Autoimmunity Reviews 13 (2014) 751–755
Contents lists available at ScienceDirect
Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev
Review
The use of biosimilars in immune-mediated disease: A joint Italian
Society of Rheumatology (SIR), Italian Society of Dermatology
(SIDeMaST), and Italian Group of Inflammatory Bowel Disease (IG-IBD)
position paper
Gionata Fiorino a,⁎, Giampiero Girolomoni b, Giovanni Lapadula c, Ambrogio Orlando d,
Silvio Danese a, Ignazio Olivieri e,⁎⁎, on behalf of SIR, SIDeMaST, and IG-IBD
a
IBD Center, IRCCS Humanitas, Rozzano, Milan, Italy
Department of Medicine, Section of Dermatology and Venereology, University of Verona, Verona, Italy
Interdisciplinary Department of Medicine, University of Bari, Bari, Italy
d
Internal Medicine, “Cervello” Hospital, Palermo, Italy
e
Rheumatology Deparment of Lucania, San Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera, Italy
b
c
a r t i c l e
i n f o
Article history:
Received 5 February 2014
Accepted 13 February 2014
Available online 19 March 2014
a b s t r a c t
Biological agents are widely used in rheumatology, dermatology and inflammatory bowel disease. Evidence
about their efficacy and safety has been strengthened for all those therapeutic indications over the last decade.
Biosimilar agents are monoclonal antibodies similar to previously approved biologics. In the European Union,
they have been approved for all the indications in the management of immune-mediated inflammatory diseases
(IMIDs), although data only in rheumatoid arthritis and ankylosing spondylitis are currently available. Direct
evidence on efficacy, safety, and immunogenicity of biosimilars is mandatory in psoriasis, psoriatic arthritis,
and inflammatory bowel disease, as well as in children. Based on the current evidence in the literature, we
present the joint official position of the Italian Societies of Rheumatology, Dermatology and Inflammatory
Bowel Disease on the use of biosimilars in IMIDs.
© 2014 Elsevier B.V. All rights reserved.
Contents
1.
Introduction . . . . . . . . . . . . . .
2.
General aspects of biosimilars . . . . . .
3.
Traceability and interchangeability . . . .
4.
Biosimilars in rheumatology . . . . . .
5.
Biosimilars in dermatology . . . . . . .
6.
Biosimilars in inflammatory bowel disease
7.
Discussion . . . . . . . . . . . . . . .
Conflict of interest . . . . . . . . . . . . .
Take-home messages . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . .
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⁎ Correspondence to: G. Fiorino, IBD Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy. Tel.: +39 0282245555;
fax: +39 0282242591.
⁎⁎ Correspondence to: I. Olivieri, Rheumatology Unit, Deparment of Lucania, San Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera, Contrada Macchia Romana,
85100 Potenza, Italy. Tel.: +39 0971613039; fax: +39 0971613036.
E-mail addresses: [email protected] (G. Fiorino), [email protected] (I. Olivieri).
http://dx.doi.org/10.1016/j.autrev.2014.02.004
1568-9972/© 2014 Elsevier B.V. All rights reserved.
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G. Fiorino et al. / Autoimmunity Reviews 13 (2014) 751–755
1. Introduction
The introduction of monoclonal antibodies, commonly known as
biologics and fusion proteins has dramatically changed the clinical management and the course of immune mediated inflammatory diseases
(IMIDs), such as rheumatoid arthritis (RA), ankylosing spondylitis
(AS), psoriatic arthritis (PsA), psoriasis (Pso), Crohn's disease (CD)
and ulcerative colitis (UC) [1–3]. The use of anti TNFs, such as infliximab,
etanercept, adalimumab, certolizumab, and golimumab, and new
molecules, such as ustekinumab, an anti-IL-12/23 monoclonal antibody,
represents important therapeutic options in patients refractory to
conventional immunosuppressive treatments, or that need prolonged
and frequent courses of steroids. In addition, prolonged maintenance
therapy with anti TNFs may avoid severe complications and improves
patients' quality of life.
The main limitation of biologics is related to their costs [4]. Biologics
are very complex and large molecules (about 1000 times the size of
chemically synthesized drugs) produced by living cell cultures, thus
requiring large investments. In spite of a better control of immunemediated inflammatory diseases, their use may result very expensive
overtime [4–6], especially for National Healthcare Systems. In times of
expense reduction, this issue becomes highly important, and may
limit their use.
