Assessment of optimal insulin administration timing for standard carbohydrates-rich meals using continuous glucose monitoring in children with type 1 diabetes: A cross-over randomized study.

AIMS/INTRODUCTION: The present study was an assessment of postprandial glucose concentration after carbohydrates-rich meals using continuous glucose monitoring in 30 children with type 1 diabetes treated using continuous subcutaneous insulin infusion with a rapid-acting insulin analog. MATERIALS AND METHODS: Over a period of 3 days, participants administered simple boluses with different delay times between insulin administration and the beginning of carbohydrates-rich meal consumption (meal no. 1 containing 197 kcal, no. 2 containing 247 kcal and meal no. 3 containing 323 kcal; containing practically no protein and fat). In the present cross-over randomized study, we analyzed the average glucose concentration profiles in 5-min intervals, mean glucose at insulin administration, mean glucose after 120 and 180 min, mean and peak glucose, glucose peak time, areas under the glucose and glucose increase curves, and time period lengths with glucose <50, 70 mg/dL, and >140 and 200 mg/dL. RESULTS: For test meals at 20-min versus 0-min delay time, the study exposed a longer median time period to reach peak glucose (95 vs 65 min, P = 0.01) after meals. A tendency to the lowest peak and mean glucose, and the longest time with glucose within a normal range was observed in patients who administered bolus insulin 20 min before a meal. CONCLUSIONS: For carbohydrates-rich meals, administration of a proper dose of a rapid-acting insulin analog is crucial. The influence of rapid-acting insulin analog administration timing seems to be of minor importance in comparison with correct insulin dose adjustment; however, a tendency to achieve more balanced glucose profiles was found in a group who administered insulin 20 min before a meal.

Formulary Considerations for Insulins Approved Through the 505(b)(2) "Follow-on" Pathway.

OBJECTIVE: To summarize formulary-relevant issues for follow-on insulins approved through the Food and Drug Administration (FDA) 505(b)(2) approval pathway (Basaglar and Admelog). DATA SOURCES: A search of the MEDLINE database was performed for articles pertaining to clinical and formulary considerations for follow-on insulin products through July 2018. STUDY SELECTION AND DATA EXTRACTION: All clinical trials used in the 505(b)(2) approval process for follow-on insulin glargine and insulin lispro products were included and summarized. DATA SYNTHESIS: Follow-on insulin glargine and insulin lispro products have been recently approved as the first lower-cost alternatives to innovator insulin products. The follow-on insulins were approved via the 505(b)(2) pathway, making them neither generics nor biosimilars. Current data do not suggest any clinically relevant differences between the follow-on insulins and their respective innovator products. Clinicians should be aware that follow-on insulins will be reclassified as biologic products in the year 2020. Relevance to Patient Care and Clinical Practice: This article provides information about currently available follow-on insulin products that were approved through the 505(b)(2) pathway, including product characteristics and efficacy and safety data. These products will likely be considered for both clinical use and formulary placement because of their potentially lower cost compared with innovator products. CONCLUSIONS: Follow-on insulin products approved through the 505(b)(2) pathway are supported by robust efficacy and safety data. As new follow-on insulins are approved and the regulatory change that will occur with these products in 2020 approaches, formulary decisions and clinical policies (eg, substitution) will continue to be revisited.

Biosimilar insulins.

Until now most insulin used in developed countries is manufactured and distributed by a small number of multinational companies. Other pharmaceutical companies - many of these are located in countries such as India or China - are also able to manufacture insulin with modern biotechnological methods. Additionally, the patents for many insulin formulations have expired or are going to expire soon. This enables such companies to produce insulins and to apply for market approval of these as biosimilar insulins (BIs) in highly regulated markets such as the EU or the US. To understand the complexity of BIs' approval and usage, scientific and regulatory aspects have to be discussed. Differences in the manufacturing process (none of the insulin-manufacturing procedures are identical) result in the fact that all insulin that might become BIs differ from the originator insulin to some extent. The question is, have such differences in the structure of the insulin molecule and or the purity and so on clinically relevant consequences for the biological effects induced or not. The guidelines already in place in the EU for market approval require that the manufacturer demonstrates that his insulin has a safety and efficacy profile that is similar to that of the 'original' insulin formulation. Recently guidelines for biosimilars were issued in the US; however, these do not cover insulin. Although a challenging approval process for insulins to become BI might be regarded as a hurdle to keep companies out of certain markets, it is fair to say that the potential safety and efficacy issues surrounding BI are substantial and relevant, and do warrant a careful and evidence-driven approval process. Nevertheless, it is very likely that in the next years, BIs will come to the market also in highly regulated markets.

Making the unit of insulin: standards, clinical work, and industry, 1920-1925.

The standardization of insulin is generally considered by historians to have been a process conducted by physiologists under the direction of Henry Dale. This article shows that it actually involved many actors and began with the earliest administration to patients in Canada and the United States. During this first phase, the drug company Eli Lilly also contributed actively to the standardization, under the scientific direction of George Clowes. This is not to undermine the role of Dale, whose political leadership was paramount for the international phase of the standardization. His scientific contribution, however, was a continuation of previous work led by physiologists, clinicians, and pharmacists. The production and packaging of insulin in standardized units thus appears to be the result of the impressive working of a transdisciplinary and transnational network. It also highlights how new modes of drug regulation were elaborated by state bodies in the early 1920s and paved the way for more extensive reforms.

H.H. Dale and the London Centre for WHO standards--some milestones of the early years.

Henry Dale, a Nobel laureate and statesman of science, helped to organize the meetings in 1923 and 1925 to set up international standards for insulin and other biologicals. He made the National Institute for Medical Research one of the two world centres for standards. Some milestones in the work of the London centre are described: (i) the first standards; (ii) vitamins and hormones; (iii) WHO standards for many antibiotics; (iv) the provision of an international working standard for ACTH; (v) the old and new methods of ampouling; (vi) the impact of research and immunoassay on the need for standards; and (vii) the special ECBS sessions for endocrinology and haematology. Dale tells how he had to preserve the first batch of insulin for use as the standard instead of for treatment.

Fees for certifying insulin drugs--FDA. Interim rule; opportunity for public comment.

The Food and Drug Administration (FDA) is issuing interim regulations to revise the fee schedule for insulin certification services. Under the revision, FDA will charge a fixed fee for each master lot or batch submitted for certification. The changes in fee schedule reflect a change in agency testing policy for certification and release of batches of insulin. The changes in fees will allow FDA to continue to maintain an adequate insulin certification program as required by the Federal Food, Drug, and Cosmetic Act (the act). The fees are intended to recover the full costs of operation of FDA's insulin certification program, including the unfunded liability of the Civil Service Retirement Fund and appropriate overhead costs of the Public Health Service and Department of Health and Human Services.

Insulin update.

The rapid changes that have taken place in insulin products over the past decade seem to be slowing somewhat. However, research continues to develop new methods of delivering insulin as well as new products such as nasal insulin, insulin analogues, and other products that may someday enhance the effect of insulin. As these products come onto the market, we will report on them.