Best Use of Biologics in 2014
Dig Dis 2014;32(suppl 1):8287
DOI: 10.1159/000367833
Biosimilars: Are They Bioequivalent?
Fernando Gomolln
IBD Unit, Digestive Diseases Service, Hospital Clnico Universitario Lozano Blesa, IIS Aragn, CIBEREHD,
Zaragoza, Spain
Key Words
Biologics Biosimilars Regulatory authorities
Abstract
Biologics have revolutionized several areas of medical thera-
peutics, and dozens of them are used by millions of patients.
Monoclonal antibodies are only one type of biologics, but
more than 900 are now in different phases of development.
These drugs are complex to make and not cheap. The market
is constantly increasing, and several biosimilars (copies of
biologics) are being used, while many are still waiting to be-
come available to the public. Biosimilars are more complex
than generics, and regulatory agencies have very stringent
criteria for approval. In the IBD field, the biosimilar infliximab
(Inflectra, Remsima) has been recently approved by the
EMA, but not by Canadian authorities. The EMA has consid-
ered that high similarity in preclinical studies together with
clinical data from two trials in ankylosing spondylitis and
rheumatoid arthritis warrant the extrapolation for all ap-
proved indications for original infliximab (Remicade), spe-
cifically Crohns disease and ulcerative colitis. Canadian au-
thorities have not accepted extrapolation, based on differ-
ences in glycosylation (fucosylation) that could be related to
properties important in Crohns disease. Most scientific soci-
eties do support the idea of asking for specific clinical trials
before approval, although they acknowledge that following
2014 S. Karger AG, Basel
02572753/14/03270082$39.50/0
E-Mail karger@karger.com
www.karger.com/ddi
EMA, FDA, and WHO guidelines warrant safe products. Prac-
tical issues such as interchangeability and substitution re-
main unsolved, and it is very likely that there will be different
solutions at the national level. Pharmacovigilance plans will
be key for obtaining reliable data. Biosimilars are not better
drugs, but can be clearly cheaper and may facilitate access
to new treatments in many populations.
2014 S. Karger AG, Basel
Introduction
Biologics (also known as biopharmaceuticals, biother-
apeutics, or biologicals) can be defined as a medicinal
product or vaccine that consists of, or has been produced
by the use of living organisms [1]. Biologics are not new
drugs; in fact, antiserum for diphtheria, the first drug fit-
ting the concept, was introduced in the 19th century [1].
However, in the last 20 years this part of medical thera-
peutics has literally exploded, and dozens of them are al-
ready in use in clinics, with more than 900 currently in
development. Among them, monoclonal antibodies rep-
resent the most important group. In fact, infliximab was
the first monoclonal antibody able to demonstrate clear
clinical efficacy in a immunological human disease, rheu-
matoid arthritis, and was also quickly found to be very
useful in Crohns disease (CD).
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Fernando Gomolln, MD, PhD
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Servicio de Aparato Digestivo
Hospital Clnico Universitario Lozano Blesa
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Avenida San Juan Bosco, 15, ES50009 Zaragoza (Spain)
E-Mail fgomollon@salud.aragon.es
 Although relatively new, this field has shown rapid de-
velopment and has completely changed the practice of
medicine in several fields such as oncology and rheuma-
tology. In IBD, our current approach to refractory CD,
perianal CD, or severe ulcerative colitis (UC) could not
be even understood without biologics. Infliximab and
adalimumab (and in some countries certolizumab) are
prescribed in many patients, golimumab has recently
been added, and vedolizumab should be available in the
near future. Natalizumab, however, is used only in a very
select group of patients due to the risk of complications.
In fact, the general algorithms and clinical reasoning has
changed in the last 15 years in IBD, and is expected to
continue developing rapidly in the near future [2].
Biologics are not simple to make. Although the manu-
facturing of monoclonal antibodies has advanced a lot
from Milsteins and Vilceks times, biologics are expen-
sive drugs, with a typical patient spending EUR 10,000
20,000 (or even more) for a year of treatment. In many
IBD units throughout the world, biologics are the current
main drivers of cost. IBD is only a small piece of the pie,
however, and the global market of biologics is constantly
increasing at a two-figure rate in most countries, and is
expected to rise even more. Patents are not eternal, and
biologic business is a very attractive one: Samsung, whose
main business is with electronics and cars, is seriously
considering entering the field. So, dozens of companies
are in the business of making copies of original (or so-
called innovators) biologics to enter the market. Since
2005, regulators (EMA, FDA, WHO, etc.) have made or
are making efforts to regulate this rather complex issue.
