Table 6: Sponsor’s summary of ongoing safety concerns Summary of ongoing safety concerns Important identified risks Hypoglycaemia Medication errors (insulin mix ups) Injection site reactions Hypersensitivity reactions Important potential risks Malignancies Antigenicity Medication error (inappropriate dose injected, following needle blocked in absence of compliance with instructions for use) Missing information Use in pregnancy (U300 only) Use in paediatric population (U300 only) Comment: The ongoing safety concerns differ from those previously accepted for Lantus as follows: The addition of the important potential risk: ‘Medication error (inappropriate dose injected, following needle blocked in absence of compliance with instructions for use)’. The addition of the missing information: ‘Use in paediatric population (U300 only)’, to reflect the lack of paediatric data for the higher concentration formulation and to capture any such off label use. Specifying the missing information: ‘Use in pregnancy’ is applicable only to the U300 presentation to reflect the significant exposure of pregnant women to the marketed U100 dosage form and the limited use in pregnancy during clinical development with U300. Notwithstanding the evaluation of the nonclinical and clinical aspects of the Safety Specification, the above summary of the Ongoing Safety Concerns is considered acceptable. Reconciliation of issues outlined in the RMP report Table 7 summarises the first round evaluation of the RMP, the sponsor’s responses to issues raised by the RMP evaluator and the evaluation of the sponsor’s responses. Table 7: Reconciliation of issues outlined in the RMP report Recommendation in RMP evaluation report Sponsor’s response RMP evaluator’s comment 1. The sponsor should provide copies of the targeted structured forms used to follow up ICSRs related to the important identified risk: ‘Medication errors (insulin mix ups)’ and to the important potential risk: ‘Medication error (inappropriate dose injected, The sponsor has provided copies of the targeted structured forms as specified and stated: “Please note there are no proposed targeted structured forms to follow up ICSRs related to the 3 new important potential risks incorporated in the updated This is acceptable
Results Primary endpoint 8: Primary endpoint (6 month change in HbA1c) Study N U300 U100 Baseline HbA1c% U300 U100 6 HbA1c% U300 U100 Change U300 U100 Difference 95% CI 12456 T1DM 273 273 8.13 8.12 7.70 7.68 -0.40 -0.44 0.04 (-0.098, 0.185 11628 T1DM Basal insulin experienced Mealtime insulin +/- oral agents 404 400 8.13 8.14 7.23 7.27 -0.90 -0.87 -0.03 (-0.144, 0.083) T2DM Basal insulin experienced also on oral agents 403 405 8.27 8.22 7.47 7.49 -0.73 -0.70 -0.03 (-0.168, 0.099) 12347 T2DM Insulin naïve Also on oral agents 432 430 8.49 8.58 7.08 7.05 -1.42 -1.46 0.04 (-0.090, 0.174) Pooled 12347/11629 Also on oral agents 835 835 8.38 8.40 7.27 7.27 -1.08 -1.09 0.01 (-0.083, 0.106) Comment: All results met the pre-specified non-inferiority margin of 0.4%. That is, none of the upper 95% confidence limits were above 0.4%. There is an argument that the non-inferiority margin should be 0.3%, p11 of the EMA Guideline on medicinal product for diabetes: (CPMP/EWP/1080/00 Rev. 1 2012); this margin was also met. Insulin dose Table 9: Insulin dose Study Baseline U300 U100 6 month U300 U100 Increase U300 U100 12456 T1DM 33.5U 31.5U 40.5U 34.1U 21% 8%