Summary Basis of Decision for Abrilada (formerly Adalimumab Injection)

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 Abrilada (formerly Adalimumab Injection) is located below.

Recent Activity for Abrilada (formerly Adalimumab Injection)

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 Abrilada (formerly Adalimumab Injection)

Updated:  2023-08-29

The following table describes post-authorization activity for Abrilada (formerly Adalimumab Injection), 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 that are found in PAATs.

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

Drug Identification Number (DIN):

  • DIN 02511045 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-dose prefilled pen (auto-injector)
  • DIN 02511053 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-dose prefilled syringe
  • DIN 02511061 - 20 mg/0.4 mL adalimumab, solution, subcutaneous injection, single-dose prefilled syringe
  • DIN 02511088 - 10 mg/0.2 mL adalimumab, solution, subcutaneous injection, single-dose prefilled syringe
  • DIN 02511096 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-dose vial

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02511061) market notification Not applicable Date of first sale: 2023-03-13 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 259979 2022-01-17 Issued NOC 2022-11-14 Submission filed as a Level I – Supplement to add a new indication to align with the reference biologic drug, Humira. The indication authorized was: the treatment of pediatric ulcerative colitis - inducing and maintaining clinical remission in pediatric patients 5 years of age and older with moderately to severely active ulcerative colitis 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.
Drug product (DIN  02511053) market notification Not applicable Date of first sale: 2022-03-07 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Drug product (DIN 02511045) market notification Not applicable Date of first sale: 2022-02-24 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 255017 2021-07-26 Issued NOC 2021-07-26 Submission filed as a Level I – Supplement to update the inner, outer, and package insert mock-up labels. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 252317 2020-04-30 Issued NOC
2021-06-29		 Submission filed to change the brand name of the product from Adalimumab Injection to Abrilada. An NOC was issued.
NDS # 235685 2020-01-31 Issued NOC
2021-01-14		 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Abrilada (formerly Adalimumab Injection)

Date SBD issued: 2021-09-23

The following information relates to the New Drug Submission for Abrilada (formerly Adalimumab Injection).

Adalimumab

Drug Identification Number (DIN):

  • DIN 02511045 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-dose prefilled pen (auto-injector)
  • DIN 02511053 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-dose prefilled syringe
  • DIN 02511061 - 20 mg/0.4 mL adalimumab, solution, subcutaneous injection, single-dose prefilled syringe
  • DIN 02511088 - 10 mg/0.2 mL adalimumab, solution, subcutaneous injection, single-dose prefilled syringe
  • DIN 02511096 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-dose vial

Pfizer Canada ULC

New Drug Submission Control Number: 235685

 

On January 14, 2021, Health Canada issued a Notice of Compliance (NOC) to Pfizer Canada ULC for Adalimumab Injection, 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. Adalimumab Injection contains the medicinal ingredient adalimumab, which has been demonstrated to be highly similar to adalimumab contained in the reference biologic drug, 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. To be considered a biosimilar, the weight of evidence is provided by the structural and functional studies; the non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, pharmacokinetic and pharmacodynamic, and clinical studies.

The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor’s submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug for 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 Adalimumab Injection 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 Adalimumab Injection for all of the indications that were authorized for Humira at the time of the submission.

The market authorization was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between Adalimumab Injection and Humira. 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 Adalimumab Injection is considered to be similar to the benefit-risk profile of Humira, and is therefore considered favourable for the following indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.

 

1 What was approved?

 

Adalimumab Injection, a biological 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. Adalimumab Injection 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, Adalimumab Injection should be given in combination with methotrexate.

Adalimumab Injection can be given as monotherapy in case of intolerance to methotrexate or when treatment with methotrexate is contraindicated.

Polyarticular Juvenile Idiopathic Arthritis

  • In combination with methotrexate, reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients, 2 years of age and older who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs. Adalimumab Injection can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is not appropriate. Adalimumab has not been studied in pediatric patients with polyarticular juvenile idiopathic arthritis aged less than 2 years.

