Summary Basis of Decision for Simlandi

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 Simlandi is located below.

Recent Activity for Simlandi

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

 

The following table describes post-authorization activity for Simlandi, a product which contains the medicinal ingredient adalimumab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

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

 

Updated: 2024-07-29

 

Drug Identification Number (DIN):

DIN 02523949 - 40 mg/0.4 mL adalimumab, solution, subcutaneous administration, single-dose prefilled syringe

DIN 02523957 - 40 mg/0.4 mL adalimumab, solution, subcutaneous administration, single-dose prefilled pen (auto-injector)

DIN 02523965 - 80 mg/0.8 mL adalimumab, solution, subcutaneous administration, single-dose prefilled syringe

 

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 283309

2024-01-31

Issued NOL 2024-04-25

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process, a change in the parameters of an approved holding step or addition of a new holding step, and a change in the labelled storage conditions for the drug product or the diluted or reconstituted product. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 276017

2023-06-06

Issued NOL 2023-08-25

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls (in-process tests and/or acceptance criteria) applied during the drug product manufacturing process or on intermediates, and a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug Recall

Not applicable

Posted 2023-04-17

Drug Recall posted on the Healthy Canadians website for the general public.

SNDS # 265443

2022-06-23

Issued NOC 2022-12-09

Submission filed as a Level I – Supplement to update the inner and outer labels, PM, and package inserts. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 267859

2022-09-14

Issued NOL 2022-11-24

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 266615

2022-08-03

Issued NOL 2022-09-09

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a drug product testing site. The submission was considered acceptable, and an NOL was issued.

Drug product (DINs 02523949, 02523965) market notification

Not applicable

Date of first sale: 2022-05-19

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 02523957) market notification

Not applicable

Date of first sale: 2022-04-13

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 244990

2021-01-07

Issued NOC 2022-01-05

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

Date SBD issued: 2022-04-14

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

Adalimumab

Drug Identification Number (DIN):

  • DIN 02523949 - 40 mg/0.4 mL adalimumab, solution, subcutaneous administration, single-dose prefilled syringe
  • DIN 02523957 - 40 mg/0.4 mL adalimumab, solution, subcutaneous administration, single-dose prefilled pen (auto-injector)
  • DIN 02523965 - 80 mg/0.8 mL adalimumab, solution, subcutaneous administration, single-dose prefilled syringe

JAMP Pharma Corporation

New Drug Submission Control Number: 244990

 

On January 5, 2022, Health Canada issued a Notice of Compliance to JAMP Pharma Corporation for Simlandi, 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. Simlandi contains the medicinal ingredient adalimumab, which has been demonstrated to be highly similar to adalimumab contained in the reference product, Humira.

Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. To be considered a biosimilar, the weight of evidence is provided by the structural and functional studies; the non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, pharmacokinetic and pharmacodynamic, and clinical studies.

The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought.

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

In this drug submission, Humira is the reference biologic drug. Similarity between Simlandi and Humira was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Within the submission, the sponsor requested the authorization of Simlandi for all of the indications that are currently authorized for Humira. However, the available presentations of Simlandi (prefilled syringe or prefilled pen [auto-injector]) are designed to deliver a single 40 mg dose, and lower doses are required for some dosing regimens for pediatric patients. The indications approved for Simlandi were therefore revised to align with the available presentations.

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 Simlandi is considered to be similar to the benefit-risk profile of the reference product, and is therefore considered favourable for the following indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.

 

1 What was approved?

 

Simlandi, 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.

Simlandi can be used alone or in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDs).

When used as first-line treatment in recently diagnosed patients who have not been previously treated with methotrexate, Simlandi should be given in combination with methotrexate. Simlandi 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, weighing ≥30 kg, who have had an inadequate response to one or more DMARDs. Simlandi 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. Simlandi can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • Reducing the 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. Simlandi 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.

Adult Ulcerative Colitis

  • Treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy including corticosteroids and/or azathioprine or 6-mercaptopurine (6-MP) or who are intolerant to such therapies. The efficacy of Simlandi in patients who have lost response to or were intolerant to tumour necrosis factor (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, Simlandi 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, weighing ≥30 kg, who have had an inadequate response to or are intolerant to conventional therapy, or in whom conventional therapy is inappropriate.

