Summary Basis of Decision for Semglee
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 Semglee is located below.
Recent Activity for Semglee
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.
Summary Basis of Decision (SBD) for Semglee
Date SBD issued: 2022-08-23
The following information relates to the new drug submission for Semglee.
Insulin glargine
Drug Identification Number (DIN):
- DIN 02526441 - insulin glargine 100 units/mL, solution, subcutaneous injection
BGP Pharma ULC
New Drug Submission Control Number: 252068
On April 8, 2022, Health Canada issued a Notice of Compliance (NOC) to BGP Pharma ULC for Semglee, a biosimilar to Lantus (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. Semglee contains the medicinal ingredient insulin glargine, which has been demonstrated to be highly similar to insulin glargine contained in the reference biologic drug, Lantus.
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, Lantus is the reference biologic drug. Similarity between Semglee and Lantus 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 Semglee for all of the indications that are currently authorized for Lantus.
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 Semglee is considered to be similar to the benefit-risk profile of the reference biologic drug, and is therefore considered favourable:
- for once-daily subcutaneous administration in the treatment of patients over 17 years of age with Type 1 or Type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.
- in the treatment of pediatric patients (over 6 years old) with Type 1 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.
1 What was approved?
Semglee, an antidiabetic agent, was authorized:
- for once-daily subcutaneous administration in the treatment of patients over 17 years of age with Type 1 or Type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.
- in the treatment of pediatric patients (over 6 years old) with Type 1 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.
Health Canada has authorized an indication for pediatric use (over 6 years old) as the data submitted and reviewed established the safety and efficacy of Semglee in pediatric patients over 6 years of age with Type 1 diabetes mellitus.
Evidence from clinical studies and experience suggests that use in the geriatric population (over 65 years old) is associated with differences in safety or effectiveness. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions.
Semglee is contraindicated during episodes of hypoglycemia and in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Semglee is a biosimilar to Lantus. Both drugs contain the medicinal ingredient insulin glargine. Insulin glargine is an analog of human insulin that binds to surface-exposed insulin receptors. This leads to an increase in glucose transporters at the surface of insulin receptor-expressing cells, resulting in an increase in glucose uptake and a decrease in blood glucose levels.
Similarity between Semglee and the reference biologic drug, Lantus, has been established on the basis of comparative structural, analytical, and functional data, as well as data obtained from both non-clinical and clinical studies in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Semglee (insulin glargine 100 units/mL) is presented as a solution for subcutaneous injection. In addition to the medicinal ingredient, the solution contains glycerol 85%, m-cresol, zinc, and water for injection. Hydrochloric acid and sodium hydroxide are added for pH adjustment.
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 Semglee 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 Semglee approved?
Based on Health Canada's review, the benefit‑risk profile of Semglee is considered to be similar to that of the reference biologic drug, and is therefore considered favourable:
- for once-daily subcutaneous administration in the treatment of patients over 17 years of age with Type 1 (T1DM) or Type 2 (T2DM) diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.
- in the treatment of pediatric patients (over 6 years old) with Type 1 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.
Similarity between Semglee and Lantus was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Semglee is considered to be biosimilar to Lantus. Lantus is authorized and marketed in Canada for multiple indications and clinical uses, including once-daily subcutaneous administration in the treatment of patients over 17 years of age with T1DM or T2DM who require basal (long-acting) insulin for the control of hyperglycemia, as well as for the treatment of pediatric patients (over 6 years old) with T1DM who require basal (long-acting) insulin for the control of hyperglycemia. The New Drug Submission (NDS) filed for Semglee requested authorization for all of the indications and clinical uses that are currently authorized for Lantus. The indications have been authorized on the basis of demonstrated similarity between Semglee and the reference biologic drug.