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. Adalimumab Injection can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • Reducing signs and symptoms in adult 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. Adalimumab Injection 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 (TNF) alpha (TNF-α) 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 and/or azathioprine or 6-mercaptopurine or who are intolerant to such therapies. The efficacy of adalimumab in patients who have lost response to or were intolerant to TNF blockers has not been established.

Hidradenitis Suppurativa

  • Treatment of active moderate to severe hidradenitis suppurativa in adult and adolescent patients (12 to 17 years of age weighing ≥30 kg) who have not responded to conventional therapy (including systemic antibiotics).

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, Adalimumab Injection should be used after phototherapy has been shown to be ineffective or inappropriate.

Adult Uveitis

  • Treatment of non-infectious uveitis (intermediate, posterior and panuveitis) in adult patients with inadequate response to corticosteroids or as corticosteroid sparing treatment in corticosteroid-dependent patients.

Pediatric Uveitis

  • Treatment of chronic non-infectious anterior uveitis in pediatric patients from 2 years of age who have had an inadequate response to or are intolerant to conventional therapy, or in whom conventional therapy is inappropriate.

Adalimumab, the medicinal ingredient in Adalimumab Injection, has not been studied in pediatric patients with polyarticular juvenile idiopathic arthritis less than 2 years of age or in pediatric patients with a weight below 10 kg. The safety and efficacy of adalimumab were authorised 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. There are no clinical trials with adalimumab in adolescent patients with hidradenitis suppurativa. The dosage of adalimumab in these patients has been determined based on pharmacokinetic and pharmacodynamic modeling and simulation. Adalimumab has not been studied in pediatric patients with uveitis less than 2 years of age. Very limited data are available for pediatric patients with uveitis between 2 and less than 3 years of age.

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

Adalimumab Injection 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, tuberculosis, and opportunistic infections.
  • Patients with moderate to severe heart failure (New York Heart Association [NYHA] class III/IV).

Adalimumab Injection is a biosimilar to Humira. Both drugs contain adalimumab. As a recombinant human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against TNF-α, adalimumab is a biologic disease modifying anti-rheumatic agent used in the management of a variety of autoimmune inflammatory conditions.

Similarity between Adalimumab Injection and the reference biologic drug, Humira, has been established on the basis of comparative structural, functional, non-clinical, and clinical studies, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Adalimumab Injection 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.

Adalimumab Injection is presented as a solution in a single-dose prefilled auto-injector (40 mg/0.8 mL adalimumab), a single-dose prefilled syringe (10 mg/0.2 mL, 20 mg/0.4 mL, and 40 mg/0.8 mL adalimumab), and a single-dose vial (40 mg/0.8mL adalimumab). In addition to the medicinal ingredient, the solution contains edetate disodium dihydrate, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, sucrose, and water for injection.

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

 

2 Why was Abrilada (formerly Adalimumab Injection) approved?

 

Based on Health Canada’s review, the benefit-risk profile of Adalimumab Injection is considered to be similar to the benefit-risk profile of the reference biologic drug, and is therefore considered favourable for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis. Similarity between Adalimumab Injection and Humira was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Adalimumab Injection is considered to be biosimilar to Humira. 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 Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis. The New Drug Submission filed for Adalimumab Injection requested authorization for all of the indications and clinical uses that were authorized for Humira at the time of the submission. The indications have been authorized on the basis of demonstrated similarity between Adalimumab Injection and the reference biologic drug, Humira.

Tumour necrosis factor (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 patients with rheumatoid arthritis, including polyarticular juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis, and play an important role in both pathologic inflammation and joint destruction; both hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques, which contribute to the inflammatory response, to the proliferation and decreased maturation of keratinocytes, and to the associated vascular damages that are characteristic of the disease. Increased levels of TNF are also found in hidradenitis suppurativa lesions.

