REVIEW URRENT C OPINION
Update on biosimilars of granulocyte colonystimulating factor – when no news is good news Miriam Schulz a,b and Halvard Bonig a,c,d
Purpose of review With the approval of the first biosimilar granulocyte colony-stimulating factor (G-CSF), biosimilars – copies of therapeutic biologicals whose patent protection has expired – have finally reached the US healthcare market. Its advent is an occasion for a closer look at recent insights into biosimilar G-CSF and an attempt at prognosticating the future (future role) of biosimilars in general. Recent findings Recent literature regarding biosimilar G-CSF orbits significantly around patient access and effects on healthcare expenditure. The advent of biosimilar G-CSF has induced unexpectedly large price reductions for short-acting G-CSF. On the clinical side, little excitement is tangible, probably appropriately so, since clinical data indicate nothing short of biological similarity. Although formal clinical trials are few, the plethora of case series and historic comparisons which have come forth offer reassurance about the appropriateness of the regulators’ assessment of biosimilar G-CSF as indeed in all respects biologically similar to the originator. Summary All evidence points to an overwhelming similarity of originator and biosimilar G-CSF in all indications. Overall clinical acceptance, albeit possibly significantly dictated by economic pressures, is good. Price reductions exceed predictions and may jeopardize the economic viability of biosimilar programs. A concurrent shift towards long-acting G-CSF (‘biobetters’) is observed in Europe. Keywords biobetter, extrapolation, generic, growth factor, healthcare expenditure
INTRODUCTION Biosimilars are copies of biological drugs which have gone off-patent. Their licensing is primarily contingent on a rigorous manufacturing process and a very detailed biochemical and biological in-vitro similarity assessment relative to the originator. By contrast, relatively little clinical evidence of similarity is required, acknowledging the comparatively insensitive read-out of clinical trials as opposed to the above. It is assumed that safety, tolerability, and efficaciousness were amply proven for the originator, and that the overwhelming similarity of the biosimilar reasonably suggests similar in-vivo efficacy [1,2 ]. Although clinical experience supports this view, some skepticism remains within the medical community, which may hamper biosimilar acceptance. The US biosimilar legislation largely follows the European Union’s, as well as several other countries having adopted essentially identical regulations. Several brands of short-acting biosimilar granulocyte colonystimulating factor (G-CSF), copies of Amgen’s Escherichia coli-expressed, nonglycosylated Filgrastim &&
G-CSF (Thousand Oaks, California, USA), have become available in Europe since 2008 and in some countries now outsell the originator G-CSFs [3]. With the Food and Drug Administration (FDA) approval in March 2015 of the biosimilar G-CSF ‘Zarxio’ by Sandoz (Holzkirchen, Germany) (modeled, like all other short-acting rhG-CSF biosimilars, after Amgen’s ‘Neupogen’), biosimilars have, with almost 10 years’ delay, finally reached the USA [4–6]. Zarxio is licensed for all clinical indications a
German Red Cross Blood Service Baden-Wu¨rttemberg-Hesse, Frankfurt, bDepartment of Medicine/Hematology and Oncology, University Hospital Heidelberg, Heidelberg, cInstitute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany and d Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA Correspondence to Halvard Bonig, MD, German Red Cross Blood Service Baden-Wu¨rttemberg-Hesse, Sandhofstraße 1, 60528 Frankfurt, Germany. Tel: 49 69 6782177; fax: +49 69 6782258; e-mail: [email protected], [email protected] Curr Opin Hematol 2016, 23:61–66 DOI:10.1097/MOH.0000000000000204
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KEY POINTS Biosimilar G-CSF, now also licensed in the USA, has got a 7-year track record in Europe of similarity to the originator in terms of safety and effectiveness.
similarity of the compounds. The goal posts for what degree of dissimilarity is acceptable are defined largely by the heterogeneity of batches of the originator product over time. With respect to the drugs modeled after Filgrastim G-CSF, this was a comparatively easy task [2 ]. The amino acid sequence was readily accessible; single-chained and nonglycosylated, the molecule was relatively easy to manufacture. All available assays demonstrated not just so-so similarity but, at the currently available resolution, near-identity of originator and biosimilar (for a recent example of such studies, see [7]). More modern manufacturing and purification methods resulted in lower levels of impurities of the biosimilar, which is the only aspect in which the quality of a biosimilar may exceed that of the originator. A contributory role of these impurities to the pharmaceutical effect of G-CSF was proposed not even by biosimilar adversaries (if it had, the ‘biosimilar’ label would not have applied). All effects of G-CSF – desirable or not – appear to be mediated through the G-CSF receptor [2 ]; identical on–off kinetics and down-stream signals further confirmed the impression of biosimilarity for each of the many biosimilar G-CSF preparations [7]. After successful demonstration of physical, chemical, biochemical, and in-vitro biological similarity, one comparative clinical trial of originator vs. biosimilar powered for nondifference in a ‘sensitive indication’ is required for the biosimilar to be approved. At the end of this exercise, its success provided, the biosimilar is licensed for all indications for which the originator is approved, even though it was not tested for these, provided the applicants can reasonably argue that the molecular mechanism of action is the same (a process called ‘extrapolation’) [1,2 ,8]. The biosimilar will also list in its product information all adverse events recorded for the originator, irrespective of whether they were ever observed with the biosimilar. Few have taken issue with extrapolation of adverse effects and contraindications, whereas extrapolation of therapeutic effects has been met with some doubts and even criticism. Specifically for G-CSF, concerns have been expressed about unrelated (registry) donor mobilization with biosimilar GCSF, although specific reasons there were not mentioned [9–11]. The regulators’ decision to extrapolate both the good (efficacy) and the bad (adverse effects) is expression of their reasonable confidence that the aggregate assessment has unequivocally demonstrated similarity between originator and biosimilar [2 ]. Because of pharmacological effects or toxicity, most clinical trials with biologicals can only be performed in patients. Also, biological/pharmacological &&
Biosimilar G-CSFs are biochemically near-identical to the originator, no differences between individual brands of biosimilar G-CSF were identified. Price reductions triggered by the advent of biosimilars may improve access to costly biologicals. The dramatic cost cuts of originators and introduction of, or shift to ‘biobetters’ at the time of biosimilar introduction may threaten the economic success of biosimilars.
