Biosimilar insulins: Narrative review of the regulatory framework and registration studies

Biosimilar insulins have been commercially available in the EU since 2014. Currently, six biosimilar insulins are approved in the EU and four in the US. However, commercial success has been limited, which may be in part due to concerns among physicians and people with diabetes that biosimilar insulins are substandard in efficacy, safety, and quality compared to reference products. Indeed, unlike generic drugs, which are identical chemical copies of their reference counterparts, in a biological manufacturing process, subtle differences can arise between products, even if the tertiary molecular structures are the same. Therefore, there is a clear regulatory pathway for the approval of biosimilars. For biosimilar insulins, preclinical (hormone receptor and cell) studies are needed to investigate potential differences in the response to biosimilar insulins and their reference medicinal products. In addition, there is a requirement for pivotal clinical pharmacology studies involving the euglycaemic glucose clamp technique to investigate comparative time-action profiles, whereas later-phase clinical safety, efficacy, and immunogenicity studies usually are no longer needed for the approval of biosimilar insulins. This narrative review provides an overview of pivotal phase 1 clamp and supportive larger phase 3 studies that supported the registration of biosimilar insulins in the EU and US, and discusses the need for interchangeability and immunogenicity studies. Overall, the current regulatory approach in the EU and in the USA ensures that there are no relevant differences between biosimilar insulins and their reference products. Therefore, people with diabetes and prescribers can use EU or US approved biosimilars without any concerns. PLAIN LANGUAGE SUMMARY: Six biosimilar insulins are approved by the EU regulator, the European Medicines Agency, and are currently available on the EU market. Three biosimilar insulins are approved by the US regulator, the Food and Drugs Agency, and are currently available on the US market. However, commercial success has been limited, which may be in part due to concerns among physicians and people with diabetes that biosimilar insulins are perhaps not quite the same as the original products with respect to efficacy, safety, and quality. Such concerns could be valid, because unlike generic drugs, which are identical chemical copies of their reference counterparts, biosimilar protein biosimilar and originator drugs cannot be chemically identical. In a biological manufacturing process, subtle difference can and will arise between products, even if the tertiary molecular structures, that is the amino acid sequence, the interactions between different parts of the protein and the three-dimensional folding, are the same. To assure that these unavoidable subtle differences do not result in differences in efficacy, safety and quality, there is a clear regulatory pathway for the approval of biosimilars. In addition to chemical studies, preclinical studies are needed to investigate potential differences in the response to biosimilar insulins and their reference medicinal products. These include e.g. studies investigating affinity to the insulin receptor, and how the insulins induce their effect in cell models. Next, pivotal clinical pharmacology studies involving the euglycaemic glucose clamp technique to investigate comparative time action profiles are required. Later phase clinical safety, efficacy and immunogenicity studies usually are no longer needed for the approval of biosimilar insulins. This narrative review provides an overview of pivotal phase 1 clamp and supportive larger phase 3 studies which supported registration of biosimilar insulins in the EU and US, and discusses the need for interchangeability and immunogenicity studies. Overall, the current regulatory approach in the EU and in the USA ensures that there are no relevant differences between biosimilar insulins and their reference products. Therefore, people with diabetes and prescribers can use EU or US approved biosimilars without any concerns.