Diabetes is a chronic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Type 1 diabetes mellitus usually begins at a young age (less than 20 years of age) and is mainly due to autoimmune destruction of the pancreatic β cells that produce insulin. As a result, patients with T1DM require lifelong insulin supplementation for survival. Type 2 diabetes mellitus, the most common form of diabetes (accounting for over 90% of all diabetes cases), most often appears in middle-aged and older people. In T2DM, the combined impact of impaired insulin secretion and insulin resistance results in elevated blood glucose levels.
Insulin is the most effective available glucose-lowering treatment for diabetes mellitus. Insulin preparations differing both in their time of onset and duration of action are available for insulin substitution therapy. It is generally accepted that the basal-bolus insulin regimen yields the best glycemic control in diabetes. Basal-bolus insulin regimens consist of a long- or intermediate-acting insulin to cover basal insulin requirements in combination with a short- or rapid-acting insulin to cover meal-related glucose loads.
Insulin glargine, the medicinal ingredient in Semglee and the reference biologic drug, is a long-lasting human insulin analog. The primary activity of insulin glargine is the regulation of glucose metabolism. It does this by binding to insulin receptors on muscle and fat cells, leading to decreased blood glucose by facilitating cellular uptake of glucose while simultaneously inhibiting output of glucose from the liver.
The biosimilar and the reference biologic drug were judged highly similar in terms of quality attributes (based on comparative structural and functional studies).
No toxicity and tolerability concerns were identified following Semglee administration in a single comparative 28‑day repeat-dose toxicity study performed in rats when compared to those identified for the reference biologic drug, Lantus.
The pivotal clinical study in this submission was a Phase I randomized, double-blind, single-dose, three-treatment, six-period, six-sequence, fully replicated, euglycemic glucose clamp study (Study MYL-1501D-1003) in 95 healthy subjects. Of these, 88 subjects contributed to the pharmacokinetic analysis set and 87 subjects contributed to the pharmacodynamic analysis set. The primary objective was to assess the comparative bioavailability of Semglee with the reference biologic product, Lantus. Pre-defined comparability margins of 80.0% to 125.0% for the 90% confidence intervals for the primary pharmacokinetic endpoint were met. Pre-defined comparability margins for the primary pharmacodynamic endpoints based on pre-specified criteria for a highly variable drug product were also met.
Supportive clinical efficacy data were derived from a Phase III randomized, open-label, multicentre, switching study, where 127 patients with T1DM were randomized in a 1:1 ratio to undergo one of two treatment regimens. One group was treated with Lantus sourced from the United States (Lantus‑US) consistently for a 36‑week duration. The other group was treated with Semglee for a 12‑week treatment period, followed by Lantus‑US for a 12‑week treatment period, and then a final Semglee 12‑week treatment period. No clinically meaningful differences in efficacy were observed between the treatment group that switched between Semglee and Lantus‑US, compared to the Lantus‑US-only treatment group.
The safety profile of Semglee was consistent with the safety profile of the reference biologic drug, Lantus. No clinically meaningful differences were noted in the type, frequency, seriousness, or severity of treatment-emergent adverse events or serious adverse events over the 36‑week treatment period. No clinically relevant differences in the immunogenic profiles of Semglee and Lantus were observed; anti-drug antibody titer did not correlate with changes in efficacy, and the incidence of neutralizing antibodies was low.
The demonstration of similarity enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized. Appropriate warnings and precautions are in place in the authorized Semglee Product Monograph to address the identified safety concerns, as is found in the Product Monograph for Lantus. As with Lantus, a Serious Warnings and Precautions box describing the risk of hypoglycemia and uncorrected hypoglycemic or hyperglycemic reactions, as well as important dosage and administration considerations, is in place in the authorized Semglee Product Monograph to address the identified safety concerns.
A Risk Management Plan (RMP) for Semglee 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.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Semglee 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 Semglee was accepted.
Overall, based on the totality of evidence derived from the non-clinical and clinical data submitted in this NDS, the benefit-risk profile of Semglee is considered to be comparable to that of the reference biologic drug Lantus and is favourable for all the indications authorized for the reference biologic drug.
This NDS 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 Semglee?