Treatment with Simlandi (adalimumab) should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of the diseases indicated, and who are familiar with the efficacy and safety profile of adalimumab.

In pediatric patients (<18 years of age):

  • Adalimumab 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. Simlandi is available for pediatric patients with polyarticular juvenile idiopathic arthritis who require the full 40 mg dose based on body weight.
  • Clinical trials have not been conducted with adalimumab in adolescent patients with hidradenitis suppurativa. The dosage of Simlandi in these patients has been determined based on pharmacokinetic/pharmacodynamic modelling 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 <3 years of age.
  • The prefilled syringe and prefilled pen (auto-injector) are not designed to deliver less than the full 40 mg dose contained in the packaging, and must not be used in pediatric patients who require a dose lower than 40 mg.

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

Simlandi is a biosimilar to Humira. Both drugs contain the medicinal ingredient adalimumab, which is produced in Chinese hamster ovary cells using recombinant deoxyribonucleic acid (DNA) technology.

Similarity between Simlandi and the reference biologic drug, Humira, has been established on the basis of comparative structural and functional studies and clinical trials in patients with plaque psoriasis, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Simlandi (40 mg/0.4 mL or 80 mg/0.8 mL adalimumab) is presented as a sterile solution for injection. In addition to the medicinal ingredient, the solution contains sodium chloride, sucrose, polysorbate 80, and water for injection.

The use of Simlandi is contraindicated in:

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

 

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Simlandi Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.

 

2 Why was Simlandi approved?

 

Based on Health Canada's review, the benefit-risk profile of Simlandi is considered to be similar to that of the reference product, and is therefore considered favourable for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.

Similarity between Simlandi and the reference product, Humira, was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Humira is authorized and marketed 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 Simlandi requested authorization for all of the indications and clinical uses that are currently authorized for Humira. However, some dosing regimens for polyarticular juvenile idiopathic arthritis and the maintenance dose for pediatric Crohn’s disease require the administration of doses lower than 40 mg, which are unattainable with the available presentations of Simlandi (a prefilled syringe or prefilled pen [auto-injector]), as they are not designed to deliver less than the full 40 mg dose contained in the packaging. The indications proposed for Simlandi were therefore restricted to align with the available presentations. Specifically, the indication for polyarticular juvenile idiopathic arthritis was limited to patients who require the full 40 mg dose, and the indication for pediatric Crohn’s disease was not approved. The other indications have been authorized on the basis of demonstrated similarity between Simlandi and the reference biologic drug.

Adalimumab, the medicinal ingredient in Simlandi, binds specifically to tumour necrosis factor (TNF) α, blocking its interaction with the cell surface TNF receptors p55 and p75. Tumour necrosis factor is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF play key roles in the pathogenesis of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, and hidradenitis suppurativa.

The quality attributes of the biosimilar and the reference biologic drug were determined to be highly similar based on evidence from comparative structural and functional studies. A comparative efficacy, safety, and immunogenicity study in patients with plaque psoriasis provided the main clinical basis to support the biosimilarity (quality) assessment. The demonstration of similarity enables the biosimilar assessment to rely on the safety and efficacy information of the reference biologic drug for the authorized indication.

Simlandi has demonstrated a comparable safety profile with the reference product, Humira. Therefore, the Adverse Reactions section of the Simlandi Product Monograph is based on the clinical experience with the reference biologic drug. As with Humira, the major identified safety concerns include hepatosplenic T-cell lymphoma, infections, and pediatric malignancy. These risks have been listed in the Serious Warnings and Precautions box in the Simlandi Product Monograph, as can be found in the Humira Product Monograph.

A Risk Management Plan (RMP) for Simlandi was submitted by JAMP Pharma Corporation 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.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Simlandi Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

The sponsor submitted a brand name assessment that included testing for look-alike sound-alike attributes. Upon review, the proposed name Simlandi was accepted.

Overall, Simlandi is considered to have a benefit-risk profile comparable to that established for the reference biologic drug Humira. The approved indications for Simlandi have been aligned with the available presentations. The benefits of Simlandi are considered to outweigh the potential risks in the target patient populations. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Simlandi Product Monograph to address the identified safety concerns and are based on the information presented in the labelling for the reference product Humira.

