Summary Basis of Decision for Apidra ™
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:
ApidraTM
Insulin glulisine, 100 U/mL, Solution, Subcutaneous
sanofi-aventis Canada Inc.
Submission control no: 087892
Date issued: 2007-07-12
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02279460 - 10 mL vial
- 02279479 - 3 mL cartridge
- 02279487 - 3 mL OptisetTM
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On April 12, 2006, Health Canada issued a Notice of Compliance to sanofi-aventis Canada Inc. for the drug product Apidra™.
Apidra™ contains the medicinal ingredient insulin glulisine (rDNA origin), a recombinant human insulin analogue that is a rapid-acting, parenteral blood glucose lowering agent.
Apidra™ is indicated for the treatment of adult patients with Type 1 or Type 2 diabetes mellitus where treatment with insulin is required. Following subcutaneous administration, Apidra™ has a more rapid onset of action and a shorter duration of action than regular human insulin. Apidra™ should normally be used in regimens that include a longer -acting insulin or basal insulin analogue to maintain adequate glucose control.
The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from preclinical and clinical studies. The safety and efficacy of Apidra™ were studied in 2408 patients with Type 1 and Type 2 diabetes. The results of the clinical trials established Apidra™ as fast-acting with a short duration of action. Post-meal administration of Apidra™ was found to be as efficacious in glycemic control as regular insulin administered 30-45 minutes prior to a meal. Apidra™ was well tolerated and no new safety issues were raised as compared to other human insulin analogues in all Phase III clinical trials.
Apidra™ (100 U/mL, insulin glulisine) is presented as a solution for subcutaneous injection. The dosage of Apidra™ should be individualized and determined based on the physician's advice in accordance with the needs of the patient. Apidra™ should be given by injection within 15 minutes before or within 20 minutes after starting a meal and should normally be used in regimens that include a longer acting insulin or basal insulin analogue. Dosing guidelines are available in the Product Monograph.
Apidra™ is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Apidra™ should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Apidra™ are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Apidra™ is favourable for the treatment of adult patients with Type 1 or Type 2 diabetes mellitus where treatment with insulin is required.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Apidra™ contains the medicinal ingredient insulin glulisine, a rapid-acting, recombinant human insulin analogue. Apidra™ has a rapid onset, early peak effect on lowering blood glucose, and a short duration of action that enables it to be administered within 15 minutes before or within 20 minutes after starting a meal. Thus, the intrinsic pharmacokinetic properties of glulisine are closely aligned with the physiologic release of insulin. This characteristic is achieved by the exchange of two amino acids in the B-chain of human insulin.
Manufacturing Process and Process Controls
The manufacture of insulin glulisine is based on an E. coli K12 I35 master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with ICH guidelines. Results of these tests confirmed cell line identity and absence of adventitious agents/viral contaminants.Genetic characterization (restriction endonuclease mapping and copy number analysis) also demonstrated stability of the master cell bank ranging from storage to production at the limit of in vitro cell age.
The manufacture of insulin glulisine comprises of a series of steps which include cell culture, harvest and purification. The purification is performed via a combination of chromatographic and viral inactivation/removal steps. The manufacturing process consistency is ensured through defined production procedures, critical quality tests, in-process limits, and insulin glulisine analysis specifications. Microbial control is maintained throughout the manufacturing process by testing for bioburden as well as for bacterial endotoxins. In-process controls performed during manufacture were reviewed and considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterization studies were performed to provide assurance that insulin glulisine consistently exhibits the desired characteristic structure. Results from process validation studies also indicate that the methods used during processing adequately control the levels of product and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Control of Drug Substance
Validation reports are considered satisfactory for all analytical procedures used for in-process and release testing of insulin glulisine. The drug substance specifications, and analytical methods used for quality control of insulin glulisine are considered acceptable.
