Despite a stringent approval process, acceptance of biosimilars in the medical community continues to be low, and especially in extrapolated* indications. Members of the European Medicines Agency’s (EMA) Biosimilar Medicinal Products Working Party (BMWP) address these concerns using extrapolation of indications in biosimilar epoetin as an example .
Recombinant erythropoietin (epoetin) is approved for indications including the treatment of renal anaemia and chemotherapy-induced anaemia. The major concern with epoetins is immunogenicity, i.e. the rare development of neutralizing, cross-reacting anti-epoetin antibodies which can cause pure red cell aplasia (PRCA).
Although rare, PRCA were reported after the formulation of the originator biological Eprex (epoetin alfa) was changed .
To ensure the absence of clinically relevant differences, EMA guideline for the development of epoetin biosimilars requires several functional and clinical studies, including at least one clinical trial in patients with renal anaemia (the population most at risk from PRCA) who do not have major complications that may impair the response to epoetin.
To date, no PRCA cases have been observed in cancer patients (making them a low-risk population). Despite this fact, the approval of epoetin biosimilars in the cancer indication has been questioned. The main argument for this being the absence of safety data for the high doses required in cancer patients.
The scientific arguments below supported the extrapolation from the renal anaemia to the cancer indication:
- All licensed epoetin biosimilars exhibit the same amino acid sequence as their reference product and structural differences are confined to the micro-heterogeneous pattern of the molecule.
- Pharmacodynamic studies indicated comparable stimulation of reticulocytes.
- Clinical trials in patients with renal anaemia confirmed equivalent effects on haemoglobin (Hb) concentrations.
- The desired pharmacological effect of epoetin is mediated via a single cell receptor and the mechanism of action is the same in all approved indications.
- Equivalent effects of the biosimilar and the reference epoetin on reticulocyte count and Hb values provide reassurance that adverse events can be expected at similar frequencies, also at the high doses used in cancer patients.
- No differences in the safety profile and anti-epoetin antibody response were detected between the biosimilars and their reference products.
To date, no specific efficacy or safety issues have been identified in clinical practice for biosimilar epoetins licensed in Europe. Post-marketing studies of biosimilar epoetin in the cancer indication have shown it to be well tolerated and efficacious and justifies EMA’s decision on extrapolation [3, 4].
*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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Extrapolation for biosimilars
1. Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK. Biosimilars: the science of extrapolation. Blood. 2014 Oct 8. pii: blood-2014-06-583617. [Epub ahead of print]
2. GaBI Online – Generics and Biosimilars Initiative. Epoetin alfa and pure red cell aplasia [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Dec 12]. Available from:www.gabionline.net/Biosimilars/Research/Epoetin-alfa-and-pure-red-cell-aplasia
3. GaBI Online – Generics and Biosimilars Initiative. Biosimilars in the treatment of chemotherapy-induced anaemia [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Dec 12]. Available from: www.gabionline.net/Biosimilars/Research/Biosimilars-in-the-treatment-of-chemotherapy-induced-anaemia
4. GaBI Online – Generics and Biosimilars Initiative. Positive post-marketing data for biosimilar epoetin [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Dec 12]. Available from: www.gabionline.net/Biosimilars/Research/Positive-post-marketing-data-for-biosimilar-epoetin