for which the originator is approved, despite the lack of formal clinical trials in all but one. Sandoz is currently being challenged in court by the maker of the originator, which at this moment still impedes Zarxio’s availability. Zarxio being the first licensed biosimilar in the USA, this concise article, although largely focused on the topic of ‘biosimilar G-CSF’, will also risk some predictions about more general issues pertaining to biosimilars and their expected effects on the healthcare market. A plethora of scholarly articles about biosimilar G-CSF continues to come forth, albeit real clinical trials, even uncontrolled ones, are now few. What is mostly being published are, in approximately equal number, monocentric case series about biosimilar G-CSF-treated patients with comparison to historical outcomes (hardly suitable to address more minor differences between biosimilar and originator), and articles considering pharmaco–economic aspects of the advent of biosimilars. This reflects, probably not inappropriately, the predominantly economic impact that is expected of biosimilars, whereas clinicians mostly remain rather dispassionate.
ASSESSMENT OF BIOSIMILARITY AND BIOSIMILAR LICENSING The manufacturing of biologicals is significantly more complex than that of small molecule drugs. No two batches of biologicals are alike, in contrast to the maximum likeness of individual batches of synthetic drugs. Therefore, when originator biologicals go off-patent, follow-on drugs cannot use the well established generics pathway; instead, a specific set of guidelines for the approval of follow-on biologicals or ‘biosimilars’ was generated to regulate their approval [2 ]. The focus of the approval process lies on demonstration of biophysical and biochemical &&
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read-outs of effectiveness may often be relatively long-term. Once more, G-CSF is endowed with useful properties facilitating the required clinical bioequivalence studies: for one, G-CSF is safe to give to healthy volunteers, secondly, the rapid mobilization of mature and immature hematopoietic cells in volunteers is an excellent, sensitive, and objectively quantifiable measure of pharmacodynamics. Thirdly, as mentioned above, the mechanism(s) by which G-CSF exerts its pharmacological (and adverse) effects are known; they are mediated exclusively through a transmembrane receptor, G-CSFR, by addressing well defined intracellular signaling pathways. It is thus scientifically reasonable and largely unrefuted to accept similar effectiveness for one indication as pars pro toto, that is, to extrapolate pharmacological similarity to all other indications for which G-CSF is used and consequently to license biosimilar G-CSF for all these, as was done. The situation for biologicals working through mixed and/or only partly understood pharmacological mechanisms immediately becomes more complex and even controversial, and extrapolation to certain indications may be denied. Of note, extrapolation was granted in the case of one biosimilar monoclonal antibody as well as for glatiramer acetate in spite of their (partly) unknown pharmacological mechanisms, so rules seem to be somewhat pliable [12]. Healthy donor mobilization being a quantitatively minor indication, most licensing trials of biosimilar G-CSF have used duration of postchemotherapeutic neutropenia as read-out, clearly a less than sensitive indication to detect potential differences in vivo. With respect to the question how dissimilar two G-CSF preparations (e.g., originator and copy) would have to be before a difference could be detected, one should be reminded that even for the molecularly quite dissimilar compounds Filgrastim and Lenograstim – their dissimilarity easily demonstrated in vitro in all kinds of assays – clinical trials have failed to demonstrate reproducibly different outcomes [13,14]. We would therefore argue that evidence of similar mobilization capacity (even less so, length of neutropenia) is of modest additional value over the biochemical read-outs already provided (e.g., [7]). Absence of differential adverse events, specifically with respect to immunogenicity, is also quite meaningless because of the small size and short follow-up of the observational groups. In other words, we posit that the added value of the kind of clinical trials that are currently required for biosimilar approval is probably not great. So what is new on the clinical trials front? Not much more than the minimally required clinical trials were sponsored (published several years back)
