Summary Basis of Decision for Admelog

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.

Product type:

Drug

Contact: Office of Regulatory Affairs, Biologic and Radiopharmaceutical Drugs Directorate

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Admelog is located below.

Recent Activity for Admelog

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 Admelog

Updated: 2023-10-31

The following table describes post-authorization activity for Admelog, a product which contains the medicinal ingredient insulin lispro. 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 Anchor List of abbreviations found in Post-Authorization Activity Tables (PAATs).

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

Drug Identification Numbers (DINs):

DIN 02469901 - insulin lispro 100 units/mL solution (vial), subcutaneous injection
DIN 02469898 - insulin lispro 100 units/mL solution (cartridge), subcutaneous injection
DIN 02469871 - insulin lispro 100 units/mL solution (SoloStar prefilled pen), subcutaneous injection

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number	Date Submitted	Decision and Date	Summary of Activities
SNDS # 269271	2022-10-31	Issued NOC 2023-05-29	Submission filed as a Level I – Supplement for changes to the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 267481	2022-08-30	Issued NOL 2022-10-14	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 253748	2021-06-14	Issued NOC 2021-12-03	Submission filed as a Level I – Supplement to correct a discrepancy in the PM to ensure proper use of Admelog. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to Part III: Patient Medication Information of the PM and to the package inserts. An NOC was issued.
SNDS # 247793	2020-12-21	Issued NOC 2021-05-20	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information regarding localized cutaneous amyloidosis. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; Dosage and Administration; and Clinical Pharmacology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package inserts. An NOC was issued.
NC # 231963	2019-09-26	Issued NOL 2019-11-27	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a modification of a primary container closure system. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DINs 02469898, 02469901, 02469871) market notification	Not applicable	Date of first sale: 2019-11-22	The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 231645	2019-09-16	Issued NOC 2019-11-22	Submission filed as a Level I – Supplement to update the PM with safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to Part III: Patient Medication Information of the PM and to the package insert. An NOC was issued.
SNDS # 230563	2019-08-08	Issued NOC 2019-10-18	Submission filed as a Level I – Supplement to update the foil label on the cartridge tray. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 213712	2018-02-16	Issued NOC 2018-04-30	Submission filed as a Level I – Supplement to update the Admelog PM, labels and package inserts to include mention of the new AllStar PRO reusable pen, to be used with the existing cartridges. The submission was reviewed and considered acceptable, and an NOC was issued.
NDS # 200792	2016-11-30	Issued NOC 2017-11-16	Notice of Compliance issued for New Drug Submission.

Summary Basis of Decision (SBD) for Admelog

Date SBD issued: 2017-12-28

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

Insulin lispro
100 units/mL, solution, subcutaneous injection

Drug Identification Number (DIN):

DIN 02469901 - 100 units/mL solution (vial)
DIN 02469898 - 100 units/mL solution (cartridge)
DIN 02469871 - 100 units/mL solution (SoloStar prefilled pen)

Sanofi-aventis Canada Inc.

New Drug Submission Control Number: 200792

On November 16, 2017, Health Canada issued a Notice of Compliance (NOC) to Sanofi-aventis Canada Inc. for Admelog, a biosimilar to Humalog (the reference biologic drug, marketed by Eli Lilly Canada Inc.). 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. Admelog and Humalog contain highly similar versions of the medicinal ingredient, insulin lispro.

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

The demonstration of similarity between the biosimilar and its reference biologic drug enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

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

In this drug submission, Humalog is the reference biologic drug. Similarity between Admelog and Humalog 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 Admelog for the indications that are currently authorized for Humalog (100 units/mL).

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 Admelog (insulin lispro injection) is considered to be highly similar to that of the reference biologic drug for the treatment of patients with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis. Admelog insulin is also indicated for the initial stabilization of diabetes mellitus. Admelog (insulin lispro injection) is a short acting insulin analogue and is for use in conjunction with a longer acting insulin, except when used in a subcutaneous insulin infusion pump.

