Summary Basis of Decision for Hadlima / Hadlima PushTouch

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 Hadlima / Hadlima PushTouch is located below.

Recent Activity for Hadlima / Hadlima PushTouch

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.

The following table describes post-authorization activity for Hadlima / Hadlima PushTouch, products that contain 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.

Updated: 2023-03-03

Drug Identification Number (DIN):

  • DIN 02473097 (Hadlima) – 40 mg/0.8 mL adalimumab, solution, subcutaneous administration (prefilled syringe)
  • DIN 02473100 (Hadlima PushTouch) – 40 mg/0.8 mL adalimumab, solution, subcutaneous administration (auto-injector)
  • DIN 02533472 (Hadlima) – 40 mg/0.4 mL adalimumab, solution, subcutaneous administration (prefilled syringe)
  • DIN 02533480 (Hadlima PushTouch) – 40 mg/0.4 mL adalimumab, solution, subcutaneous administration (auto-injector)

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 260018 2021-12-31 Issued NOC 2022-12-14 Submission filed as a Level I – Supplement for new strengths (40 mg/0.4 mL) of Hadlima and Hadlima PushTouch. The submission was reviewed and considered acceptable, and an NOC was issued. Two new DINs (02533472, 02533480) were issued. A Regulatory Decision Summary was published.
SNDS # 247844 2021-01-07 Issued NOC 2021-08-04 Submission filed as a Level I – Supplement to add an alternate site for manufacturing and testing of the drug substance. The data were reviewed and considered acceptable, and an NOC was issued.
Drug product (DINs 02473097, 02473100) 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 # 234258 2019-12-13 Issued NOC 2020-11-26 Submission filed as a Level I – Supplement for new indications and to update the PM to align with that of the reference biologic drug, Humira. The indications authorized were: treatment of active to severe hidradenitis suppurativa in adult and adolescent populations (12 to 17 years of age weighing >30 kg) who have not responded to conventional therapy (including systemic antibiotics), and 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. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications, Warnings and Precautions, Adverse Reactions, Dosage and Administration, Dosage Forms, Strengths, Composition and Packaging, and Action and Clinical Pharmacology; sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued. A Regulatory Decision Summary was published.
SNDS # 234071 2019-12-02 Issued NOC 2020-07-15 Submission filed as a Level I – Supplement to add alternate sites for manufacturing and testing of the drug substance and drug product. The data were reviewed and considered acceptable, and an NOC was issued.
NC # 222615 2018-11-30 Issued NOL 2019-03-13 Submission filed as a Level II (90 day) Notifiable Change to update the PM to align with that of the reference biologic drug, Humira. As a result of the NC, modifications were made to the Warnings and Precautions, Adverse Reactions, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NDS # 203250, 203292 2017-03-02 Issued NOC 2018-05-08 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Hadlima / Hadlima PushTouch

Date SBD issued: 2018-08-20

The following information relates to the new drug submission for Hadlima / Hadlima PushTouch.

Hadlima
Adalimumab
40 mg / 0.8 mL, solution, subcutaneous (single-dose prefilled syringe)

Hadlima PushTouch
Adalimumab
40 mg / 0.8 mL, solution, subcutaneous (single-dose auto-injector)

Drug Identification Number (DIN):

  • 02473097 (Hadlima)
  • 02473100 (Hadlima PushTouch)

Samsung Bioepis Co., Ltd.

New Drug Submission Control Numbers: 203250, 203292

 

On May 8, 2018, Health Canada issued a Notice of Compliance (NOC) to Samsung Bioepis Co., Ltd. for Hadlima / Hadlima PushTouch, biosimilars 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. Hadlima / Hadlima PushTouch and Humira contain highly similar versions of the medicinal ingredient, adalimumab. Hadlima and Hadlima PushTouch have an identical formulation and differ only in the type of device for subcutaneous injection (a prefilled syringe versus an auto-injector).

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 biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.