2. General aspects of biosimilars
The concomitant patent's expiration of some biologics, such as
infliximab, and the development of their biosimilars have raised an
important debate on their use to save resource for the treatment of
chronic inflammatory diseases [7]. Although the strictly controlled
manufacturing process makes biosimilars very similar to originators,
the lack of solid data on their long-term safety and effectiveness raises
some concerns.
The European Medical Agency (EMA) defines a biosimilar as a
biological medicinal product, which is similar to a biological medicine
that has already been authorized, the so-called “reference medicinal
product”. A biosimilar and its reference product are expected to have
the same safety and efficacy profile, and are generally used to treat the
same conditions. The reference product is defined as a medicinal product which has been granted a marketing authorization by a Member
State or by the European Commission on the basis of a complete dossier,
i.e. with the submission of quality, pre-clinical and clinical data [8]. As
far as the biosimilar product is concerned, such comparability must be
clearly supported by scientific evidence. Between 2003 and 2005, the
EMA has addressed this challenge by establishing that the development
of biosimilars should satisfy the so-called “comparability exercise”. As
far as comparability is concerned, however, some issues have raised.
Because of the complexity of the molecule itself and the diversity of
manufacturing processes, it is generally clear that an identical copy of
a biological agent cannot be made. Even minor differences may result
and their clinical relevance could be potentially very challenging.
Thus, clinicians may be reluctant to switch to a biosimilar agent which
has not been tested enough [9,10]. Moreover, the clinical comparability
exercise is the least sensitive method to detect differences. Even if present, disparities may not be revealed in clinical studies with a limited
sample size, particularly when the biosimilar differs from the reference
product mostly for safety, immunogenicity or rare adverse events. The
scientific principles underlying the required comparability for changes
in the manufacturing process (also known as microheterogeneity) of a
given biological drug and for the development of a biosimilar medicinal
product are the same. However, data requirements for biosimilars must
be higher than those imposed to assess the microheterogeneity [11–14].
Therefore, in 2012, the European Commission changed its position on
the use of the reference medicinal product in the comparability exercise [15]. Previous requirements of an exclusive use of products licensed
in the European Economic Area (EEA) were changed in accepting
critical data for comparisons from reference products authorized in
regulated markets outside EEA. This new position left the applicant
the responsibility to establish the equivalence from the non-EU to the
EU reference product, and to demonstrate that the former is representative of the latter with additional comparisons of both originators.
Based on current published data, which report some differences in
terms of pharmacokinetics and dosing properties [16], the Italian
Medicines Agency (AIFA) states that biosimilars cannot be considered
interchangeable or simple substitutes of originators, except on case of
documented equality [17]. Moreover, it also states that in case of multiple indications (as it is the case for anti TNF-alpha) the biosimilarity has
to be demonstrated for each indication. Finally, the decision to prescribe
the originator or the biosimilar is left to the clinician [18]. Whether the
clinicians are aware of all the issues concerning biosimilarity is still to be
investigated.
3. Traceability and interchangeability
Particular emphasis should be placed on the traceability, which
means to provide a reliable identification system, related to all production and distribution phases, either the originator or the biosimilar used
in clinical practice, so that the frequency and severity of adverse events
can be certainly identified for each product. The interchangeability, that
means the possibility to switch among similar molecules as they are the
same molecules, cannot be defined in the approval phase due to the
possible difference in rare adverse events and different susceptibility
to induce anti-drug antibodies. This topic has been discussed by the
World Health Organization since 2006 [19]. They recognize that
‘biosimilar’ is a regulatory and legal term distinct from the International
Non-proprietary Name (INN) assignment process. Although the policy
for the assignment of INNs should be applicable to biologicals in general,
according to the EU position, the variability related to different glycosylation is to be considered, and they recognize that significant variability
can be found between innovator biological products with the same
INN, or even for the same manufacturer [19]. Japan and South Korea
proposed to add every time the commercial name after the assigned
INN, in order to better identify the molecule, rather than only the active
principle [19]. The needed post-marketing process to identify relevant
safety issues related to biosimilars cannot be performed precisely if
differentiation between molecules, beyond the INN, is not specified in
the safety reports.