1 What was approved?

Admelog (insulin lispro injection), an anti-diabetic agent, was authorized for the treatment of patients with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis. Admelog insulin is also indicated for the initial stabilization of diabetes mellitus. Admelog (insulin lispro injection) is a short acting insulin analogue and is for use in conjunction with a longer acting insulin, except when used in a subcutaneous insulin infusion pump.

Admelog is a biosimilar to Humalog. Both drugs contain the medicinal ingredient, insulin lispro. Insulin lispro is produced by recombinant deoxyribonucleic acid (rDNA) technology utilising Escherichia coli as the production organism.

Similarity between Admelog and the reference biologic drug, Humalog, has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, comparative bioavailability studies, and clinical studies in patients with diabetes mellitus, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Admelog is contraindicated during episodes of hypoglycemia and in patients sensitive to insulin lispro or any of the excipients.

Admelog 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.

Admelog (100 units/mL insulin lispro) is presented as a solution. In addition to the medicinal ingredient, the solution contains m-Cresol, glycerol, dibasic sodium phosphate, water for injections, and zinc oxide. Hydrochloric acid and sodium hydroxide may be used to adjust the pH to 7.0-7.8.

For more information, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.

Additional information may be found in the Admelog Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Admelog approved?

Health Canada considers that the benefit-risk profile of Admelog is highly similar to that of the reference biologic drug, Humalog, for the treatment of patients with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis, for the initial stabilization of diabetes mellitus, and for use in conjunction with a longer acting insulin, except when used in a subcutaneous insulin infusion pump. Similarity between Admelog and Humalog was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Admelog is considered to be biosimilar to Humalog. Humalog is a short acting insulin analogue authorized for the treatment of diabetes mellitus in patients who require insulin for the maintenance of normal glucose homeostasis and for the initial stabilization of diabetes mellitus. Humalog has been authorized in Canada since 1996 and has an established favourable benefit/risk profile for the treatment of diabetes mellitus.

Diabetes mellitus is a chronic disease characterized by hyperglycemia from defects in insulin secretion, insulin action, or both. It has been established that uncontrolled, high levels of blood glucose are a factor for chronic microvascular and macrovascular complications that can result in retinopathy, nephropathy, neuropathy and premature cardiovascular morbidity and mortality. Studies have shown that improving the control of blood glucose levels in patients with diabetes mellitus reduces the risk of these complications.

The New Drug Submission (NDS) filed for Admelog requested authorization for the indications and clinical uses that are currently authorized for Humalog (100 units/mL). The indications have been authorized on the basis of demonstrated similarity between Amalog and the reference biologic drug.

To support the similarity of Admelog to Humalog, the sponsor provided evidence of comparable pharmacokinetic and pharmacodynamic (PK/PD) activity of Admelog and Humalog in adult patients with type 1 diabetes mellitus (T1DM). The results from Study PDY12704 are considered valid and support the demonstration of biosimilarity between Admelog and the reference product, Humalog. No issues were identified in this review that would preclude the issuance of a Notice of Compliance for Admelog for the same indications as Humalog. The PK/PD information for Admelog and the comparative PK/PD information that supported biosimilarity of Admelog to Humalog are adequately reported in the Admelog Product Monograph.

Clinical studies were also conducted to support the similarity between Admelog and Humalog. Two Phase III, randomized, active-controlled clinical studies in adult patients with T1DM (Study EFC12619) and type 2 diabetes mellitus (T2DM, Study EFC13403) showed no clinically meaningful differences in safety, efficacy, or immunogenicity between Admelog and Humalog.

In each of the Phase III clinical studies, Admelog was non-inferior to Humalog in terms of the change in glycated hemoglobin (HbA1c) from baseline to Week 26 at the 0.3% non-inferiority margin. Both studies support the clinical similarity of Admelog and Humalog for the control of hyperglycemia in patients with T1DM and T2DM.

The adverse drug reaction profiles for Admelog and Humalog were also comparable. In both Phase III studies, the types, frequency and severity of adverse events were comparable between the biosimilar and the reference biologic drug. A Serious Warnings and Precautions box describing serious warnings and precautions has been included in the Product Monograph for Admelog, as is found in the Product Monograph for Humalog.

