Table 2.

Overview of Biosimilar Insulin Regulatory Guidelines of Different Regulatory Authorities.

Authorities	Definition	Nonclinical evaluation	Clinical evaluation
EMA 16	“A recombinant insulin-containing product highly similar to another already approved biological medicine (the ‘reference medicinal product’)”	Target binding to both human insulin receptors; receptor autophosphorylation and metabolic activity (≥3 assays). If in vitro comparability is satisfactory, animal studies are not required	Comparability demonstrated in the stepwise process using PK and PD, followed by limited immunogenicity studies unless waived a
WHO 18	“A biotherapeutic product which is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product”	In vitro assays such as receptor-binding studies or cell-based assays; animal studies for relevant biological/PD activity and toxicity	PK, PD, (confirmatory PK/PD), efficacy, and safety
US FDA17,22 (draft)	“A biological product highly similar to the reference product notwithstanding minor differences in clinically inactive components”	Structural analyses; functional assays; animal data	Human pharmacology data; clinical immunogenicity assessment (usually unnecessary); comparative clinical studies (if residual uncertainty whether there are clinically meaningful differences)

Abbreviations: EMA, European Medicines Agency; FDA, Food and Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics; WHO, World Health Organization.

^aPrelicensing safety study including immunogenicity assessment may be waived if (1) biosimilarity between the biosimilar and the reference insulin can be convincingly concluded from the physicochemical and functional characterization and comparison using sensitive, orthogonal, and state-of-the-art analytical methods, and from the comparison of the PK and PD profiles, and (2) the impurity profile and the nature of excipients of the biosimilar do not give rise to concerns.