The sponsor filed two separate submissions to seek marketing authorization of Hadlima and Hadlima PushTouch as biosimilars to Humira, the reference biologic drug, on the basis of comparative quality, non-clinical and clinical studies. Identical data packages were provided in support of both drug submissions. The main difference between the two submissions was in the indications sought. One submission (Control Number 203292) was submitted to seek authorization of the following indications: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, uveitis, and polyarticular juvenile idiopathic arthritis (patients 4 years of age and older and who require a full 40 mg dose). Along with these six indications, the second submission (Control Number 203250) sought authorization of three additional indications: adult Crohn's disease, ulcerative colitis, and hidradenitis suppurativa. Therefore, the sponsor requested authorization of nine of the ten indications that are currently authorized for Humira.

Similarity between Hadlima / Hadlima PushTouch and Humira was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The market authorization was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. Similarity was established through data derived from comparative structural, functional, non-clinical, and clinical studies. Based on Health Canada's review, the benefit-risk profile of Hadlima (or Hadlima PushTouch) is considered to be highly similar to the reference biologic drug 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. Hadlima (or Hadlima PushTouch) 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, Hadlima (or Hadlima PushTouch) should be given in combination with methotrexate.

Hadlima (or Hadlima PushTouch) 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, 4 years of age and older, who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs. Hadlima (or Hadlima PushTouch) can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is not appropriate Adalimumab (the medicinal ingredient in Hadlima / Hadlima PushTouch) has not been studied in pediatric patients with polyarticular juvenile idiopathic arthritis aged less than 2 years.
  • Hadlima and Hadlima PushTouch are available for pediatric polyarticular juvenile idiopathic arthritis patients who require the full 40 mg dosage based on body weight and height.

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. Hadlima (or Hadlima PushTouch) 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. Hadlima and Hadlima PushTouch are 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.

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 tumor necrosis factor (TNF) blockers has not been established.

Hidradenitis suppurativa

  • treatment of active moderate to severe hidradenitis suppurativa in adult patients, 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, Hadlima (or Hadlima PushTouch) should be used after phototherapy has been shown to be ineffective or inappropriate.

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.
1 What was approved?

Hadlima and Hadlima PushTouch are tumor necrosis factor alpha (TNF-α) inhibitors. They were 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. Hadlima (or Hadlima PushTouch) 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, Hadlima (or Hadlima PushTouch) should be given in combination with methotrexate.

Hadlima (or Hadlima PushTouch) 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, 4 years of age and older, who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs. Hadlima (or Hadlima PushTouch) can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is not appropriate. Adalimumab (the medicinal ingredient in Hadlima / Hadlima PushTouch) has not been studied in pediatric patients with polyarticular juvenile idiopathic arthritis aged less than 2 years.
  • Hadlima and Hadlima PushTouch are available for pediatric polyarticular juvenile idiopathic arthritis patients who require the full 40 mg dosage based on body weight and height.

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. Hadlima (or Hadlima PushTouch) 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. Hadlima and Hadlima PushTouch are 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.

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 patients, 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, Hadlima (or Hadlima PushTouch) should be used after phototherapy has been shown to be ineffective or inappropriate.

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.

Hadlima and Hadlima PushTouch are biosimilars to Humira. All three drugs contain the medicinal ingredient adalimumab. Adalimumab is a recombinant human immunoglobulin (IgG1) monoclonal antibody specific for human TNF. Hadlima and Hadlima PushTouch have an identical formulation and differ only in the type of device for subcutaneous injection (a prefilled syringe and an auto-injector, respectively).

Similarity between Hadlima / Hadlima PushTouch and the reference biologic drug, Humira, has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, a comparative pharmacokinetic study in healthy subjects and a comparative efficacy and safety study in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Hadlima and Hadlima PushTouch are 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).

Evidence from clinical studies and experience suggests that use of adalimumab in the geriatric population is not associated with differences in effectiveness. No dose adjustment is needed for this population.

Hadlima and Hadlima PushTouch were approved for use under the conditions stated in their Product Monograph taking into consideration the potential risks associated with the administration of these drug products.

