Summary Basis of Decision for Basaglar

Review decision

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


Product type:

Drug

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

Recent Activity for Basaglar

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 Basaglar

Updated:

2020-10-06

The following table describes post-authorization activity for Basaglar, a product which contains the medicinal ingredient insulin glargine. 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 Guidance.

Drug Identification Numbers (DINs):

  • DIN 02444844 - 100 units/mL, insulin glargine, solution, subcutaneous (Cartridge)
  • DIN 02444852 - 100 units/mL, insulin glargine, solution, subcutaneous (KwikPen)
  • DIN 02461528 - 100 units/mL, insulin glargine, solution, subcutaneous (KwikPen delivers up to 80 units per injection)

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
NC # 2385372020-04-16Issued NOL
2020-06-16
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug product.
DIN (02444852) cancelled (post-market)Not applicableDiscontinuation date:
2019-08-22
The manufacturer notified Health Canada that sale of the drug has been discontinued post-market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
SNDS # 2099622017-10-10Issued NOC
2018-05-10
Submission filed as a Level I - Supplement to add a manufacturing site for the production of the drug product. The information was reviewed and considered acceptable. An NOC was issued.
Drug product (DIN 02461528) market notificationNot applicableDate of first sale:
2017-08-18
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 2061882017-06-01Issued NOL
2017-07-28
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 1968392016-07-15Issued NOC
2017-02-20
Submission filed as a Level I - Supplement for a new drug product manufacturing site. The information was reviewed and considered acceptable. An NOC was issued.
NC # 2002892016-11-15Issued NOL
2017-02-17
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update the PM. As a result of the NC, modifications were made to the Dosage and Administration section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 1968392016-07-15Issued NOC
2017-02-10
Submission filed as a Level I - Supplement to add a secondary container closure system. The information was reviewed and considered acceptable. An NOC was issued. A new DIN (02461528) was issued for the new container closure system.
NC # 1948052016-05-05Cancellation Letter Received
2016-05-20
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a secondary container closure system. The request exceeded the scope of a Notifiable Change. The submission was therefore cancelled administratively by the sponsor, so as to be filed as a Supplemental New Drug Submission.

Drug product (DINs 02444844, 02444852) market notification

Not applicableDate of first sale:
2015-12-18

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

NDS #1774052014-08-29Issued NOC
2015-09-01

Notice of Compliance issued for New Drug Submission.

Summary Basis of Decision (SBD) for Basaglar

Date SBD issued: 2015-10-21

The following information relates to the new drug submission for Basaglar.

Insulin glargine, 100 units/mL, solution, subcutaneous

Drug Identification Number (DIN):

  • DIN 02444844 - 100 units/mL (Cartridge)
  • DIN 02444852 - 100 units/mL (KwikPen)

Eli Lilly Canada Inc.

New Drug Submission Control Number: 177405

On September 1, 2015, Health Canada issued a Notice of Compliance to Eli Lilly Canada Inc. for the drug product, Basaglar.

Basaglar (active ingredient insulin glargine) was filed as a Subsequent Entry Biologic product to the Canadian authorized product, Lantus (active ingredient insulin glargine, marketed by Sanofi-Aventis Canada Inc.). The term "subsequent entry biologic" is used by Health Canada to describe a biologic drug that enters the market subsequent to a version previously authorized in Canada, with demonstrated similarity to a reference biologic drug. In this drug submission, Lantus is the reference product. Similarity between Basaglar and Lantus was established in accordance with the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), for the authorized indications.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Basaglar is 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. Basaglar is also indicated in the treatment of pediatric patients (>6 years old) with type 1 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.

1 What was approved?

Basaglar (insulin glargine) injection is a recombinant human insulin analogue that is a long-acting, parenteral blood-glucose-lowering agent. Basaglar is produced by recombinant deoxyribonucleic acid (rDNA) technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12) as the production organism. Insulin glargine (rDNA) differs from natural human insulin in that the amino acid asparagine at position 21 of the A-chain is replaced by glycine and two arginines are added to the C-terminus of the B-chain. The similarity between the subsequent entry biologic (SEB) product Basaglar and the reference product Lantus (insulin glargine) was established in accordance with the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs).