This submission was a refiling of a previous submission under control number 202772.
A Notice of Deficiency (NOD) was issued to the Sponsor on December 20, 2017 due to deficiencies in the pivotal comparative bioavailability study (Study GLARGCT100111). A Response to the NOD was received from the Sponsor on April 30, 2018. Although the response to NOD comments for the two supportive Phase III studies (Studies MYL-GAI-3001 and MYL-GAI-3002) were deemed acceptable, the post-hoc analysis conducted on Study GLARGCT100111 was not deemed sufficient. Therefore, the Sponsor withdrew the submission on February 15, 2019.
This New Drug Submission (NDS) under control number 252068 addresses the gaps in the previous submission via two Phase I single-dose, replicative crossover euglycemic clamp comparative bioavailability studies performed in healthy subjects. A new insulin glargine detection assay was also developed for these studies. The pivotal clinical study in this submission is Study MYL-1501D-1003, which assesses the comparative bioavailability of Semglee with the reference biologic drug sourced from the United States (Lantus‑US). The Sponsor also submitted study data from two additional supportive Phase III studies to assess the comparative efficacy, safety, and immunogenicity between Semglee and Lantus‑US.
Overall, based on the totality of evidence derived from the non-clinical and clinical data submitted in this NDS, the benefit/risk profile of Semglee is considered comparable to that of the reference biologic drug Lantus and is favourable for all the indications authorized for the reference biologic drug.
The review of the quality, non-clinical, and clinical components of the NDS for Semglee was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the Australia’s Therapeutic Goods Administration (TGA), 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 NDS for Semglee was made independently and 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: Semglee
| Submission Milestone | Date |
|---|---|
| New Drug Submission Control Number: 202772 | |
| Pre-submission meeting | 2016-10-17 |
| New Drug Submission filed | 2017-02-10 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2017-04-20 |
| Review 1 | |
| Review of Risk Management Plan completed | 2017-11-20 |
| Non-clinical evaluation inactive | 2017-12-19 |
| Clinical/medical evaluation inactive | 2017-12-19 |
| Labelling review inactive | 2017-12-20 |
| Notice of Deficiency issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate (comparative bioavailability issues) | 2017-12-20 |
| Response to Notice of Deficiency filed | 2018-03-15 |
| Screening of Response to Notice of Deficiency (Screening 1) | |
| Screening Acceptance Letter issued | 2018-04-30 |
| Review of Response to Notice of Deficiency (Review 1) | |
| Review of Risk Management Plan completed | 2018-08-07 |
| Quality evaluation inactive | 2019-02-15 |
| Non-clinical evaluation inactive | 2019-02-15 |
| Clinical/medical evaluation inactive | 2019-02-15 |
| Submission cancelled by sponsor | 2019-02-15 |
| New Drug Submission Control Number: 252068 | |
| Pre-submission meeting | 2019-11-25 |
| New Drug Submission filed | 2021-04-23 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2021-06-14 |
| Review 1 | |
| Review of Risk Management Plan completed | 2022-02-16 |
| Non-clinical evaluation completed | 2022-04-05 |
| Clinical/medical evaluation completed | 2022-04-05 |
| Quality evaluation completed | 2022-04-06 |
| Biostatistics evaluation completed | 2022-04-08 |
| Labelling review completed | 2022-04-08 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2022-04-08 |
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 Semglee 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 Semglee 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.
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
As described above, the review of the quality component of the New Drug Submission for Semglee was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Semglee was developed as a biosimilar to the reference biologic drug, Lantus. 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.
This submission was originally filed as a submission under control number 202772 in February of 2017. It received a Notice of Deficiency (NOD) on December 20, 2017. A Response to the NOD was received on April 30, 2018. Health Canada identified some major concerns centred on the precision and accuracy of the in-house reversed-phase high-performance liquid chromatography (RP-HPLC) test method for the quantification of insulin glargine. Significant variability was observed in the results generated from this test method and was noted in the biosimilarity assessment, batch analyses results, stability results, and process validation. The variability was such that it precluded Health Canada from arriving at a conclusion regarding the biosimilarity of Semglee to the reference biologic drug and demonstrated a failure in the manufacturing process of being capable of consistently producing material of the desired product quality. On February 15, 2019, the sponsor elected to cancel the submission.
