Comparison of EPARs for G-CSF biosimilars approved in Europe

EMA approved its first biosimilar granulocyte colony-stimulating factor (G-CSF, filgrastim) for use in Europe back in 2008, since then, several biosimilar G-CSFs have been approved, including Biograstim, Filgrastim ratiopharm, Ratiograstim, Tevagrastim, Filgrastim Hexal, Zarzio and Nivestim. All biosimilar G-CSFs were approved using Amgen’s Neupogen as the reference product. Filgrastim ratiopharm was withdrawn on 20 April 2011.

Granulocyte colony-stimulating factors (G-CSFs) are growth factors which are used to restore neutrophil production in patients undergoing chemotherapy. Febrile neutropenia is a life-threatening complication for patients undergoing chemotherapy. It causes a loss of neutrophils and fever.

EMA publishes a full scientific assessment report called a European public assessment report (EPAR) for every medicine granted a central marketing authorization by the European Commission. Information on how the biosimilars were evaluated by EMA can be obtained from studying these EPARs, see Table 1.

Table 1: Comparison of EPARs for G-CSF biosimilars approved in Europe

Product characteristics	Zarzio/filgrastim hexal	Biograstim/filgrastim ratiopharm/ratiograstim/ tevagrastim (XM02)	Nivestim
Produced in	Escherichia coli
Strengths	300 mg/0.5 mL 480 mg/0.5 mL	300 mg/0.5 mL 480 mg/0.8 mL	120 mg/0.2 mL 300 mg/0.5 mL 480 mg/0.5 mL
Product	Different buffer systems: glutamate for Zarzio and Filgrastim hexal, and acetate for Neupogen no buffer specified	Buffered with acetate. Differs from Neupogen in pH and in concentration of filgrastim and polysorbate 80	Buffered with acetate
Preclinical studies	Six primary PD studies (four in vitro); three toxicology studies (comparative repeat-dose toxicity, toxicokinetics, local tolerance); no secondary PD studies; no safety pharmacology studies; no PK studies	Six primary PD studies (three in vitro); one secondary PD study (in vitro); three safety pharmacology studies; two PK studies; six toxicology studies (repeat dose toxicity study non-comparative)	Primary PD studies: PD response was determined in a neutropenic rat model, as well as in healthy rat in a repeat-dose toxicity study; no secondary PD studies; no safety pharmacology studies; PK assessed as part of the repeat-dose toxicity study; no single-dose toxicity study
Clinical data Phase I (PK/PD) studies	Four PK/PD studies in healthy volunteers	Two PK/PD studies in healthy volunteers	Two PK/PD studies in healthy volunteers
Phase III studies	One non-controlled study in patients with breast cancer	Three RCTs (patients with breast cancer, lung cancer, NHL)	One RCT in patients with breast cancer
Efficacy data	Similar to Neupogen The comparability of the efficacy based on a PPD study in healthy volunteers (absolute neutrophil and CS34⁺ cell counts) was considered acceptable by the CHMP	Similar to Neupogen There were no statistically significant differences between XM02 and Neupogen with regard to the mean ANC nadir and with regard to time to ANC recovery in the studies	Similar to Neupogen There was therapeutic equivalence between the two products in terms of efficacy with regard to the mean ANC nadir and with regard to time to ANC recovery
Safety data	Similar to Neupogen
PD: pharmacodynamic; PK: pharmacokinetic; RTC: randomised controlled trial; NHL: non-Hodgkin’s lymphoma; ANC: absolute neutrophil count; CHMP: Committee for Medicinal Products for Human Use. Source: EMA

All of the G-CSF biosimilars are manufactured in facilities with state-of-the-art technology. All products have passed the regulatory requirements for approval, by EMA, which includes phase I and phase III trials, pharmacodynamic and pharmacokinetic evaluations and studies on efficacy and safety. Despite these rigorous comparisons of the biosimilars and the reference product, there are still some concerns regarding their long-term evaluation, in particular, the limited experience at the time of approval of these products in terms of efficacy, safety and immunogenicity. The author of the study therefore recommends pharmacovigilance for all biosimilars.

EMA guidelines allow extrapolation of data to additional indications, for example, paediatric indication and peripheral blood progenitor cells in healthy donors. However, the author of the study acknowledges that a lot of work remains to be done in terms of clarification with regard to substituting a biosimilar G-CSF for the originator product. And in fact this is a decision that is not made by EMA, but that is made on a country-by-country basis in the EU.

Ultimately, only clinical trials and effective post-marketing pharmacovigilance will provide definitive evidence that a biosimilar is comparable to the reference product in terms of efficacy and safety.

Conflict of interest
The author of the study declared that he has received honoraria from Amgen and from Sandoz for lecturing.

Source: www.gabionline.net

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