On the basis of the study results mentioned above, and considering the similarity demonstrated in comparative structural, functional, and non-clinical studies, the totality of data supports the authorization of Admelog for the same authorized indication as Humalog (100 units/mL).

A Risk Management Plan (RMP) for Admelog was submitted by Sanofi-aventis Canada Inc. 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 Admelog was accepted. The submission was also cleared from a labelling perspective.

Overall, the therapeutic benefits of Admelog therapy are expected to be similar to the known benefits of the reference biologic drug, Humalog and are considered to outweigh the potential risks.

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

3 What steps led to the approval of Admelog?

Submission Milestones: Admelog

Submission Milestone	Date
Pre-submission meeting:	2016-09-28
Submission filed:	2016-11-30
Screening
Screening Acceptance Letter issued:	2017-01-20
Review
On-Site Evaluation:	2017-03-20 - 2017-03-24
Quality Evaluation complete:	2017-10-11
Clinical Evaluation complete:	2017-11-09
Biostatistics Evaluation complete:	2017-11-09
Review of Risk Management Plan complete:	2017-07-04
Labelling Review complete, including Look-alike Sound-alike brand name assessment:	2017-11-15
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate:	2017-11-16

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

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

The onus is on the Admelog 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 Admelog Product Monograph as appropriate. New safety issues that are first identified with the biosimilar, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both the biosimilar and the reference biologic drug. For more information, refer to the Fact Sheet: Biosimilars.

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

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Admelog is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

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

Admelog was developed as a biosimilar to the reference biologic drug, Humalog. For biosimilars, the weight of evidence is provided by structural and functional studies. In addition to a typical chemistry and manufacturing data package that is submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity with the reference biologic drug.

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

Comparative Structural and Functional Studies

Admelog is a biosimilar to the reference biologic drug, Humalog. Humalog from the European Union (EU) was identified by the sponsor as the reference product; however Humalog sourced from the United States was also included in the biosimilarity assessment. The EU and United States Humalog formulations are deemed to be similar to the Canadian formulation of Humalog.

Detailed similarity studies evaluated the physicochemical properties and the stability of Admelog against Humalog EU and Humalog United States. Studies confirmed similarity of primary, secondary, tertiary, and higher order structures, as well as activity. Formulation content (assay insulin lispro, content m-cresol, pH, and zinc) were comparable to label values of Humalog. The in vitro pharmacology was assessed, examining receptor affinity, activation, and binding kinetics, as well as downstream effects on metabolic activity, mitogenic potency, and glucose uptake, with comparable results. The levels of impurities and high molecular weight proteins were highly similar, as supported by statistical analysis. Stability studies investigating in-use, long-term, accelerated, and stressed conditions, as well as photostability, demonstrate similar stability profiles and degradation pathways. Taken together, the data provided by the sponsor supports biosimilarity between Admelog and Humalog; therefore, the claim of biosimilarity was considered acceptable.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that the drug substance, insulin lispro, consistently exhibits the desired characteristic structure and biological activity.

Insulin lispro is identical in structure to human insulin except for amino acids 28 and 29 of the B-chain; the analogue is Lys(B28) Pro(B29) whereas human insulin is Pro(B28) Lys(B29).

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

The drug substance, insulin lispro is produced by recombinant deoxyribonucleic acid (rDNA) technology utilising Escherichia coli as the production organism.

The drug substance manufacturing process consists of cultivation steps (fermentation and harvest), basic downstream processing, and purification steps by chromatography, followed by precipitation and drying.

The drug product manufacturing process consists of dissolving weighed drug substance into the formulated buffer solution to become the drug product. The drug product then undergoes fill, and finish operations.

The commercial drug substance process was successfully validated at the commercial scale. The validation batches consistently met the predefined ranges for operational parameters and the specifications for performance parameters. The batch analysis data for final drug substance batches were of consistent and comparable quality, and were well within the specifications. The commercial scale material was evaluated and found to be comparable to material from earlier processes used in the clinical studies.