Stability
Based on the real-time and accelerated stability data submitted, the proposed shelf-life, storage and shipping conditions for insulin glulisine are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Apidra™ is presented as an aqueous solution for injection containing 100 units of insulin glulisine and 3.5 mg/mL of m-cresol (antimicrobial preservative). The amount of insulin glulisine in the drug product is equimolar to 100 international units (IU) of insulin per millilitre. Apidra™ also contains the non-medicinal ingredients trometamol, sodium chloride, polysorbate 20, sodium hydroxide and/or hydrochloric acid, and water for injection.
Apidra™ is approved in two multiple-dose packages: a 10 mL colourless injection vial (glass type I, Ph. Eur. and USP) with a flanged aluminum cap with tear-off lid and chlorobutyl rubber inserted gasket, and a 3 mL colourless cartridge (glass type I, Ph. Eur. and USP) with a bromobutyl rubber plunger stopper and flanged aluminum cap with inserted bromobutyl rubber gasket. Both multiple-dose containers enable repeated individual dosing according the medical requirements of the patient. The 3 mL cartridge is intended to be inserted directly into a pen injection device designed for this cartridge (Optipen® Pro) or may be an integral part of the disposable pen (Optiset™).
All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of insulin glulisine with the excipients is demonstrated by the stability data presented for the proposed commercial formulation.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section included composition of Apidra™, rationale for choice of formulation, manufacturing process including packaging, information on batches used in the in vitro studies for characterization, and discussion on the effect of formulation change on the safety and/or efficacy of Apidra™. Studies which justified the type and proposed concentration of excipients that are used in the drug product were also reviewed and are considered to be acceptable.
Manufacturing Process and Process Controls
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Apidra™ is tested to verify that the identity, appearance, content uniformity, and levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
Validation reports submitted for all analytical procedures used for in-process and release testing of the drug product are satisfactory, and are in compliance with ICH guidelines.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specification of the drug product.
Stability
Based upon the long-term and accelerated stability data submitted, the proposed 24-month shelf-life at 2-8°C for Apidra™ is considered acceptable. The drug product is not photostable and must be protected from light.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of facilities involved in the manufacture and testing of Apidra™ was not performed for this submission. An OSE was performed by Health Canada in 2001 at the same facilities for another drug submission and found to be compliant. This was considered satisfactory to support the submission for Apidra™. The design, operations and controls of the facilities and equipment which are involved in the production are considered suitable for the activities and products manufactured. All facilities are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Pre-harvest culture fluid from each lot is tested to ensure freedom of adventitious microorganisms (bioburden, mycoplasma, and viruses). Steps from the purification process designed to remove and inactivate viruses are adequately validated.
Raw materials of animal and recombinant origin used in the manufacturing process are adequately tested to ensure freedom of adventitious agents. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Apidra™ has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Based on a battery of pharmacodynamic (PD) studies both in vitro (human and rat cells) and in vivo (rats and dogs), it was shown that the relative receptor binding affinity, and activation of the metabolic insulin signaling cascade of insulin glulisine were similar to that of human insulin. However, insulin glulisine exhibited a reduced affinity for the IGF-1 receptor (25% when compared to human insulin). Insulin glulisine induced a preferential activation of the IRS-2 relative to the IRS-1 signaling pathway in muscle cells but this did not affect the metabolic response of insulin glulisine relative to human insulin. Insulin glulisine and human insulin were shown to be equally effective in the final pathway (i.e., activation of glucose transport). Although it was demonstrated that insulin glulisine was approximately half as potent as human insulin in isolated rat adipocytes, the same maximal response as human insulin was reached, and was as effective in lowering blood glucose. Insulin glulisine had a faster onset of action than human insulin, reaching its maximum plasma concentration (Cmax) earlier, with a shorter duration of action. Based on these findings, it was concluded that the time action profile of insulin glulisine was that of a rapid-acting insulin, clearly distinct from that of regular human insulin. It was also demonstrated that insulin glulisine retained its time-action profile when mixed with NPH human insulin immediately prior to subcutaneous (SC) injection.
