Summary Basis of Decision for Hulio
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Hulio is located below.
Recent Activity for Hulio
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 Hulio
Updated: 2025-01-29
The following table describes post-authorization activity for Hulio, 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 02502380 - 20 mg/0.4 mL adalimumab, solution, subcutaneous injection, single-dose prefilled syringe
DIN 02502399 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-dose prefilled syringe
DIN 02502402 - 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-dose prefilled pen (auto-injector)
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN # 02502402) market notification | Not applicable | Date of first sale: 2024-03-20 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| SNDS # 272126 | 2023-02-08 | Issued NOC 2023-07-20 | Submission filed as a Level I – Supplement to update the PM and package insert to align with that of the reference biologic drug Humira, and to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable, and an NOC was issued. |
| NDS # 273910 | 2023-03-31 | Issued NOC 2023-05-15 | Submission filed to transfer ownership of the drug product from BGP Pharma ULC to Biosimilar Collaborations Ireland Limited (BCIL). An NOC was issued. |
| NC # 271782 | 2023-01-26 | Issued NOL 2023-03-27 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the labelled storage conditions for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 268520 | 2022-10-07 | Issued NOL 2022-12-22 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the labelled storage conditions for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 257327 | 2021-10-06 | Issued NOC 2022-08-12 | Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Pediatric ulcerative colitis- inducing and maintaining clinical remission in pediatric patients 5 years of age and older with moderately to severely active ulcerative colitis 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 02502380) market notification | Not applicable | Date of first sale: 2022-04-11 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| SNDS # 244607 | 2020-09-30 | Issued NOC 2021-05-14 |
Submission filed as a Level I – Supplement for a new drug substance manufacturing site and a scale-up of the drug substance and drug product manufacturing processes. The information was reviewed and considered acceptable. An NOC was issued |
| SNDS # 244779 | 2020-10-02 | Issued NOC 2021-03-11 |
Submission filed as a Level I – Supplement to introduce an onboarding toolkit for training purposes only. The onboarding toolkit consists of a resettable pen, which does not contain a needle or drug. The submission was reviewed and considered acceptable, and an NOC was issued. |
| Drug product (DINs 02502399, 02502402) market notification | Not applicable | Date of first sale 2021-02-16 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NC # 245053 | 2020-10-07 | Issued NOL 2021-01-06 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a testing site for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NDS # 229124 | 2019-08-12 | Issued NOC 2020-11-24 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Hulio
Date SBD issued: 2021-07-13
The following information relates to the New Drug Submission for Hulio.
Adalimumab
Drug Identification Number (DIN):
- DIN 02502380 – 20 mg/0.4 mL adalimumab, solution, subcutaneous injection, single-dose prefilled syringe
- DIN 02502399 – 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-dose prefilled syringe
- DIN 02502402 – 40 mg/0.8 mL adalimumab, solution, subcutaneous injection, single-dose prefilled pen (auto-injector)
BGP Pharma ULC
New Drug Submission Control Number: 229124
On November 24, 2020, Health Canada issued a Notice of Compliance (NOC) to BGP Pharma ULC for Hulio, 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. Hulio 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 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 Hulio 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 Hulio 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 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 Hulio is considered to be similar to the benefit-risk profile of the reference biologic drug, 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?
Hulio, 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. Hulio 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, Hulio should be given in combination with methotrexate. Hulio 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. Hulio can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is not appropriate. Adalimumab injection 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. Hulio 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. Hulio 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 injection 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, Hulio 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 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 injection were authorized 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 injection in adolescent patients with hidradenitis suppurativa. The dosage of adalimumab injection in these patients has been determined based on pharmacokinetic/pharmacodynamic modelling and simulation. Adalimumab injection 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 injection in the geriatric population (over 65 years of age) is not associated with differences in effectiveness.
Hulio is a biosimilar to Humira. Both drugs contain the medicinal ingredient, adalimumab. Adalimumab is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody that binds to soluble and membrane-bound tumour necrosis factor alpha (TNF-α) and prevents its interaction with its cell surface receptor, p55 and p75. Tumour necrosis factor alpha is a cell signalling protein involved in systemic inflammation. Dysregulation of TNF-α production has been implicated in a variety of autoimmune diseases.