The commercial drug product process was successfully validated. Analysis of the release and stability data demonstrated that the quality of the drug product produced was comparable and well within the current acceptance criteria. Appropriate and recent media fill data was provided to demonstrate that the sponsor is able to manufacture in an aseptic manner.

Control of the Drug Substance and Drug Product

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

A variety of different approaches were implemented to ensure the consistent production of Admelog. These methods include design control, process control, raw material control, in-process control testing, release testing, stability testing, process performance qualification testing, and characterization. In addition, continued process verification will be performed during initial commercial production to gain sufficient data for statistical evaluation in order to detect relevant process trends and to assess the quality of incoming materials, in-process material, and finished drug substance. The proposed commercial release and stability specifications for Admelog have been appropriately justified and are acceptable.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life at 2° and 8°C for Admelog (unopened) is considered acceptable. Once opened, the vial or cartridge must be kept at room temperature below 30°C and must be used within 28 days or be discarded.

The container closure system was evaluated for compatibility with the drug product, safety, product protection, performance, and transportation impact. It was demonstrated that the drug product container closure system is suitable for its intended use.

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 (OSE) of the facility involved in the manufacture and testing of the drug substance and the drug product has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.

Adventitious Agents Safety Evaluation

No animal and/or human derived material is used in the manufacture of Admelog. This applies to the drug substance and all drug product excipients used for the manufacture of Admelog. The drug product complies with the requirements of the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01 Rev. 3).

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 Admelog 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.

Admelog is a biosimilar to the reference biologic drug, Humalog. Humalog from the European Union (EU) was identified by the sponsor as the reference product; however Humalog sourced from the United States was also included in the biosimilarity assessment. Both of the EU and United States Humalog formulations are deemed to be similar to the Canadian formulation of Humalog.

Based on non-clinical pharmacology studies, Admelog had similar pharmacodynamic properties compared with Humalog-EU and Humalog- United States (solution for injection, 100 units/mL), including binding affinity to Insulin Receptor (IR)-B, IR-A and Insulin-like Growth Factor (IGF)-1R, binding kinetics to IR-B and IR-A, induction of autophosphorylation of IR-B, IR-A and IGF-1R, metabolic activity by inhibition of lipolysis, glucose uptake and gene regulation of glucose 6-phosphatase, and mitogenic potency by stimulation of radiolabelled thymidine incorporation into DNA.

Non-clinical toxicology studies demonstrated a similar toxicological profile of Admelog compared to Humalog (solution for injection, 100 units/mL). Twice daily subcutaneous administration of Admelog or Humalog (United States or EU) at 0, 5, 25, or 100 units/Kg for 29 days was associated with a similar increase in body weight and food consumption, and a similar effect on blood glucose levels in male and female rats. In rabbits, no local tolerance issue was identified following single-dose administration of Admelog or Humalog via subcutaneous, intravenous, paravenous, and intramuscular injection.

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

For more information, refer to the Admelog 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 degree of similarity at the quality level determines the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Comparative Pharmacokinetic and Pharmacodynamic Studies

Insulin lispro, the active pharmaceutical ingredient in Admelog, is created by inverting the natural Pro-Lys sequence in human insulin at positions 28 and 29 in the C-terminal portion of the B-chain. This change in amino acid sequence slightly modifies the physicochemical properties of the molecule relative to native human insulin in such a manner that insulin lispro self-associates less avidly and dissociates into its monomeric form more rapidly than regular insulin. As a result, insulin lispro is absorbed more rapidly than regular soluble insulin from subcutaneous sites of injection and also has a shorter duration of action.

The primary activity of insulins, including Admelog, is the regulation of glucose metabolism. In addition, all insulins have several anabolic and anti-catabolic actions on many tissues in the body. In muscle and other tissues (except the brain), insulin causes rapid transport of glucose and amino acids intracellularly, promotes anabolism, and inhibits protein catabolism. In the liver, insulin promotes the uptake and storage of glucose in the form of glycogen, inhibits gluconeogenesis and promotes the conversion of excess glucose into fat.

