Primary Effect on glucodynamics ABEA PK and PD Pharmacology in a euglycaemic clamp ABEM PK and PD study ABEI PK and PD ABEE PK and PD Secondary Effect on C-peptide levels ABEA PK Pharmacology in healthy volunteers# ABEM PK ABEI PK Gender other Effect of gender Not genetic and done Differences in PD Effect of age Not Response done Comparison of Bridge’ to ABEN PK and PD ‘Scientific Lantus EU support Phase III studies Lantus US use of both sources of Lantus Population PD and Healthy subjects Not PK-PD analyses done Target population Not done * Indicates the primary aim of the study. § Subjects who would be eligible to receive the drug if approved for the proposed indication. # C-peptide levels are presented graphically as Figures only. None of the pharmacodynamic studies had deficiencies that excluded their results from consideration. Evaluator’s conclusions on pharmacodynamics The Phase I studies were more successful as PD studies than as PK studies notwithstanding the duration of most studies (24 hours). The Phase I studies adequately address the requirements of the adopted EU guideline EMEA/CHMP/BMWP/32775/2005 Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Non-Clinical And Clinical Issues - Guidance On Similar Medicinal Products Containing Recombinant Human Soluble Insulin, noting that the short duration of studies in healthy volunteers could not capture the full duration of action of insulin glargine and that the study in patients with T1DM did not capture the full duration of action of insulin glargine in a minority of subjects in each and/or both periods: clinical activity of an insulin preparation is determined by its time-effect profile ‘The of hypoglycaemic response, which incorporates components of pharmacodynamics and pharmacokinetics. Pharmacodynamic data are of primary importance to demonstrate comparability of a similar rh-insulin. The double-blind, crossover hyperinsulinaemic euglycaemic clamp study is suitable for this characterisation. Data on comparability regarding glucose infusion rate and serum insulin concentrations should be made available. The choice of study population and study duration should be justified. Plasma glucose levels should be obtained as part of the PK study following subcutaneous administration.‘
Primary Pharmacology Effect on glucodynamics in a euglycaemic clamp study ABEA ABEM ABEI ABEE PK and PD PK and PD PK and PD PK and PD Secondary Pharmacology Effect on C-peptide levels in healthy volunteers# ABEA ABEM ABEI PK PK PK Gender other genetic and Differences in PD Response Effect of gender Not done Effect of age Not done Comparison of Lantus EU Lantus US ‘Scientific Bridge’ to support Phase III studies use of both sources of Lantus ABEN PK and PD Population PD and PK-PD analyses Healthy subjects Not done Target population Not done * Indicates the primary aim of the study. § Subjects who would be eligible to receive the drug if approved for the proposed indication. # C-peptide levels are presented graphically as Figures only. None of the pharmacodynamic studies had deficiencies that excluded their results from consideration. Evaluator’s conclusions on pharmacodynamics The Phase I studies were more successful as PD studies than as PK studies notwithstanding the duration of most studies (24 hours). The Phase I studies adequately address the requirements of the adopted EU guideline EMEA/CHMP/BMWP/32775/2005 Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Non-Clinical And Clinical Issues - Guidance On Similar Medicinal Products Containing Recombinant Human Soluble Insulin, noting that the short duration of studies in healthy volunteers could not capture the full duration of action of insulin glargine and that the study in patients with T1DM did not capture the full duration of action of insulin glargine in a minority of subjects in each and/or both periods: ‘The clinical activity of an insulin preparation is determined by its time-effect profile of hypoglycaemic response, which incorporates components of pharmacodynamics and pharmacokinetics. Pharmacodynamic data are of primary importance to demonstrate comparability of a similar rh-insulin. The double-blind, crossover hyperinsulinaemic euglycaemic clamp study is suitable for this characterisation. Data on comparability regarding glucose infusion rate and serum insulin concentrations should be made available. The choice of study population and study duration should be justified. Plasma glucose levels should be obtained as part of the PK study following subcutaneous administration.‘
auspar-insulin-glargine-150828.docx