (-0.22, 0.20). It is noted that the original study protocol designated DAS28-CRP as the primary endpoint and that the equivalence margin was designated to be +/-0.6. Thus, these results are supportive of biosimilarity.

The overall safety profile did not identify major differences between the two treatment arms. The incidence of adverse events over the 24-week study period (any adverse event) was 50.0% versus 54.6%, respectively, for Amgevita versus Humira-US. The difference in the incidence of investigator assessed treatment-related adverse events was negligible between treatment arms (18.5% versus 21.0%, Amgevita versus Humira-US). Patients administered Humira had slightly more adverse events overall and slightly more adverse events with a severity of ≥Grade 3. Serious adverse events also occurred slightly more often among patients treated with Humira. None of these small differences raised concerns with respect to the biosimilarity of Amgevita and its reference biologic drug, Humira.

Study 20120263 was a double-blind, randomized (1:1), multicentre, parallel-group study that enrolled 350 patients (n = 175, Amgevita; n = 175, Humira-EU). Patients were 18 to 75 years of age with stable plaque psoriasis for at least 6 months up to the time of screening. The planned enrollment was 340 patients, which was chosen to provide a greater than 90% power to demonstrate equivalence at a significance level of 0.025 on the primary endpoint of Psoriasis Area and Severity Index (PASI) percent improvement from baseline at Week 16 with an equivalence margin of -15% to 15%. The study included a 4-week screening and randomization period, a 14-week treatment period, and a 2-week follow-up period, after which, the primary endpoint (PASI percent improvement) was to be assessed at Week 16. After Week 16, patients originally randomized to the Humira-EU arm that achieved at least a 50% reduction from baseline in the PASI score (PASI50) were re-randomized (1:1) to continue receiving Humira-EU (Humira/Humira group) or, switch to Amgevita (Humira/Amgevita group). Patients who were initially randomized to Amgevita and who achieved a PASI50 by Week 16 continued on Amgevita. Treatment after re-randomization continued for 34 weeks and included a 4-week follow-up period. Patients were not permitted to receive concomitant immunosuppressive agents (e.g., methotrexate). Amgevita and Humira-EU were administered as per the Canadian product monograph for the reference biologic drug, Humira. The initial treatment arms (baseline to Week 16) were well balanced with respect to demographic and baseline disease characteristics.

The study met its primary endpoint of demonstrating that the difference in mean percent PASI improvement between treatment arms was within the predefined equivalence margins of -15% to 15%. The treatment difference at Week 16 was -2.18% (95% CI: -7.39, 3.02). The result was supported by the per-protocol analysis and by additional sensitivity analyses.

During the review, two concerns were identified with respect to the sponsor’s analysis of the primary endpoint. The first was the use of the Last-Observation-Carried-Forward method as the primary method of handling missing data in the analysis. To alleviate this concern, the sponsor provided a tipping-point analysis to support the robustness of the result. The second concern arose due to the comparison of percentage change from baseline rather than the absolute change in PASI score. Therefore, the sponsor provided analysis of the absolute change in PASI score between treatment arms at various time points. At Week 16, the difference between treatment arms (Amgevita versus Humira) in mean PASI change from baseline (absolute score) was 0.57 (95% CI: -0.56, 1.70), which is supportive of the similarity observed in the primary analysis.

The overall safety profile observed from baseline to Week 16 did not identify major differences between the two treatment arms. The incidence of adverse events (any adverse event) for Amgevita and Humira-EU was 67.2% versus 63.6%, respectively. The difference in the incidences of treatment-related adverse events was negligible between treatment arms (24.7 versus 24.9%, Amgevita versus Humira-EU). Very few patients experienced adverse events that were ≥Grade 3, were considered serious, or that led to study discontinuation. Thus, it is difficult to make comparisons with respect to these adverse event categories; however, the results do not suggest differences between treatment arms. Serious adverse events and events ≥Grade 3 occurred with comparable frequencies between treatment arms. None of these small differences raise concern with respect to the similarity of these two products.

After re-randomization (Week 16 to Week 52), patients who received Amgevita throughout the study (Amgevita/Amgevita), or those who switched to Amgevita from Humira (Humira/Amgevita), had slightly more adverse events and discontinuations due to adverse events than patients who received Humira throughout the study (Humira/Humira) (71.1%, 70.1%, and 65.8%, respectively, for Amgevita/Amgevita, Humira/Amgevita, and Humira/Humira). When adjusted for exposure, a slight increase in adverse events (per 100 patient-years) was observed in patients who received Amgevita after re-randomization (less than 1 additional adverse event per patient-year). Few patients in any treatment arm had adverse events or treatment-related adverse events that were ≥Grade 3 (2% or less in all arms). Serious adverse events occurred with similar frequency in the Humira/Amgevita and Humira/Humira arms and were slightly less frequent in patients who received Amgevita throughout the study.