The real question is not one of simple bioequivalence,
as this would be perfectly adequate for chemical, simple,
relatively easy-to-manufacture drugs. The key important
question for clinicians, pharmacists, and patients is
whether these copies, called biosimiliars, are reliable? In
other words: Can I use a biosimilar with the same confi-
dence as the original biologic? [3]. It is not a simple ques-
tion to answer.
Moreover, we have to remember that this is a big busi-
ness, which is expected to amount to USD 250,000 mil-
lion in 2020. Most of the top-selling drugs in the world
are biologics. One aspect of the problem is that potential
conflicts of interest are huge in this topic, and the only
way to minimize these issues is through strict adherence
to rigorous scientific principles. Regulatory agencies do
not have an easy sea to navigate. In my view, scientific
societies should also collaborate in the process because
clinical experience is of great value when designing stud-
ies for evaluating drugs.
Biosimilars: Are They Bioequivalent?
Concept
The first point to discuss is the very concept of bio-
similars, a new word suggested by the EMA several years
ago, which has two components: bio for biologics and
similar for comparable, both terms that are qualitative.
A good definition would be: copy version of an already
authorized biological medicinal product with demon-
strated similarity in physicochemical characteristics, ef-
ficacy and safety, based on a comprehensive comparabil-
ity exercise [4]. This seems to be a clear statement that
could be supported by most experts. However, this is
only a qualitative definition, and we need much more
detailed and quantitative definitions in practice. Interna-
tional pharmaceutical authorities and regulatory agen-
cies have developed many specific guidelines to further
define similarity. In fact, the EMA was the first to make
specific requirements clearly detailed, and they have
been clarified and updated in several rounds; the FDA
has been somewhat late in the field, and only recently has
released a draft for public discussion. For the EMA to
consider approving a a biosimilar, the applicant must en-
ter into a complex negotiation process with the EMA, in
which a very detailed list of comparability issues need to
be solved, usually over several months. The applicant has
to demonstrate comparability in three different main
phases (each phase may contain numerous steps): (1)
high quality and reliability in manufacturing, in each of
the several complex steps involved, (2) nonclinical com-
parability, e.g. in the presumed mechanisms in several
adequate models, and (3) clinical comparability. Clinical
comparability includes not only pharmacokinetics (PK)
and, when possible, pharmacodynamics (PD), but also at
least one clinical trial, especially for safety. The EMA re-
quests equivalence trials, with the null hypothesis being
that the two drugs are equivalent, or alternatively that
both are nonequivalent. Of course, the equivalence mar-
gin (the ) is critical and established according to previ-
ous differences in clinical trials from the reference prod-
uct. There are several differences among diverse regula-
tory agencies, such as the FDA asking for noninferiority
trials. However, most steps of the process are very similar
in Europe, Japan, Canada, and Australia. Regulatory
norms are not as strict in China, India, and other coun-
tries, with local particularities in the interpretation of
patent regulations, and a considerably easier path to ap-
proval.
In summary, most regulatory agencies do require a
very strict process of approval, which implies many dif-
ferent experiments to finally demonstrate highly similar
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characteristics between the biosimilar and the reference
product. The process can be long (it may take years)
and is not cheap. Sandoz and other leading companies in
this field estimate that the complete process can have
costs ranging from EUR 40 to 200 million and take 69
years large figures when compared with a mean of EUR
25 million to develop a typical generic drug in 12 years.
Comparability
In the specific case of monoclonal antibodies, the first
step of comparability, that of quality, is not an easy task.
Antibodies are complex proteins [5], and the primary
structure (e.g. the amino acid sequence) is probably the
easiest part. Higher-order structures, glycosylation
(quantities, types, positions), purity, content, and charge
variants should all be demonstrated. The applicant is re-
sponsible for this, and regulatory agencies can change re-
quirements in the case of new, more detailed analytical
tools becoming available. In the specific case of large pro-
teins, these steps are very important because the manu-
facturing process can be responsible for subtle differenc-
es that can have important consequences in the action of
the drug. In fact, it has been said that for biologics, the
product is the process.
