263published in full manuscript form [ 4 , 5 ]. CT-P13 has been marketed as Remsima by
Celltrion, Inc., in Europe and other countries around the world, and as Inflectra by
Pfizer Inc. in the USA. This chapter will review the complex processes involved in
the developmentand manufacturing of these drugs including the physiochemical,
pharmacodynamic (PD), and pharmacokinetic (PK) steps and review the evidence
presently available on CT-P13 that demonstrated efficacy, immunogenicity, and
safety. Included in the discussion will be (1) the stepwise fashion used to demonstrate
the “totality of evidence” required by the FDA for the approval of a biosimilar drug;
(2) the controversial issue of data extrapolation of the results from the RA and AS
trials for CT-P13 and the RA and psoriasis trials for ABP 501 to other disease states;
(3) the issues of interchangeability between the originator drug and the biosimilar,
which is an important motivating factor for the pharmaceutical and biotechnology
industries; and (4) the pharmacoeconomic considerations regarding the use of anti-
TNF drugs in IBD.
FDA Guidance for Biosimilar Drug Development
The FDA guidance for biosimilar approval details a stepwise approach requiring
demonstration of biosimilarity to the original compound using comparisons of
structure, function, animal toxicity, human pharmacokinetics and pharmacody-
namics, clinical efficacy, safety, and immunogenicity. This is adequate to provide
the totality of evidence that may lead to FDA approval [ 6 ]. These factors will
determine statistical comparison of PK and PD results,manufacturing processes,
dose and route of administration selection between reference and biosimilar prod-
ucts, clinical study design, and long-term follow-up. From a biosimilar study
design perspective, the FDA recommends a calculation of a 90% confidence inter-
val for the ratio between the means of the parameters studied to be tested.
However, an appropriate limit for the confidence interval may range between 80
and 125% of the ratios comparing the reference and biosimilar product [ 7 ].
Features addressing quality standards in biosimilar manufacturing are outlined in
Table 15.1.
Table 15.1 Features of quality considerations in demonstrating biosimilarity
- Expression system
- Manufacturing process
- Assessment of physiochemical properties
- Functional activities
- Receptor binding and immunochemical properties
- Measurement of impurities
- Stability under multiple stress conditions (high temperature, freeze-thaw, light exposure,
agitation) - Effects of product formulation and packaging
15 Biosimilars in Inflammatory Bowel Disease 2017: State of the Science