Traceability will be possible only through large databases accumulated in post-marketing surveillance from safety studies or specific
registries. It should be possible to detect any significant difference in
side effects or immunogenicity, if these data will be effectively and
accurately collected. In this way, the clinical community will be given
enough assurances about the safety of biosimilars with greater favorable response. For the same concerns, interchangeability between the
originator and its biosimilar is an important issue to discuss. If two
molecules are considered interchangeable, then it will be possible to
switch from one to another. Currently, there are limited data on switching
to a biosimilar in terms of maintenance of response, immunogenicity or
other safety issues [20,21]. Probably, in some cases, switching can be
possible, but the final decision should be tailored on the patient by the
clinician; in the case of automatic replacement, a certain risk of loss of
response and loss of tolerance should be taken into account.
In the present paper, we report the current literature evidence
regarding biosimilars in chronic inflammatory rheumatic diseases, Pso,
and inflammatory bowel diseases, and the perspective of the Italian
Society of Rheumatology (SIR), Italian Society of Dermatology
(SIDeMaST), and Italian Group of Inflammatory Bowel Disease (IG-IBD).
4. Biosimilars in rheumatology
Clinical trials on efficacy and safety comparisons between biosimilars
and originators are undertaken with a sample size usually smaller than
G. Fiorino et al. / Autoimmunity Reviews 13 (2014) 751–755
normally required for the development of a biologic product. The
extrapolation of information related to clinical comparability with
other previously licensed originators is easier if the same mechanism
of action of the monoclonal antibody is involved. Nevertheless, for
certain indications, not only the reactions of Fab fragments with the
target, but also the interaction of monoclonal antibody with some
FcγR sub-types, may play a role in the mechanism of action and, in
this case, it is important to consider further experimental results [22].
In particular, as far as the first biosimilar monoclonal antibody to
infliximab (CT-P13) is concerned, which was approved for marketing
in South Korea for all the six indications of infliximab, the approval
was based on a single equivalence trial conducted in patients with RA
[23], and supplemented by a pharmacokinetic study in patients with
AS [24]. They showed that infliximab and its biosimilar result are not
different in terms of clinical efficacy, safety and immunogenicity, both
at 30 and 104 weeks [20,21].
The FDA and the EMA require at least one clinical study in the most
sensitive patient population, measuring the most sensitive clinical
endpoint(s) to detect clinically meaningful difference both for efficacy
and safety, including immunogenicity. Caution is recommended for
different safety risk profiles across indications due to different comorbidities and concomitant medications. The large sample size
required for a comparative exercise trial [22] is the main reason to
give a particular warning when considering the use of infliximab
biosimilars in the pediatric population, since the pharmacokinetics of
biologics and biosimilars in children is still poorly defined and must
represent an aspect to be investigated before approving the free
administration of biosimilars as equivalent to original products.
Moreover, we should consider that the non-inferiority (or equivalence)
evaluation margin of biosimilars is small based on the difference
in efficacy between the reference product and the placebo (placeboadjusted response) [25] and that RA was associated with the smallest
placebo-adjusted response to infliximab, compared to other indications.
In other words, RA is likely to be the less sensitive clinical model
to detect a potential difference in efficacy between CT-P13 and
infliximab, particularly as studied in the equivalence trial of CT-P13
patients [22].
Immunogenicity of monoclonal antibodies is the most important
general safety concern on biosimilars. Anti-drug antibodies, in case of
biological products, may cause adverse events and/or inhibit the action
of the drug. For example, a minor change in the manufacturing process
of an erythropoietin product caused the production of autoantibodies to
endogenous as well as exogenous erythropoietin, increasing the
incidence of pure red cell aplasia (PRCA), a rare but fatal anemic condition [26]. This means that the immunogenicity profile should be studied
in the patient population that carries the highest risk of an immune
response and immune-related adverse events [27]. However, RA is
associated with the fewest proportion of antibodies to infliximab
(10%), mainly at a low titer [28], compared to other IMIDs, thus being
the less appropriate population, from whom data on immunogenicity
can be extrapolated for the other indications to infliximab.