Adalimumab, the medicinal ingredient in Adalimumab Injection, is a recombinant human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody capable of binding to TNF alpha (TNF-α) and blocking its interaction with the p55 and p75 cell surface TNF receptors, thereby, neutralizing the effect of TNF found in inflammatory conditions. Adalimumab lyses surface TNF-expressing cells in vitro in the presence of complement and 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 10-10M). Adalimumab does not bind or inactivate lymphotoxin (TNF-beta).

Adalimumab Injection and Humira were judged to be highly similar in a comparative pharmacokinetic study (Study B5381007) conducted in healthy subjects. Each subject received a single 40 mg subcutaneous dose of either Adalimumab Injection, Humira sourced from the European Union (Humira-EU), or Humira sourced from the United States (Humira-US). Serum samples were collected up to Day 50 and a non-compartmental analysis method was used to estimate pharmacokinetic parameters. The point estimate for the Adalimumab Injection and Humira-EU geometric least square mean ratio for the maximum serum concentration and the 90% confidence intervals (CI) for the area under the serum concentration versus time curve to the time of the last quantifiable concentration were within the comparability margins of 80.0% to 125.0%.

The confirmatory clinical study (Study B5381002) was a Phase III, multicentre, randomized, double-blind study in patients with moderately to severely active rheumatoid arthritis. All patients received a 40 mg subcutaneous dose of either Adalimumab Injection or Humira-EU every other week throughout the study. The primary endpoint was the 20% improvement in the American College of Rheumatology clinical response criteria (ACR20) at Week 12. The difference in the ACR20 response rate at Week 12 for Adalimumab Injection was compared to that for Humira-EU and was found to be within a predefined equivalence margin of (-14%, 14%) to establish clinical comparability. At Week 12, 68.4% and 71.3% of patients achieved an ACR20 response in the Adalimumab Injection and Humira-EU arms, respectively. The difference in ACR20 response rate between Adalimumab Injection and Humira-EU was -2.98% (95% CI [-10.38, 4.44]).

At the end of Week 26, adverse events were reported in 143 (48.1%) and 143 (47.8%) patients in the Adalimumab Injection and Humira-EU arms, respectively. There were 11 (3.7%) discontinuations in the Adalimumab Injection arm and 14 (4.7%) discontinuations in the Humira-EU arm that were due to an adverse event. Treatment-related adverse events were reported in 55 (18.5%) and 69 (23.1%) patients in the Adalimumab Injection and Humira-EU arms, respectively. The system organ class “Infections and Infestations” had the highest proportion of patients with treatment-related adverse events, occurring in 26 (8.8%) patients in the Adalimumab Injection arm and 35 (11.7%) patients in the Humira-EU arm. The most frequently reported adverse event was injection site reactions observed in 5 (1.7%) patients in the Adalimumab Injection arm and 6 (2.0%) patients in the Humira-EU arm. Severe adverse events were reported in 12 (4%) and 13 (4.3%) patients in the Adalimumab Injection and Humira-EU arms, respectively. One death was reported during this period; a patient in the Humira-EU arm suffered a myocardial infarction on Day 131 that was related to coronary artery disease.

Through to the end of Week 52, adverse events were reported in 123 (43.5%) and 60 (44.4%) patients in the Adalimumab Injection and Humira-EU groups, respectively. There were 6 (2.1%) discontinuations in the Adalimumab Injection arm and 8 (5.9%) discontinuations in the Humira-EU arm that were due to an adverse event. Treatment-related adverse events occurred in 32 (11.3%) and 22 (16.3%) patients in the Adalimumab Injection and Humira-EU groups, respectively. The system organ class “Infections and Infestations” had the highest proportion of patients with treatment-related adverse events, occurring in 49 (17.3%) patients in the Adalimumab Injection arm and 23 (17%) patients in the Humira-EU arm. The most frequently reported adverse event was viral upper respiratory tract infection, observed in 15 (5.3%) patients in the Adalimumab Injection arm and 5 (3.7%) patients in the Humira-EU arm. Patients who were switched from Humira-EU to Adalimumab Injection between Week 26 and Week 52 had comparable incidence and types of adverse events.