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 Simlandi?

 

The review of the quality component of the New Drug Submission (NDS) for Simlandi was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Simlandi NDS was made independently based on the Canadian review.

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

 

Submission Milestones: Simlandi

Submission Milestone Date
New Drug Submission filed 2020-12-22
Screening  
Screening Acceptance Letter issued 2021-02-26
Review  
Review of Risk Management Plan completed 2021-11-24
Quality evaluation completed 2021-12-22
Clinical/medical evaluation completed 2021-12-24
Labelling review completed 2021-12-31
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2022-01-05

 

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 Simlandi sponsor to monitor the post-market safety profile of this biosimilar as well as the Product Monograph of the reference biologic drug for safety signals that could impact the biosimilar, and make safety updates to the Simlandi 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.

 

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

 

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 Simlandi 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

 

As described above, the review of the quality component of the New Drug Submission for Simlandi was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Simlandi was developed as a biosimilar to the reference biologic drug, Humira. For biosimilars, the weight of evidence is provided by structural and functional studies. Biosimilars are manufactured to the same regulatory standards as other biologic drugs. In addition to a typical chemistry and manufacturing data package that is submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity with the reference biologic drug.

The biological activity of Simlandi is considered to be representative of the mechanism of action and pharmacological effect of Humira.

Comparative Structural and Functional Studies

The biosimilarity assessment for Simlandi was based on head-to-head analytical similarity assessments to compare Simlandi, Humira authorized in the European Union (EU-Humira), and Humira authorized in the United States (US-Humira). The reference biologic drug, EU-Humira, is considered a suitable proxy for Canadian-marketed Humira, as it meets the requirements for the use of non-Canadian reference biologic drugs outlined in Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The results of the biosimilarity assessment indicate that Simlandi is identical to EU-Humira with respect to primary structure, and highly similar with respect to higher order structures, post-translational modifications, and potency. Some product-related substances and impurities were detected at higher levels in Simlandi, but are not expected to translate into clinically meaningful differences between Simlandi and EU-Humira. Furthermore, the degradation profiles of adalimumab in Simlandi and EU-Humira were comparable following exposure to different stress conditions. Collectively, the results demonstrate that Simlandi is highly similar to EU-Humira and support the quality requirements for Simlandi to be considered a biosimilar to the reference biologic drug.

Characterization of the Drug Substance

Detailed characterization studies demonstrated that adalimumab, the medicinal ingredient in Simlandi, consistently exhibits the desired characteristic structure and biological activity. The primary and higher order structures, purity, impurities, post-translational modifications, potency, and biological activity of adalimumab were all confirmed through appropriately qualified methods.

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

The drug substance, adalimumab, is produced using Chinese hamster ovary (CHO) cells that have been genetically engineered to express this protein. A culture of these cells is initiated from a single vial from a working cell bank and expanded through a fed-batch process to reach commercial scale. As the cell culture expands, the cells express adalimumab, which is secreted into the culture medium. When set criteria are reached, the cell culture medium is harvested and clarified, generating the cell-free harvest material which contains the drug substance. The drug substance is purified through a series of chromatography and viral inactivation steps, filtered, formulated, and stored frozen at -70 °C.

Manufacturing of the drug product, Simlandi, begins with thawing of the formulated drug substance, followed by pooling and mixing, bioburden reduction filtration, and sterile filtration. The solution is aseptically filled into syringes, which are then stoppered and visually inspected. The syringes are further assembled into either a prefilled syringe with a safety guard or a prefilled pen (auto-injector).

Process validation was conducted using batches of the drug substance and drug product manufactured at commercial scale at the proposed manufacturing site.  All batches of the drug substance and drug product met the relevant acceptance criteria and release specifications, reflecting consistency in both manufacturing processes. A continuous process verification protocol has been implemented for both the drug substance and drug product manufacturing processes to ensure that they remain in a validated state of control during commercial manufacturing.

None of the non-medicinal ingredients (excipients) found in the drug product are prohibited by 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

Control of the drug substance and drug product manufacturing processes has been achieved through in-process controls with action limits or acceptance criteria. The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications, and analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

Simlandi is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use, and the results support the consistency of the manufacturing process.

