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.‘
to the pediatric population as well for the purpose of labeling. The sponsor agrees that adequate data are not available for children younger than 2 years and will include this age category as important missing data in the RMP.’ The sponsor should conduct a study (or assign an existing study) to investigate the potential risk of malignancies further, in particular in children. ‘The initial concern over the relationship of insulin glargine and malignancy was raised in 2009 in a published Pharmacoepidemiology survey. Sanofi-Aventis, the Lantus® sponsor, conducted 3 additional surveys, covering a total of almost 2 million patient lives, to explore this question, with conflicting results. In addition, Sanofi altered the secondary endpoints of the ORIGIN study, a 12,000-patient, prospective, 6 year longitudinal study in prediabetic and diabetic patients to explore the incidence of malignancy and also conducted a prospective study in patients with breast cancer who were newly diagnosed as diabetic and were insulin naïve. This study was planned after Committee for Medicinal Products for Human Use (CHMP) concluded that the other potential risks of a causal relationship between the use of insulin analogues and malignancy had apparently been discharged. The CHMP report from 31 May 2013 concluded ‘that overall the data did not indicate an increased risk of cancer with insulin glargine, noting that there is no known mechanism by which the insulin glargine would cause cancer and that a cancer risk has not been seen in laboratory studies.’ Neither the initial report nor any subsequent reports have reported an increased risk of malignancy in children insulin analogues. The paediatric diabetic population is increasing in prevalence but remains small, and the number of diabetic children who either have or are likely to develop a malignancy is also quite This is not considered acceptable. The OPR evaluator acknowledges that the reported incidence of malignancy is low and that a paediatric diabetic population is receiving more medical monitoring. However, considering that many paediatric malignancies may be discovered late, that medical monitoring for diabetes not necessarily increase the probability of detecting a malignancy, and that insulin glargine is a widely used medicine, the sponsor should conduct a study (or assign an existing study) to investigate the potential risk of malignancies in children further. This recommendation remains.