Table 3.

Requirements for demonstration of biosimilarity under CSL and ToE development paradigms

Requirements for demonstration of biosimilarity	CSL	ToE
Reference version bridging studies	None if selected reference is from a highly regulated jurisdiction and complies with other requirements [3]	Yes, in most jurisdictions
Comprehensive analytical studies	Yes—should use multiple orthogonal techniques and most sensitive and specific tests	Yes—should use multiple orthogonal techniques
Nonclinical in vitro functional tests	Yes—must include all functionalities thought to be active in vivo	Yes
Nonclinical in vivo studies	None	Depends upon jurisdiction
Human PK study	Yes, as confirmation of composition	Yes
Human PD studies	None. Potential exception for biosimilar insulins and analogs	Yes, if relevant PD marker available
Human immunogenicity study with ‘transition’	Yes—integrated into PK study	Yes. ‘Transition’ required by US only
Powered human efficacy study	None as routine	Yes, unless adequate human PD study conducted. May require > 1 study if molecule has > 1 mechanism of action
Local clinical studies	None	Sometimes required

CSL confirmation of sufficient likeness, PD pharmacodynamic, PK pharmacokinetic, ToE totality of evidence