This submission under control number 252068 included a detailed approach to address the issue of assay variability in the RP-HPLC assay test method. The results from the revised method displayed consistently low variability and demonstrate that the RP-HPLC assay-related concerns present in the initial submission have been satisfactorily addressed.
The biological activity of Semglee is considered to be representative of the mechanism of action and pharmacological effect of Lantus.
Comparative Structural and Functional Studies
The sponsor performed head-to-head studies of primary, secondary, and higher-order structures, content by RP-HPLC, in vitro/in vivo activity, and aggregates by size exclusion high-performance liquid chromatography (SE-HPLC) to compare the drug substance (insulin glargine) and drug product (Semglee) to Lantus sourced from the United States (Lantus‑US) and from the European Union (Lantus‑EU). All results for Semglee were well within the quality ranges and showed limited variability. Overall, Semglee was found to be highly similar to the reference biologic drug in terms of physicochemical, functional, and stability studies.
Characterization of the Drug Substance
The drug substance manufacturing process has been optimized and scaled up during development. The changes introduced at each generation of the manufacturing process were adequately described and comparatively addressed. The sponsor performed two drug substance comparability studies whereby manufacturing processes IV and V and manufacturing processes V and VI (the to-be-marketed process) were assessed. All results from batch analyses, long term and accelerated stability data, forced degradation studies, and extended characterization met the acceptance criteria. Collectively, these findings demonstrate that the drug substance materials are comparable across development, with improvements in purity over time.
Manufacturing Process of the Drug Substance and Drug Product and Process Controls
The manufacture of the Semglee drug substance consists of a series of stages which include cell expansion, cell separation, enzyme reaction, precipitation, purification, lyophilization, and storage. Controls of critical steps of the drug substance manufacturing process were established during manufacturing development and were based on a risk assessment and the results of process characterization.
The results of process validation studies demonstrated that the manufacturing process is capable of consistently producing drug substance with the desired product quality.
Semglee is supplied as a functional pre-filled pen for subcutaneous injection. The manufacture of the Semglee drug product consists of formulation, sterile filtration, and aseptic filling into cartridges followed by sealing, visual inspection, and release testing. A cartridge is assembled into a pen injector system composed of a pen cap, cartridge holder, and pen body subassembly. The pre-filled pens are assembled using automated machinery with 100% visual inspection.
Controls of critical steps of the drug product manufacturing process were established during manufacturing development, and were based on a risk assessment and the results of process characterization. Process validation was conducted at commercial scale and demonstrated that the manufacturing process is capable of consistently manufacturing drug product with the desired product quality.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of insulin glargine with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
Specifications and their limits were set to ensure the overall quality, safety, purity, potency, and identity of the drug substance, insulin glargine. The proposed acceptance criteria were established in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, as well as release and stability data obtained for drug substance and drug product lots. Acceptance criteria were set based on published limits, stability limits, and non-stability limits. All non-compendial test methods were validated and found to be suitable for the intended purpose. All drug substance batches met the release and stability specifications.
The proposed release and stability specifications for the Semglee drug product were established based on ICH guidelines, manufacturing experience, and batch release and stability testing. All drug product batches met the release and stability acceptance criteria.
Semglee 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.
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 when stored at 2 to 8 °C and the proposed in-use shelf life of 28 days when stored between 15 to 30 °C is considered acceptable for the Semglee drug product when protected from light.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
An on-site evaluation of the facility involved in the manufacture and testing of Semglee drug substance and drug product was waived since the facility was recently evaluated and obtained a satisfactory rating.