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 24-month shelf life for Simlandi at 2 °C to 8 °C (refrigerated) is considered acceptable. The product must be protected from light and must not be frozen.

If needed, the Simlandi auto-injector or prefilled syringe can be stored at room temperature (up to 25 °C) for a single maximum period of 14 days. Additional information and special handling instructions are included in the Simlandi Product Monograph.

Facilities and Equipment

Although an on-site evaluation (OSE) was recommended for the drug substance manufacturing facility, it was not feasible to conduct an OSE during the review cycle due to travel limitations resulting from the coronavirus disease 2019 (COVID-19) pandemic. Additional documentation was requested from the sponsor to conduct a review of some aspects of the drug substance manufacturing processes.

Based on a risk assessment score determined by Health Canada, an OSE was not recommended or conducted for the drug product manufacturing facility.

Adventitious Agents Safety Evaluation

The master and working cell banks were extensively characterized and confirmed to be free of adventitious agents (mycoplasma, bacteria, fungi, and viruses).

The manufacturing processes incorporate adequate control measures to prevent contamination and maintain microbial control. Purification process steps designed to remove and inactivate adventitious viruses are adequately validated. The proposed strategy was found to be capable of consistently reducing viral contamination to levels below the acceptable limits.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) agents 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 comparative in vivo studies were not included in the review of the New Drug Submission for Simlandi, which is acceptable based on the determination of similar quality attributes. Non-clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty.

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

 

 

7.3 Clinical basis for decision

 

The purpose of the clinical program for a biosimilar is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The structural complexity of the biologic drug and availability of a relevant and sensitive pharmacodynamic endpoint determine the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Adalimumab, the medicinal ingredient in Simlandi, binds specifically to tumour necrosis factor (TNF) α, blocking its interaction with the cell surface TNF receptors p55 and p75. Tumour necrosis factor is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF play key roles in the pathogenesis of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, and hidradenitis suppurativa.

Comparative Pharmacokinetic and Pharmacodynamic Studies

The pharmacokinetics of Simlandi, Humira authorized in the European Union (EU-Humira), and Humira authorized in the United States (US-Humira) was evaluated in Study AVT02-GL-101, which was conducted in healthy adult subjects. The designated Canadian reference product is EU-Humira, and therefore the review focused on the comparison between Simlandi and EU-Humira.

Each subject received a single 40 mg subcutaneous dose of one of the three versions of adalimumab: Simlandi, EU-Humira, or US-Humira. Serum samples were collected at a suitable frequency up to Day 64, and pharmacokinetic parameters were estimated using a non-compartmental analysis method. The point estimate for the geometric least squares mean ratio for the maximum serum concentration (Cmax) for Simlandi and EU-Humira was within the comparability margins of 80.0% to 125.0%, as was the 90% confidence interval (CI) for the area under the concentration-time curve (AUC) to the time of the last quantifiable concentration (AUCT). Pharmacokinetic comparability was therefore demonstrated between Simlandi and EU-Humira.

Study AVT02-GL-102 compared the administration of Simlandi using the auto-injector presentation versus the prefilled syringe in healthy adult subjects. A 40 mg subcutaneous dose of Simlandi was delivered to subjects using either an auto-injector or a prefilled syringe. The point estimate for the auto-injector and prefilled syringe geometric least squares mean ratio for the Cmax and the 90% CI for the AUCT were within the comparability margins of 80.0% to 125.0%. Bioequivalence was therefore demonstrated between the auto-injector and prefilled syringe presentations of Simlandi.

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

Comparative Clinical Efficacy, Safety and Immunogenicity

A comparative clinical efficacy and safety study (AVT02-GL-301) was conducted to compare the efficacy and safety profiles of Simlandi and Humira in 412 adult patients with moderate to severe chronic plaque psoriasis. Patients enrolled in the study had a body surface area (BSA) of 10% or greater affected by psoriasis, a psoriasis area severity index (PASI) score of 12 or higher, and a physician global assessment score (sPGA) of 3 or higher at baseline, with stable disease for at least two months. Additionally, patients must have previously had an inadequate response or intolerance to at least one systemic antipsoriatic therapy. Patients were randomized in a 1:1 ratio to either the Simlandi or Humira treatment group. Demographic characteristics and baseline disease characteristics were similar between the two treatment groups. Patients received an 80 mg loading dose of the assigned study drug during Week 1 of the study, followed by a 40 mg dose of the assigned study drug every other week from Week 2 to Week 14.