In conclusion, the Italian Society of Rheumatology states that
biosimilars should be limited to the indications for whom the “comparability test” was executed. Any claim must be validated with specific
clinical trial, in particular for the extension of use of biosimilars in
axial spondyloarthritis, enteropathic or psoriatic arthritis, and, overall,
pediatric patients. Validation should be conducted by direct comparison
of the results coming from well-designed clinical trials on the innovative product and the original treatment. This would result in a great
potential for the appropriate use of biological therapies in pediatric
rheumatic diseases and enteropathic arthritis, in terms of management
of the disease, and in terms of cost reduction.
However, as currently usual for the available biologics, the final
clinical decisions should always be made on an individual basis, taking
into account both the characteristics of the individual patient and the
clinician's advice.
753
5. Biosimilars in dermatology
The introduction of biological therapeutics for the treatment of
chronic plaque Pso has significantly improved several important patient
outcomes including quality of life, and allowing an effective long-term
control of the skin disease. Indeed, the proportion of patients who
maintain the therapy is significantly higher for those receiving TNF-α
blockers than conventional treatments, most likely because the formers
are much better tolerated. Conventional drugs more easily induce organ
toxicity and negatively affect cardiometabolic comorbidities which are
very common in patients with Pso. In particular, cyclosporine induces
nephrotoxicity and hypertension, methotrexate liver damage, and
acitretin can result in skin and mucosal toxicity [29]. Currently approved
biologics for the treatment of chronic plaque Pso include the TNF-alpha
inhibitors adalimumab, etanercept and infliximab, and ustekinumab, an
anti-IL-12/23 monoclonal antibody. Although biosimilars may improve
access to expensive biological agents, concerns have been raised
regarding their clinical use. In particular, due to the complexities of
manufacturing copies of biological therapeutics, SIDeMaST has
questioned whether biosimilars will confer identical biological function,
efficacy and toxicity to reference products, both in the short and long
terms. Thus, the key question for biosimilars is not whether differences
exist compared with the reference, but whether differences are clinically
relevant. The acceptance of biosimilars among dermatologists requires
understanding the regulatory processes governing their approval. For
EMA and FDA, a biosimilar clinical development program must demonstrate equivalence to a reference product already licensed (and
manufactured) for use in Europe or in the USA, respectively. The
demonstration of biosimilarity is significantly different from generic
drug approval, where only pharmacokinetics equivalence must be
shown. Extensive, non-clinical physiochemical and biological characterization is required to address structural, functional and immunogenicity concerns, prior to efficacy and safety trials. Thus, the chemistry,
manufacturing and portion controls of a biosimilar application are likely
larger and more detailed than that of the reference product. A clinical
data requirement that must be demonstrated is equivalent to reference
product, as opposed to superior safety and efficacy. Both EMA and FDA
require randomized controlled trials (RCT) to be of sufficient size to
establish clinical equivalence; however, rare adverse events and longterm efficacy and safety will be assessed only through post marketing
surveillance. Thus, as for reference agents, stringent post-approval
pharmacovigilance is paramount. Extrapolation of clinical data permits
the approval of a biosimilar for a therapeutic indication in which it has
not been clinically evaluated, but for which the reference agent is
approved. However, extrapolation may be less appropriate when the
two therapeutic indications involve distinctly different practices and
disease biology, and will therefore be considered by EMA/FDA ‘caseby-case’ [30]. We believe that consideration of separate clinical trials
for biosimilars in different therapeutic indications would be therefore
very important. Automatic substitution would enable pharmacists to
dispense a biosimilar, instead of the reference agent, without prior
consent of the prescribing physician. EMA has recently designated a
biosimilar as automatically substitutable, although each country will
follow its own national guidelines [17,31]. Finally, nomenclature must
allow physicians to identify biosimilar products and communicate
prescriptions accurately with pharmacists. It is important that physicians distinguish between biological ‘intended copies’ and biosimilars.
To attain the biosimilar status, an agent must undergo the required
comparability qualification in accordance with scientific principles
endorsed by authorities, such as EMA or FDA. Despite these stringent
approval processes, significant savings in costs are expected. Once available, physicians who prescribe biological therapies must be aware of
any developments concerning biosimilars, and be vigilant in their use.
Currently, there are no biosimilar monoclonal antibodies and soluble
receptor constructs that have been approved by EMA or FDA for treatment of chronic plaque Pso with specifically designed RCTs, and all
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G. Fiorino et al. / Autoimmunity Reviews 13 (2014) 751–755
these aspects should be considered at the time of the introduction of
biosimilars for the management of skin diseases.