Similarity between Hulio 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.
Hulio is contraindicated in:
- Patients with known hypersensitivity to Hulio (adalimumab injection) or any of its components.
- Patients with severe infections such as sepsis, tuberculosis, and opportunistic infections.
- Patients with moderate to severe heart failure (New York Heart Association [NYHA] class III/IV).
Hulio 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.
Hulio (20 mg/0.4 mL adalimumab) is presented as a solution in a single-dose prefilled syringe. Hulio (40 mg/0.8 mL adalimumab) is presented as a solution in a single-dose prefilled syringe and as a solution in a single-dose prefilled auto-injector. In addition to the medicinal ingredient, the solution contains diluted hydrochloric acid, methionine, monosodium glutamate, polysorbate 80, sorbitol, and distilled water for injection.
For more information, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical and Basis for Decision sections.
Additional information may be found in the Hulio Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Hulio approved?
Based on Health Canada’s review, the benefit-risk profile of Hulio 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 Hulio and Humira was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Hulio 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 (NDS) filed for Hulio 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 Hulio and the reference biologic drug.
The target diseases for Hulio include a host of immune-mediated conditions with shared inflammatory pathways involving tumour necrosis factor alpha (TNF-α). Tumour necrosis factor alpha is a naturally occurring cytokine that promotes normal inflammatory and immune responses. Elevated levels of TNF-α 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. Increased levels of TNF-α 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-α are also found in hidradenitis suppurativa lesions.
Adalimumab, the medicinal ingredient in Hulio, is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody that binds with high affinity and specificity to soluble and membrane-bound TNF-α. The binding to TNF-α decreases its ability to bind to the TNFR1 and TNFR2 cell surface receptors, also known as p55 and p75, which in turn disrupts downstream effects such as proinflammatory cytokine stimulation and infiltration of inflammatory cells.
Hulio and Humira were judged to be highly similar in terms of quality attributes based on comparative structural and functional studies. A comparable pharmacokinetic profile between Hulio and the reference biologic drug, Humira sourced from the United States (Humira-US), was established in Study FKB327-001, a Phase I, randomized, double-blind, single-dose comparative pharmacokinetic study conducted in healthy adult subjects. Comparable efficacy, safety, and immunogenicity between the two products were demonstrated in Study FKB327-002 (also known as ARABESC), a pivotal, randomized, double-blind, controlled Phase III study in adult patients with moderate to severe rheumatoid arthritis. The primary endpoint of equivalence in ACR20 (a 20% improvement in 2010 American College of Rheumatology core set measurements) response rate at Week 24 was achieved based on pre-specified equivalence margins. The safety of Hulio was also assessed in an open-label extension of Study FKB327-002. Numerical differences in some adverse events were reported between Hulio and Humira in the clinical studies, but they were not considered to be clinically meaningful.
This demonstration of similarity enables the sponsor’s submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought. Therefore, the Adverse Reactions section of the Hulio Product Monograph is based on the clinical experience with the reference biologic drug, Humira. As with Humira, a Serious Warnings and Precautions box describing reports of hepatosplenic T-cell lymphoma, infections, and pediatric malignancies in patients treated with TNF blockers has been included in the Hulio Product Monograph.
A Risk Management Plan (RMP) for Hulio was submitted by BGP Pharma 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 Look-alike Sound-alike brand name assessment was performed and the proposed name Hulio was accepted.
Overall, the benefits of Hulio therapy are expected to be similar to the known benefits of the reference biologic drug, Humira, and are considered to outweigh the potential risks. Appropriate warnings and precautions are in place in the Hulio Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical and Basis for Decision sections.