The results obtained from three mitogenicity assays demonstrated that the mitogenic potential of insulin glulisine was lower than, or of the same order, as that of human insulin. After a single SC injection of 0.3 or 1.0 U/kg body weight (bw) of insulin glulisine to Beagle dogs, there was a decrease in systolic blood pressure, a transient increase in heart rate and respiratory rate, and an increase in the corrected QT interval. These findings have previously been reported during insulin-induced hypoglycemia in man, including studies with human insulin.
3.2.2 Pharmacokinetics
Insulin glulisine administered SC to rats was completely and rapidly absorbed and eliminated. Seven days post-dosing, excretion of radioactivity in the urine and feces was 87% and 8.9% of the administered dose (AD), respectively, with >80% elimination occurring by 24 hours post-dosing. Excretion of trichloroacetic acid-insoluble radioactivity in the urine was 3.7% of the AD. Exposure increased proportionally with the dose. No accumulation and no gender differences were observed. Radioactivity was distributed throughout the tissues and organs, except for the central nervous system, where concentrations were low. At 30 minutes post-dosing, the highest concentrations were seen at the injection site, followed by the thyroid. The distribution pattern was similar at 1, 2, and 4 hours post-dosing. At 8 hours post-dosing, the overall distribution had decreased in most tissues and organs, except for in the thyroid gland, where the highest level of radioactivity was still evident.
In dogs, absorption was slightly delayed, with 40% bioavailability. Elimination from serum was relatively fast with a half-life of 1.11 hours. Animals were systemically exposed over 2 to 3 hours to a substantial concentration of insulin glulisine. No accumulation and no gender differences were observed.
In in vitro stability investigations, the specific metabolite, des (1BB-3B) insulin glulisine, which results from cleavage at the B3Lys modification, was not found in rat plasma. This metabolite might have been expected due to peptidase activities in plasma since B3-Lys is the only structural change in insulin glulisine that is relevant for biodegradation in comparison to endogenous insulin. It was therefore concluded that proteolytic degradation of insulin glulisine proceeds by cleavage at various positions, similar to the human insulin molecule.
There was no generation of anti-insulin antibodies in the 6-month or 1-year rat studies. An increase in insulin antibodies in a few dogs was observed during the course of the 6-month study, however this did not impact the interpretation of the study results based on the toxicokinetic data, as well as by the PD insulin effects seen throughout the study.
No immunotoxic effects were noted during the study.
Due to the similarity in biotransformation to endogenous insulin which has no known PK drug-drug interactions, no PK drug interaction studies were performed with insulin glulisine.
3.2.3 Toxicology
Acute Studies
The acute LD50 of insulin glulisine, when administered by SC or intravenous (IV) injection to Sprague Dawley rats, or by SC injection to CD-1 mice, was determined to be >1000 U/kg bw (highest dose level tested). There were no outstanding clinical signs of toxicity. After SC injection to Beagle dogs, the approximate lethal dose level was 40 U/kg bw. General clinical signs of toxicity were not observed in any of the test animals.
Repeat-dose Studies
Sub-chronic and/or chronic toxicity tests were conducted in Sprague-Dawley rats and Beagle dogs. Rats were administered insulin glulisine by SC injection at dose levels of 0, 50, 150, or 500 U/kg bw/day for a 4-week period. Dose levels were for the most part well-tolerated. Treatment-related mortality observed at 150 and 500 U/kg bw/day, and clinical signs of toxicosis observed only at 500 U/kg bw/day, were attributed to hypoglycemia induced by the test material.
