A Look at the Regulatory Process for Approval of Biosimilar Insulins in Europe

The emergence of biosimilar insulins may help broaden access to modern insulins, increase individualized treatment options, and reduce the cost of insulin therapy. Yet many healthcare providers may not understand the concept of biosimilarity and how biosimilar medications are similar, not identical, to their reference products. An extensive review, published in DIABETICMedicine, explains the European Union’s regulatory requirements for biosimilar basal insulins and the potential benefits and concerns relevant to their use.

In 2014, the first biosimilar insulin in Europe, LY2963016 insulin glargine (Abasaglar), was approved by the European Medicines Agency (EMA),which was followed by the approval of MK-1293 insulin glargine (Lusduna) in January 2017. A few other biosimilar insulins are currently in development. The EMA was the first regulatory agency to issue guidelines outlining the principles of biosimilarity, quality, and nonclinical and clinical aspects of biosimilars. These guidelines created a framework for demonstrating similarity between a biological drug and the reference molecule, and include quality characteristics, biological activity, safety, and efficacy in a tailored development program.

Guidances were subsequently issued for specific types of biosimilars, including those that contain recombinant human insulin and insulin analogs. The process includes preclinical and clinical comparative studies of biosimilar insulin programs that include in vitro bioassays for insulin and insulin-like growth factor 1 receptor binding, assessment of in vitro biological activity, evaluation of pharmacokinetic (PK) and pharmacodynamic (PD) profiles in phase 1 studies, and assessment of long-term safety and efficacy in phase 3 studies.

In addition, manufacturing and quality considerations are important issues in biosimilar development because the manufacturing process for biological drugs is a source of variability among products. The typical insulin-manufacturing process consists of gene isolation and insertion into a host cell (eg, Escherichia coli or yeast), establishment and expansion of cell lines to produce insulin, isolation, purification, formulation, packaging, and distribution. Minor changes to any of the manufacturing steps might affect the properties of the final product.

EMA requirements for the approval of biosimilar insulins—as well as for other biological compounds—include evaluation of drug composition, physical properties, primary and higher-order structures, and purity and impurity characterizations. Differences between the biosimilar and reference products should be justified, and may require further clinical evaluation.

Preclinical Studies

Preclinical studies include in vitro studies comparing a biosimilar candidate’s binding affinity and functional activity at the insulin receptor, and the assessment of metabolic activities and mitogenicity in cell culture models. Statistical analyses must support the conclusion that overall, the candidate biosimilar has a similar in vitro pharmacological profile to that of the reference insulin.

PK/PD Studies.

Primary PK assessment includes area under the concentration-versus-time curve from 0 to 24 hours and maximum drug concentration. The primary PD parameters include maximum glucose infusion rate and total glucose infusion over-the-clamp duration. (Clamp studies are used to quantify insulin secretion and resistance.) These PK and PD parameters are used to confirm bioequivalence criteria.

Phase 3 Studies.

Phase 3 studies are conducted in people with type 1 and type 2 diabetes to confirm efficacy findings from PK/PD studies and to evaluate safety (such as incidence of hypoglycemia), immunogenicity, allergic reactions, and injection-site reactions. Phase 3 studies are also used to demonstrate non-inferiority to reference insulin with respect to glycated hemoglobin changes from baseline.

Finally, introduction of biosimilars have raised concerns about interchangeability and substitution. The possibility of medically unsupervised substitution of insulin products has important implications, as it might prevent proper attribution of adverse events to specific insulin products. In Europe, current requirements for the approval of biosimilars do not include robust evidence supporting substitution (as requirements do in the United States). Criteria are decided by local authorities, and therefore could differ among countries.