Pharmacokinetic (PK) properties were compared, between Admelog and two regionally sourced versions of Humalog (United States, EU), in a randomized, double-blind, 3-treatment, 3-period, 6-sequence cross-over study. Thirty fasted male type 1 diabetes mellitus (T1DM) patients received single subcutaneous administrations of insulin lispro (Admelog or Humalog US/EU) on 3 separate occasions. A fully validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method was employed to detect insulin lispro concentrations immediately before and at timepoints up to 12-hours post subcutaneous administration. The ratios of the geometric mean area under the concentration versus time curve to the last quantifiable concentration (AUC_T) and 90% confidence intervals (CI) were fully contained within 80% to 125% for each comparison. The ratios of the geometric mean maximum concentrations (C_max) were also contained within 80% to 125%. Based on these data, Admelog is considered to have comparable pharmacokinetics to the reference product Humalog.

As a component of the study described above, a euglycemic clamp procedure, lasting up to 12 hours, was conducted to comparatively assess the pharmacodynamic (PD) effect of Admelog against the two regionally sourced versions of Humalog. The primary PD endpoint was the area under the body weight standardized glucose infusion rate (GIR) vs. time curve from 0 to 12 hours post-investigational medicinal product administration (GIR-AUC_0-12). The maximum GIR was a key secondary endpoint. The treatment ratios and 95% CIs for the GIR-AUC_0-12, which reflects the metabolic effect of insulin, were within pre-defined and accepted criteria when Admelog was compared to either version of Humalog. In addition, the mean maximum GIR ratio and 95% CI also fell within 80% to 125% in both instances. Based on the data described, no clinically meaningful differences have been observed in the level of blood glucose control offered by Admelog in comparison to either version of Humalog.

Overall, the methods employed to measure insulin lispro serum concentrations as well as to measure the PD effect are considered to be of high quality. Based on this high quality PK/PD study, Admelog can be considered to be highly similar, in terms of pharmacokinetics and pharmacodynamics, to both Humalog- United States and Humalog-EU. In addition, there was no evidence that the two regionally sourced Humalog products had PK or PD differences that would preclude them being used together in the Phase III clinical studies.

No clinically meaningful differences, between the biosimilar and the reference biologic drug, were identified in the comparative bioavailability study submitted.

Comparative Clinical Efficacy, Safety, and Immunogenicity Studies

Two Phase III comparative clinical studies were conducted to investigate clinically meaningful differences in the clinical efficacy, safety, and immunogenicity of Admelog and Humalog: Study EFC12619 in adult patients with type I diabetes mellitus (T1DM) and Study EFC13403 in patients with type II diabetes mellitus (T2DM).

Study EFC12619 was a randomized, open-label, multicentre, non-inferiority study of Admelog vs. Humalog in T1DM patients. Both treatment arms also received long-acting insulin glargine (LANTUS). A total of 507 adult T1DM patients were randomized to receive Admelog (number of patients [n] = 253) or Humalog (n = 254) for a primary treatment period of 6 months, followed by a 6-month treatment extension period.

Study EFC13403 was a 6-month, open-label, randomized, multicentre, non-inferiority study to compare Admelog vs. Humalog in adult T2DM patients. Both treatment arms also used LANTUS. A total of 505 patients were randomized to receive either Admelog (n = 253) or Humalog (n = 252).

Efficacy

Both studies met their primary efficacy endpoint by demonstrating that Admelog was non-inferior to Humalog at the pre-specified 0.3% non-inferiority margin with respect to the change in glycated hemoglobin (HbA1c) from baseline to Week 26. In Study EFC12619, the Least Square (LS) mean difference was 0.06% (95% CI: -0.084 to 0.197) and in Study EFC13403 the LS mean difference was -0.07% (95% CI: -0.215 to 0.067). Secondary endpoints, including the change in fasting plasma glucose, did not indicate any clinically meaningful differences between the two treatment groups. To further support comparability, the mealtime insulin dose and total insulin dose between the Admelog and Humalog groups were similar, indicating that the individualized insulin dosing did not bias the data towards comparable hyperglycemia control. These data support the clinical similarity of Admelog and Humalog for the control of hyperglycemia in patients with T1DM and T2DM.