Amgevita demonstrated a comparable safety profile to the reference product Humira. Therefore, the Adverse Reactions section of the Amgevita Product Monograph is based on the clinical experience with the reference biologic drug. As with Humira, a Serious Warnings and Precautions box describing reports of hepatosplenic T-cell lymphoma, infections, and pediatric malignancies in patients treated with TNF-blockers has been included in the Amgevita Product Monograph.

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

Overall, the efficacy and safety profile of Amgevita is considered to be comparable to that which has been established for the reference biologic drug, Humira. Appropriate warnings and precautions are in place in the approved Amgevita Product Monograph to address the identified safety concerns, as they are in the Humira Product Monograph.

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

Comparative Immunogenicity

The comparative immunogenicity of Amgevita and its reference biologic drug, Humira, was also evaluated in Study 20120262 and Study 20120263, where the development of anti-drug antibodies (ADA) was comparatively assessed in rheumatoid arthritis patients (Study 20120262) and plaque psoriasis patients (Study 20120263). The studies employed the same detection methodologies, which were validated and fit for purpose.

In Study 20120262, the incidences of ADA occurring in patients with rheumatoid arthritis were comparable between Amgevita and Humira-US at the time points observed from baseline to Week 24. Median ADA concentrations were also similar between treatment arms at each observation. The overall post-baseline incidences of binding ADA among rheumatoid arthritis patients were 38.3% versus 38.2%, respectively, for patients who received Amgevita versus Humira-US.

In Study 20120263, ADA were measured from baseline to Week 16 for patients receiving either Amgevita or Humira-EU and also from Week 16 to Week 52 for patients who continued treatment, some of whom were re-randomized from Humira-EU to Amgevita. A higher proportion of patients receiving Humira-EU (57.2%) had binding antibodies post baseline through Week 16 compared to patients receiving Amgevita (48.9%). Throughout the entire study, ADA was elicited in a greater proportion of patients randomized to Humira-EU (74.7%) compared to Amgevita (68.4%). When patients were switched from Humira-EU to Amgevita, the overall incidence of ADA in these patients (72.7%) was similar to patients who received only Humira-EU (74.7%). A graphical analysis of the incidence of ADA at each time point, assessed using the Amgevita assay, suggested that switching to Amgevita from Humira may be associated with a higher incidence of ADA at specific time points after the switch. However, the increased rate of ADA after switching was not observed when samples were tested using the Humira-EU assay. In any case, it was evident that patients who received Amgevita throughout the study developed ADA less frequently than those who received Humira-EU at any time. Overall, there were no concerning differences in ADA concentrations identified during the study.

Indications

Amgevita is considered to be biosimilar to Humira, the reference biologic drug. Humira is authorized and marketed in Canada for several indications and clinical uses. The specific diseases for which Humira is authorized are rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, and plaque psoriasis.

Within this drug submission, the sponsor requested authorization for all of the indications and clinical uses that were authorized for Humira at that the time of the submission, with the exception of polyarticular juvenile idiopathic.

Similarity between Amgevita and Humira 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 Amgevita and the reference biologic drug in comparative structural, functional, non-clinical, bioavailability, and immunogenicity studies, and in clinical studies in patients with moderate to severe rheumatoid arthritis and moderate to severe plaque psoriasis.

Indication

Amgevita was authorized for the following indications:

Rheumatoid Arthritis

  • Reducing the signs and symptoms, inducing major clinical response and clinical remission, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis (RA). Amgevita can be used alone or in combination with methotrexate or other disease-modifying anti-rheumatic drugs.

  • When used as first-line treatment in recently diagnosed patients who have not been previously treated with methotrexate, Amgevita should be given in combination with methotrexate. Amgevita can be given as monotherapy in case of intolerance to methotrexate or when treatment with methotrexate is contraindicated.

Psoriatic Arthritis

  • Reducing the signs and symptoms of active arthritis and inhibiting the progression of structural damage and improving the physical function in adult psoriatic arthritis patients. Amgevita can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • Reducing signs and symptoms in patients with active ankylosing spondylitis who have had an inadequate response to conventional therapy.

Adult Crohn’s Disease

  • Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy, including corticosteroids and/or immunosuppressants. Amgevita is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Pediatric Crohn’s Disease

  • Reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 13 to 17 years of age weighing ≥40 kg with severely active Crohn’s disease and/or who have had an inadequate response or were intolerant to conventional therapy (a corticosteroid and/or aminosalicylate and/or an immunosuppressant) and/or a tumour necrosis factor alpha antagonist.

Ulcerative Colitis

  • Treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy including corticosteroids, azathioprine and/or 6-mercaptopurine or who are intolerant to such therapies. The efficacy of Amgevita in patients who have lost response to or were intolerant to tumour necrosis factor-blockers has not been established.

Plaque Psoriasis

  • Treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, Amgevita should be used after phototherapy has been shown to be ineffective or inappropriate.

 

 

 

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