by the manufacturers of biosimilars. The dearth of IITs suggests that clinicians largely accept the regulators’ verdict of biosimilarity. Lack of excitement by clinicians is underscored by the fact that none of the top-tier journals have published any of these clinical trials – one can easily imagine the editors’ verdict of ‘predictable – reject’. In the last year, reports from observational ‘studies’ lacking concurrent control groups have come forth about autologous mobilization and transplantation in children [15], autologous mobilization in adults [16–18], growth factor support after autologous transplantation in adults [18–21], and postchemotherapy neutropenia [22]; the impression from all was one of the overwhelmingly similar results as would have been expected with originator G-CSF. Manko et al. [23 ] report on a 1 : 1 randomized trial of Filgrastim vs. Zarxio G-CSF in autologous donor mobilization and transplantation which revealed no differences. Although matched related donor treatment with biosimilar or originator G-CSF was previously shown to be equally efficient and associated with the same adverse effects one has learned to expect from the drug (of course entirely predicted by the pharmacokinetic/pharmacodynamic studies in healthy volunteers all biosimilar G-CSFs go through [24]) and biosimilar-mobilized allogeneic transplants performed as expected [25], mobilization of matched unrelated donors remains a sensitive issue. The interim analysis of a prospective 10-year study in 230 unrelated stem cell donors treated with the Zarxio G-CSF was presented. Mobilization efficiency and acute side-effects of mobilization and apheresis in donors, as well as graft performance in recipients, were entirely in agreement with expected outcomes [26]. &
WHAT IS THE EXPECTED BENEFIT OF BIOSIMILARS? The expectation was, and to a significant degree this has been confirmed, that the advent of biosimilars would lead to cost reductions for specific biologicals [3,27 ,28–30]. Consequently, less restrictive prescribing could be encouraged, and thus patient access to these costly but highly effective drugs improved [31,32]. Indeed, since the advent of biosimilars the price of first-generation G-CSF has dropped by as much as 80% [3,29,30,33], that is, much more than the 25–30% which had been predicted. The six or so biosimilar G-CSF products licensed in Europe together now outsell the originator [28,34]. Estimates were provided that additional competitors will exert additional pressure on G-CSF price [29], although at the current level this is hard to conceive. Meanwhile, in the UK total healthcare
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expenditure for short-acting G-CSF has fallen, even though the number of dispensed doses has increased by about 5% per year since the advent of biosimilar G-CSF [31]. Thus, at first glance the strategy has been a success. A closer look reveals, however, that the stark drop in price has been achieved without biosimilars necessarily gaining a large share of the market, because of concurrent drastic price reductions for the originator [3]. This development may acutely benefit the market, but not the (individual) biosimilar makers [35]. Their revenue may no longer be high enough for amortization of the investment for development, specifically since the currently very low revenue is distributed among an ever-increasing number of manufacturers each needing to recoup development costs. Precisely this had been foreseen by health economists as a potential impediment to biosimilar development so that they had proposed to actually prohibit relevant price adjustments of the originators [36]. The suggestion was apparently not adopted by lawmakers which may now come back to haunt us. At the same time, prescription habits have significantly shifted towards pegylated G-CSF [27 ], a typical representative of the class of so-called ‘biobetters’, the nemesis of the biosimilar. As a consequence, the share of biosimilars of the total G-CSF market in Europe really remains in the low teens [27 ]. Similar trends towards shifting of patients to ‘biobetters’ are observed with other biologicals whose original patents are running out. Quo vadis, biosimilars? As alluded to above, the complexity of biosimilar process development and approval is reflected in their significant costs; numbers in the 100 s of millions of dollars have been mentioned [27 ,28,37]. These must be recouped, which naturally requires significant market penetration as well as reasonably high margins and hence prices. As a result of the currently very lean margins, the first developers of biosimilars are already retreating from the market. We predict that once a couple of attempts to enter the biosimilar market have been thwarted by too rapidly deteriorating prices or too many competitors, few contenders will remain in the biosimilar business. Specifically in the USA, the makers of originators are routinely fighting approval of biosimilars by the FDA and/or postapproval market access by petitions and legal court action, as we are currently seeing for biosimilar G-CSF and other biosimilars. This not only extends originator monopolies, it also delays return on investment of the biosimilar makers, which could become another significant impediment to biosimilar development. Moreover, we expect that the very high development costs will limit biosimilar development to blockbuster biologicals, whereas costs for the &&
