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whether differences in posttranslational afucosylation may yield to differences in
pharmacokinetics and determined that no meaningful differences were present.
Differences also can emerge in the design and construction of cell production bio-
reactors, filtration, and chromatographic purification steps. Notably, theFDA does
not require an approach to “independently establish the efficacy and safety of the
biosimilar,” but rather “a demonstration of the biosimilarity between the proposed
product and a reference product.” Figure 15.2 depicts the relative weights it places
on the different steps in determining biosimilarity.
As a first step, structural analyses are required that the proposed product will
encode for the same primary amino acid sequence as the reference product as well
as an analysis ofsecondary, tertiary, and quaternary structures. A detailed physio-
chemical analysis of CT-P13 has been carried out to the reference infliximab.
Detailed biochemical techniques used to compare the two are beyond the scope of
this chapter and are reviewed in detail elsewhere [ 9 ]. Higher-order structures were
found to be indistinguishable by multiple assays between the reference infliximab
andCT-P13. Importantly,comparable biologic activity of CT-P13 and the reference
drug was demonstrated based on its mechanism of action, including invitro TNF
neutralization activity, TNF-binding affinity based on ELISA, and cell-based TNF-
binding affinity (Fig.15.3a, b). Bridging assays for reference USinfliximab and ref-
erence European Union (EU) infliximab demonstrated similar findings between the
two products [ 10 ].

“Stand-alone” Development Program, 351(a)

Goal: To establish safety and efficacy

of a new product

“Abbreviated” Development Program, 351(k)

Goal: To demonstrate biosimilarity

(or interchangeability)

Additional

Clinical studies

Clinical

Pharmacology

Nonclinical

Analytical

Clinical

Safety & Efficacy

(Phase 1,2,3,)

Clinical Pharmacology

Non-clinical

Analytical

Fig.15.2 Considerations for extrapolation of biosimilarity. Adapted from http://www.fda.gov/
downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/
UCM486171.pdf [ 75 ]

15 Biosimilars in Inflammatory Bowel Disease 2017: State of the Science