Adventitious Agents Safety Evaluation
The drug substance and drug product manufacturing processes incorporate adequate control measures to prevent contamination and maintain microbial control. The cell banks, drug substance, and drug product are tested during production to ensure the absence of bioburden and endotoxin. Viral clearance studies were not performed as the Semglee drug substance is manufactured in Pichia pastoris cells that do not support the growth of viruses.
No raw materials of animal origin are used in the preparation of the Research Cell Bank or the manufacture of the drug substance and drug product.
7.2 Non-Clinical Basis for Decision
As described above, the review of the non-clinical component of the New Drug Submission for Semglee was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
The non-clinical data submitted in support of the proposed use of Semglee included data comparing the pharmacodynamics and toxicology of Semglee to those of Lantus, the reference biologic drug.
Results from in vitro pharmacodynamic assays demonstrated biosimilarity between Semglee and insulin glargine sourced from the United States (Lantus‑US) and the European Union (Lantus‑EU) in terms of binding affinity to Insulin Receptor A, Insulin Receptor B, and Insulin Growth Factor 1 Receptor; potency for promoting insulin receptor phosphorylation; and cell based mitogenic and metabolic potency.
In the pivotal comparative 28‑day repeat-dose toxicity study (Study U-16176), rats were administered Semglee or reference insulin glargine (Lantus‑US) at doses of 0.08, 0.16, or 0.38 mg/kg by subcutaneous injection once per day (equal to 2.2, 4.4, and 10.45 International Units/kg per day, respectively). Two deaths were observed in males administered high-dose Semglee, which were attributed to treatment-related hypoglycemia. Hypoglycemic deaths are generally expected when healthy rats are administered insulins and such deaths were reported in previous studies conducted with reference insulin glargine. The rats that received Semglee did not develop any toxicity or tolerability concerns that differed from those given reference insulin glargine.
The data submitted were in compliance with the requirements for non-clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document, and are considered to provide supportive evidence of the similarity of Semglee and Lantus. The results of the comparative non-clinical studies as well as the potential risks to humans have been included in the Semglee Product Monograph. In view of the intended use of Semglee, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Semglee Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Clinical basis for decision
As described above, the review of the clinical component of the New Drug Submission (NDS) for Semglee was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
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.
This submission was a refiling of a previous submission under control number 202772. A Notice of Deficiency (NOD) was issued to the Sponsor on December 20, 2017 due to deficiencies in the pivotal comparative bioavailability study (GLARGCT100111) for that submission. A response to the NOD was received from the Sponsor on April 30, 2018, however, the Sponsor ultimately withdrew the submission on February 15, 2019.
A total of four new comparative studies were submitted in this NDS to provide support for the determination of biosimilarity between Semglee and the reference biologic drug Lantus.
Comparative Pharmacokinetic and Pharmacodynamic Studies
The primary activity of insulin glargine, the medicinal ingredient in Semglee, is the regulation of glucose metabolism. Insulin and its analogues lower blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.
Under the previous submission under control number 202772, a NOD was issued to the Sponsor due to deficiencies in the pivotal comparative bioavailability study (GLARGCT100111). These deficiencies were centered on the sensitivity of the detection method for plasma insulin glargine, the exclusion of >33% of patients from the primary pharmacokinetic analysis for area under the concentration-time curve (AUC), and the failure of the pharmacodynamic endpoint (the area under the glucose infusion rate curve [AUCGIR]) to meet pre-specified margins for bioequivalence.
In the response to the NOD, the post-hoc analysis conducted on study GLARGCT100111 was not deemed sufficient. This was due to continuing concerns regarding participant exclusion from the analyses and post hoc data handling rules, a low statistical power for the assessment of pharmacodynamics, and a lack of sample reanalysis using a sufficiently sensitive detection method.
This submission under control number 252068 addresses the gaps in the previous submission via two Phase I single-dose, replicative crossover euglycemic clamp comparative bioavailability studies performed in healthy subjects (MYL-1501D-1003 and MYL-1501D-1004). A new insulin glargine detection assay was also developed for these studies.
