Biosimilars and New Insulin Versions

Anne L. Peters, MD; R. Daniel Pollom, MD; Jason S. Zielonka, MD; Michelle A. Carey, PhD; Steven V. Edelman, MD


Endocr Pract. 2015;21(12):1387-1394. 

In This Article

Biosimilar and New Insulin Versions

Humulin® insulin, approved by the FDA in 1982, was the first biological manufactured using recombinant DNA technology.[1] Other human insulin products soon followed, including regular insulin, neutral protamine Hagedorn insulin, rapid-acting analogues, basal analogues, and premixed insulins from several companies, including Eli Lilly and Company, Novo Nordisk, and Sanofi-Aventis. Patent protections for several insulin preparations have or will expire in the near future, allowing the entry of new insulin versions into the marketplace.

Worldwide, several companies have started to manufacture and market similar insulin products under local standards that may differ from the standards that exist in more established regions. These include the human premixed insulin formulations, Gensulin® (Bioton S.A., Warsaw, Poland), Insugen® (Biocon Ltd, Bangalore, India), Wosulin® (Wockhardt Ltd, Mumbai, India), and Biosulin® (MJ Biopharm Pvt Ltd, Mumbai, India).[21] Gensulin® was introduced in Poland in 2001 under local regulations, prior to the entry of Poland into the EU.[21] Insugen® has been available in India since 2004 and in Nigeria since 2010.[21] Wosulin®, available in India since 2003, is currently undergoing several Phase I and Phase III clinical trials.[21] Biosulin® (approved in South Africa for use in 2005) achieved similar glycemic control compared with existing human premixed insulins, with no reported new or severe adverse events.[22] Biocon released Basalog®, a biosimilar insulin glargine, in India in 2009.[23] In patients with type 1 diabetes mellitus, Basalog® was found to have similar efficacy and safety as Lantus®.[24]

Regulatory requirements for biosimilar drug approval may differ globally due to a lack of regulatory harmonization.[25] Variability in global regulatory requirements and differences in clinical trial design may make direct comparisons between similar biologic products produced in different regions of the world difficult. An example would be the regional differences in recommended noninferiority margins and the consequent effect on sample size. Biocon Limited (Bangalore, India) used a noninferiorty margin of ≤0.5% in their Type 1 Phase III clinical trial comparing their insulin glargine Basalog® to insulin glargine Lantus®.[24] In contrast, the U.S. guidance suggests a 0.4% noninferiorty margin.[26]

The first European application for biosimilar insulin was submitted by Marvel Life Sciences Private Ltd (Mumbai, India) in March 2007 for 3 insulin formulations: Marvel Rapid, Marvel Long, and a 30:70 premix.[27–29] Marvel later withdrew its application following a decision of the Committee for Medicinal Products for Human Use not to grant a second extension to respond to their list of questions.[30] In December 2011, Marvel submitted European applications for marketing authorizations for Solumarv, Isomarv medium, and Combimarv (human insulins), which were withdrawn the following year.[31] The withdrawal letter indicated the company needed "sufficient time to repeat and submit bioequivalence (PK and PD) data on each clamp study in order to comply with the planned new biosimilar insulin guideline".[31]

In September 2014, the EU approved Abasaglar™ (Eli Lilly and Company), an insulin glargine product, as the first insulin to use the EU biosimilar pathway.[32] In the U.S., the same product under the trade name Basaglar™ (Eli Lilly and Company), received tentative approval under the 505(b)(2) pathway (August 2014) for use with Kwikpen® (Eli Lilly and Company), a prefilled device.[33,34] Tentative approval is a designation indicating that the product met all scientific and regulatory criteria for approval but could not be approved pending resolution of patent litigation.[34]