Table 2. Summary of Regulartory Guidelines Regarding Extrapolation of Clinical Data for Biosimilars.

Concern	FDA	EMA	KFDA/WHO
Mechanism of action may be distinct in each therapeutic indication	Extrapolation will be considered on a case-by-case basis. Where the mechanism of action differs between indications or are not fully understood, separate clinical trials are likely to be necessary		The clinically relevant mechanisms of action and/or the involved receptors should be the same for the different indications
For a given mechanism of action, several mechanisms may exist	Almost superimposable biological data must be provided, covering all functional aspects of the agent, even if not considered clinically relevant. Where mechanisms of action are not fully understood, separate clinical trials are likely to be necessary		See above
Risk of undertreating patients/varied safety profiles in different patient groups	Data should be produced using a patient population and clinical end point most sensitive to detect clinically meaningful differences in efficacy and safety		A sensitive clinical test model should be used that is able to detect potential differences between the follow-on and reference products.
			The safety and immunogenicity profiles of the follow-on products should be sufficiently characterized.
Individual patient characteristics may influence the response	Careful consideration must be given to comorbidities/concomitant medications and intersubject variability	Homogenous population should be used- differences in response can then be attributed to the biosimilar

FDA, Food and Drug Administration; EMA, European Medicines Agency; KFDA, Korean Food and Drug Administration; WHO, World Health Organization.

Adapted with permission from Lee H. Springer Science+Business Media.21