6. Biosimilars in inflammatory bowel disease
Infliximab and adalimumab are the only biologics currently
approved for the treatment of Crohn's disease (CD), and, together
with golimumab [32], for ulcerative colitis (UC) in the European Union
(EU) [33]. In the Western countries outside EU, also certolizumab
pegol and natalizumab are approved for Crohn's disease. At present,
two infliximab biosimilars have been filed for the EMA, Inflectra®, and
Remsima® [34,35], although there are currently no studies comparing
infliximab and biosimilars in IBD. In this particular case, EMA has
accepted the regulatory filing of the biosimilar companies by extrapolating data from chronic inflammatory rheumatic diseases, in particular
from the PLANETRA trial [23], which investigated combination therapy
with biosimilar infliximab and methotrexate in RA. However, there are
several data which show that evidence on rheumatic diseases cannot
be directly translated on inflammatory bowel diseases, starting from
different mechanisms on pathogenesis [36]. Etanercept and abatacept
work well in rheumatic diseases, but are completely ineffective in IBD
[37,38]. The dosage of anti TNFs used in rheumatology is sometimes
different from those used in IBD, and also the dose optimization is different [39]. It is thus needed to conduct well-designed non-inferiority or
equivalence trials to compare biosimilars and infliximab.
The Italian Group for the study of Inflammatory Bowel Disease states
that adequate studies and surveillance are urgently required, before
approving the use of biosimilars in IBD, in line with the position of the
European Crohn's and Colitis Organization [40].
7. Discussion
The development of biosimilars for the treatment of immunemediated disease may be important to decrease the costs of biological
therapy. However, it is required to demonstrate their equality in terms
of efficacy and safety. Studies on erythropoietin demonstrated that a
simple change in the formulation of the molecule can lead to relevant
unexpected adverse events, especially concerning immunogenicity [9,
16,41]. Given the complexity of anti TNFs and their relevant immunogenicity, this point should be carefully considered. Moreover, clinicians
often do not know that also original molecules can undergo modifications in manufacturing after the approval from Regulatory Agencies,
which can somehow impact on the effects of the agent itself [42]. This
should be also taken into account for biosimilars, which come already
from a modification in the manufacturing process compared to the
originator. Post-translational modifications, such as glycosylation, may
occur from changes in cell lines and/or manufacturing processes,
resulting in products that are highly similar, but not identical to
approved ‘reference’ agents, hence the term is ‘biosimilar’, rather than
‘bioidentical’. The potential for protein modification to alter biological
function is especially true for complex therapeutic proteins, such as
monoclonal antibodies and soluble receptor constructs. Subtle changes
in protein conformation may result in altered function, insolubility or
increased immunogenicity that is a major determinant to loss of clinical
efficacy in patients who undergo biological treatments [43]. Activity of
monoclonal antibodies and soluble receptor constructs depends not
only upon interactions with target antigen, but also upon Fc receptor
(FcγR) function [44]. Mutations of one amino acid are sufficient to
impair Fc interactions, thereby altering complement activation and/or
antibody-dependent cytotoxicity, and reducing the efficacy of therapeutic monoclonal antibodies.
The methodological issues in comparing biosimilars and originator
are a key point. A non-inferiority comparison is the most correct
approach, but it is limited by the large sample size required. Moreover,
phase III are usually underpowered for safety, thus a well-designed
comparative trial for biosimilars should start with α = 0.25 and
β = 0.90, which results in a higher sample size required than the common placebo-controlled trials for efficacy [45]. The absence of placebo
and the lower response due to immunogenicity should be also taken
into account in the sample size calculation. Li et al. [45] have proposed
an asymmetrical biosimilarity margin with different non-inferiority
and non-superiority margin, which can improve the feasibility of the
trial. Probably, such trial needs an interim analysis to adjust the sample
size during the investigation phase, and get statistically significant
results [45]. The trial design should also consider the different outcomes, and get an adequate sample size for all of them.
Finally, clinicians and patients should be aware of all matters
concerning biosimilarity. The similarity, but not equality, should be
clear, and the current lack of data for biosimilars in certain diseases
should be also underlined. The interchangeability and substitution
between molecules should be left to the expert and informed clinicians.
The point of view of patients' associations should also be carefully
considered. A consensus between clinicians, patients, payers, and/or
public health organizations needs to be reached, especially to carefully
consider advantages and issues related to the use of biosimilars, from
different points of views [46].