The primary efficacy endpoint was the percent improvement in the PASI score from baseline to Week 16. The 95% confidence interval of the difference between the scores for the Simlandi and Humira treatment groups (89.2% and 86.9%, respectively) was contained entirely within the predefined equivalence margins of (-10%, 10%), thereby demonstrating therapeutic similarity between the two drugs.

The primary analysis period continued up to Week 24. At this point, patients in the Simlandi group continued treatment until Week 48, and patients in the Humira group were randomized again (in a 1:1 ratio) to receive either Simlandi or Humira through Week 48. The study was ongoing at the time of authorization, with the final assessment expected at Week 50.

Treatment-emergent adverse events (TEAEs) were reported at comparable frequencies between the Simlandi and Humira treatment groups (44.9% and 44.0%, respectively). No deaths or new safety signals were reported in the study. Injection site reactions, most commonly erythema/redness and pruritus/itching, were reported in both treatment groups (16.6% and 15.9% of patients in the Simlandi and Humira groups, respectively). Nasopharyngitis was reported in 5.4% of patients in the Simlandi group and 5.3% of patients in the Humira group.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). Comparable frequencies of ADAs and neutralizing antibodies were reported between the two treatment groups. In the Simlandi group, 88.8% of patients were positive for ADAs and 66.3% were positive for neutralizing antibodies. In the Humira group, 90.8% of patients were positive for ADAs and 73.4% of patients were positive for neutralizing antibodies. The impacts of ADAs and neutralizing antibodies on safety and efficacy are expected to be comparable between Simlandi and Humira, and are described in the Product Monographs for both drugs.

As with Humira, the major identified safety concerns for Simlandi include hepatosplenic T-cell lymphoma, infections, and pediatric malignancy. These risks are highlighted in a Serious Warnings and Precautions box in the Simlandi and Humira Product Monographs.

Overall, the clinical evidence indicates no clinically meaningful differences in efficacy and safety between Simlandi and Humira.

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

Indications

Simlandi 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.

Within this drug submission, the sponsor requested the authorization of Simlandi for all of the indications that are currently authorized for Humira. However, some dosing regimens for polyarticular juvenile idiopathic arthritis and the maintenance dose for pediatric Crohn’s disease require the administration of doses lower than 40 mg. The available presentations of Simlandi (a prefilled syringe or prefilled pen [auto-injector]) are not designed to deliver less than the full 40 mg dose contained in the packaging. The indications proposed for Simlandi were therefore restricted to align with the available presentations. Specifically, the indication for polyarticular juvenile idiopathic arthritis was limited to patients who require the full 40 mg dose, and the indication for pediatric Crohn’s disease was not approved.

Similarity between Simlandi 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 Simlandi and the reference biologic drug, in structural and functional studies, mechanism of action, pharmacological effect, pathophysiological mechanisms of the diseases involved, safety profile, and clinical experience with the reference biologic drug.

To support the safe and effective use of the product, Health Canada approved Simlandi 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.

Simlandi can be used alone or in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDs).

When used as first-line treatment in recently diagnosed patients who have not been previously treated with methotrexate, Simlandi should be given in combination with methotrexate. Simlandi 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, weighing ≥30 kg, who have had an inadequate response to one or more DMARDs. Simlandi 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. Simlandi can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • Reducing the 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. Simlandi 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.

Adult Ulcerative Colitis

  • Treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy including corticosteroids and/or azathioprine or 6-mercaptopurine (6-MP) or who are intolerant to such therapies. The efficacy of Simlandi in patients who have lost response to or were intolerant to tumour necrosis factor (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, Simlandi 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, weighing ≥30 kg, who have had an inadequate response to or are intolerant to conventional therapy, or in whom conventional therapy is inappropriate.

 

 

 

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