Rheumatology 2014;53:389–390

RHEUMATOLOGY doi:10.1093/rheumatology/ket210
Advance Access publication 22 July 2013

Editorial
Biosimilars in rheumatology: perspective and

EDITORIAL
concerns
What all rheumatologists should know?

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Unlike traditional pharmaceuticals, biologic drugs are product. Besides the concerns of the manufacture of bio-
derived from living organisms. Recombinant DNA biotech- similars, it is fundamental that rheumatologists are aware
nology has allowed large-scale production based on that demonstration of similarity with the innovator product
master cell banks from different sources. Many biologic during all critical steps of synthesis cannot be labelled as
drugs are used in internal medicine, for example insulin, highly similar without proper clinical trials comparing the
growth hormone, erythropoietin, IFN-a and monoclonal similar with the innovator. The similar then has to be pow-
antibodies [1]. In the past decade, rheumatology has ered to detect bioequivalence followed by an extensive
been transformed with the introduction of monoclonal post-license marketing period. Canadian rheumatologists
antibodies directed against cytokines involved in the expressed their concerns in a recent article that focused
pathogenesis of inflammatory arthritis, such as RA, AS on patient safety and long-term outcomes [4–6].
and autoimmune diseases associated with arthritis such In Latin America, the regulation of biosimilar agents
as psoriasis and IBD [2]. varies considerably, but most of these countries are im-
The first three anti-TNFs commercially available at the plementing specific requirements for the approval of bio-
start of the past decade were etanercept, infliximab and similars [7]. However, in some countries where regulations
adalimumab. These three became blockbuster drugs (with have not yet been established, intended copies of biologic
sales revenues of more than $US 1 billion annually) and products are already being registered for etanercept and
have continued to do so for the past few years. Patents for rituximab. In Africa and Asia, although regulations have
biologics that were first marketed towards the end of been implemented in several countries (similar to those
1980s are now beginning to expire, opening up the devel- in Latin America), registration of intended copies of ritux-
opment of non-proprietary versions. However, the same imab and etanercept are already in place without any clin-
regulatory process that controls the use of generic medi- ical trials in patients with RA (Table 1).
cation should not be applied for biosimilars. Government In China, Shanghai CP Guojian Pharmaceutical Co. Ltd
and industry are still evolving processes to deal with launched a new compound in 2006 that is supposedly a
biosimilars. copy of etanercept. In the USA, patent expiry for etaner-
The manufacture of a biopharmaceutical product is cept was extended for another 17 years in 2011 so
complex and involves several steps of purification. The rheumatologists in the USA will see an etanercept biosi-
major differences are in the dimension of the compound milar product later than other parts of the world. In India, a
and its synthesis, stability and immunogenicity. The first rituximab biosimilar was launched by a local manufacturer
step is to introduce the gene for the required protein into a and is approved for the treatment of RA and lymphoma
living cell line and then, through the final version of the [8]. However, India is a semi-regulated market for biosimi-
product, several variations can occur, which are inherent lars and only short trials are required to assess bioequi-
to any biologic system so long as regulatory processes valence for licensing procedures. The first true biosimilar
are in place for the development of a biosimilar from a in rheumatology was registered in Korea in October 2012
synthetic product (based on a molecular structure). and is a copy of infliximab. The trial that led to this license
Minor changes in the production process can affect the appears to be well done and powered to detect differ-
safety and efficacy of the proposed biosimilar copy, which ences in efficacy and safety. It is now under review in
is usually not an issue for the production of synthetic Europe and Brazil as a validated biosimilar.
molecules. Biosimilars will continue to be an area of interest
The European Medicines Agency was the first to publish through 2013 and 2014. Although no biosimilars have
guidelines recognizing that specific regulatory processes yet been approved for the treatment of inflammatory arth-
were needed for the development of biosimilar-derived ritis, Europe may possibly approve its first biosimilar
products where patents are expected to expire over the monoclonal antibody product (infliximab) for the treatment
next few years [3]. The FDA, through the Patient of RA by the end of 2013. Rheumatologists should be
Protection and Affordable Care Act, endorsed it into a concerned when true biosimilars become available, not
law in 2010 and created a shorter licensing pathway only for safety and efficacy, but also for other issues
where it is possible to show the presence of biosimilarity such as immunogenicity of the biosimilar product and
or interchangeability with an FDA-licensed biologic well-designed comparative trials. In the case of traditional

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Editorial
TABLE 1 Intended copies of biologics licensed without
biosimilar regulations
Year Rituximab Etanercept
2007 India
2008 Peru Colombia
2010 Chile, Bolivia and Mexico
2011 Jamaica and Ecuador
2012 Paraguay Mexico
chemical compounds, synthesis is initiated from commer-
cially available substrates; this is not the case with bio-
logic compounds. Cell lines used in biopharmaceutical
production have unique features inherent to cell systems
so that a biologic derived from different production sys-
tems can never be identical. Therefore head-to-head trials
with adequate power are recommended, which is not the
case with the copy of synthetic drugs.
The immunogenicity issue was well illustrated when bio-
similar epoietins were introduced in the market without
proper attention to the possibility that the biosimilar
could generate autoantibodies against the natural erythro-
poietin resulting in cases of drug-derived pure red cell
aplasia mainly outside the USA [9, 10].
We believe that rheumatologists should be aware of two
things in their respective countries. First, the biosimilar
product can only really be classified as a biosimilar copy
or an intended copy with proper head-to-head trials
against the innovator. This information will most likely
influence a rheumatologist’s prescription towards a
branded product in favour of a biosimilar unless the reim-
bursement in their respective country affects the status of
the originator brand [11]. Second, although in emerging
markets the advent of biosimilars may reduce the high
cost of biologic therapies for the patient, the practicing
rheumatologist should be aware of the proper develop-
ment of a biosimilar, as it may have been licensed using
relaxed standards and may not be a truly bioequivalent
biosimilar [12]. The bioequivalence of generic drugs is well
established; however, when dealing with large biologic
products, complex molecules and extensive glycosyla-
tion, a completely different kind of assessment is required,
including laboratory testing to prevent production and
clinical evaluation pitfalls [13]. Importantly, before pre-
scribing a biosimilar, rheumatologists should be aware
of whether the similarity between the intended copy and
the innovator or originator is met and of the fundamental
challenges that are required to be labelled a truly biosimi-
lar product. Finally, one has to be careful about unproven
molecules from foreign sources reaching countries as
an alternative to the branded biologic with licensing
390
pathways that would not usually meet FDA or EMEA
standards.
Disclosure statement: The authors have declared no
conflicts of interest.
Morton A. Scheinberg1 and Valderilio F. Azevedo2
1
Clinical Research Division Hospital Abreu Sodré – AACD,
São Paulo and 2Rheumatology Section Federal University of
Paraná, Paraná, Brazil.
Accepted 16 April 2013
Downloaded from https://academic.oup.com/rheumatology/article-abstract/53/3/389/1780195 by guest on 27 September 2018
Correspondence to: Morton A. Scheinberg, Clinical Research
Division Hospital Abreu Sodre AACD, São Paulo, Brazil.
Email: morton@osite.com.br
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