In conclusion, we can clearly state that:
- Biosimilars cannot be considered interchangeable or simple substitutes of originator, until recent and preliminary data will be
confirmed. The complexity of the molecule, dosing, and immunogenicity issues needs careful investigation on these aspects.
- Biosimilars should be demonstrated to be effective and safe in
immune mediated-diseases in RCTs of sufficient dimension. Efficacy
assessment merely based on clinical response is not always comprehensive, as specific endpoints should be also investigated.
- The use of biosimilars in children affected by chronic immunemediated diseases, such as RA, AS, PsA, Pso and IBD needs to be
carefully investigated, especially in terms of safety.
- Biosimilars need to be tested by well-designed trials with an
adequate sample size calculation.
- Post-marketing surveillance for safety and immunogenicity has to
clearly differ the biosimilars from the originator. The name
“infliximab” should not be used in the reports, but rather the
commercial name, in order to monitor particular effects which can
differentiate between the agents. In this context, we did not find
anything correct to identify an originator monoclonal antibodies
and its biosimilar with the same INN.
- Interchangeability cannot be automatic, unless its effectiveness and
safety will be exhaustively demonstrated. It should be currently
left to the clinician's responsibility to choose whether to switch
from an originator to a biosimilar, based on patients' characteristics.
Neither other paramedical characters nor Healthcare payers should
be allowed to change the prescription or impose the use of
biosimilars instead of their originator.
Conflict of interest
G.F. served as a consultant and a member of Advisory Boards for
MSD, Takeda Pharmaceuticals, and Janssen Pharmaceuticals; G.G. has
received advisory/speaker honoraria and/or research funding from
AbbVie, Almirall, Boehringer Ingelheim, Celgene, Dompè, Eli-Lilly,
Galderma, GSK, Janssen, Leo Pharma, Otsuka, Merck-Serono, Maruho,
MSD, Novartis and Pfizer. G.L. served as a consultant and a member of
Advisory Boards for MSD, Pfizer, AbbVie, BMS, UCB and ROCHE, and
has received advisory/speaker honoraria and/or research funding from
MSD, Pfizer, AbbVie, BMS, UCB and ROCHE; A.O. served as an advisory
board member for AbbVie and MSD, and received lecture grants for
AbbVie, Sofar, Chiesi, and Takeda Pharmaceuticals; S.D. Silvio Danese
has served as a speaker, consultant and advisory board member for
Schering-Plough, Abbott Laboratories, Merck & Co., UCB Pharma,
Ferring, Cellerix, Millennium Takeda, Nycomed, Pharmacosmos,
G. Fiorino et al. / Autoimmunity Reviews 13 (2014) 751–755
Actelion, Alpha Wasserman, Genentech, Grunenthal, Pfizer, Astra
Zeneca, Novo Nordisk, Cosmo Pharmaceuticals, Vifor, and Johnson &
Johnson; I.O. has received advisory/speaker honoraria from AbbVie,
Roche, MSD, Novartis, and Pfizer.
Take-home messages
• Biosimilar agents are monoclonal antibodies similar to previously
approved biologics.
• Biosimilarity for monoclonal antibodies has been investigated only in
rheumatoid arthritis and ankylosing spondylitis.
• EMA approved the use of biosimilars for all indications, including
psoriasis and inflammatory bowel disease.
• Biosimilars still need to be tested for efficacy and safety by welldesigned trials with an adequate sample size calculation, especially
for psoriasis and inflammatory bowel diseases.
• Caution is recommended for extrapolation of data across indication,
interchangeability and traceability.
• Post-marketing surveillance for safety and immunogenicity is strongly
required.
Acknowledgments
We thank the IG-IBD members Fernando Rizzello, Vito Annese,
Alessandro Armuzzi, Livia Biancone, Fabrizio Bossa, Emma Calabrese,
Fabiana Castiglione, Michele Comberlato, Salvatore Cucchiara, Marco
Daperno, Walter Fries, Paolo Gionchetti, Giovanni Latella, Anna Kohn,
Gianmichele Meucci, Claudio Papi, Maria Beatrice Principi, Antonio
Rispo, Simone Saibeni, and Maurizio Vecchi for their suggestions and
critical revision of the final version of the manuscript.
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