3 What steps led to the approval of Hulio?
Submission Milestones: Hulio
| Submission Milestone | Date |
|---|---|
| Submission filed | 2019-08-12 |
| Screening | |
| Screening Acceptance Letter issued | 2019-09-26 |
| Review | |
| Quality Evaluation complete | 2020-07-10 |
| Non-clinical Evaluation complete | 2020-07-13 |
| Clinical/Medical Evaluation complete | 2020-07-14 |
| Review of Risk Management Plan complete | 2020-07-16 |
| Labelling Review complete | 2020-07-20 |
| Intellectual Property Hold | |
| Submission placed on Intellectual Property Hold | 2020-07-22 |
| Notice of Compliance issued by Director General, Biologics and Radiopharmaceutical Drugs Directorate | 2020-11-24 |
The Canadian regulatory decision on the review of Hulio was based on a critical assessment of the data package submitted to Health Canada, with foreign review used as added reference.
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 Hulio 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 Hulio 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 Hulio, Health Canada requested and the sponsor agreed to several commitments to be addressed post authorization. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include but are not limited to providing Health Canada the following:
- Annual Periodic Benefit Risk Evaluation Reports for the first three years after authorization, followed by Periodic Safety Update Reports submitted every 3 years as per the already-established reporting schedule with the European Medicines Agency.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Quality Basis for Decision
Hulio 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 the Hulio drug substance and drug product to the reference biologic product, Humira sourced from the United States (Humira-US). A comparability study between Humira-US and Humira sourced from the European Union (Humira-EU) also demonstrated a high degree of similarity, thereby supporting the use of Humira-EU in the non-clinical studies. Overall, the use of Humira-US as the reference biologic product has been sufficiently justified.
A combination of characterization and stability studies to compare Hulio to Humira-US established a high degree of similarity in the primary and higher order structures, physico-biochemical properties, as well as the purity, biological activity, and the degradation profiles of both drugs. Some differences were observed with regard to the structural and physico-biochemical properties, however, these differences were determined to be minor and unlikely to translate into clinically meaningful differences between Hulio and the reference biologic drug. Taken together, these studies suggest a high degree of similarity between Hulio and reference biologic drug.
Characterization of the Drug Substance
The drug substance, adalimumab, is a recombinant human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that consists of 1,330 amino acids and has a molecular weight of 148 kDa. Adalimumab binds to soluble and membrane-bound tumour necrosis factor alpha (TNF-α) and prevents its interaction with its cell surface receptors p55 and p75. Tumour necrosis factor alpha is a cell signaling protein involved in systemic inflammation. Dysregulation of TNF-α production has been implicated in a variety of autoimmune diseases.
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
The drug substance, adalimumab, is expressed in Chinese hamster ovary cells as a secreted protein. The manufacturing process of the drug substance begins with the thawing of working cell vials, followed by a series of expansions culminating in the production bioreactor. The clarified harvest from the bioreactor is processed through a Protein A chromatography step and undergoes a low pH viral inactivation step. The adalimumab material is then purified through a multimodel column and a cation exchange step prior to a viral filtration step. The resulting pool is formulated to a target concentration with the excipients through ultrafiltration and diafiltration before filling into 20 L storage bags and frozen.
The sponsor has demonstrated that the drug substance manufacturing facility is capable of consistently manufacturing adalimumab of acceptable quality. Appropriate in-process controls have been implemented throughout the process to ensure the consistent production of high quality drug substance. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.
The manufacturing process of the drug product includes thawing of the drug substance, formulation to a target concentration of 50 mg/mL (40 mg/0.8 mL and 20 mg/0.4 mL), sterile filtration, filling into syringe barrels, stoppering, and inspection. The prefilled syringes are then assembled with safety devices or as auto-injector pens, and processed for labelling and final packaging. The safety devices and auto-injector components are not part of the primary container closure system and have no contact with the sterile fluid path. Extensive data were provided to support the design, performance, and compatibility of the safety device and auto-injector. The auto-injector met all applicable International Organization for Standardization requirements and showed a comparable dose delivery profile to that of the prefilled syringe with a safety device.
The sponsor has demonstrated that the drug product manufacturing facility is capable of consistently producing Hulio of acceptable quality. Controls of critical steps of the drug product manufacturing process were appropriately defined throughout development based on a risk assessment and current process understanding.
Analytical methods were validated or qualified at the appropriate testing facilities.