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multitude of niche biologicals will be maintained if not increased to compensate for lost income with products with biosimilar competition. At the same time, the healthcare market will be shouldered indirectly with the aggregate development costs of the many G-CSF biosimilars, whereas the makers of the originators will try to shift lost revenue from short-acting G-CSF to on-patent biologicals and ‘biobetters’. Whether the healthcare system, as a whole, will at the end of the day actually spend less on biologicals altogether remains to be seen. Without specific market regulating action by lawmakers, the authors of this article are certainly skeptical. The need for a comparative clinical trial to obtain a marketing authorization for a biosimilar was already briefly discussed, including these authors’ lack of confidence in their informational value. Technical and recruitment issues for such trials are to be expected [37–39] which regulators possibly failed to anticipate. The incentive for patients to participate in clinical trials is typically the expectation that the investigational treatment could potentially be better than the standard – if not for the participating individual, then for future patients. By definition, however, a biosimilar is at best equal to the originator; in other words, the only potential benefit is fiscal. What, therefore, would be the incentive for patients for participation in or for ethics committees for approval of biosimilar clinical trials is not immediately apparent. One conceivable tangible benefit from participation in such trials, access to otherwise unavailable treatments (originator or copy), does not apply in Germany and other countries with universal access, but – ethically questionable – could provide an incentive in countries with underfunded or otherwise limited access to healthcare. With respect to feasibility of trials, few biologicals offer rapid pharmacodynamic read-outs like insulin or G-CSF which vary relatively little and can be readily assessed in healthy volunteers (lowering of blood glucose levels or leukocytosis/stem cell mobilization, respectively), thus greatly facilitating the performance of comparative clinical trials. Biologicals with slower read-out, such as reduction of multiple sclerosis flares in patients on beta-interferon or glatiramer acetate or remissions in patients with B-cell malignancies on rituxan, will require large studies with very long follow-up. If regulators were convinced of the predictive power of the in-vitro comparability exercise, clinical trials would not be required, as with generics. The FDA’s recent decision to approve Sandoz’ version of the multiple sclerosis drug glatiramer acetate without a formal comparative trial, vainly challenged by the maker of the originator (ironically, themselves the world’s largest maker of Volume 23 Number 1 January 2016
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Update on biosimilars of G-CSF Schulz and Bonig
generics), suggests that regulators might share these authors’ skepticism about the added benefit of clinical trials. In summary, in the field of biosimilar G-CSF, no news is good news, and such is the case. Tedious studies and case series suggest that biosimilar G-CSF is just as (in)tolerable, effective and safe as originator G-CSF in all indications that were studied. No evidence of immunogenicity has emerged nor have seven years of copious use in Europe raised any other concerns about long-term safety, although universal long-term follow-up is missing for biosimilars as for originators. Clinical experience is currently restricted to postchemo/postauto-transplant neutropenia and autologous/allogeneic stem cell mobilization. Thus far, no data were reported on granulocyte mobilization for preparative apheresis [40] or on congenital and acquired neutropenias [41,42]. While several studies report financial benefits for the healthcare system, these focus on G-CSF costs and prescribing behavior. They mostly fail to address, however, the big picture, that is, total healthcare expenditure, by failing to include in the analyses the issues of ‘biobetters’ as impediments to market access of biosimilars and of potential compensatory price increases of competitor-free products. In countries with limited access to healthcare, price reductions brought on by biosimilars may induce more generous prescribing habits in the interest of previously undertreated patients. Acknowledgements None. Financial support and sponsorship H.B. is a member of LOEWE Cell and Gene Therapy Frankfurt faculty, funded by Hessian Ministry of Higher Education, Research and the Arts ref.no.: III L 4- 518/ 17.004 (2013). Conflicts of interest H.B. has received research funding and has served on the advisory board and speakers’ bureau of Sandoz-Hexal, makers of a biosimilar Filgrastim G-CSF, as well as research funding from Chugai, makers of Lenograstim G-CSF. M.S. has got no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Bonig H, Becker PS, Schwebig A, Turner M. Biosimilar granulocyte-colonystimulating factor for healthy donor stem cell mobilization: need we be afraid? Transfusion 2015; 55:430–439.