Basaglar is indicated 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. Basaglar is also indicated in the treatment of pediatric patients (>6 years old) with type 1 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.

Basaglar is contraindicated for patients who are hypersensitive to insulin glargine or to any ingredient in the formulation or component of the container. Basaglar was approved for use under the conditions stated in the Basaglar Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Basaglar (100 units/mL, insulin glargine) is presented as a solution for injection in 3 mL cartridges and in a KwikPen (a 3 mL prefilled pen). The non-medicinal ingredients in the 3 mL cartridges and KwikPen are glycerin, m-cresol, zinc oxide, and water for injection. Hydrochloric acid and sodium hydroxide are added for pH adjustment.

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

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

2 Why was Basaglar approved?

Health Canada considers that the benefit/risk profile of Basaglar is 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. The benefit/risk profile of Basaglar is also favourable in the treatment of pediatric patients (>6 years old) with type 1 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. Insulin glargine, the active ingredient of Basaglar, lowers blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production.

Basaglar is considered comparable to the Canadian authorized drug product Lantus (active ingredient insulin glargine, marketed by Sanofi-Aventis Canada Inc.). Basaglar was filed as a Subsequent Entry Biologic (SEB) to Lantus. Similarity between Basaglar and Lantus was established in accordance with the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), for the indications stated above. See question 1. What was approved?

Insulin glargine, marketed as Lantus, is life-saving pharmacotherapy for patients with type 1 diabetes mellitus (T1DM) and is useful in controlling hyperglycemia in patients with type 2 diabetes mellitus (T2DM). Lantus has been authorized in Canada for over a decade and has proven to be safe and effective in the aforementioned groups of patients and in pediatric (>6 years) patients with T1DM. This New Drug Submission (NDS) was submitted to support the authorization of Basaglar, an SEB to Lantus, for all of the indications and uses currently authorized for Lantus on the basis of comparative physicochemical, biological and clinical studies. Clinical studies have demonstrated that Basaglar provides comparable clinical efficacy with an acceptable safety profile for adult patients with type 1 or type 2 diabetes mellitus. In addition, pharmacokinetic and pharmacodynamic comparability has been satisfactorily demonstrated in healthy volunteers. Authorization for the treatment of pediatric patients >6 years old with T1DM required extrapolation. Scientific rationales and expert opinion submitted by the sponsor were found to be adequate to support extrapolation to pediatric patients with T1DM based on an assessment against the principles of extrapolation as outlined in the Canadian guidance document: Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs). The benefit/risk assessment for Basaglar, in each of the requested indications, was considered positive.

Basaglar has been shown to be efficacious in two Phase III safety and efficacy clinical studies that compared Basaglar and Lantus. The safety profile of Basaglar was consistent with that previously reported for the reference product, Lantus, in patients with T1DM or T2DM. The most frequently reported treatment-emergent adverse events (TEAEs) included nasopharyngitis (Basaglar 9.9%, Lantus 10.4%), upper respiratory tract infection (Basaglar 6.4%, Lantus: 5.6%), and diarrhea (Basaglar 3.3%; Lantus 3.7%).

Hypoglycemia is the most common adverse effect of insulins. Hypoglycemia may occur if the insulin dose is too high in relation to the insulin requirement. A Serious Warnings and Precautions Box describing the risks of hypoglycemia, as well as warnings on the administration of the product have been included in the Basaglar Product Monograph.

A Risk Management Plan (RMP) for Basaglar was submitted by Eli Lilly 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.

Health Canada reviewed the Look-alike Sound-alike report submitted by the sponsor and accepted the proprietary name for the drug product.

Overall, the therapeutic benefits seen in the pivotal studies are comparable to the reference product, Lantus, and the benefits of Basaglar therapy are considered to outweigh the potential risks. Basaglar has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and adequate monitoring. Appropriate warnings and precautions are in place in the Basaglar 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 Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Basaglar?

The Basaglar New Drug Submission (NDS) was filed as a Subsequent Entry Biologic (SEB) product to the Canadian authorized product, Lantus (active ingredient insulin glargine, marketed by Sanofi-Aventis Canada Inc.). The term "subsequent entry biologic" is used by Health Canada to describe a biologic drug that enters the market subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug.

