Insulin Detemir (rys) cartridge 3mL (Penfill®), prefilled device 3 mL (FlexPen®), 100U/mL, Levemir ®, July 2005
Public Summary Document for Insulin Detemir (rys) cartridge 3mL (Penfill® ), prefilled device 3 mL (FlexPen®), 100U/mL, Levemir ®, July 2005.
Page last updated: 11 November 2005
Product: Insulin Detemir (rys) cartridge 3mL (Penfill® ), prefilled device 3 mL (FlexPen®),
100U/mL, Levemir ®,
Sponsor: Novo Nordisk Pharmaceuticals Pty Lid
Date of PBAC Consideration: July 2005
1. Purpose of Application
This application sought listing of insulin detemir on the Pharmaceutical Benefits Scheme (PBS) on a cost minimisation basis compared with insulin glargine, should the latter be recommended for listing.
This is the first submission seeking listing of insulin detemir on the PBS.
3. Registration Status
Insulin detemir was approved for registration by the Therapeutic Goods Administration (TGA) on the 8 June 2004. The approved dose forms areinsulin detemir (rys) 100 U/mL, 3mL cartridge (Levemir Penfill), 3mL pre-filled pen (Levemir FlexPen) and 3mL syringe (Levemir InnoLet).
The TGA approved indication is:
“Treatment of diabetes mellitus where used as basal insulin in combination with meal-related short- or rapid-acting insulin. Not recommended for diabetes mellitus type 2 patients who still respond to oral hypoglycaemic agents.”
4. Listing Requested and PBAC’s View
The application requested the following listing.
Authority required listing for the treatment of diabetes mellitus where used in combination with meal-related short- or rapid-acting insulin.
The sponsor also indicated its willingness to consider an alternative listing consistent with any applied to insulin glargine.
The Pharmaceutical Benefits Advisory Committee (PBAC) did not comment on this proposal at this time (see Recommendation and Reasons).
5. Clinical Place for the Proposed Therapy
The management of insulin dependent diabetes in some patients can be complicated by the trade-off between achieving better glycaemic control, as measured by a reduction in HbA1c levels, and a greater risk of hypoglycaemia resulting from a temporary relative oversupply of insulin seen with existing intermediate acting insulins. Insulin detemir is a soluble, basal insulin analogue with a prolonged duration of effect.
The submission nominated two comparators: insulin NPH (neutral protamineHagedorn) and insulin glargine, but requested listing on a cost-minimisation basis with insulin glargine. Insulin glargine is not currently listed on the PBS.
The PBAC considered that, in the absence of a positive listing recommendation for insulin glargine, insulin NPH would be an appropriate comparator.
7. Clinical Trials
The submission provided comparisons of insulin detemir with insulin NPH (6 studies, five in type I diabetes and one in type II diabetes) and of insulin glargine with insulin NPH (9 studies, eight in type I diabetes and one in type II diabetes), together with an indirect comparison of insulin detemir with insulin glargine (using insulin NPH as the common comparator).
The submission also presented meta-analyses for each comparison.
Twelve of the individual studies were published at the time of submission, as follows.
|Trial/first author||Protocol title||Publication citation|
|NN304-1335/ Russell-Jones D||A Six Month, Multi-centre, Open-label, Parallel Efficacy and Safety Comparison of Insulin detemir and NPH insulin in Patients with Type 1 Diabetes on a Basal-bolus Regimen.||Clinical Therapeutics,2004 26(5):724-736.|
|NN304-1448/ Home P||A 16 week, multi-centre, multi-national, open, randomised three-group parallel study comparing administration of insulin detemir at 12 hour intervals, insulin detemir morning and bedtime and NPH morning and bedtime in patients with Type 1 diabetes: A Phase III Trial||Diabetes Care, 2004, 27(5):1081-1087|
|NN304-1336/ Haak T||A Six-Month, Multi-centre, Open, Asymmetrically Randomised, Parallel, Efficacy and Safety Comparison of Insulin Detemir and NPH Insulin in Patients with Type 2 Diabetes on a Basal - Bolus Regimen.||Diabetes Obesity & Metabolism 2005; 7:56-65.|
|Rosenstock J||Basal insulin glargine (HOE 901) versus NPH insulin in patients with type 1 diabetes on multiple daily insulin regimens.||Diabetes Care, 2000, 23(8):1137-1142.|
|1–3. Hershon K||2004. Once-daily insulin glargine compared with twice-daily NPH insulin in patients with type 1 diabetes.||1.Endocrine Practice, 2004, 10(1):10-17.
3.Diabetes, 2001,50(Suppl 2):A116-A117.
|Rossetti P||Intensive replacement of basal insulin in patients with type 1 diabetes given rapid-acting insulin analog at mealtime: a 3-month comparison between administration of NPH insulin four times daily and glargine insulin at dinner or bedtime.||Diabetes Care, 2003, 26(5):1490-6.|
|1. Schober E
2. Van Dyke J
3. Schober E
|Pediatric Study Group of Insulin Glargine. Comparative trial between insulin glargine and NPH insulin in children and adolescents with type 1 diabetes mellitus.||1.Journal of Pediatric Endocrinology & Metabolism, 2002, 15(4):369-76.