The immunogenicity profile of Adalimumab Injection was comparable to Humira-EU, and overall, there were no clinically meaningful differences in the efficacy and safety of Adalimumab Injection, compared to the reference biologic drug.

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

A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name, Abrilada, was rejected. The submission was recommended for approval with the common name, Adalimumab Injection. The sponsor committed to filing a labelling-only supplemental new drug submission to propose a new brand name. The submitted inner and outer labels, package insert and Patient Medication Information section of the Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements. However, due to the issue with the brand name, the approaching target date, and the fact that the sponsor’s label site was working on printing labels for other products related to the coronavirus disease 2019, the sponsor was unable to provide revised inner and outer mock-ups with the brand name removed, however text labels were provided and attestation that all previously reviewed design elements remained the same. Therefore, the sponsor is required to provide to Health Canada, within 20 days of the issuance of the Notice of Compliance, revised mock-ups of all applicable labels for review.

Overall, the totality of evidence, including structural, functional, non-clinical, clinical pharmacokinetic, clinical efficacy, and safety comparisons, provides adequate evidence to establish clinical biosimilarity between Adalimumab Injection and the reference biologic drug, Humira. The benefits of Adalimumab Injection therapy are expected to be similar to the known benefits of the reference biologic drug and are considered to outweigh the potential risks. Appropriate warnings and precautions are in place in the Adalimumab Injection Product Monograph to address the identified safety concerns, including a Serious Warnings and Precautions box that describes reports of hepatosplenic T-cell lymphoma, infections, and pediatric malignancies in patients treated with TNF-blockers.

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

 

3 What steps led to the approval of Abrilada (formerly Adalimumab Injection)?

 

Submission Milestones: Abrilada (formerly Adalimumab Injection)

Submission Milestone Date
Pre-submission meeting 2018-11-13
Submission filed 2020-01-31
Screening  
Screening Acceptance Letter issued 2020-03-20
Review  
Review of Risk Management Plan complete 2020-12-04
Quality Evaluation complete 2020-12-30
Non-clinical Evaluation complete 2021-01-13
Clinical/Medical Evaluation complete 2021-01-13
Labelling Review pending as of 2021-01-14
Notice of Compliance issued by Director General, Biologics and Radiopharmaceutical Drugs Directorate 2021-01-14

 

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 Adalimumab Injection 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 Adalimumab Injection 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 Adalimumab Injection, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include, but are not limited to, the sponsor:

  • Submitting annual Safety Reports to Health Canada once Adalimumab Injection is marketed in Canada.
  • Developing a follow-up questionnaire for reporting the risk of malignancy/pre-malignancy and submitting the questionnaire to Health Canada before marketing Adalimumab Injection.
  • Assessing the possibility of taking part in a registry and keeping Health Canada informed of developments.

Developing a Patient Support Program to provide comprehensive support to help patients manage their Adalimumab Injection treatment, including education and adherence support.

 

5 What post-authorization activity has taken place for Abrilada (formerly Adalimumab Injection)?

 

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 Adalimumab Injection 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

 

Adalimumab Injection 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.

Comparative Structural and Functional Studies

The sponsor assessed the comparability of Adalimumab Injection to the reference biologic drug, Humira sourced from the European Union (Humira-EU). The biosimilarity assessment was conducted as a three-way physicochemical and functional similarity assessment using Adalimumab Injection, Humira-EU, and Humira sourced from the United States (Humira-US).

The biosimilarity study evaluated a variety of attributes including physicochemical properties, biological activity, purity and impurity profiles, and stability profiles including forced degradation conditions. Quality attributes were identified and assessed for their potential to affect activity, pharmacokinetics, pharmacodynamics, safety, and immunogenicity, as well as their relevance in establishing biosimilarity.

Adalimumab Injection was found to be similar to Humira. No new impurities were detected in Adalimumab Injection compared to Humira. Minor differences were observed for N-linked glycosylation and for binding to the FcγRIIIa 158F receptor. However, these differences did not affect potency and are unlikely to translate to a clinically meaningful difference between Adalimumab Injection and the reference biologic drug.