Eli Lilly Canada Inc. developed Basaglar as a similar biological medicinal product to the drug product, Lantus. Both products contain the active ingredient insulin glargine, and have the same formulation.

Submission Milestones: Basaglar

Submission MilestoneDate
Pre-submission meeting:2013-09-06
Submission filed:2014-08-29
Screening
Screening Acceptance Letter issued:2014-10-24
Review
On Site Evaluation:
Quality Evaluation complete:2015-08-11
Clinical Evaluation complete:2015-08-19
Labelling Review complete:2015-08-19
Patent Hold
Submission placed on Patent Hold:2015-08-20
Notice of Compliance issued by Director General:2015-09-01

The Canadian regulatory decision on the non-clinical and clinical review of Basaglar was based on a critical assessment of the Canadian data package. The foreign reviews completed by the United States Food and Drug Administration (FDA) were used as an added reference.

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.

6 What other information is available about drugs?

Pour obtenir des renseignements à jour sur les produits pharmaceutiques, veuillez suivre les liens suivants :

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Basaglar was submitted as a Subsequent Entry Biologic to the reference product Lantus, (marketed by Sanofi-Aventis Canada Inc.). Both products have the same active ingredient insulin glargine. Similarity between Basaglar and Lantus was established in accordance with the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs).

Basaglar demonstrated similarity to Lantus through comparative chemistry and manufacturing studies, comparative non-clinical studies and comparative pharmacokinetic/pharmacodynamic (PK/PD) and clinical studies. The biological activity of Lantus is considered to be representative of the mechanism of action and pharmacological effect of Basaglar. In both products, insulin glargine regulates glucose metabolism. Insulin glargine lowers blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. It also inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.

Two pivotal comparative bioavailability studies were conducted in healthy volunteers. Both studies were a single-site, randomized, double-blind, single-dose, 2-treatment, 4-period, crossover, replicate treatment, euglycemic clamp study. Each study investigated the comparative PK and PD of Basaglar versus (vs.) Lantus sourced from the United States or European Union (EU). A third study of similar design investigated the comparative PK/PD of United States Lantus vs. European Union Lantus thus providing a clinical bridge between the two reference products that allowed for the use of both reference products in the Phase III clinical safety and efficacy studies. Each of the three studies demonstrated comparable PK properties based on the mean area under the plasma concentration time curve (AUC) over the dosing interval (0-24 hours) and the peak plasma concentration.

In each of the PK/PD studies, the effect of insulin on blood glucose was investigated using a euglycemic clamp procedure in which the glucose infusion rate was varied over 24 hours in order to maintain a euglycemic state. The parameters of total glucose infused and maximal glucose infusion rate were the primary endpoints compared to investigate PD similarity. Basaglar was shown to have comparable PD properties to both United States- and European Unionourced Lantus. In addition, United States- and European Union-sourced Lantus were also found to be comparable to each other.

Duration of action was compared in a Phase I, single-site, randomized, subject and investigator blind, single-dose, 2-period, crossover euglycemic clamp study (42 hour duration). In this study, Basaglar and Lantus were compared in 20 patients with type 1 diabetes mellitus (T1DM). The study demonstrated that the two products were comparable with respect to the mean duration of action, which was approximately 24 hours for both products.

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

Clinical Efficacy

Two clinical efficacy and safety studies were performed to demonstrate the absence of clinically meaningful differences between Basaglar and the reference product, Lantus. The first study was conducted in adults with T1DM (Study ABEB) and was an open-label, 52-week, Phase III, randomized, multicentre, active-controlled, parallel, non-inferiority study designed to compare the efficacy and safety of Basaglar and Lantus. A total of 535 patients were randomized and received at least one dose of study drug. Basaglar and Lantus were each used in combination with mealtime insulin lispro. The second study was a 24-week, Phase III, randomized, multicentre, double-blind, active-controlled, parallel, non-inferiority study designed to compare the efficacy and safety of Basaglar and Lantus in adult patients with T2DM (Study ABEC). A total of 756 patients were randomized and received at least one dose of study drug. Basaglar and Lantus were each used in combination with at least two oral antihyperglycemic medications.