2. Weise M, Kurki P, Wolff-Holz E, et al. Biosimilars: the science of extrapolation. Blood 2014; 124:3191–3196. Very insightful review article into regulatory issues of biosimilar licensing. 3. Farfan-Portet MI, Gerkens S, Lepage-Nefkens I, et al. Are biosimilars the next tool to guarantee cost-containment for pharmaceutical expenditures? Eur J Health Econ 2014; 15:223–228. 4. FDA approves first biosimilar product Zarxio. http://www.fda.gov/News Events/Newsroom/PressAnnouncements/ucm436648.htm. [Accessed 11 October 2015] 5. Ledford H. First biosimilar drug set to enter US market. Nature 2015; 517:253–254. 6. Traynor K. FDA advisers recommend approval of biosimilar filgrastim. Am J Health Syst Pharm 2015; 72:262; 264. 7. Crobu D, Spinetti G, Schrepfer R, et al. Preclinical and clinical phase I studies of a new recombinant Filgrastim (BK0023) in comparison with Neupogen. BMC Pharmacol Toxicol 2014; 15:7. 8. Ebbers HC. Biosimilars: in support of extrapolation of indications. J Crohns Colitis 2014; 8:431–435. 9. Barosi G, Bosi A, Abbracchio MP, et al. Key concepts and critical issues on epoetin and filgrastim biosimilars. A position paper from the Italian Society of Hematology, Italian Society of Experimental Hematology, and Italian Group for Bone Marrow Transplantation. Haematologica 2011; 96:937–942. 10. European Group for Blood and Marrow Transplantation(EBMT). Position statement: biosimilar granulocyte-colony stimulating factor (G-CSF) for stem cell mobilization in related and unrelated donors. http://www.worldmarrow.org/fileadmin/Committees/CLWG/Biosimilars/Biosimilars_9Jan09.pdf. 2009. [Accessed 8 July 2015] 11. Shaw BE, Confer DL, Hwang WY, et al. Concerns about the use of biosimilar granulocyte colony-stimulating factors for the mobilization of stem cells in normal donors: position of the World Marrow Donor Association. Haematologica 2011; 96:942–947. 12. Cortes J, Curigliano G, Dieras V. Expert perspectives on biosimilar monoclonal antibodies in breast cancer. Breast Cancer Res Treat 2014; 144:233–239. 13. Sourgens H, Lefrere F. A systematic review of available clinical evidence: filgrastim compared with lenograstim. Int J Clin Pharmacol Ther 2011; 49:510–518. 14. Bonig H, Silbermann S, Weller S, et al. Glycosylated vs nonglycosylated granulocyte colony-stimulating factor (G-CSF)–results of a prospective randomised monocentre study. Bone Marrow Transplant 2001; 28:259–264. 15. Cesaro S, Tridello G, Prete A, et al. Biosimilar granulocyte-colony-stimulating factor for mobilization of autologous peripheral blood stem cells in pediatric hematology-oncology patients. Transfusion 2015; 55:246–252. 16. Uddin S, Russell P, Farrell M, et al. Use of biosimilar filgrastim compared with lenograstim in autologous haematopoietic stem-cell transplant and in sibling allogeneic transplant. Ther Adv Hematol 2015; 6:53–60. 17. Schmitt M, Publicover A, Orchard KH, et al. Biosimilar G-CSF based mobilization of peripheral blood hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Theranostics 2014; 4:280–289. 18. Remenyi P, Gopcsa L, Marton I, et al. Peripheral blood stem cell mobilization and engraftment after autologous stem cell transplantation with biosimilar rhG-CSF. Adv Ther 2014; 31:451–460. 19. Marchesi F, Cerchiara E, Dessanti ML, et al. Comparison between biosimilar filgrastim vs other granulocyte-colony stimulating factor formulations (originator filgrastim, peg-filgrastim and lenograstim) after autologous stem cell transplantation: a retrospective survey from the Rome Transplant Network. Br J Haematol 2015; 169:293–296. 20. Cioch M, Jawniak D, Kotwica K, et al. Biosimilar granulocyte colony-stimulating factor is effective in reducing the duration of neutropenia after autologous peripheral blood stem cell transplantation. Transplant Proc 2014; 46:2882– 2884. 21. Bassi S, Stroppa EM, Moroni CF, et al. Safety and efficacy of granulocyte colony-stimulating factor biosimilars in engraftment after autologous stem cell transplantation for haematological malignancies: a 4-year, single institute experience with different conditioning regimens. Blood Transfus 2015; 13:478–483. 22. Tesch H, Ulshofer T, Vehling-Kaiser U, et al. Prevention and treatment of chemotherapy-induced neutropenia with the biosimilar filgrastim: a non-interventional observational study of clinical practice patterns. Oncol Res Treat 2015; 38:146–152. 23. Manko J, Walter-Croneck A, Jawniak D, et al. A clinical comparison of the & efficacy and safety of biosimilar G-CSF and originator G-CSF in haematopoietic stem cell mobilization. Pharmacol Rep 2014; 66:239–242. Albeit small, one of the rare controlled trials of originator vs. biosimilar G-CSF. 24. Matsuguma K, Matsuki S, Sakamoto K, et al. A comparative pharmacokinetic and pharmacodynamic study of FSK0808 versus reference filgrastim after repeated subcutaneous administration in healthy Japanese men. Clin Pharmacol Drug Dev 2015; 4:99–104. 25. Schmitt M, Xu X, Hilgendorf I, et al. Mobilization of PBSC for allogeneic transplantation by the use of the G-CSF biosimilar XM02 in healthy donors. Bone Marrow Transplant 2013; 48:922–925. 26. Becker PS, Brauninger S, Bialleck H, et al. Use of biosimilar G-CSF for hematopoietic stem cell mobilization in healthy unrelated donors: interim results of a 10-year follow-up study [abstract]. Bone Marrow Transplant 2015; 50:328.