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
Process design and process control elements were defined using a risk-based approach and classified according to their criticality in maintaining product consistency. Process characterization (small-scale studies and historical manufacturing) and validation studies support the proposed commercial operating ranges and acceptance criteria for in-process controls for the drug substance and drug product processes. The proposed release and stability specifications include assays for identity, quantity, biological activity, purity and impurities, safety, and general properties. Analytical methods were deemed suitable and supported by validation studies and consistency lot testing. A two-tiered reference program has been established. The reference standards have been well characterized and an appropriate program is in place to qualify new primary and working reference material.
Hulio 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 for the Hulio drug product is considered acceptable when stored at 2 °C to 8 °C and protected from light, with a temperature excursion to 25 °C for up to 14 days.
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.
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. One animal-derived material, fetal bovine serum, was used in the early development of the adalimumab Chinese hamster ovary cell substrate. Letters of attestation confirming that the material is free from bovine spongiform encephalopathy or transmissible spongiform encephalopathy have been provided, indicating that it is considered to be safe for human use.
The manufacturing process incorporates adequate control measures to prevent contamination and to maintain microbial control in accordance with International Council for Harmonisation guidelines. Cell substrates from the master cell bank, working cell bank, limit of in vitro cell age cell bank, and unprocessed bulk harvest stages are tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses), and appropriate limits have been established. Results from all tests met the acceptance criteria. Purification process steps designed to remove and inactivate viruses are also 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.
The non-clinical database submitted for Hulio 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.
Non-clinical studies comparing Hulio (adalimumab 20 mg/0.4 mL and 40 mg/0.8 mL) to the reference biologic drug, Humira sourced from the European Union and/or the United States (both referred to as Humira throughout this section), included pharmacodynamic, pharmacokinetic, and toxicology comparability studies.
In in vitro pharmacodynamic studies, Hulio and Humira demonstrated comparable binding to tumour necrosis factor alpha (TNF-α), C1q, and Fc receptors and neutralization of soluble TNF-α-induced cytotoxicity. Other cell-based assays such as antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis also demonstrated similarity between Hulio and Humira. In an in vivo pharmacodynamic study conducted with a transgenic mouse model of arthritis, both Hulio and Humira produced reductions in arthritic score compared to untreated mice.
In a pivotal comparative repeated-dose toxicity study, cynomolgus monkeys were administered Hulio and Humira at a dose of 30 mg/kg of body weight by subcutaneous injection once weekly for 4 weeks. Monkeys administered Hulio did not develop any unique adverse effects. Adalimumab pharmacokinetics, measured by area under the serum concentration versus time curve (AUC) and maximum serum concentration (Cmax), was comparable between Hulio and Humira. One of five animals administered Hulio developed anti-drug antibodies, while no animals developed anti-drug antibodies in the Humira group. Overall, no toxicity or tolerability concerns were reported for Hulio that differed from those for Humira. The weight of evidence supported the similarity of Hulio with Humira from a non-clinical perspective.
Hulio contains an excipient, monosodium glutamate (MSG), which is not present in the Humira formulation. While no chronic repeated-dose or juvenile toxicity studies have been conducted with MSG using the subcutaneous route of administration, non-clinical data from published literature suggest that subcutaneous injections of MSG is unlikely to pose acute toxicity, genotoxicity, reproductive, or tolerability concerns at the concentration used in Hulio.
The results of the comparative non-clinical studies as well as the potential risks to humans have been included in the Hulio Product Monograph. In view of the intended use of Hulio, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Hulio 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 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.
Hulio 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 (IgG1) monoclonal antibody produced in Chinese hamster ovary cells that specifically targets tumour necrosis factor 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, adalimumab is authorized for 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 FKB327-001, the pivotal pharmacokinetic study, was a randomized, double-blind, three-arm, parallel-group study comparing the safety and pharmacokinetics of Hulio to Humira sourced from the United States (Humira-US) and the European Union (Humira-EU). In this study, 180 healthy male and female subjects received a single 40 mg subcutaneous dose of Hulio, Humira-US, or Humira-EU. As Humira-US was the reference biologic drug, the following pharmacokinetic results focus on the comparison between Hulio and Humira-US
Serum samples were collected up to Day 65 and a non-compartmental procedure was used to estimate pharmacokinetic parameters. The study demonstrated pharmacokinetic comparability between Hulio and Humira-US. The point estimate for the Hulio/Humira-US geometric least squares mean ratio for the maximum serum concentration (Cmax) and the 90% confidence intervals (CI) for the area under the serum concentration versus time curve to the time of the last quantifiable concentration (AUCT) were within the pharmacokinetic comparability margins of 80.0% to 125.0%.