Both studies met their primary endpoints of demonstrating that Basaglar was non-inferior to Lantus, in terms of change in hemoglobin A1c (HbA1c) from baseline at the pre-specified 0.4% and 0.3% non-inferiority margins at Week 24. In Study ABEB, the least squares (LS) mean treatment difference was 0.103 [95% confidence interval (CI) -0.009, 0.215]. In Study ABEC, the LS mean treatment difference was 0.051 (95% CI -0.095, 0.196). In addition, based on protocol specified testing, Basaglar and Lantus were considered to have comparable efficacy in both studies, in terms of change in HbA1c from baseline to Week 24, at the 0.4% margin. Clinical similarity was further supported by similarity between treatment arms in LS mean daily basal insulin dose (Studies ABEB and ABEC) and LS mean daily total insulin dose (Study ABEB).

Study ABEB included a 28-week extension period, which allowed for the comparison of change from baseline in HbA1c at 52-weeks, which was a key secondary efficacy outcome. Both the actual and change from baseline HbA1c comparisons suggest comparability between the two products at 52 weeks.

No clinical studies were conducted with Basaglar in pediatric patients (>6 years of age) with T1DM. The use of Basaglar in pediatric (>6 years of age) T1DM patients is supported by the similar product quality characteristics of Basaglar and Lantus and by the similar pathophysiology of pediatric T1DM compared to the studied population (adult T1DM). In addition, comparative non-clinical, human PK and clinical efficacy and safety studies conducted in the adult population have comparable clinical profiles between Basaglar and the reference product, Lantus.

Indication

During the original filing of this New Drug Submission (NDS), the proposed indication by the sponsor was the following:

  • Basaglar [insulin glargine (rDNA origin)] injection is a novel recombinant human insulin analogue indicated 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.
  • Basaglar is also indicated in the treatment of pediatric patients with type 1 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.

Following the review of the submission, Health Canada recommended the following indication to ensure safe and effective use of the product:

  • Basaglar [insulin glargine (rDNA origin)] injection is a recombinant human insulin analogue indicated 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. 
  • Basaglar is also indicated in the treatment of pediatric patients (>6 years old) with type 1 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.

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

Clinical Safety

The clinical safety of Basaglar was assessed in two pivotal studies, Study ABEB and Study ABEC, described in the Clinical Efficacy section. Study ABEB was conducted with T1DM patients and Study ABEC with T2DM patients. A total of 1,291 patients received at least one dose of randomly assigned study drug, with a total of 644 patients receiving Basaglar, and 647 patients receiving Lantus across the two studies.

The safety profile of Basaglar was consistent with that previously reported for the reference product, Lantus, in patients with T1DM or T2DM.

In Study ABEB, treatment-emergent adverse events (TEAEs) were experienced by a similar proportion of patients in each treatment arm [Basaglar 167/268 (62.3%), Lantus 166/267 (62.2%)] and were generally comparable between arms. The most frequently reported TEAEs were nasopharyngitis [16.0% in the Basaglar arm versus (vs.) 16.9% in the Lantus arm], upper respiratory tract infection (8.2% vs. 7.9%), hypoglycemia (4.9% vs. 4.5%), and diarrhea (4.5% vs. 3.7%). During the 52-week study, 515 patients (96.3%) reported 40,393 events of total hypoglycemia, [Basaglar 256 patients (95.5%), 19,541 events; Lantus 259 patients (97.0%), 20,852 events]. The overall (52-week) proportions of patients experiencing severe hypoglycemia were also similar between the treatment arms (3.7% in the Basaglar arm vs. 4.1% in the Lantus arm).

In Study ABEC, 196 patients (52.1%) in the Basaglar arm and 184 patients (48.4%) in the Lantus arm experienced at least one TEAE. The TEAEs were generally comparable in both arms. The most frequently reported TEAEs observed at an incidence ≥ 2% in either arm were nasopharyngitis (5.6% in the Basaglar arm vs. 5.8% in the Lantus arm), upper respiratory tract infection (5.1% vs. 3.9%), diarrhea (2.4% vs. 3.7%), back pain (2.4% vs. 2.6%), influenza (1.9% vs. 2.9%), cough (2.1% vs. 2.1%), nausea (2.1% vs. 2.1%), arthralgia (1.9% vs. 2.1%), headache (2.1% vs. 1.6%), abnormal weight gain (2.7% vs. 0.8%), hypertension (2.1% vs. 0.8%) and sinusitis (2.1% vs. 0.8%). Overall, 588 patients (78.5%) reported 7,409 events of total hypoglycemia [Basaglar 296 patients (79.4%), 3,564 events; Lantus 292 patients (77.7%), 3,845 events]. The proportions of patients experiencing severe hypoglycemia were also similar between the treatment arms (0.5% in the Basaglar arm and 0.5 % in the Lantus arm).