A large number of studies are then required to demon-
strate high similarity of biological actions between the
biosimilar and the reference product. A complete analysis
is beyond the scope of this short review, but has been ex-
cellently done in a recent by Ebbers paper in the Journal
of Crohns and Colitis [6]. Analytical tools are constantly
and quickly improving, and this will make comparisons
easier and more reliable in the future [7].
When these steps are fulfilled, clinical studies follow.
The philosophy of EMA (and probably others) guide-
lines is that it would be very difficult to find real differ-
ences in clinical studies if the very strict comparability
biological requirements are adequate and supported by
extensive pharmacological reasoning [8]. In other words,
if biochemical and biologic studies do show a high simi-
larity, we could predict clinical similarity with great con-
fidence, and it would be very unlikely that any small, or
even very large, difference will become evident in clinical
trials. However, clinical trials are required especially for
two things: (1) to obtain real-world human PK and PD
data, and (2) to evaluate safety. The first goal can be
reached in trials when adequate numbers and methods
are chosen. The evaluation of safety, however, is limited,
because potential low-frequency adverse effects would be
84 Dig Dis 2014;32(suppl 1):8287
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very difficult to ascertain in typical clinical trials. This
point leads immediately to the need for a complete pro-
gram of pharmacovigilance after the release of the prod-
uct. Regulatory agencies require a detailed plan for phar-
macovigilance from the manufacturer, with a clear calen-
dar to evaluate for possible risks.
This would complete the process for one drug and one
indication. However, several biologics have been demon-
strated to have efficacy in different diseases, although dif-
ferent doses, combinations or schedules may apply for a
given disease. Should we extrapolate for all indications
and all diseases after these comparability issues have been
solved according to guidelines? Regulatory agencies, and
particularly the EMA, consider extrapolation on a case-
by-case basis. Things are not so clear in the case of ex-
trapolation for different diseases, e.g. a clinical trial done
in one disease and considered to be valid for another dis-
ease, or if the model is considered the most sensitive one
(again a qualitative term), especially in safety and immu-
nogenicity issues.
IBD: Current Situation
There are dozens of biologics currently being used in
medical practice [3, 9, 10]. However, biosimilar develop-
ment is neither easy nor cheap [11, 12], and will occur
only if three conditions are fulfilled: (1) a company iden-
tifies a biosimilar as interesting and is willing to take the
risks to develop it, (2) the patent has expired, and (3) the
regulatory authorities finally approve the new product.
Only 14 biosimilars have been approved by the EMA to
date. In the specific field of IBD, these three conditions
have occurred only in the case of Remicade in some Eu-
ropean and Asian countries. In Europe, Inflectra and
Remsima are two brands1 of the first monoclonal anti-
body approved as a biosimilar product. The reference
product was Remicade, a monoclonal chimeric antibody
that has completely changed the way we approach our
patients in the clinic, and has had extraordinary commer-
cial success. There are a number of biosimilars to Remi-
cade being developed, and also several ones (>20) to Hu-
mira the top drug in sales in 2013 worldwide, selling
more than USD 10,000 million. However, it is difficult to
predict how many of them will complete the process and
make it to the market.
1
We will use the brand Inflectra throughout this paper to avoid repetitions.
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 Inflectra was approved by the EMA after a very de-
tailed negotiation and many experiments (the summary
of the process is a public document more than 100 pag-
es long, which, by the way, most people interested in
biosimilars probably have not analyzed in detail). No
real significant differences were found in analytical,
biochemical, or biologic studies. Several biologic stud-
ies were done not only using cells from normal controls
but also from active CD patients. Although a difference
in glycosylation (fucosylation) was shown, and in some
specific media subtle differences were found in some
ADCC experiments, especially with CD cells, the ex-
perts from the EMA did think that Inflectra was highly
similar to Remicade [6]. Clinical evidence was obtained
in three studies. The first was a pilot study in 19 rheu-
matoid arthritis (RA) patients who also received metho-
trexate (duration: 102 weeks) for obtaining PK data.
The second was a large clinical trial, coded as PLANET
AS [13], done in 250 patients with ankylosing spondy-
litis receiving Inflectra or Remicade at a 5-mg/kg dose
over 54 weeks as monotherapy. No difference in clinical
efficacy, PK data, PD data (limited) or safety was appar-
ent. In another very large study (coded PLANET RA)
[14], 606 RA patients were treated with a combination
of methotrexate and Inflectra or Remicade. Again a
very high similarity was demonstrated between the
two drugs, with no apparent difference in efficacy or
safety, although some of the analysis has been ques-
tioned, for instance the choosing of ACR20 for com-
parisons instead of other probably more sensitive items.