In a 6-month toxicity study, rats were treated SC at dose levels of 0, 5, 20, or 80 U/kg bw/day, followed by a 1-month recovery period. Dose levels were for the most part well-tolerated. Treatment-related mortality and clinical signs of toxicosis observed at 20 and 80 U/kg bw/day were attributed to hypoglycemia induced by the test material. Red blood cell (RBC) counts were decreased for males in the 80 U/kg bw/day group, and prothrombin time was increased for males in the 20 and 80 U/kg bw/day groups. However, the magnitude of these findings was marginal, and values fell within the normal range and were therefore not considered to be toxicologically significant. In addition, liver weights were decreased for males at all dose levels. However, in the absence of a dose-response relationship, and in the absence of any corresponding clinical chemistry or histopathological changes, this was also not considered to be toxicologically significant.
In a 12-month rat carcinogenicity study, Sprague Dawley rats were administered insulin glulisine SC at dose levels of 0, 2.5, 5, 20, or 50 U/kg bw twice daily. The comparator drug was administered at dose levels of 5, 20, or 50 U/kg bw twice daily. There was a dose-related increase in mortality for both drugs at the dose levels of 20 and 50 U/kg bw/twice daily, with a small percentage of these animals exhibiting clinical signs of hypoglycemia. The only other finding was an increase in mean body weight gain for males in the 50 U/kg bw/twice daily groups for both insulin glulisine and the comparator, and for females in the 5, 20, and 50 U/kg bw/twice daily group for both test materials.
Sub-chronic testing in Beagle dogs was carried out for one and six months at dose levels of 1.0, 3.0, and 10.0 U/kg bw/day, and 0.5, 1.0, and 2.0 U/kg bw/day, respectively. Dose levels were for the most part well-tolerated. A dose-related decrease in blood glucose was observed at all dose levels tested, which persisted for up to 24 hours in the 1-month study, and for up to 6 hours in the 6-month study. Tonic-clonic convulsions and severe signs of hypoglycemia were seen at dose levels of 2.0 U/kg bw/day and higher, which were attributed to the pharmacological action of the test material. After one month of treatment, an increase in the severity of the deposition of sloughed germ cells in the epididymides was noted at 3.0 and 10.0 U/kg bw/day. Although this could possibly be attributed to hypoglyemia, the changes were minimal and incidence rates were comparable between the control and treatment group. Similar findings were not observed in the 6-month study at any dose level, so this finding was not considered to be toxicologically significant.
Based on the results of the sub-chronic/chronic rat and dog studies, it was concluded that other than the decrease in blood glucose, and corresponding findings related to the hypoglycemia induced by the test material, the few changes which were possibly attributable to insulin glulisine were not toxicologically significant.
Carcinogenicity
A standard battery of mutagenicity assays yielded negative results, and mitogenicity studies demonstrated that insulin glulisine was less mitogenic than human insulin. In the 6-month and 12-month rat studies, there was no evidence of treatment-related oncogenicity (pre-neoplastic or neoplastic changes). In addition, Ki-67 (a protein associated with cell proliferation) measurement in mammary tissues by immunohistochemistry were negative with regard to proliferative activity. Based on these findings, it was concluded that there was no cause for concern regarding carcinogenic potential of insulin glulisine.
Developmental and Reproductive Studies
Embryofetal developmental and reproduction toxicity testing were conducted on rats and rabbits. In rats, dose levels were 1, 3.15, 8, or 10 U/kg bw/day, and in rabbits, dose levels of 0.25, 0.5, and 1.5 U/kg bw/day were utilized. Human insulin was used as the concurrent comparator product. Treatment-related mortality and clinical signs of hypoglycemia were observed at the high-dose level for both species. Treatment with insulin glulisine or the comparator drug did not affect fertility, reproductive performance, or post-natal growth and development of progeny in either species. In rabbits, there was an increase in post-implantation loss at 0.5 and 1.5 U insulin glulisine. Morphological examination of rat fetuses revealed a slight increase in the incidence of blood in the abdominal cavity in the 10 U insulin glulisine/kg bw/day group. In rabbit fetuses, there was a slightly increased incidence of defects of the vertebral column and ribs at 1.5 U/kg bw/day of insulin glulisine. However, these findings were observed at dose levels that were clearly maternally toxic, and the comparator drug induced similar toxicity. Findings were not considered to be primary treatment-related effects, but rather the result of the hypoglycemia induced by the test materials. Based on the results obtained from these studies, it was concluded that insulin glulisine and human insulin exhibit similar developmental/reproductive effects. Precautions for use of insulin glulisine during pregnancy should therefore be similar to those listed for human insulin during pregnancy.
