271possibility of gaining approval for extrapolation, as well as for interchangeability,
is an important motivator for a biotechnology company to embark on a venture in
which large financial risks are taken with an uncertain approval process, an
unknown landscape of patent battles, and unknown physician, patient, and payer
acceptance. Considerations taken by the FDA in granting approval for extrapola-
tion for each disease state consider the “totality of the evidence.” This begins with
the establishment of biosimilarity by analysis of primary, secondary, and tertiary
structure, posttranslational profile, and in vitro functional characteristics to
include TNF binding and neutralization as discussed in the earlier sections of this
review. Clinical analysis of the data includes potential differences in mechanism
of action (MOA), pharmacokinetic (PK), and pharmacodynamic (PD) data in dif-
ferent patient populations; immunogenicity in different disease states, which may
be influenced by different concomitant immunosuppressive agents in the different
diseases; and the potential for differences in expected toxicities in different patient
populations [ 26 ]. Consideration of these same variables and data led to different
extrapolation approvals in Canada, the European Union (EU), and the United
States (USA).
However, there are a number of potential obstacles in extrapolating from RA and
AS to inflammatory bowel disease. Factors which are different between these dis-
eases include different dosages, differences in the use of methotrexate in RA, and
the variable patterns of the use of various immunosuppressants in IBD which may
affect drug levels, anti-drug antibodies, and resultant differences in clinical efficacy
[ 34 – 36 ].
An additional criterion of the FDA scientific guidelines in considering the
issue of extrapolation is to “consider whether the tested condition of use is the
most sensitive in which to detect clinically meaningful differences and safety
and effectiveness [ 8 ].” In the case of rheumatoid arthritis, however, the
PLANETRA study of CT-P13 versus infliximab trial was designed as an equiva-
lence trial, and the 95% confidence interval for the treatment difference between
CT-P13 and infliximab for the primary endpoint was −6–10%, falling within the
range of the equivalence margin selected of −15–15%. These confidence inter-
vals contained the smallest placebo- adjusted response to infliximab, 8%, previ-
ously demonstrated in any disease for which infliximab is indicated [ 4 ].
Rheumatoid arthritis may therefore be the least sensitive clinical model to detect
a potential difference in efficacy between this biosimilar and infliximab in other
indications [ 37 ]. Another challenge in extrapolating from RA to Crohn’s disease
is the divergent efficacy for different anti-TNF agents, as well as other biologics
in the two diseases, suggesting the possibility of different mechanisms of inflam-
matory pathways. For example, while anti-TNF agents are effective in both,
anakinra, abatacept, and rituximab are effective in RA, but not in Crohn’s dis-
ease [ 38 – 41 ].
In Canada, Health Canada, the national drug regulatory agency, approved
CT-P13 for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and
plaque psoriasis,based on the PLANETRA and PLANETAS trials [ 4 , 5 , 42 ]. Health
Canada also relied on these trials to demonstrate similarity in pharmacokinetic
15 Biosimilars in Inflammatory Bowel Disease 2017: State of the Science