Overall, the data support the assertion that Adalimumab Injection is biosimilar to the reference biologic drug, Humira.

Characterization of the Drug Substance

The drug substance, adalimumab, is a recombinant human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody used as a biological response modifier. Adalimumab has two identical heavy chains and two identical light chains, covalently linked with four inter-chain disulfide bonds. Adalimumab is capable of binding to tumour necrosis factor (TNF) alpha (TNF-α) and blocking its interaction with the p55 and p75 cell surface TNF receptors, thereby, neutralizing the effect of TNF found in inflammatory conditions.

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

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

Adalimumab is expressed in Chinese hamster ovary cells. The manufacturing process for the drug substance includes a series of initial culture steps up to harvest, followed by different types of chromatography and viral filtration, ultrafiltration and diafiltration, sterile filtration, and filling steps.

The sponsor has demonstrated that the drug substance manufacturing facility is capable of consistently manufacturing drug substance of acceptable quality. Appropriate in-process controls have been implemented throughout the process to ensure the consistent production of high quality drug substance.

The drug product, Adalimumab Injection, is supplied as a single-use, sterile, preservative-free solution for subcutaneous injection. Adalimumab Injection is provided as a 50 mg/mL solution in a 1 mL single-use prefilled syringe, with 0.8 mL nominal fill providing a 40 mg dose. A single-use prefilled pen (auto-injector) is also available. It contains an identical prefilled syringe (without a plunger rod or finger grips) and delivers the same 40 mg dose of the same solution. Additionally, several presentations are available for pediatric use, including 10 mg and 20 mg prefilled syringes and a 40 mg vial. All strengths have the same 50 mg/mL concentration.

The manufacturing process of the drug product (prefilled syringe and vial) involves a series of steps, including formulation, filtration, filling, assembling, labelling, and packaging. The drug product is also available as a prefilled pen. The prefilled pen assembly is performed according to Good Manufacturing Practices.

The sponsor has demonstrated that the drug product manufacturing facility is capable of consistently producing Adalimumab Injection of acceptable quality. Controls of critical steps in the drug product manufacturing process were appropriately defined throughout development based on a risk assessment and current process understanding.

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

Appropriate in-process controls have been implemented throughout the manufacturing processes and should ensure the consistent production of high quality drug substance and drug product. The proposed release and stability specifications include assays for identity, quantity, biological activity, purity and impurities, charge heterogeneity, and safety. Analytical methods were deemed suitable and supported by validation studies and consistency lot testing. A primary reference material and a working reference material have been established from the same drug substance batch. The reference standards have been well characterized and an appropriate program is in place to qualify new working reference material in the future, as the primary reference material is intended to last throughout the commercial product lifetime.

Adalimumab Injection 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 36-month shelf life at 2 to 8 °C and protected from light for Adalimumab Injection (vials, prefilled syringe, and prefilled pen) is considered acceptable. The different drug product presentations may be stored at a maximum of 30 °C for a single period of up to 30 days, but not exceeding the original expiration date.

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.

Facilities and Equipment

On-Site Evaluations (OSEs) of the facilities involved in the manufacture and testing of the drug substance and drug product were not conducted, as they were not deemed necessary based on the risk determination scores, which fell below the criterion for an OSE recommendation. Further, OSEs of these facilities were not warranted as they were recently evaluated and obtained satisfactory ratings. Information obtained through these OSEs support the issuance of a Notice of Compliance for this submission.

All sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

No raw materials of animal or human origin are used in the manufacture of the drug substance or drug product. Fetal bovine serum, an animal-derived material, was used in the early development of the adalimumab Chinese hamster ovary cell substrate. This was deemed suitable as the material is not from a country affected by bovine spongiform encephalopathy or transmissible spongiform encephalopathy, and is therefore considered to be safe for human use. Letters of attestation confirming that the materials used in the development of the recombinant cell line, the establishment of the master cell bank and working cell bank, and the manufacturing process are in compliance with the European Medicines Agency’s Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3). Viral and non-viral adventitious agent testing demonstrated that the cell banks are suitable for use and are in accordance with International Council for Harmonisation (ICH) guidelines (ICH Q5A and ICH Q5D).

