Physicians may not be well informed about the scientific concept underlying the principle of extrapolating* indications for biosimilars. This in turn may lead them to distrust biosimilars, leading to a lower than expected uptake in Europe, especially in extrapolated indications. Members of the European Medicines Agency’s (EMA) Working Party on Similar Biological (Biosimilar) Medicinal Products (BMWP) address these concerns using extrapolation of indications in biosimilar infliximab as an example .
The first biosimilar monoclonal antibody biosimilar, i.e. Inflectra/Remsima (infliximab), was approved in the European Union (EU) in September 2013 . In the EU, Korea and Japan all indications of the originator product Remicade, including ankylosing spondylitis, rheumatoid and psoriatic arthritis, psoriasis and inflammatory bowel diseases (IBD: Crohn’s disease and ulcerative colitis) were approved [2-4]. However, in Canada extrapolation from autoimmune arthritis to IBD was not granted .
Evidence suggests that the mechanism of action of infliximab is similar in the rheumatological indications and in psoriasis, namely binding to soluble and membrane-bound tumour necrosis factor-alpha (TNF-α). However, the Fragment crystallizable (Fc) region of infliximab may be involved in other potential mechanisms [antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity] that have been suggested in the literature to play a role in IBD. Therefore, extrapolation between these indications is not self-evident, especially since a difference in an ADCC activity test was observed between the biosimilar and the reference infliximab.
However, despite this the scientific arguments below supported the extrapolation to the IBD indication:
- Extensive analytical tests showed physicochemical and structural comparability except for a small difference in the proportion of afucosylated forms. The biosimilar and the reference infliximab demonstrated comparable binding to complement receptor and all types of Fc-receptors except for FcγRIIIa/b, translating into lower ADCC activity. Similar differences in ADCC and glycosylation have been observed as a result of changes in the manufacturing process of the original rituximab
- The main mode of action in all therapeutic indications is binding to the soluble and/or the membrane-bound TNF-α, which was comparable in the biosimilar and the reference infliximab
- Supplementary tests showed similar inhibition of direct effects of TNF-α on epithelial cells that play an important role in Crohn’s disease
- The biosimilar and the reference medicine displayed a similar induction of regulatory macrophages, which are implicated as a mode of action of infliximab in IBD
- Bioequivalence and comparable safety, efficacy and immunogenicity of the biosimilar and the reference infliximab were demonstrated in trials carried out in patients with ankylosing spondylitis and rheumatoid arthritis
The totality of evidence therefore indicated similar efficacy and safety of the biosimilar and the reference product in all therapeutic indications of infliximab.
Despite this evidence, some medical societies, including the American College of Rheumatology, the European CanCer Organisation, the Mexican College of Rheumatology, and the Spanish Society of Gastroenterology  have specifically recommended against use of biosimilars in extrapolated IBD indications.
Results of a survey carried out by the European Crohn’s and Colitis Organization (ECCO) reported that most respondents (63.7%) would not switch a patient onto a biosimilar monoclonal antibody, as there is no disease-specific evidence about their interchangeability .
ECCO has also stated that the equivalence margin chosen for the efficacy trial in rheumatoid arthritis would be considered too large for a trial in IBD as several drugs have been approved with this difference relative to placebo. Weise and co-authors responded to this criticism saying that ‘the 2% difference observed between biosimilar and reference products as shown in the clinical trials for the ACR20 response (outcome used in rheumatoid arthritis) and ASAS20 response (outcome used in ankylosing spondylitis) is not expected to be numerically the same across all indications.’ They add that ‘the choice of comparability margins is specific to each indication and depends on the chosen outcome.’
*Extrapolation involves extending and applying the data from clinical studies regarding one medical condition to another medical condition.
The authors of the research paper  declared that they are members or experts of the European Medicines Agency’s (EMA) Biosimilar Medicinal Products Working Party (BMWP). This paper  represents solely the views of the authors and should not be understood or quoted as being made on behalf of or reflecting the position of EMA or its committees.
Conflict of interest
The authors of the research paper  declared that there were no conflicts of interest.
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7. Derbyshire M. ECCO 2013 survey highlights lack of confidence in biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(3):154. doi:10.5639/gabij.2014.0303.034
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