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35. Haustein R, deMillas D, Ho¨er A, Ha¨ussler B. Saving money in the European healthcare systems with biosimilars. GaBi J 2011; 1:120–126. 36. Ha¨ussler B, Thiede M. Die Rolle der Biosimilars im Wettbewerb auf dem GKVArzneimittelmarkt [The role of biosimilars as competitors in the health insurance market]. Berlin, Germany: IGES Institute; 2008. 37. Garattini L, Curto A, van de Vooren K. Western European markets for biosimilar and generic drugs: worth differentiating. Eur J Health Econ 2015; 16:683–687. 38. Bui LA, Taylor C. Developing clinical trials for biosimilars. Semin Oncol 2014; 41 (Suppl 1):S15–S25. 39. Guillon-Munos A, Daguet A, Watier H. Antibody biosimilars: fears or opportunities?: First LabEx MAbImprove industrial workshop, May 28, 2013; Tours, France. MAbs 2014; 6:805–809. 40. Thorausch K, Schulz M, Bialleck H, et al. Granulocyte collections: comparison of two apheresis systems. Transfusion 2013; 53:3262–3268. 41. Sicre de FF, Moignet A, Beaupain B, et al. Severe chronic primary neutropenia in adults: report on a series 108 patients. Blood 2015; 126:1643–1650. 42. Boxer LA, Bolyard AA, Kelley ML, et al. Use of granulocyte colony-stimulating factor during pregnancy in women with chronic neutropenia. Obstet Gynecol 2015; 125:197–203.
Volume 23 Number 1 January 2016
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Update on biosimilars of granulocyte colonystimulating factor – when no news is good news Miriam Schulz a,b and Halvard Bonig a,c,d
Purpose of review With the approval of the first biosimilar granulocyte colony-stimulating factor (G-CSF), biosimilars – copies of therapeutic biologicals whose patent protection has expired – have finally reached the US healthcare market. Its advent is an occasion for a closer look at recent insights into biosimilar G-CSF and an attempt at prognosticating the future (future role) of biosimilars in general. Recent findings Recent literature regarding biosimilar G-CSF orbits significantly around patient access and effects on healthcare expenditure. The advent of biosimilar G-CSF has induced unexpectedly large price reductions for short-acting G-CSF. On the clinical side, little excitement is tangible, probably appropriately so, since clinical data indicate nothing short of biological similarity. Although formal clinical trials are few, the plethora of case series and historic comparisons which have come forth offer reassurance about the appropriateness of the regulators’ assessment of biosimilar G-CSF as indeed in all respects biologically similar to the originator. Summary All evidence points to an overwhelming similarity of originator and biosimilar G-CSF in all indications. Overall clinical acceptance, albeit possibly significantly dictated by economic pressures, is good. Price reductions exceed predictions and may jeopardize the economic viability of biosimilar programs. A concurrent shift towards long-acting G-CSF (‘biobetters’) is observed in Europe. Keywords biobetter, extrapolation, generic, growth factor, healthcare expenditure
INTRODUCTION Biosimilars are copies of biological drugs which have gone off-patent. Their licensing is primarily contingent on a rigorous manufacturing process and a very detailed biochemical and biological in-vitro similarity assessment relative to the originator. By contrast, relatively little clinical evidence of similarity is required, acknowledging the comparatively insensitive read-out of clinical trials as opposed to the above. It is assumed that safety, tolerability, and efficaciousness were amply proven for the originator, and that the overwhelming similarity of the biosimilar reasonably suggests similar in-vivo efficacy [1,2 ]. Although clinical experience supports this view, some skepticism remains within the medical community, which may hamper biosimilar acceptance. The US biosimilar legislation largely follows the European Union’s, as well as several other countries having adopted essentially identical regulations. Several brands of short-acting biosimilar granulocyte colonystimulating factor (G-CSF), copies of Amgen’s Escherichia coli-expressed, nonglycosylated Filgrastim &&
G-CSF (Thousand Oaks, California, USA), have become available in Europe since 2008 and in some countries now outsell the originator G-CSFs [3]. With the Food and Drug Administration (FDA) approval in March 2015 of the biosimilar G-CSF ‘Zarxio’ by Sandoz (Holzkirchen, Germany) (modeled, like all other short-acting rhG-CSF biosimilars, after Amgen’s ‘Neupogen’), biosimilars have, with almost 10 years’ delay, finally reached the USA [4–6]. Zarxio is licensed for all clinical indications a
German Red Cross Blood Service Baden-Wu¨rttemberg-Hesse, Frankfurt, bDepartment of Medicine/Hematology and Oncology, University Hospital Heidelberg, Heidelberg, cInstitute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany and d Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA Correspondence to Halvard Bonig, MD, German Red Cross Blood Service Baden-Wu¨rttemberg-Hesse, Sandhofstraße 1, 60528 Frankfurt, Germany. Tel: 49 69 6782177; fax: +49 69 6782258; e-mail: [email protected], [email protected] Curr Opin Hematol 2016, 23:61–66 DOI:10.1097/MOH.0000000000000204
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KEY POINTS Biosimilar G-CSF, now also licensed in the USA, has got a 7-year track record in Europe of similarity to the originator in terms of safety and effectiveness.