Hadlima and Hadlima PushTouch (40 mg/0.8 mL adalimumab) are presented as a solution in a single-dose prefilled syringe and a single-dose auto-injector, respectively. In addition to the medicinal ingredient, the solution contains citric acid monohydrate, sodium citrate dihydrate, L-histidine, L-histidine hydrochloride monohydrate, sorbitol, polysorbate 20, 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 Hadlima / Hadlima PushTouch Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Hadlima / Hadlima PushTouch approved?

Health Canada considers that the benefit-risk profile of Hadlima / Hadlima PushTouch is highly similar to the reference biologic drug Humira for the indications authorized: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, and uveitis. Similarity between Hadlima / Hadlima PushTouch and Humira was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Hadlima / Hadlima PushTouch are considered to be biosimilars to Humira. In Canada, Humira is currently authorized for the treatment of adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis and uveitis. It is also authorized for the treatment of pediatric Crohn's disease patients (13 to 17 years of age and weighing ≥40 kg), and polyarticular juvenile idiopathic arthritis patients (2 years of age and older).

The new drug submissions filed for Hadlima / Hadlima PushTouch requested authorization for nine of the indications and clinical uses that are currently authorized for Humira. The indications have been authorized on the basis of demonstrated similarity between Hadlima / Hadlima PushTouch and the reference biologic drug.

Adalimumab is a recombinant human immunoglobulin (IgG1) monoclonal antibody that binds with high affinity and specificity to soluble tumor necrosis factor alpha (TNF-α) and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration.

TNF-α is a key inflammatory cytokine that possesses a variety of biological functions and contributes to the pathology of various inflammatory diseases. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis, including polyarticular juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis patients and play an important role in both pathologic inflammation and joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques, which contribute to the inflammatory response, the proliferation and decreased maturation of keratinocytes and the associated vascular damages that are characteristic of the disease. Increased levels of TNF are also found in hidradenitis suppurativa lesions.

The biosimilar and the reference biologic drug were judged highly similar in terms of quality attributes (based on comparative structural and functional studies). Comparable pharmacokinetics between Hadlima and Humira was established in a comparative pharmacokinetic study conducted in healthy subjects. Comparable efficacy, safety and immunogenicity between the two products were also demonstrated in a randomized, double-blind, controlled study conducted in adult patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. Numerical differences in some adverse events were reported between Hadlima and Humira in the clinical studies, but they were not considered clinically meaningful.

Hadlima / Hadlima PushTouch demonstrated a comparable safety profile with the reference product, Humira. Therefore, the Adverse Reactions section of the biosimilar 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 Product Monograph for Hadlima / Hadlima PushTouch.

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

A Look-alike Sound-alike brand name assessment was performed and the proposed names Hadlima and Hadlima PushTouch were accepted.

Overall, the therapeutic benefits of Hadlima / Hadlima PushTouch 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 Hadlima / Hadlima PushTouch Product Monograph to address the identified safety concerns.

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

3 What steps led to the approval of Hadlima / Hadlima PushTouch?

Submission Milestones: Hadlima / Hadlima PushTouch

Submission Milestone Date
Pre-submission meeting: 2016-10-07
Submission filed: 2017-03-02
Screening  
Screening Acceptance Letter issued: 2017-04-24
Review  
Quality Evaluation complete: 2018-01-11
Clinical Evaluation complete 2018-02-16
Review of Risk Management Plan complete: 2017-12-05
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-02-15
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2018-05-08

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

4 What follow-up measures will the company take?

The onus is on the Hadlima / Hadlima PushTouch 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 Hadlima / Hadlima PushTouch 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 Hadlima / Hadlima PushTouch, 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) submitting to Health Canada the following:

  • periodic safety update reports (PSURs) of Hadlima / Hadlima PushTouch, on a yearly basis;
  • Hadlima / Hadlima PushTouch educational materials (at least 30 day prior to the launch of the product in Canada).
5 What post-authorization activity has taken place for Hadlima / Hadlima PushTouch?

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's life cycle.

The PAAT for Hadlima / Hadlima PushTouch 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

Quality Basis for Decision

Hadlima (or Hadlima PushTouch) was developed as a biosimilar to the reference biologic drug, Humira. For biosimilars, the weight of evidence is provided by structural and functional studies. 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 Hadlima (or Hadlima PushTouch) is considered to be representative of the mechanism of action and pharmacological effect of Humira.