Study FKB327-005 was a randomized, open-label, single-dose, parallel-group study conducted in 194 healthy adult male and female subjects to support the authorization of the auto-injector presentation of Hulio. In this study, a 40 mg subcutaneous dose of Hulio was delivered via a prefilled auto-injector or a prefilled syringe. The pharmacokinetic parameter AUCT demonstrated that the upper bound of the 90% CI for the auto-injector/prefilled syringe geometric least squares mean ratio was not contained within the comparability margins of 80.0% to 125.0% (ratio:111.3% [98.1%, 126.3%]) for the primary statistical analysis. However, the quality data provided in the submission as well as the clinical efficacy, safety, and pharmacokinetic data provided in the Phase III trial and its open-label extension (see Comparative Clinical Efficacy, Safety, and Immunogenicity section) and information from the post-market setting mitigated the concerns raised from the pharmacokinetic findings of Study FKB327-005.
In conclusion, the totality of evidence was sufficient to support authorization of the auto-injector presentation.
For further details, please refer to the Hulio Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Clinical Efficacy, Safety, and Immunogenicity
The pivotal comparative efficacy, safety, and immunogenicity study provided in the submission for Hulio was a Phase III, double-blind, active- controlled study in patients with rheumatoid arthritis (Study FKB327-002, also known as ARABESC). Patients with moderate to severe rheumatoid arthritis were treated with a 40 mg subcutaneous dose of either Hulio (number of patients [n] = 367) or Humira-US (n = 363) every other week for a primary analysis period of 24 weeks. All patients were on background methotrexate treatment at a stable dose level (mean dose of 15.8 mg/week).
In the study, 77.6% of patients were female, the mean age was 53.3 years (range: 18 to 93 years), and the mean weight was 73.5 kg. At baseline, 91.2% of patients had a Disease Activity Score-28 for Rheumatoid Arthritis with C-reactive Protein (DAS28-CRP) of >5.1, a mean tender joint count of 26.1/68, and a mean swollen joint count of 16.1/66. There were 661 patients (90.5%) who completed the study.
The primary endpoint was ACR20 (a 20% improvement in 2010 American College of Rheumatology [ACR] core set measurements) response at Week 24, a validated and commonly used method of assessing improvement in rheumatoid arthritis signs and symptoms. The primary analysis included two sets of equivalence criteria due to differing requirements from other regulatory agencies, including the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA). For the primary analysis using the EMA’s Committee for Medicinal Products for Human Use (CHMP) equivalency assessment (full analysis set [FAS] with root cause imputation, 95% CI within ±13%), equivalence between the treatment groups was demonstrated, with 74.1% of Hulio-treated patients and 75.7% of Humira-US-treated patients achieving ACR20 response at Week 24 (mean difference -1.6%, 95% CI: -7.9, 4.7). Use of non-responder imputation (NRI) and the FDA equivalence criteria (FAS with NRI, 90% CI: -12% to 15%) also showed equivalence between the treatment groups, with 72.5% of Hulio-treated patients and 74.3% of Humira-US-treated patients achieving ACR20 response (mean difference -1.8%, 90% CI: -7.3, 3.6). Sensitivity and subgroup analyses were consistent with the primary analyses. Secondary endpoints (DAS28-CRP, ACR50, ACR70, visual analogue scale scores [VAS-based tools]) also demonstrated similarity between the Hulio and Humira-US groups.
In the open-label extension to Study FKB327-002, patients were re-randomized to receive Hulio or Humira-US for 28 weeks, after which all patients received Hulio for another 46 weeks. Regardless of whether patients stayed on one medication throughout or whether they switched from one drug to another, ACR20 response rates were 77% to 84% among patients remaining on treatment.