The drug substance manufacturing process incorporates adequate in-process controls and sets appropriate limits for adventitious agents (bioburden, mycoplasma, and viruses). 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 the structural and functional studies and address potential areas of residual uncertainty.

Non-clinical studies comparing Adalimumab Injection to the reference biologic drug, Humira sourced from the European Union (Humira-EU), and/or Humira sourced from the United States (Humira-US) included pharmacodynamic, pharmacokinetic, and toxicology comparability studies.

Adalimumab Injection was found to be similar to Humira-EU and Humira-US in a number of in vitro binding and functional assays reflective of the mechanism of action of adalimumab. Minor differences were observed in binding to FcγRIIIa 158F, however these are not considered meaningful as no impact is observed in in vitro assays related to antibody-dependent cell-mediated cytotoxicity.

In a one-month comparative repeat-dose toxicity study, cynomolgus monkeys were administered Adalimumab Injection or Humira-EU at a dose of 0 mg/kg (vehicle) or 157 mg/kg by subcutaneous injection once per week. Monkeys given Adalimumab Injection did not develop any unique adverse effects or anti-drug antibodies. Overall, there were no toxicity or tolerability concerns with the administration of Adalimumab Injection that differed from that of Humira. These results may have been confounded by a previous parasitic infection in some of the study animals. Overall, the weight of evidence supports the similarity of Adalimumab Injection to the reference biologic drug from a non-clinical perspective.

The non-clinical database submitted for Adalimumab Injection 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.

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

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

 

 

7.3 Clinical basis for decision

 

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 biologic drug and the 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 to address potential areas of residual uncertainty.

Adalimumab Injection is a biosimilar to Humira, which has been authorized in Canada since 2004. Both drugs contain the medicinal ingredient adalimumab. Adalimumab is a recombinant human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that specifically targets tumour necrosis factor (TNF) alpha (TNF-α). It is a biologic disease-modifying anti-rheumatic agent used in the management of a variety of immune-mediated conditions with shared inflammatory pathways involving TNF-α. In Canada, at the time of the submission for Adalimumab Injection, adalimumab was authorized for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.

Comparative Pharmacokinetic and Pharmacodynamic Studies

Study B5381007 was a randomized, double-blind (sponsor-open), single-dose, three-arm, parallel-group study evaluating the pharmacokinetics of Adalimumab Injection, Humira sourced from the European Union (Humira-EU), and Humira sourced from the United States (Humira-US) in healthy adult male and female subjects. Each subject received a single 40 mg subcutaneous dose of either Adalimumab Injection, Humira-EU, or Humira-US. As Humira-EU is considered the reference biologic drug, the following results focus on the comparison between Adalimumab Injection and Humira-EU.

Serum samples were collected up to Day 50 and a non-compartmental analysis method was used to estimate pharmacokinetic parameters. The study demonstrated pharmacokinetic comparability between Adalimumab Injection and Humira-EU. The point estimate for the Adalimumab Injection and Humira-EU geometric least square mean ratio for the maximum serum concentration (Cmax) and the 90% confidence intervals (CI) for the area under the serum concentration versus time curve (AUC) to the time of the last quantifiable concentration (AUCT) were within the comparability margins of 80.0% to 125.0%.

Study B5381005 was a randomized, open-label, single-dose, parallel-group study conducted in healthy adult male and female subjects to support authorization of the prefilled pen presentation of Adalimumab Injection. In this study, a 40 mg subcutaneous dose of Adalimumab Injection was shown to be bioequivalent when delivered via a prefilled pen or a prefilled syringe. The point estimate for the prefilled pen and prefilled syringe geometric least square mean ratio for Cmax and the 90% CI for AUCT were within the comparability margins of 80.0% to 125.0%.

Overall, the comparative bioavailability studies indicate there are no clinically meaningful differences between Adalimumab Injection and Humira and between the prefilled pen and the prefilled syringe presentations.