Comparative Structural and Functional Studies

The sponsor performed head-to-head characterization and stability studies to compare Hadlima biosimilar to the reference biologic drug, Humira.

The studies conducted have established a high degree of similarity in the primary, secondary and tertiary structure, as well as the purity, biological activity, stability, and degradation profiles of the medicinal ingredients in the biosimilar and its reference biologic drug. Taken together, these studies suggest a high degree of comparability between Hadlima / Hadlima PushTouch and Humira.

Characterization of the Drug Substance

Adalimumab is a recombinant human immunoglobulin (IgG1) monoclonal antibody. This antibody binds specifically to tumour necrosis factor alpha (TNF-α) and neutralizes the biological function of TNF-α by blocking its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab has fully human heavy and light chain variable regions, which confer specificity to human tumor necrosis factor (TNF), and human IgG1 heavy chain and kappa light chain sequences. Adalimumab binds with high affinity and specificity to soluble tumor necrosis factor alpha (TNF-alpha) but not lymphotoxin (TNF-beta). It consists of 1,330 amino acids and has a molecular weight of approximately 148 kDa.

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

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established and acceptable limits.

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

The drug substance (adalimumab) is produced by recombinant deoxyribonucleic acid (DNA) technology in a mammalian cell expression system. The manufacturing process consists of cell culture, purification and formulation. The purification process includes a combination of chromatographic steps, including viral inactivation and viral filtration. The sponsor has demonstrated that the drug substance manufacturing facility is capable of consistently manufacturing adalimumab of satisfactory quality.

The drug product manufacturing process consists of thawing, pooling, sterile filtration, and filling into prefilled syringes. The prefilled syringes are then assembled into either safety prefilled syringes or auto-injectors, both of which are functional secondary packaging with no product contact. The sponsor has demonstrated that the manufacturing facility is able to consistently manufacture drug product of appropriate quality.

Hadlima (or Hadlima PushTouch) provides 40 mg of adalimumab in 0.8 mL sterile solution (50 mg/mL). The dosage form, strength, and presentations are the same as those authorized for Humira in Canada. However, the excipients in the formulation for Hadlima (or Hadlima PushTouch) are different from those in Humira marketed in Canada.

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 adalimumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated in compliance with International Council for Harmonisation (ICH) guidelines.

Through Health Canada's lot release testing and evaluation program, manufactured final product lots were tested using a subset of release methods. The test results confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life for Hadlima or Hadlima PushTouch is considered acceptable, when stored at 2ºC to 8ºC and protected from light.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured.

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance was not warranted since the facility was recently evaluated and obtained a satisfactory rating.

An OSE of the facility involved in the manufacture and testing of the drug product was waived, as a successful OSE had been recently performed for another product whose manufacturing process was similar.

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

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy or other human pathogens.

7.2 Non-Clinical Basis for Decision

For biosimilars, the degree of similarity at the quality level determines the scope and the breadth of the required non-clinical data. Non-clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty.

The non-clinical data submitted for Hadlima (or Hadlima PushTouch) were 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.

A series of comparative in vitro studies were conducted to demonstrate similarity between Hadlima and Humira. These studies included relevant binding and cell-based assays associated with the mode of action of adalimumab and Fc-related binding assays for assessing the Fc-related biological activities. The overall results of the in vitro assays demonstrated similarity between Hadlima and Humira sourced from the European Union (EU Humira).

An in vivo pharmacodynamic study was conducted in the Tg197 transgenic mouse model of arthritis. The efficacy of Hadlima and Humira sourced from the United States (US Humira) was assessed by arthritic scores and histopathological scores. There were no significant differences in inhibitory effects of Hadlima compared to US Humira in both arthritic score and histopathologic score.

A comparative repeat-dose toxicity study was conducted in cynomolgus monkeys. Hadlima and US Humira were well tolerated at a dose level of 32 mg/kg and there were no significant adalimumab-related toxicological findings.