The two products, Basaglar and Lantus, are considered similar with respect to their association with hypoglycemic events. Appropriate labelling is already well-established with respect to hypoglycemia for Lantus and has been applied to the Basaglar Product Monograph. A warning of hypoglycemia is included in a Serious Warnings and Precautions box within the Basaglar Product Monograph.

The safety profile observed in the Phase III clinical studies for Basaglar is considered to be consistent with the known safety profile of Lantus. The known risks of insulin glargine treatment are conveyed in the Warnings and Precautions section of the approved Basaglar Product Monograph.

Immunogenicity

Immunogenicity was assessed in T1DM patients (Study ABEB) and in T2DM patients (Study ABEC) at multiple visits over the course of each study using a sensitive and validated radio-immune assay. In Study ABEB, similar proportions of patients had detectable antibodies at 24-weeks (Basaglar 19.1%, Lantus 17.4%), 52-weeks (Basaglar 27.5%, Lantus 22.1%) and overall (Basaglar 40.4%; Lantus 39.3%). While the Basaglar arm showed a higher incidence of detectable antibodies at Week 52, this is not considered to be a clinically significant finding given that similar proportions of patients had detectable antibodies at all other timepoints and overall (all timepoints combined). Additionally, the proportions of patients having antibodies that were cross-reactive with endogenous insulin were also similar between the treatment arms after 52-weeks overall (Basaglar 21.2%, Lantus 20.2%). The effects of immunogenicity on clinical safety and efficacy endpoints were also assessed. There was no observable correlation between antibody levels (measured as percent binding) and HbA1c change from baseline to the 52-week endpoint. Additionally, there was no correlation between antibody levels and the rate of total hypoglycemia.

In patients with T2DM (Study ABEC), the incidences of patients with detectable insulin antibodies were 56 patients (15.3%) in the Basaglar arm vs. 40 patients (11.0%) in the Lantus arm. The proportion of patients with cross-reactive antibodies was similar between the 2 arms [29 patients (7.9%) in the Basaglar arm and 25 patients (6.8%) in the Lantus arm]. A significant overall difference in the proportion of patients with detectable antibodies was observed in the subgroup of patients that were previously treated with Lantus (19.2% in Basaglar arm vs. 7.9% in the Lantus arm). However, mean anti-insulin antibody levels, as measured by % binding, were similar between the two arms. In addition, the levels of insulin antibodies do not appear to correlate with clinical outcomes including change in HbA1c, insulin dose, or rate of hypoglycemia.

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

7.2 Non-Clinical Basis for Decision

The non-clinical database submitted for Basaglar was in compliance with the Subsequent Entry Biologic (SEB) data requirements for non-clinical studies, as presented in the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs).

The SEB is supported by two 1-month comparative non-clinical repeat-dose toxicity studies conducted in rats, one comparing Basaglar with United States-approved Lantus and one comparing Basaglar with European Union-approved Lantus. The spectrum of effects observed was similar between rats that received United States- or European Union-approved Lantus and those that received Basaglar. Effects included polyphagia, neuropathy and pancreatic islet cell atrophy and were typical of those associated with sustained hyperinsulinemia and/or hypoglycemia. Increased adipose tissue in the skin subcutis was also observed.

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

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

7.3 Quality Basis for Decision

Basaglar was developed as a Subsequent Entry Biologic (SEB) to the insulin glargine drug product, Lantus. The primary amino acid sequence of the Basaglar drug substance is the same as that of the active ingredient in Lantus. Therefore, the biological activity of Lantus is considered to be representative of the mechanism of action and pharmacological effect of Basaglar. The Quality review pertained to the Basaglar drug substance and drug product. In addition, comparability of Basaglar to the reference medicinal product, Lantus, was reviewed in order to evaluate Basaglar as a SEB.