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

Comparative Clinical Efficacy and Safety

To rule out clinically meaningful differences in efficacy and safety between Adalimumab Injection and the reference biologic drug, the sponsor carried out Study B5381002, a Phase III, multicentre, randomized, two-armed, double-blind, parallel-group, comparative efficacy and safety study in adult patients with rheumatoid arthritis. The primary objective of the study was to compare the treatment efficacy between Adalimumab Injection and Humira-EU in combination with methotrexate in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate. Other objectives were to evaluate the overall safety and immunogenicity of Adalimumab Injection and Humira-EU.

Eligible patients were 18 years of age or older with confirmed diagnosis of rheumatoid arthritis. The study randomized patients in a 1:1 ratio to receive Adalimumab Injection (number of patients [n] = 297) or Humira-EU (n = 299). Of these patients, 78.8% were female and 86.6% were white. The mean patient age was 52.5 years (range of 18 to 80 years) and the mean duration of disease was 6.8 years. A total of 117 patients (19.6%) were 65 years of age or older. All patients were trained to self-administer 40 mg of study treatment by subcutaneous injection every other week throughout the study.

The study was designed with three distinct treatment periods. Treatment period 1 (TP1) began with randomization at Week 0 and concluded with the completion of Week 26 pre-dose assessments. The primary efficacy endpoint and comparability was assessed in TP1. Treatment period 2 (TP2) began with study dosing for Week 26 and concluded with the completion of Week 52 pre-dose assessments. Treatment period 2 allowed for patients in the Humira-EU arm to be randomized to Adalimumab Injection in a 1:1 ratio. Safety and immunogenicity were evaluated at the end of TP1 and TP2. Treatment period 3 (TP3) began with study dosing at Week 52 and concluded at Week 78. However, at the start of TP3, patients were no longer blinded and all had been switched to receive Adalimumab Injection. Therefore, the comparative safety assessment was performed up to the end of TP2 (Week 52).

The primary endpoint was the proportion of patients achieving a 20% improvement in the American College of Rheumatology (ACR20) response criteria at Week 12. The pre-specified equivalence margin for comparability was (-14%, 14%). Equivalence and a lack of clinically meaningful difference would be concluded if the 95% confidence interval of the point estimate difference in the proportion of patients achieving an ACR20 response at Week 12 between Adalimumab Injection and Humira-EU was entirely contained within the pre-specified equivalence margin. The sponsor carried out the statistical analysis in the intention-to-treat population defined as all patients who were randomized to study treatment. The analysis for ACR20 was performed with missing data imputed using a non-responder imputation method.

At Week 12, 68.4% and 71.3% of patients achieved an ACR20 response in the Adalimumab Injection and Humira-EU arms, respectively. The difference in ACR20 response rate between Adalimumab Injection and Humira-EU was -2.98% (95% CI [-10.38, 4.44]), which was entirely contained within the pre-specified equivalence margin, supporting the conclusion of therapeutic comparability. Similar responses to Adalimumab Injection and Humira-EU were observed for key efficacy measures at additional time points.

At the end of TP1 (Week 26), adverse events were reported in 143 (48.1%) and 143 (47.8%) patients in the Adalimumab Injection and Humira-EU arms, respectively. There were 11 (3.7%) discontinuations in the Adalimumab Injection arm and 14 (4.7%) discontinuations in the Humira-EU arm that were due to an adverse event. Treatment-related adverse events were reported in 55 (18.5%) and 69 (23.1%) patients in the Adalimumab Injection and Humira-EU arms, respectively. The system organ class “Infections and Infestations” had the highest proportion of patients with treatment-related adverse events, occurring in 26 (8.8%) patients in the Adalimumab Injection arm and 35 (11.7%) patients in the Humira-EU arm. The most frequently reported adverse event was injection site reactions observed in 5 (1.7%) patients in the Adalimumab Injection arm and 6 (2.0%) patients in the Humira-EU arm. Severe adverse events were reported in 12 (4%) and 13 (4.3%) patients in the Adalimumab Injection and Humira-EU arms, respectively. One death was reported during this period; a patient in the Humira-EU arm suffered a myocardial infarction on Day 131 that was related to coronary artery disease.