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

For more information, refer to the Probuphine 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 biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

For biosimilars, the purpose of the clinical program is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The degree of similarity at the quality level determines the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Clinical studies conducted to support similarity between Hadlima and the reference biologic drug included a comparative pharmacokinetic clinical Phase I study SB5-G11-NHV in healthy subjects and a comparative efficacy and safety clinical Phase III study SB5-G31-RA in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy.

Comparative Pharmacokinetics

Study SB5-G11-NHV was a randomized, single-blind, three-arm, parallel-group, single-dose study of Hadlima, Humira sourced from the European Union (EU Humira) and Humira sourced from the United States (US Humira) conducted in healthy subjects. The study included 189 adult male and female subjects (63 subjects in each treatment arm). The primary objectives of the study were to compare the pharmacokinetics, safety, tolerability and immunogenicity of the three formulations of adalimumab.

Each subject received a single subcutaneous dose of 40 mg of Hadlima, EU Humira or US Humira. The subjects were observed for a period of 71 days, during which pharmacokinetic, safety, tolerability, and immunogenicity measurements were performed. All subjects completed the study, and one subject from the Hadlima arm and another from the US Humira arm were not included in the analysis, which led to 62 subjects being included in the respective statistical comparisons. A non-compartmental analysis method was used to estimate the pharmacokinetic parameters.

The study demonstrated pharmacokinetic comparability between Hadlima and EU Humira (designated as the reference biologic drug in the Hadlima development program).

The point estimate for the Hadlima and EU Humira geometric mean ratios for the maximum serum concentration (Cmax) and the 90% confidence interval (CI) for the area under the serum concentration-time curve measured from the time of dosing to the last measurable concentration (AUClast) were within the acceptance margins of 80% to 125%.

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

Comparative Clinical Efficacy, Safety and Immunogenicity

The comparative clinical efficacy, safety and immunogenicity of Hadlima and the reference biologic drug were evaluated in a randomized, double-blind, parallel-group, multicentre clinical Phase III study in adult patients with moderate to severe rheumatoid arthritis despite methotrexate therapy (Study SB5-G31-RA).

The primary objective was to demonstrate comparability in the American College of Rheumatology 20% improvement criteria (ACR20) response rate at Week 24 between Hadlima and EU Humira.

A total of 544 patients were randomized in a ratio of 1:1 to receive either Hadlima 40 mg or EU Humira 40 mg every other week via subcutaneous injection, up to Week 24. The patients in the EU Humira arm were then re-randomized (1:1) to either continue to receive EU Humira 40 mg or be transitioned to Hadlima 40 mg, up to Week 50. The patients who had received Hadlima at Week 0 continued to receive Hadlima 40 mg up to Week 50.

The ACR20 response rates of Hadlima and EU Humira were comparable at Week 24. The estimated treatment difference in ACR20 response rates between Hadlima and EU Humira at Week 24 based on the per-protocol population was 0.1%, and the 95% CI of the difference was -7.83% to 8.13%, which was within the predefined equivalence margins of -15% to 15%. In an analysis based on the full-analysis set in which patients with missing ACR20 response rates were considered as non-responders at Week 24, the estimated treatment difference between the two treatment groups was 0.8% and the 95% CI of the treatment difference was -7.03% to 8.56%.

Up to Week 24, the overall incidences of treatment emergent adverse events and serious adverse events were comparable between the two treatment groups. The most frequently reported treatment emergent adverse events were nasopharyngitis, headache, bronchitis, increased levels of alanine aminotransferase, spinal pain and nausea. Most of the treatment emergent adverse events reported were mild to moderate in severity. A total of 3 adverse events of special interest were reported: 1 event was reported in 1 (0.4%) subject in the Hadlima treatment group and 2 events in 2 (0.7%) subjects in the EU Humira treatment group. Six (6) treatment emergent adverse events leading to treatment discontinuation were reported in 2 (0.7%) subjects in the Hadlima treatment group and 13 were reported in 10 (3.7%) subjects in the EU Humira treatment group. Two (2) (0.7%) subjects in the EU Humira treatment group died and the deaths were not considered to be related to the treatment. Clinical laboratory data, vital signs and other safety parameters did not show any unexpected safety issues associated with adalimumab. It appears that the safety profiles between all treatment groups from Week 24 to Week 52 were comparable.