Study MYL-1501D-1003 was a Phase I randomized, double-blind, single-dose, three-treatment, six-period, six-sequence, fully-replicated, euglycemic glucose clamp study conducted in 95 healthy subjects, of which 88 subjects contributed to the pharmacokinetic dataset, while 87 subjects contributed to the pharmacodynamic dataset. The primary objective of this study was to assess the comparative bioavailability of insulin glargine between two manufacturing processes of Semglee (Process V and VI) and the reference biologic drug (Lantus sourced from the United States [Lantus‑US]). The to-be-marketed formulation of Semglee is manufactured by Process VI. The data submitted were in compliance with the requirements outlined in Health Canada’s Guidance Document: Conduct and Analysis of Guidance on Comparative Bioavailability Studies.
The primary pharmacokinetic endpoints of this study were the maximum observed insulin glargine metabolite 1 (M1) concentration (Cmax) and the area under the insulin glargine M1 concentration-time curve from 0 to 24 hours (AUC0-24). The primary pharmacodynamic endpoints were the maximum glucose infusion rate (GIRmax) and the area under the glucose infusion rate curve from 0 to 24 hours (AUCGIR 0-24). These pharmacokinetic and pharmacodynamic endpoints are considered appropriate.
The geometric least squares mean ratios between all treatment arms met Health Canada’s pre-specified criteria for bioequivalence of 80% to 125%. The geometric least squares mean ratio for Cmax (90% confidence interval [CI]) was 99.99% (95.30%, 104.33%), and was 99.33% (95.11%, 103.22%) for the AUC0-24 between Semglee (Process VI) and Lantus‑US.
Comparative bioavailability assessment of the pharmacodynamic endpoints was performed using published methods for a highly variable drug product (HVDP). This was deemed acceptable given that the intra- and inter-subject variability of the euglycemic clamp data was above the 30% threshold for a HVDP. These means and CIs were within Health Canada’s pre-specified criteria for bioequivalence across all treatment arms. The geometric least squares mean ratio (95% CI) for GIRmax was 99.56% (-0.0819) and the AUCGIR 0-24 was 98.05% (-0.1129) between Semglee (Process VI) and Lantus‑US.
Study MYL-1501D-1004 was a multicentre, randomized, double-blind, single-dose, 4-way cross-over, fully replicated, 2-treatment, 24-hour euglycemic glucose clamp trial in 48 healthy volunteers. Of these, 40 subjects were included in the pharmacokinetic analysis set, with 45 subjects were included in the pharmacodynamic analysis set. The primary objective of this study was to assess the comparative bioavailability of Semglee when administered from a vial or the to-be-marketed cartridge formulation. The geometric least squares mean (90% CI) between the vial and cartridge presentations for the primary pharmacokinetic endpoints were 97.82% (90.33%, 105.94%) for the AUC0-24, and 97.80% (91.55%, 104.48%) for the Cmax. The geometric least squares means for the pharmacodynamic endpoints (95% CI) were 99.98% (92.83%, 107.68%) for the AUCGIR 0-24 and 99.54% (92.39%, 107.24%) for the GIRmax. Both the primary pharmacokinetic and primary pharmacodynamic endpoints were within Health Canada’s pre-specified criteria for bioequivalence of 80% to 125%.
Overall, the comparative pharmacokinetic and pharmacodynamic studies indicated there are no clinically meaningful differences in pharmacokinetics or pharmacodynamics between the biosimilar and the reference biologic drug.