Other Studies
Insulin glulisine was well-tolerated locally in rabbits following SC injection, as intended for therapeutic use in humans.
Immunogenicity testing in rabbits indicated that the immunogenic potential of insulin glulisine lies between that of bovine insulin and that of human insulin. Antibody measurements in the rat and dog studies indicated that antibody development was limited to dogs and were only infrequently detected, indicating that antibody inhibition of insulin was not an issue in the toxicity studies.
3.2.4 Summary and Conclusion
Radioimmunoassays were developed for semi-quantitative determination of insulin glulisine and circulating anti-insulin antibodies in human and animal serum. All assays were shown to be sensitive, selective, specific, accurate and precise enough for the assessment of PK/PD, and to support the toxicology studies of insulin glulisine in the relevant species.
The non-clinical PK/PD data for insulin glulisine demonstrated that it had the time-action profile of a rapid-acting insulin and was as effective as human insulin in lowering blood glucose. There were no specific risks identified, nor any indication of an enhanced mitogenic potential.
The non-clinical toxicology testing of insulin glulisine in rats, dogs and rabbits demonstrated that insulin glulisine is as safe as human insulin.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology
Early phase clinical studies were evaluated and found to be conducted without major discrepancies. Although the sample size was small, a variety of populations were included. No serious safety concerns were raised from the clinical pharmacology part of the review.
In 13 clinical pharmacology studies, a total of 248 adult subjects (195 non-diabetics, 37 subjects with Type I diabetes, 16 subjects with Type 2 diabetes) received one or more doses of insulin glulisine, and in an additional study 20 pediatric subjects also received one dose of insulin glulisine, for a total of 268 subjects.
In comparison to regular insulins, Apidra™ demonstrated the following characteristics:
- A more rapid absorption and shorter residing PK profile, and a more rapid PD profile with a more rapid onset and shorter duration of blood glucose lowering activity;
- A PK profile characterized by higher earlier fractional drug exposure levels (AUC), a higher maximum plasma concentration (Cmax) occurring sooner, and a shorter mean residence time;
- A PD profile in line with the PK findings and characterized by higher earlier fractional AUCs (for glucose infusion rates), an earlier maximum glucose infusion rate, and a shorter duration of action.
These characteristics were consistent across a wide range of subjects, including non-diabetic lean subjects, subjects with Type 1 or Type 2 diabetes, Japanese expatriates, non-diabetic obese subjects, subjects with impaired renal function, and pediatric subjects with type 1 diabetes.
Insulin glulisine could be injected into the abdominal, deltoid, or femoral anatomical areas while maintaining its rapid onset and shorter duration of action.
Only two doses were tested, 0.1 and 0.3 U/kg, in dose-response studies for both early (Study 1003) and commercial (Study 1009) formulations. The following findings were demonstrated:
- When mixed with Neutral Protamine Hagedon (NPH) insulin in a syringe immediately before injection, the maximum concentration of Apidra™ was attenuated by about 27% after pre-mixing; however, the time to maximum concentration was not affected.
- When the dose increased from 0.1 U/kg to 0.3 U/kg, the PD effect also increased, however, it was not proportional. Dose-proportionality was obtained for Cmax and AUC in PK profiling.