similarity of the compounds. The goal posts for what degree of dissimilarity is acceptable are defined largely by the heterogeneity of batches of the originator product over time. With respect to the drugs modeled after Filgrastim G-CSF, this was a comparatively easy task [2 ]. The amino acid sequence was readily accessible; single-chained and nonglycosylated, the molecule was relatively easy to manufacture. All available assays demonstrated not just so-so similarity but, at the currently available resolution, near-identity of originator and biosimilar (for a recent example of such studies, see [7]). More modern manufacturing and purification methods resulted in lower levels of impurities of the biosimilar, which is the only aspect in which the quality of a biosimilar may exceed that of the originator. A contributory role of these impurities to the pharmaceutical effect of G-CSF was proposed not even by biosimilar adversaries (if it had, the ‘biosimilar’ label would not have applied). All effects of G-CSF – desirable or not – appear to be mediated through the G-CSF receptor [2 ]; identical on–off kinetics and down-stream signals further confirmed the impression of biosimilarity for each of the many biosimilar G-CSF preparations [7]. After successful demonstration of physical, chemical, biochemical, and in-vitro biological similarity, one comparative clinical trial of originator vs. biosimilar powered for nondifference in a ‘sensitive indication’ is required for the biosimilar to be approved. At the end of this exercise, its success provided, the biosimilar is licensed for all indications for which the originator is approved, even though it was not tested for these, provided the applicants can reasonably argue that the molecular mechanism of action is the same (a process called ‘extrapolation’) [1,2 ,8]. The biosimilar will also list in its product information all adverse events recorded for the originator, irrespective of whether they were ever observed with the biosimilar. Few have taken issue with extrapolation of adverse effects and contraindications, whereas extrapolation of therapeutic effects has been met with some doubts and even criticism. Specifically for G-CSF, concerns have been expressed about unrelated (registry) donor mobilization with biosimilar GCSF, although specific reasons there were not mentioned [9–11]. The regulators’ decision to extrapolate both the good (efficacy) and the bad (adverse effects) is expression of their reasonable confidence that the aggregate assessment has unequivocally demonstrated similarity between originator and biosimilar [2 ]. Because of pharmacological effects or toxicity, most clinical trials with biologicals can only be performed in patients. Also, biological/pharmacological &&
Biosimilar G-CSFs are biochemically near-identical to the originator, no differences between individual brands of biosimilar G-CSF were identified. Price reductions triggered by the advent of biosimilars may improve access to costly biologicals. The dramatic cost cuts of originators and introduction of, or shift to ‘biobetters’ at the time of biosimilar introduction may threaten the economic success of biosimilars.
for which the originator is approved, despite the lack of formal clinical trials in all but one. Sandoz is currently being challenged in court by the maker of the originator, which at this moment still impedes Zarxio’s availability. Zarxio being the first licensed biosimilar in the USA, this concise article, although largely focused on the topic of ‘biosimilar G-CSF’, will also risk some predictions about more general issues pertaining to biosimilars and their expected effects on the healthcare market. A plethora of scholarly articles about biosimilar G-CSF continues to come forth, albeit real clinical trials, even uncontrolled ones, are now few. What is mostly being published are, in approximately equal number, monocentric case series about biosimilar G-CSF-treated patients with comparison to historical outcomes (hardly suitable to address more minor differences between biosimilar and originator), and articles considering pharmaco–economic aspects of the advent of biosimilars. This reflects, probably not inappropriately, the predominantly economic impact that is expected of biosimilars, whereas clinicians mostly remain rather dispassionate.
ASSESSMENT OF BIOSIMILARITY AND BIOSIMILAR LICENSING The manufacturing of biologicals is significantly more complex than that of small molecule drugs. No two batches of biologicals are alike, in contrast to the maximum likeness of individual batches of synthetic drugs. Therefore, when originator biologicals go off-patent, follow-on drugs cannot use the well established generics pathway; instead, a specific set of guidelines for the approval of follow-on biologicals or ‘biosimilars’ was generated to regulate their approval [2 ]. The focus of the approval process lies on demonstration of biophysical and biochemical &&
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read-outs of effectiveness may often be relatively long-term. Once more, G-CSF is endowed with useful properties facilitating the required clinical bioequivalence studies: for one, G-CSF is safe to give to healthy volunteers, secondly, the rapid mobilization of mature and immature hematopoietic cells in volunteers is an excellent, sensitive, and objectively quantifiable measure of pharmacodynamics. Thirdly, as mentioned above, the mechanism(s) by which G-CSF exerts its pharmacological (and adverse) effects are known; they are mediated exclusively through a transmembrane receptor, G-CSFR, by addressing well defined intracellular signaling pathways. It is thus scientifically reasonable and largely unrefuted to accept similar effectiveness for one indication as pars pro toto, that is, to extrapolate pharmacological similarity to all other indications for which G-CSF is used and consequently to license biosimilar G-CSF for all these, as was done. The situation for biologicals working through mixed and/or only partly understood pharmacological mechanisms immediately becomes more complex and even controversial, and extrapolation to certain indications may be denied. Of note, extrapolation was granted in the case of one biosimilar monoclonal antibody as well as for glatiramer acetate in spite of their (partly) unknown pharmacological mechanisms, so rules seem to be somewhat pliable [12]. Healthy donor mobilization being a quantitatively minor indication, most licensing trials of biosimilar G-CSF have used duration of postchemotherapeutic