Overall, the safety profile of Hadlima / Hadlima PushTouch is considered to be comparable to that which has been established for the reference biologic drug Humira. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warning and Precautions section of the Hadlima / Hadlima PushTouch Product Monograph, as they are in the Product Monograph for Humira.

In study SB5-G31-RA, the incidence of anti-drug antibodies and neutralizing antibodies were comparable between the two treatment groups. Overall incidences of positive anti-drug antibodies from the baseline to Week 24 were 32.1% and 31.2%, for the Hadlima and EU Humira treatment group, respectively. At Week 24, 47.8% of the patients with positive anti-drug antibodies from both treatment groups had neutralizing antibodies. Between the two treatment groups, both overall pharmacokinetic profiles and pharmacokinetic profiles of the patients with positive anti-drug antibodies were similar. No meaningful differences in immune-related adverse events were reported. Subgroup analyses indicated that the ACR20 response rate at Week 24 from the patients with positive anti-drug antibodies in the Hadlima treatment group was lower. However, the results from subsequent analyses based on the ACR20 response rates over time and on other clinical endpoints did not show clinically meaningful differences.

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

Supportive studies

Comparability of Hadlima and Hadlima PushTouch was evaluated in two supportive studies (SB5-G12-NHV and SB5-G21-RA).

Clinical Phase I study SB5-G12-NHV was a randomized, open-labelled, two-arm, parallel-group, single-dose study to compare the pharmacokinetics, safety, and tolerability of Hadlima and Hadlima PushTouch in healthy subjects. A total of 190 healthy adult subjects (mean age of 30.8 years, 90% male) were randomized (1:1) to receive a single dose of Hadlima or Hadlima PushTouch. The primary objective was to compare the pharmacokinetic profiles of Hadlima PushTouch and Hadlima. Comparability criteria were met for the pharmacokinetic parameters Cmax and AUClast as the point estimate for the Hadlima PushTouch and Hadlima geometric mean ratios for Cmax and the 90% CI for the AUClast were within the acceptance margins of 80% to 125%.

Study SB5-G21-RA was an open-labelled, single-arm, multicentre clinical study to primarily compare the injection site-related pain scores after a subcutaneous injection of adalimumab via a prefilled syringe (Hadlima) or an auto-injector (Hadlima PushTouch).

in adult rheumatoid arthritis patients. Forty-nine (49) patients self-administered the first two doses of adalimumab as Hadlima and the remaining 4 doses as Hadlima PushTouch. The injection site pain scores, assessed by the patients using an 11-point visual numeric scale immediately after injection and 15 to 30 minutes post injection, were comparable between Hadlima at Week 2 and Hadlima PushTouch at Week 6.

Indications

Hadlima and Hadlima PushTouch are considered to be biosimilars 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 Crohn's disease, pediatric Crohn's disease, ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, and uveitis.

Within these drug submissions, the sponsor requested authorization of Hadlima / Hadlima PushTouch for nine of the ten indications currently authorized for Humira. The indications proposed by the sponsor were generally in line with those listed in the Humira Product Monograph. A revision was made to the proposed wording for the polyarticular juvenile idiopathic arthritis indication. Since both Hadlima and Hadlima PushTouch are designed to deliver a full dose of 40 mg adalimumab via subcutaneous injection, their clinical use is restricted to pediatric polyarticular juvenile idiopathic arthritis patients (4 years of age and older) who require the full 40 mg dosage based on body weight and height.

Similarity between Hadlima / Hadlima PushTouch 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 biosimilar assessment to rely on the safety and efficacy information of the reference biologic drug in the indications authorized, and therefore clinical trials are not required to support each indication. The indications have been authorized on the basis of demonstrated similarity between Hadlima / Hadlima PushTouch and the reference biologic drug, in structural and functional, non-clinical and clinical studies.

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