- The absolute bioavailability of insulin glulisine after femoral, deltoid and abdominal SC injection of 0.1 U/kg and an IV bolus of 0.1 U/kg were 68%, 71%, and 73%, respectively. However, the corresponding PD effect was not observed. Instead, 124%, 119%, and 122% bio-effectiveness [measured by AUC(0-clamp end)] was obtained following femoral, deltoid, or abdominal SC injection, respectively, as compared to IV administration.
3.3.2 Clinical Efficacy
The clinical efficacy and safety of insulin glulisine were examined in three Phase III pivotal studies. Study 3001 assessed the safety and efficacy of insulin glulisine in Type 1 diabetes patients compared to another rapid-acting insulin analog, lipso; Study 3002 assessed the safety and efficacy of insulin glulisine in Type 2 diabetes patients compared with regular human insulin; and Study 3004 assessed the safety and efficacy of pre-meal administration of insulin glulisine compared to regular insulin and post-meal administration of insulin glulisine. The three studies examined a total of 2408 patients.
The following conclusions on efficacy were determined:
- The efficacy of insulin glulisine is comparable to other marketed short-acting insulins such as regular human insulin, lispro, or aspart in glycemic control in patients with Type 1 and 2 diabetes mellitus, as indicated by the primary efficacy parameter, change in glycosylated hemoglobin (GHb) from baseline to endpoint in all related clinical trials.
- In terms of secondary efficacy parameters, symptomatic hypoglycemia, blood glucose levels, and blood glucose excursion, insulin glulisine is comparable to other short-acting insulins.
- Post-meal administration of insulin glulisine is as efficacious in glycemic control as regular insulin administered 30-45 minutes prior to a meal.
- Insulin glulisine is effective in glycemic control when administered by SC insulin pump.
- Mixing with NPH insulin immediately before injection did not alter the efficacy of insulin glulisine.
- No noteworthy differences in the efficacy of insulin glulisine were detected in subjects receiving oral hypoglycemic agents (OHA) and those not receiving OHA.
Sub-group analyses were also performed to assess the consistency of treatment effects across sub-populations. The efficacy of insulin glulisine was consistently maintained over all sub-populations. Factors examined included: age, BMI, sex, race, duration of diabetes, baseline GHb, pre-study basal insulin, OHA treatment at baseline, mixing with NPH, and pre-treatment with rapid-acting insulin.
3.3.3 Clinical Efficacy
In addition to the three pivotal studies described in section 3.3.2 Clinical Efficacy, 13 clinical pharmacology studies were also assessed in the safety analysis. As required, data were analyzed for each study individually. The safety analysis also pooled data from each of the following groups: Type 1 diabetes subjects, Type 2 diabetes subjects, or all insulin glulisine-treated or comparator-treated subjects. In general, no safety issues of strong concern were identified.
In the clinical studies, incidence of treatment-emergent adverse events (TEAEs) with insulin glulisine was relatively low, and comparable to other short-acting insulins. There were no major differences between insulin glulisine and comparator insulin preparations in the occurrence of all categories of TEAEs (69.4%) when all Phase III clinical trials were pooled and analyzed. A total of 12 (0.9%) life-threatening TEAEs were observed in the insulin glulisine groups vs. 8 (0.5%) in the comparator groups. The majority of these AEs were hypoglycemia, and therefore considered to be treatment-related. The non-hypoglycemia-related AEs were isolated occurrences and were not considered treatment-related. Deaths were rare in all Phase III studies and were not considered to be related to study medication.
In subjects with Type 1 diabetes, the incidence of cardiac TEAEs was greater in the insulin glulisine group than in the comparator group. This imbalance of cardiac TEAEs between the two study groups was likely attributable to an imbalance of cardiac risk factors at study entry between the two groups. Overall, a similar number of cardiac TEAEs occurred in insulin glulisine and comparator groups in the pooled Phase III studies.
More subjects with Type 2 diabetes than with Type 1 diabetes had eye disorder TEAEs. However, within each type, there was no significant difference between insulin glulisine and comparator treatment groups.
