Anemia Management
Figure 2: Comparison of the Efficacy of Epoetin Alfa and Epoetin Zeta in the Correction and Maintenance of Mean Hemoglobin Levels following Intravenous Administration in Patients with Chronic Kidney Disease
A 100
10 20 30 40 50 60 70 80 90
0 2468 10 12 Weeks Epoetin zeta B
10 11 12 13 14 15 16
0 1 2 3 4 5 6 7 8 9
Epoetin zeta Treatment
A: Proportion of patients with cumulative treatment success, defined as hemoglobin concentrations of ≥11 g/dl for two consecutive weeks, in the correction phase study comparing epoetin alfa and epoetin zeta. B: Hemoglobin levels during the randomized period of the maintenance-phase study comparing epoetin alfa and epoetin zeta. The boundaries of the box = the upper and lower quartiles; the height of the box = the interquartile range; the line of the box = the median; the filled circle = the arithmetic mean of the data; and the whiskers = maximum and minimum values of the data. Source: Krivioshiev et al., 200846
and Wizemann et al., 2008.47
It should be noted that more patients were evaluated in the therapeutic studies of epoetin zeta than in those studies used to evaluate biosimilar epoetin alfa (see Table 3). Firmer conclusions on clinical efficacy and short- to medium-term safety data can therefore be drawn for epoetin zeta compared with biosimilar epoetin alfa. In addition, patient exposure at first approval for epoetin zeta is similar to that for the innovator product in the US, Epogen® (Amgen, Thousand Oaks, CA, USA), at its initial approval in 1989 (see Table 3).50
Approval of Biosimilars in the US
In March 2010, legislature for the establishment of a regulatory framework for the manufacture and approval of biosimilars in the US was passed, The Biologics Price Competition and Innovation Act (BCPIA) of 2009.5,51,52
abbreviated Biologic License Application (aBLA). Indeed, some quarters have called for the FDA to adopt the guidelines developed by the EMA and the European approach has been endorsed by several stakeholders.5 However, there is some debate over which of the European guidelines will be adopted, or even if a US framework based on EMA guidelines will ever be used.19
Even at this stage, differences are apparent between the EU and US frameworks. For instance, whereas the EMA guidelines stress the need for biosimilars to demonstrate comparability to reference products, the US legislation emphasizes that biosimilars need to be ‘highly similar’.5
In
This regulatory framework is likely to enable the Food and Drug Administration (FDA) to approve or deny marketing authorization for individual biosimilars, in a manner analogous to the EMA, through an
88
fact, the FDA uses the term ‘comparability’ only when referring to the comparison of biologics following a major change to the manufacturing process. Similarly, in the EU, comparability must be demonstrated for quality, safety, and efficacy, whereas in the US emphasis is put on safety, purity, and potency. Although the terminology used is different, both the EMA and FDA will only approve biosimilars if they have met extremely
US NEPHROLOGY Epoetin alfa Epoetin alfa
Figure 3: Therapeutic Equivalence of Mean Hemoglobin Levels following Subcutaneous Administration of Two Epoetins in Patients with Chronic Kidney Disease
10 11 12 13 14
8 9
7 Epoetin zeta Treatment
Mean hemoglobin levels during the last four weeks of treatment are shown. The boundaries of the box represent the upper and lower quartiles; the height of the box = the interquartile range; the line within the box = the median; the cross = the arithmetic mean of the data; and the whiskers = the maximum and minimum values of the data. Source: Krivoshiev et al., 2010.48
Epoetin alfa 14 16 18 20 22 24
Table 3: Comparison of Number of Patients in Trials Leading to the Initial Approvals of Epoetin Zeta (Retacrit), Biosimilar Epoetin Alfa (Binocrit) and Epoetin Alfa (Epogen)
Number of Individuals
Health volunteers
(non-clinical studies)
Total number of 922
renal patients (clinical studies) Number evaluable 780
for efficacy (PP population)
PP population = per protocol population. Data obtained from the Retacrit EPAR, 2008,41 Summary Basis of Approval, 1989.50
the Binocrit EPAR, 200940 and the Epogen 478 325 1010 371
Epoetin Zeta (Retacrit)
72
Biosimilar Epoetin Epoetin Alfa Alfa (Binocrit)
150
(Epogen) 108
Mean hemoglobin level (g/dl)
Patients (%)
Hemoglobin (g/dl)
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