Anaemia Management
Table 1: Some Key Characteristics and Properties of Commonly Used Epoetins Epoetin Alfa
Reference epoetin
Brand name(s) in Europe Carbohydrate proportion (%)
Half-life (h) IV
SC
Time to peak after SC administration (h) SC bioavailability (%)
Frequency of administration for renal anaemia (x/week)
and Deicher and Hörl, 2004.24 N/A
Eprex® 40
4–6 ~24
12–18 ~20 2
Epoetin Beta N/A
NeoRecormon® 40
4–12
13–28 12–28 23–42 1–3
Darbepoetin Alfa Methoxy Polyethylene Glycol-epoetin Beta Epoetin alfa Aranesp® 52
Epoetin beta Mircera® ND
21 73 54 37
0.5–1 134
139–142 72–95 62–54
0.25–0.5
IV = intravenous; N/A = not applicable; ND = not determined; SC = subcutaneous. Data obtained from the relevant European Medicines Agency summary of product characteristics for each product82–85
Figure 1: Comparison of Isoform Heterogeneity Between Epoetin Zeta and the Originator Product Epoetin Alfa
35
30 25 20 15 10 5 0
In the EU, this requirement has been recognised and guidelines for the approval of biosimilars have been developed by the EMA.51
In the
first instance, the guidelines address the manufacturing process and the consequences for the properties of the biosimilar.52
Thereafter, 0 1 2
3 45 6789 Isoform number
Epoetin zeta Epoetin alfa
Isoform number = number of isoforms in each epoetin; Per cent of isoform = percentage of total product represented by each isoform. Data held on file by Hospira.
renal anaemia,33–38 although there is still some controversy over which treatment targets achieve the best outcomes.39–41
Following the patent expiration of epoetin alfa and epoetin beta in the European Union (EU),42
zeta, known as ‘biosimilar epoetins’, have been developed.23
recombinant erythropoietin, epoetin theta, was developed as a standalone product43
but for practical purposes can be regarded as such.44
guidelines are based on a ‘comparability approach’ between the biosimilar and an appropriate reference product authorised in the EU, with only limited extrapolation permitted.51
Comparable
quality studies between the biosimilar and reference product must evaluate physicochemical characteristics, biological activity, purity and specifications.52
The outcomes of these quality studies may
have an impact on the extent of subsequent non-clinical and clinical comparisons,52
but comprehensive assessments, including
non-clinical studies and clinical pharmacokinetic, pharmacodynamic, efficacy and safety studies, are typically required.53
In addition, great
‘generic’ alternatives, epoetin alfa and epoetin Another
and is therefore strictly speaking not a biosimilar, A critical step in the
development process has been the establishment of guidelines for the approval of biosimilars by the European Medicines Agency (EMA).45–49
This review summarises the EMA regulatory policy regarding the approval of biosimilars and examines the key pharmacokinetic, pharmacodynamic, efficacy and safety data for currently licensed biosimilar epoetins. Furthermore, in-practice experience with biosimilar epoetins in treating renal anaemia and economic issues governing their use will be discussed.
Requirements for the Approval of Biosimilars in the EU
Manufacturers of generic alternatives to innovative drugs that are chemically synthesised need demonstrate only that the two products are chemically identical and bioequivalent in order to obtain market authorisation, i.e. data from randomised clinical trials for the generic drug are not required as this information is extrapolated from the results of the trials using the innovative drug.46,47,50
This relatively
straightforward procedure is insufficient for biosimilars because their chemical and therefore clinical, characteristics are dependent on the manufacturing process, which cannot be precisely duplicated.46–50 It is therefore impossible for a manufacturer to produce a biosimilar
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emphasis is placed on pharmacovigilance and long-term safety must be monitored closely on an ongoing basis during the post-approval phase, primarily to screen for immunogenic responses and the development of neutralising antibodies.53,54
This is of particular
importance for biosimilar epoetins since pure red cell aplasia (PRCA) due to the production of neutralising anti-EPO antibodies to traditional epoetins has been documented.55,56
EMA guidelines for non-clinical and
clinical issues relating to biosimilar epoetins specify requirements for the development of this group of biosimilars,57 product is considered on a case-by-case basis.51,53
but each new biosimilar Importantly, the
guidelines for the approval of biosimilars devised by the EMA are seen as a possible framework for the development of guidelines by authorising bodies in other countries or regions.46,48–50
Comparability of Biosimilar and Originator Epoetins
Since 2007, two biosimilar epoetins, biosimilar epoetin alfa and epoetin zeta, have been approved by the EMA and trade under five different brand names (see Table 2). Despite the difference in nomenclature, both biosimilar epoetins use epoetin alfa as the originator product.46,48
In the
following sections, the comparability of the quality, safety and efficacy of biosimilar epoetins to the originator epoetin will be examined.
Quality
Approvals for biosimilar epoetin alfa and epoetin zeta were based on submissions that closely followed the EMA guidelines and demonstrated comparability to epoetin alfa.58,59
The correct protein structure of both biosimilar epoetin alfa and epoetin zeta was confirmed and although the EUROPEAN NEPHROLOGY
of sufficient similarity to the innovative product to eliminate the requirement for detailed quality, efficacy and safety data.
Per cent of isoform
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