2.J Peadiatric Endocrinology Metabolism, 2000, 13(Suppl):34.
3. Diabetes Care, 2001, 24(11):2005-6.
|Raskin P||A 16-week comparison of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes.||Diabetes Care, 2000, 23(11):1666-71.|
|Pieber TR||Efficacy and safety of HOE 901 versus NPH insulin in patients with type 1 diabetes. The European Study Group of HOE 901 in type 1 diabetes.||1. Diabetes Care, 2000, 23(2):157-62.
2. Diabetes, 1998, 47:242.
3. Diabetiologia, 1998, 41:187
|1. Ratner RE
2-3. Garg SK
|Less hypoglycaemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes.||1. Diabetes Care, 2000, 23(5):639-43.
2. Diabetes, 2001, 50:A435-6.
3. Diabetes, 1998, 47:1390
|Porcellati F||Better long-term glycaemic control with the basal insulin glargine as compared with NPH in patients with Type 1 diabetes mellitus given meal-time lispro insulin.||1. Diabetic Medicine, 2004, 21(11):1213-1220.
2. Diabetes, 2002, 51(Suppl 2):A53.
|1. Rosenstock J
2. Fonseca V
3. Fonseca V
|Less symptomatic hypoglycaemia with bedtime insulin glargine (LANTUS) compared to bedtime NPH insulin in patients with type 2 diabetes.||1. Diabetes Care, 2000, 23(8):1137-1142.
2. Diabetes, 2001, 5O (Suppl 2):All2.
3. Diabetologia, 2001, 44:796.
8. Results of Trials
The meta-analysis presented in the submission showed no significant differences inglycosylated haemoglobin (HbA 1c) between insulin detemir and insulin NPH in both the ‘all patients group’( type 1 and type 2 diabetes patients), and in the patient group with Type 1 diabetes. No significant difference in HbA1c was found in the comparison of insulin glargine versus insulin NPH for the comparable patient groups. The indirect comparison between insulin detemir and insulin glargine also suggested no difference between the two groups in terms ofHbA1c .
The main measure of toxicity used in the submission was hypoglycaemic events; ‘major events’ were defined generally as blood glucose <2.8mmol/L. The submission’s meta-analysis of all hypoglycaemic events suggested that insulin detemir in Type 1 diabetes was approximately 12% less likely to cause hypoglycaemic events than insulin NPH. For theinsulin glargine and insulin NPH comparison, the submission’s meta-analysis of all hypoglycaemic events in Type 1 diabetes indicated a slight benefit in favour of insulin glargine treatment (approximately 24%). However, the result was borderline and heterogeneity was statistically significant.
The indirect comparison between insulin detemir and insulin glargine suggested no difference between the two groups in terms of hypoglycaemia.
The PBAC did not assess the clinical trial evidence presented at this time, but noted that there were several areas of disagreement between the sponsors and the evaluators regarding theanalyses presentedin the submission (see Recommendation and Reasons).
9. Clinical Claim
The submission claimed that insulin detemir has significant advantages in effectiveness and less toxicity than insulin NPH. The submission also claimed that insulin detemir is no worse than insulin glargine in terms of effectiveness and toxicity.
The PBAC did not make a judgement on the validity of the submission’s claims at this time (see Recommendation and Reasons).
10. Economic Analysis
The submission claimed that insulin detemir, insulin NPH and insulin glargine are equi-potent, and that the price for insulin detemir should be the same as the price per unit for glargine.
A preliminary or modelled economic evaluation was not presented.
The PBAC did not make a judgement on the validity of the submission’s economic analysis at this time, but noted that the areas of disagreement between the sponsors and the evaluators regarding the analysis of the clinical trial results may also affect the economic analysis (see Recommendation and Reasons).
11. Estimated PBS Usage and Financial Implications
The submission estimated the net financial cost per year for the PBS to be up to $25 – $50 million in year 4 of listing.
The PBAC did not make a judgement on the validity of this estimate at this time (see Recommendation and Reasons).
12. Recommendation and Reasons
The PBAC deferred the application and resolved to ask the sponsor how it wishes to proceed in the absence of the sponsor’s precondition for listing, namely a recommendation to list insulin glargine. The PBAC considered that insulin NPH would be the appropriate comparator, but noted that the submission may not contain all the relevant information to allow the Committee to consider whether to make a recommendation for listing with insulin NPH as the comparator. Further issues that will arise if the sponsor advises that the PBAC should proceed to consider insulin determir with insulin NPH as the comparator are the respective TGA-approved indications of insulin NPH and insulin detemir and the wording of any PBS restriction.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor will continue to seek a recommendation for PBS listing.