PK detailed data were almost identical for most com-
parisons.
With these data, the EMA finally approved Inflectra
for the same indications as the innovator in RA and AS.
Moreover, the EMA considered that the very small dif-
ferences found in some of the experiments was no ob-
stacle for extrapolation, and gave the biosimilar the
same indications as the innovator, including all the in-
dications in CD and UC. The dates of patent expiration
are not the same in different European countries, and
Inflectra has reached the market in several countries
(e.g. Portugal, Finland and Poland), and most likely will
be available in the rest or the EU in 2014 or 2015. Price
advantages are also very different in the different mar-
kets. Experience with previous biosimilars makes pre-
dictions even more difficult, as they have had very vari-
able penetration in markets, with some having anywhere
from 0 to 70% of the market in different countries, with
great diversity at regional levels as well.
Biosimilars: Are They Bioequivalent?
Controversy: Is Extrapolation Adequate?
In a recent ECCO survey with 307 responders that was
presented at ECCO 2014 in Copenhagen by Silvio Danese
and Pierre Michetti, it was shown that the confidence of
ECCO members on biosimilars was not very good: 32.7%
declared they were not confident at all and 28.3% said
they were only a little confident, i.e. roughly 2 out of 3
clinicians were not confident with biosimilars. It is very
likely that one of the reasons could be lack of information
on the very strict procedures of the EMA, although this is
speculative. In informal conversations among gastroen-
terologists, confidence in the procedures of regulatory
authorities is not very high. It may be that the way scien-
tific societies and EMA collaborate are not ideal and
should be improved.
Position statements from different medical societies
have appeared in recent years [15, 16]. In these docu-
ments, biosimilars are generally welcome to the field, and
the EMAs and other regulators guidelines recognize
them as adequate. However, some controversial points
are evident. In a recent ECCO position statement, direct
evidence from trials done in CD and UC patients with
enough potency were considered necessary. The argu-
ments for this were: (1) biologics do not work in all the
indications, e.g. etanercept is very useful in RA, but has
no efficacy (at doses used in trials) in CD; (2) immunoge-
nicity is not exactly the same between diseases and seems
to be more common in CD, and the pathophysiology of
immunogenicity from monoclonal antibodies is far from
clear and is unpredictable in many clinical scenarios; (3)
specific pathophysiological mechanisms could account
for theoretical differences between drugs, as intestinal
immunology is very complex; (4) clinical experience in
CD and UC could reveal some differences not previously
seen in other diseases; (5) no evidence of the combination
of the biosimilar with thiopurines, and considerable in-
teraction has been shown with the innovator drug, which
is the most common combination used in IBD patients,
and (6) RA is probably not the most sensitive model (the
is not very wide between placebo and drug), and pso-
riasis, which usually shows the greatest differences, could
have been a much better model. On the contrary, experts
from the EMA defended extrapolation, indicating that
the biochemical and biologic experiments were so de-
tailed that high similarity was demonstrated, and that
the models studied in clinical trials gave enough informa-
tion on PK and safety, confirming the molecular similar-
ity. An excellent paper by Ebbers [6], with very detailed
argumentation for extrapolation, was immediately pub-
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lished in the ECCO journal. However, not all experts
agree [17]. The subtle differences that were not consid-
ered relevant by the EMA experts precluded extrapola-
tion when Inflectra was approved in Canada. After basic
scientists evaluated exactly the same data as those from
the EMA, they asked for more data. They did, however,
approve the drug for AS and RA, the diseases in which
clinical studies had been performed. In fact, the compa-
nies have started a CD clinical trial, but the final results
are estimated to become available in 2017.