Through to the end of TP2 (Week 52), adverse events were reported in 123 (43.5%) and 60 (44.4%) patients in the Adalimumab Injection and Humira-EU groups, respectively. There were 6 (2.1%) discontinuations in the Adalimumab Injection arm and 8 (5.9%) discontinuations in the Humira-EU arm that were due to an adverse event. Treatment-related adverse events occurred in 32 (11.3%) and 22 (16.3%) patients in the Adalimumab Injection and Humira-EU groups, respectively. The system organ class “Infections and Infestations” had the highest proportion of patients with treatment-related adverse events, occurring in 49 (17.3%) patients in the Adalimumab Injection arm and 23 (17%) patients in the Humira-EU arm. Viral upper respiratory tract infection was the most frequently reported adverse event, observed in 15 (5.3%) patients in the Adalimumab Injection arm and 5 (3.7%) patients in the Humira-EU arm. Patients in TP2 who were switched to Adalimumab Injection had comparable incidence and types of adverse events.

The immunogenicity profile of Adalimumab Injection was comparable to Humira-EU. Specifically, no clinically meaningful differences were observed in the percentage of patients with anti-drug antibodies and immune-based adverse effects.

Overall, Adalimumab Injection demonstrated a comparable safety profile to the reference biologic drug, Humira. Therefore, the Adverse Reactions section of the biosimilar product monograph is based on the clinical experience with the reference biologic drug. As in the Humira Product Monograph, appropriate warnings and precautions are in place in the Adalimumab Injection Product Monograph to address the identified safety concerns, including a Serious Warnings and Precautions box that describes reports of hepatosplenic T-cell lymphoma, infections, and pediatric malignancies in patients treated with TNF-blockers.

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

Indications

Adalimumab Injection is considered to be biosimilar to Humira, the reference biologic drug. Humira is authorized in Canada for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis. The New Drug Submission (NDS) filed for Adalimumab Injection requested authorization for all of the indications and clinical uses that were authorized for Humira at the time of the submission.

Similarity between Adalimumab Injection 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 Adalimumab Injection and the reference biologic drug in comparative structural, functional, non-clinical and clinical studies.

To ensure safe and effective use of the product, Health Canada authorized Adalimumab Injection 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. Adalimumab Injection 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, Adalimumab Injection should be given in combination with methotrexate.

Adalimumab Injection can be given as monotherapy in case of intolerance to methotrexate or when treatment with methotrexate is contraindicated.

Polyarticular Juvenile Idiopathic Arthritis

  • In combination with methotrexate, reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients, 2 years of age and older who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs. Adalimumab Injection can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is not appropriate. Adalimumab has not been studied in pediatric patients with polyarticular juvenile idiopathic arthritis aged less than 2 years.

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. Adalimumab Injection can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • Reducing signs and symptoms in adult 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. Adalimumab Injection 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 and/or azathioprine or 6-mercaptopurine or who are intolerant to such therapies. The efficacy of adalimumab in patients who have lost response to or were intolerant to tumour necrosis factor blockers has not been established.

Hidradenitis Suppurativa

  • Treatment of active moderate to severe hidradenitis suppurativa in adult and adolescent patients (12 to 17 years of age weighing ≥30 kg) who have not responded to conventional therapy (including systemic antibiotics).

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, Adalimumab Injection should be used after phototherapy has been shown to be ineffective or inappropriate.

Adult Uveitis

  • Treatment of non-infectious uveitis (intermediate, posterior and panuveitis) in adult patients with inadequate response to corticosteroids or as corticosteroid sparing treatment in corticosteroid-dependent patients.

Pediatric Uveitis

  • Treatment of chronic non-infectious anterior uveitis in pediatric patients from 2 years of age who have had an inadequate response to or are intolerant to conventional therapy, or in whom conventional therapy is inappropriate.

 

 

 

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