Safety

In Study EFC12619, no clinically meaningful differences were noted in the type, frequency, or severity of treatment-emergent adverse events (TEAEs). In particular, the incidence of severe hypoglycemia (Admelog13.5%, Humalog 13.4%), hypersensitivity (Admelog 5.2%, Humalog 3.9%), and injection site reactions (Admelog 1.2%, Humalog 1.2%) was comparable between the two groups over the 52-week treatment period. One death was reported for a patient receiving Admelog due to cardiac disease. This death was not considered related to the investigational product.

In Study EFC13403, the percentage of patients with hypoglycemia was comparable between the Admelog and Humalog groups. The rate of severe hypoglycemia was higher with Admelog (9 events, 0.08 per patient-year) than with Humalog (4 events, 0.03 per patient-year) due to 1 patient who reported 4 events in the Admelog group. The TEAEs were experienced by a similar proportion of patients in each group (Admelog 46.6%, Humalog 42.9%). The percentage of patient with serious TEAEs was lower in the Admelog group (5.5%) than in the Humalog group (10.7%). Hypersensitivity (Admelog: 4.3%, Humalog 3.6%) and injection site reactions (Admelog 0.4%, Humalog 1.6%) were reported in a similar percentage of patients in each group. One patient in the Admelog group and 2 patients in the Humalog group died during the study. These deaths were not considered related to the study treatments.

Immunogenicity

Anti-insulin antibodies (AIAs) were measured in Study EFC12619 (T1DM) and Study EFC13403 (T2DM) using a validated radioimmuno-assay.

In Study EFC12619, the percentage of T1DM patients with detectable anti-insulin antibodies (AIAs) was comparable at baseline (Admelog 47.4%, Humalog 49.2%), at Week 26 (Admelog 45.6%, Humalog 50.2%), and at Week 52 (Admelog 44.8%, Humalog 47.2%). No differences were observed in the proportion of patients with at least one positive AIA sample (Admelog 62.5%, Humalog 63.1%) or the incidence of treatment-emergent AIAs (Admelog 22.6%, Humalog 24.2%) over the 52-week treatment period. An in vitro assay to determine the neutralizing capacity of the binding antibodies was not conducted. However, the sponsor demonstrated that safety and efficacy outcomes were not impacted by treatment-emergent AIA status or AIA titre.

In Study EFC13403, similar percentages of patients in the Admelog group (38.4%) and Humalog group (36.7%) were positive for AIAs for at least one timepoint between baseline and Month 6. The incidence of treatment-emergent AIAs was higher in the Admelog group (18.8%) compared with the Humalog group (14.5%). However, there was no evidence that treatment-emergent AIA impacted efficacy or safety. Also, there was no relationship between the AIA titres and efficacy or safety parameters, regardless of treatment-emergent AIA status.

Based on the Phase III studies, no clinically meaningful differences in immunogenicity were observed between the biosimilar and the reference biologic drug, in patients with diabetes mellitus.

Indications

Admelog is considered to be biosimilar to Humalog, the reference biologic drug. Similarity between Admelog and Humalog 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 Admelog for the same indications that are currently authorized for Humalog (100 units/mL).

The demonstration of similarity between the biosimilar and its reference biologic drug enables the biosimilar, Admelog, to be authorized with the same indications as Humalog (100 units/mL).

Health Canada authorized the following indications:

Admelog (insulin lispro injection) is indicated for the treatment of patients with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis. Admelog insulin is also indicated for the initial stabilization of diabetes mellitus. Admelog (insulin lispro injection) is a short acting insulin analogue and is for use in conjunction with a longer acting insulin, except when used in a subcutaneous insulin infusion pump.