In sub-populations defined by age, body mass index, sex, race, or Hispanic ethnicity, the incidence of TEAEs or serious hypoglycemia was comparable between the pooled insulin glulisine and comparator groups.
There were no potential systemic hypersensitivity reaction TEAEs in the clinical pharmacology studies and Phase III clinical studies showed no significant differences between insulin glulisine and comparator treatments. In addition, there were no significant changes in cross-reactive antibodies to insulin or E. coli proteins. In the few case where a shift of antibodies from negative to borderline or to positive was reported, there were no correlations between the changes in antibody formation and general hypersensitivities or injection site reactions.
Clinical safety data examined included hematology, clinical chemistry, and lipid profiles. There were no clinically relevant changes or abnormalities in laboratory findings during any clinical pharmacology or Phase III study.
A study was also conducted to assess the suitability of insulin glulisine applied by external insulin pumps. Safety issues related to the use of pumps include catheter occlusion, unexplained hyperglycemia, as well as infusion site reactions. The rate of occurrence of TEAEs for these safety parameters was low, and no significant difference in the occurrence of TEAEs between groups was observed.
No focussed drug interaction studies were performed. Insulin has no known pharmacokinetic drug-drug interactions. Drugs that can influence plasma glucose concentrations may indirectly modify the effects of insulin.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Insulin glulisine was demonstrated in clinical trials to be fast-acting and with short duration of action. Its effect on glycemic control is comparable to other short-acting insulin preparations such as lispro, aspart and regular human insulin. The efficacy was assessed by the primary efficacy parameter, change in GHb from baseline to endpoint, and the secondary parameters, such as frequency of hypoglycemia, blood glucose (BG) and BG excursion. Insulin glulisine produced a similar reduction in blood GHb levels compared with comparator insulin preparations in both type 1 and 2 diabetes subjects. Post-meal administration was demonstrated to be non-inferior to regular insulin administered 30-45 minutes prior to a meal. Post-meal administration of insulin glulisine also was demonstrated to be non-inferior to pre-meal administration. Therefore, insulin glulisine has the potential advantage to be a useful medication for glycemic control in diabetic patients.
Insulin glulisine was well tolerated in all Phase III clinical trials. The adverse events are all those commonly related to insulin preparations. The frequency and seriousness of these events were comparable to the previously authorized and marketed insulin preparations. No new safety issues were raised specifically related to the recombinant insulin glulisine. Use of insulin glulisine by external insulin pumps did not show alarming issues in terms of safety. Adverse events related to pump use occurred with low frequency, and there were no significant differences between insulin glulisine and the comparator, aspart. No adverse events were specifically related to the pump types used in the clinical trial. Deaths were rare in all clinical trials and were not deemed to be related to the study medication. Incidence of serious hypoglycemic TEAEs was low and not different from regular insulin preparations.
Therefore, the benefits of insulin glulisine clearly outweigh the risks in the treatment of adult patients with Type 1 or Type 2 diabetes mellitus.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Apidra™ is favourable for the treatment of adult patients with Type 1 or Type 2 diabetes mellitus where treatment with insulin is required. The 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.
4 Submission Milestones
Submission Milestones: ApidraTM
| Submission Milestone | Date |
|---|---|
| Submission filed | 2003-11-04 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2004-01-13 |
| Review 1 | |
| Quality Evaluation complete: | 2006-03-31 |
| Clinical Evaluation complete: | 2006-03-29 |
| Labelling Review complete: | 2006-04-05 |
| NOC issued by Director General: | 2006-04-12 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| APIDRA | 02279479 | SANOFI-AVENTIS CANADA INC | INSULIN GLULISINE (RECOMBINANT DNA ORIGIN) 100 UNIT / ML |
| APIDRA | 02279460 | SANOFI-AVENTIS CANADA INC | INSULIN GLULISINE (RECOMBINANT DNA ORIGIN) 100 UNIT / ML |