Perhaps not only for scientific reasons but also psy-
chological ones, IBD clinicians would like to see data on
IBD patients. In fact, clinical experience on every-day
practice constantly shows that UC and CD are very com-
plex diseases a view clearly confirmed in the enormous
genetic complexity demonstrated in the last 10 years, not
to mention transcriptomics, proteomics, and micro-
biomics. Furthermore, most clinicians have been educat-
ed in evidence-based medicine and ask for clinical trials
to support any new change in clinical practice. In fact, this
used to be the way regulatory authorities managed these
issues in the past, and physicians were often criticized by
methodologists for making so many experience-based
decisions. Meta-analysis and clinical trials have been con-
sidered the Holy Grail of evidence. But, when biosimi-
lars reach the field, clinicians are asked to trust biochem-
ical and biologic experimental evidence, and directly ex-
trapolate to clinics. This concept seems difficult to accept,
and should be explained in detail. Educational efforts are
clearly needed.
Moreover, PK concepts are not easy to grasp, and most
clinicians have difficulties in understanding these new
concepts [18]. New trials could be useful to confirm EMA
arguments in real practice, and these trials should be de-
signed to obtain responses for clinically important issues,
e.g. PK data can further improve our knowledge of the
usefulness of drug levels in practice. Critics of the EMA
position argue that biosimilars do not represent any clin-
ical advantage to original biologics, and if we only win in
price, strict requirements of safety should include clinical
experience, exactly as in previous biologics development:
it would be ethically difficult to accept some damage for
patients only because of cost-savings, without any advan-
tage in efficacy. Curiously, the EMA says that basic data
are the key, but more than 50% of the pages of the official
summary are devoted to clinical trials data. The EMA
website has a lot of information, but it is not an easy site
to navigate: information should be readily available and
easy to use to improve understanding of concepts for all
stakeholders.
86 Dig Dis 2014;32(suppl 1):8287
DOI: 10.1159/000367833
But, Are Biosimilars Reliable?
For the specific question of bioequivalence, the an-
swer in the only approved biosimilar for IBD, Inflectra, is
a clear yes. PK data from two large clinical trials are rath-
er clear: both with and without concomitant methotrex-
ate, Inflectra is bioequivalent to Remicade. But the real
important question is not that. A better good question is:
Can I be as confident as with Remicade in all the indica-
tions I have been using it in my IBD patients? Most of the
available data suggest that the answer should be yes.
While this, in fact, is the response from the European reg-
ulatory authorities, it is not the answer from Canada. As
physicians who have cared for IBD patients for many
years, we would like to have direct clinical evidence ob-
tained in CD and UC patients, with the focus on PK, im-
munogenicity and safety. Pharmacovigilance can be the
adequate response for some issues [19], safety or immu-
nogenicity for instance, but clinical trials would be desir-
able to obtain high-quality information on efficacy, with-
out the inherent bias of observational studies.
Interchangeability, Switching and Name
Being highly similar does not mean that switching is
a good idea. In this particular point, my recommendation
would be to avoid it at least until data from clinical trials
are available, e.g. changes from infliximab to adalimumab
have been not very successful [20], although there are
other opinions to consider [21]. Curiously, clinicians
with direct experience with patients are much more reluc-
tant than pharmacists who have no direct clinical experi-
ence in the management of patients. Biosimilars compa-
nies defend the use of generic names while the companies
manufacturing reference products do prefer brand names.
For adequate pharmacovigilance, the brand name and a
complete registry of batches should always be registered,
as unexpected changes in the manufacturing process can
have big molecular consequences.
Conclusion
Biosimilars are here to stay and most likely will be very
important actors in the fields of rheumatology [22] and
IBD. Regulatory, clinical, and economic issues are so
complex that continuous education is clearly needed [23],
as a lack of accurate information of clinicians is apparent
according to recent data. Regulators, clinicians, pharma-
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cists, patients, health authorities, and providers should
develop consistent guidelines to optimize use of these ex-
pensive resources that can make a real difference in a pa-
tients life. A social perspective is clearly needed. The fu-
ture will be more and more complex. First, new strategies
will make possible great improvements in the develop-
ment of therapeutic antibodies [24]. Second, at some
point in the future we will be able to speak of biogenerics:
erythropoietin has been obtained by complete chemical
synthesis recently [25], and this could change everything.
A brave new world of chemical synthesis could be await-
ing us [26], making this short review obsolete in only a
few years.
Disclosure Statement
F.G. has been a consultant for Abbvie, MSD, Faes-Farma, and
Pharmacosmos, has received research grants from MSD, and has
received speaker fees from Abbvie, MSD, Ferring, and Falk-Phar-
ma.

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DOI: 10.1159/000367833
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