For further details, please refer to the Semglee Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Clinical Efficacy, Safety, and Immunogenicity
Study MYL-1501D-3003, an extension study of MYL-GAI-3001, was designed as a randomized, open-label, multicentre, switching study. In this study, 127 patients with Type 1 diabetes mellitus were randomized in a 1:1 ratio to undergo one of two treatment regimens. One group was treated with Lantus‑US consistently for a 36‑week duration. The other group was treated with Semglee for a 12‑week treatment period, followed by Lantus‑US for a 12‑week treatment period, and then a final Semglee 12‑week treatment period. The review of this study was limited to assessing comparative efficacy, safety, and immunogenicity data for the purpose of determining if any clinically meaningful differences between the treatment groups would preclude a determination of biosimilarity based on results from the Phase I studies (see Comparative Pharmacokinetic and Pharmacodynamic Studies).
In Study MYL-1501D-3003, no clinically meaningful differences in efficacy were observed with respect to change in glycosylated hemoglobin (HbA1c) from baseline to Week 36 between the treatment group that switched between Semglee and Lantus‑US and the Lantus‑US-only treatment group, with a least squares mean difference of 0.01 (95% CI: ‑0.089, 0.101). No clinically meaningful differences were noted in the type, frequency, seriousness, or severity of treatment-emergent adverse events (TEAEs) over the 36‑week treatment period. Immunogenicity data revealed no clinically relevant differences in the incidence of titer of anti-drug antibodies between Semglee and Lantus‑US throughout the treatment period. Anti-drug antibody titer did not correlate with any changes in efficacy, and the incidence of neutralizing antibodies was low across all studies.
Study MYL-1501D-3004 was a randomized, double-blind, multicentre, non-inferiority trial of Semglee produced from two manufacturing processes (Process V and Process VI) in combination with insulin lispro in a total of 219 patients with Type 1 diabetes mellitus. The to-be-marketed product used manufacturing Process VI; however, Process V was used for the comparative clinical efficacy and safety studies. Therefore, this study provides additional supportive bridging data by assessing comparative efficacy and safety data between Process V and Process VI. Its primary efficacy endpoint was met by demonstrating that Semglee manufactured using Process VI is non-inferior to Semglee manufactured using Process V at the pre-specified 0.4% non-inferiority margin with respect to change in HbA1c from baseline to Week 18 with a least squares mean difference of ‑0.03 (95% CI: ‑0.171, 0.110).
No clinically meaningful differences between manufacturing Process V and VI were noted in the type, frequency, seriousness, or severity of TEAEs over the 18‑week treatment period. The incidence of severe hypoglycemia (2.8% in the Process V group vs. 3.6% in the Process VI group) and local/systemic allergic reactions (0 cases in the Process V group vs. 1 case in the Process VI group) was comparable between manufacturing processes. No clinically relevant differences were observed in anti-drug antibody incidence or titer between Semglee manufactured via Process V or Process VI (the to-be-marketed product).
Overall, the efficacy, safety, and immunogenicity profile of Semglee is considered to be comparable to that which has been established for the reference biologic drug Lantus.
Appropriate warnings and precautions are in place in the approved Semglee Product Monograph to address the identified safety concerns, as is found in the Product Monograph for Lantus. As with Lantus, a Serious Warnings and Precautions box describing the risk of hypoglycemia and uncorrected hypoglycemic or hyperglycemic reactions, as well as important dosage and administration considerations, is in place in the approved Semglee Product Monograph to address the identified safety concerns.
For more information, refer to the Semglee Product Monograph, approved by Health Canada and available through the Drug Product Database.
Indications
Semglee is considered to be biosimilar to Lantus, the reference biologic drug. Lantus is authorized and marketed in Canada for multiple indications and clinical uses. Specifically, Lantus is authorized for once-daily subcutaneous administration in the treatment of patients over 17 years of age with Type 1 or Type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia, as well as for the treatment of pediatric patients over 6 years of age with Type 1 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.
Within this drug submission, the sponsor requested the authorization of Semglee for all of the indications that are currently authorized for Lantus.
Similarity between Semglee and Lantus 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 Semglee and the reference biologic drug, in comparative structural, analytical and functional data, as well as data obtained from both non-clinical and clinical studies.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SEMGLEE | 02526441 | BIOCON SDN.BHD | INSULIN GLARGINE 100 UNIT / ML |