In terms of the drug safety profile in Study FKB327-002, there were few marked differences between the Hulio and Humira-US arms. There was a slightly higher proportion of Hulio patients with severe adverse events (AEs), AEs leading to discontinuation, and AEs of special interest (AESIs) of serious infections and (non-serious) hypersensitivity reactions. Treatment-emergent AEs (TEAEs), serious AEs (SAEs), adverse drug reactions (ADRs), and dosing interruptions due to AEs were slightly higher in the Humira-US arm. The types of AEs that occurred in the study were consistent with the known safety profile of Humira, with infections being the most common in both treatment groups (approximately 29%). The only TEAE that occurred in >5% of patients was nasopharyngitis (7.1% Hulio and 8.0% Humira-US). One Hulio-treated patient died after a severe, treatment-related SAE of disseminated tuberculosis after a new-onset positive QuantiFERON test at Week 22 and rapid decline in health thereafter. Tuberculosis is known to be a serious potential side effect of adalimumab.
By the end of the open-label extension, there had been a cumulative exposure to Hulio of 674 patient-years (n = 614) and to Humira-US of 175 patient-years (n = 321). After adjustment for exposure, severe AEs (6.8 per 100 patient-years) and discontinuations due to AEs (9.1 per 100 patient-years) were higher in the Hulio group, while TEAEs (208 per 100 patient-years) and ADRs (64.4 per 100 patient-years) were higher in the Humira-US group. There were equal incidences of SAEs (9.1 per 100 patient-years) and deaths (0.6 per 100 patient-years). In terms of the types of safety events, the profile remained consistent with the known Humira profile, with infections remaining the most common events. After adjustment for exposure, malignancies (0.4 per 100 patient-years) and neutropenia (1.2 per 100 patient-years) AESIs were more common in Hulio-treated than in Humira-US-treated patients at the completion of the open-label extension.
Based on results from the blinded Study FKB327-002 and its open-label extension, the safety profiles of Hulio and the reference biologic drug, Humira-US, are clinically comparable and are consistent with the known safety profile of Humira as currently labelled in Canada. Discrepancies between groups were not of substantial magnitude or consistency to conclude that there were clinically meaningful differences in safety profile between the two drugs.
In terms of immunogenicity, there were approximately 60% of patients in each treatment arm that developed anti-drug antibodies (ADAs) by the end of Study FKB327-002 and approximately 90% by the completion of the open-label extension. Nearly all patients with ADAs also tested positive for neutralizing antibodies (NAbs). The development of ADAs (and NAbs) was associated with lower serum adalimumab, which in turn was associated with a marginal decrease in efficacy of approximately 5% fewer patients achieving ACR20. However, the incidence of antibodies and the impacts on exposure and efficacy were similar in both the Hulio and Humira-US arms. There did not appear to be an association with safety endpoints, including injection-related reactions, in patients that developed antibodies.
Further, there were no apparent differences in the efficacy or safety profile, nor any notable differences in the pharmacokinetics as measured by serum trough concentrations, between the devices used to administer Hulio: the prefilled syringe (in Study FKB327-002) or the auto-injector (the majority of patients in the open-label extension). Therefore, while the clinical pharmacology trial failed to meet the required criteria for equivalence between the prefilled syringe and the auto-injector by a small margin, the totality of the clinical data supported the use of the auto-injector and indicated no meaningful differences compared to dosing with the prefilled syringe. A decision was therefore made to authorize the auto-injector device based on the totality of data.
Overall, Hulio demonstrated a comparable safety profile with 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. Appropriate warnings and precautions are in place in the Hulio Product Monograph to address the identified safety concerns, as they are in the Humira Product Monograph. 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 Hulio Product Monograph.
For more information, refer to the Hulio Product Monograph, approved by Health Canada and available through the Drug Product Database.
Indications
Hulio 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 Hulio requested authorization for all of the indications and clinical uses that were authorized for Humira at the time of the submission.
Similarity between Hulio 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 Hulio and the reference biologic drug, in structural, functional, non-clinical and clinical studies.
Indication
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. Hulio 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, Hulio should be given in combination with methotrexate. Hulio 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. Hulio can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is not appropriate. Adalimumab injection 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. Hulio 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. Hulio 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 injection 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, Hulio 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.