Basaglar is available as a solution for injection at a strength of 100 U/mL. Basaglar is administered as a subcutaneous injection and will be made available in 3 mL cartridges for use with Eli Lilly's reusable pen-injectors and in 3 mL cartridges sealed in prefilled pen-injectors (KwikPen).

Characterization of the Drug Substance

Insulin glargine, the drug substance of Basaglar, is produced by recombinant deoxyribonucleic acid (rDNA). Insulin glargine (rDNA) differs from natural human insulin in that the amino acid asparagine at position 21 of the A-chain is replaced by glycine and two arginines are added to the C-terminus of the B-chain. The similarity between the SEB product Basaglar [insulin glargine (rDNA)] and the reference product Lantus (insulin glargine) was established in accordance with the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs).

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

A two-pronged approach was used by the sponsor to demonstrate that Basaglar is highly similar to the reference product, United States-sourced Lantus. First the sponsor performed an assessment between the United States- and the European Union-sourced Lantus products of the following elements: structure; batch release data, including chromatographic profile comparison; biological potency; and any changes during stability. A total of eleven United States and three European Union batches were used in the studies and provided convincing evidence that the United States- and European Union-sourced Lantus products are comparable. 

The sponsor then chose a two-tiered approach in comparing Basaglar with Lantus. The published properties of commercial insulin glargine were demonstrated to compare well with the Basaglar drug substance. The sponsor then deformulated both Basaglar and Lantus drug products and compared the resulting drug substances in extensive head-to-head studies, including forced degradation and accelerated stability studies. Some minor differences, not expected to impact product safety or efficacy, were observed. Taking all of the data into account, the sponsor has demonstrated that Basaglar is comparable to Lantus (either United States- or European Union-sourced). There is no practical difference in the stability of the two drug products when they are stored under the recommended storage conditions which include excursions for one month at room temperature. Thus, there is no expected impact to patient safety or product efficacy when the Basaglar drug product is stored as per the manufacturer's recommendations. In conclusion, through extensive studies, the sponsor has demonstrated that Basaglar is comparable to Lantus, and there are no objections to accepting this as a SEB. 

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

Basaglar [insulin glargine (rDNA)] is produced by rDNA technology. The manufacture of insulin glargine (rDNA) is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested in accordance with International Conference on Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The manufacturing process of the drug substance, insulin glargine (rDNA), consists of a series of stages which include fermentation, granule isolation, and purification. The purification process includes the isolation of inclusion bodies and a combination of chromatographic steps. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use. The in-process controls and critical steps for the cell culture and purification processes have been defined and are based on manufacturing experience and process robustness studies. They were later confirmed during the process validation studies.

The manufacturing of the drug product, Basaglar, includes compounding, sterile filtration, and filling steps. The in-process controls have been established. The drug product manufacturing process was validated by manufacturing batches at the commercial site. The data from these batches consistently met the process validation acceptance criteria and the proposed commercial release specifications. It was demonstrated that the drug product manufacturing process is capable of consistently producing the product to meet the desired quality.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are valid and considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

The specification tests for the drug substance were chosen to monitor critical quality attributes based on characterization studies, including appearance, identity, purity and impurities, potency, content, microbiological quality and general characteristics related to product composition. The established test specifications and validated analytical test methods are considered acceptable.

The proposed commercial specifications for the drug product in cartridges and for the pen-injector are appropriately justified. The batch analysis data from available clinical and commercial drug product batches support the specifications. The specification methods have been appropriately validated or qualified.

The container closure system has been 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.

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

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24-month shelf-life at 2-8°C for Basaglar is considered acceptable. Additionally, the data from the in-use stability study, including the antimicrobial effectiveness testing demonstrate the drug product stability for up to 32 days at 30°C and support the proposed in-use shelf-life of up to 28 days at 30°C.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

On-Site Evaluations (OSEs) of two of the facilities involved in the manufacture and testing of the drug substance and drug product were not conducted by Health Canada, as the OSEs conducted previously for these facilities were considered sufficient in this case. The other facility was not in production during the review period.

The facilities involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

Not applicable No components of biological origin are used in drug substance or drug product manufacture.