neutropenia as read-out, clearly a less than sensitive indication to detect potential differences in vivo. With respect to the question how dissimilar two G-CSF preparations (e.g., originator and copy) would have to be before a difference could be detected, one should be reminded that even for the molecularly quite dissimilar compounds Filgrastim and Lenograstim – their dissimilarity easily demonstrated in vitro in all kinds of assays – clinical trials have failed to demonstrate reproducibly different outcomes [13,14]. We would therefore argue that evidence of similar mobilization capacity (even less so, length of neutropenia) is of modest additional value over the biochemical read-outs already provided (e.g., [7]). Absence of differential adverse events, specifically with respect to immunogenicity, is also quite meaningless because of the small size and short follow-up of the observational groups. In other words, we posit that the added value of the kind of clinical trials that are currently required for biosimilar approval is probably not great. So what is new on the clinical trials front? Not much more than the minimally required clinical trials were sponsored (published several years back)
by the manufacturers of biosimilars. The dearth of IITs suggests that clinicians largely accept the regulators’ verdict of biosimilarity. Lack of excitement by clinicians is underscored by the fact that none of the top-tier journals have published any of these clinical trials – one can easily imagine the editors’ verdict of ‘predictable – reject’. In the last year, reports from observational ‘studies’ lacking concurrent control groups have come forth about autologous mobilization and transplantation in children [15], autologous mobilization in adults [16–18], growth factor support after autologous transplantation in adults [18–21], and postchemotherapy neutropenia [22]; the impression from all was one of the overwhelmingly similar results as would have been expected with originator G-CSF. Manko et al. [23 ] report on a 1 : 1 randomized trial of Filgrastim vs. Zarxio G-CSF in autologous donor mobilization and transplantation which revealed no differences. Although matched related donor treatment with biosimilar or originator G-CSF was previously shown to be equally efficient and associated with the same adverse effects one has learned to expect from the drug (of course entirely predicted by the pharmacokinetic/pharmacodynamic studies in healthy volunteers all biosimilar G-CSFs go through [24]) and biosimilar-mobilized allogeneic transplants performed as expected [25], mobilization of matched unrelated donors remains a sensitive issue. The interim analysis of a prospective 10-year study in 230 unrelated stem cell donors treated with the Zarxio G-CSF was presented. Mobilization efficiency and acute side-effects of mobilization and apheresis in donors, as well as graft performance in recipients, were entirely in agreement with expected outcomes [26]. &
WHAT IS THE EXPECTED BENEFIT OF BIOSIMILARS? The expectation was, and to a significant degree this has been confirmed, that the advent of biosimilars would lead to cost reductions for specific biologicals [3,27 ,28–30]. Consequently, less restrictive prescribing could be encouraged, and thus patient access to these costly but highly effective drugs improved [31,32]. Indeed, since the advent of biosimilars the price of first-generation G-CSF has dropped by as much as 80% [3,29,30,33], that is, much more than the 25–30% which had been predicted. The six or so biosimilar G-CSF products licensed in Europe together now outsell the originator [28,34]. Estimates were provided that additional competitors will exert additional pressure on G-CSF price [29], although at the current level this is hard to conceive. Meanwhile, in the UK total healthcare
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expenditure for short-acting G-CSF has fallen, even though the number of dispensed doses has increased by about 5% per year since the advent of biosimilar G-CSF [31]. Thus, at first glance the strategy has been a success. A closer look reveals, however, that the stark drop in price has been achieved without biosimilars necessarily gaining a large share of the market, because of concurrent drastic price reductions for the originator [3]. This development may acutely benefit the market, but not the (individual) biosimilar makers [35]. Their revenue may no longer be high enough for amortization of the investment for development, specifically since the currently very low revenue is distributed among an ever-increasing number of manufacturers each needing to recoup development costs. Precisely this had been foreseen by health economists as a potential impediment to biosimilar development so that they had proposed to actually prohibit relevant price adjustments of the originators [36]. The suggestion was apparently not adopted by lawmakers which may now come back to haunt us. At the same time, prescription habits have significantly shifted towards pegylated G-CSF [27 ], a typical representative of the class of so-called ‘biobetters’, the nemesis of the biosimilar. As a consequence, the share of biosimilars of the total G-CSF market in Europe really remains in the low teens [27 ]. Similar trends towards shifting of patients to ‘biobetters’ are observed with other biologicals whose original patents are running out. Quo vadis, biosimilars? As alluded to above, the complexity of biosimilar process development and approval is reflected in their significant costs; numbers in the 100 s of millions of dollars have been mentioned [27 ,28,37]. These must be recouped, which naturally requires significant market penetration as well as reasonably high margins and hence prices. As a result of the currently very lean margins, the first developers of biosimilars are already retreating from the market. We predict that once a couple of attempts to enter the biosimilar market have been thwarted by too rapidly deteriorating prices or too many competitors, few contenders will remain in the biosimilar business. Specifically in the USA, the makers of originators are routinely fighting approval of biosimilars by the FDA and/or postapproval market access by petitions and legal court action, as we are currently seeing for biosimilar G-CSF and other biosimilars. This not only extends originator monopolies, it also delays return on investment of the biosimilar makers, which could become another significant impediment to biosimilar development. Moreover, we expect that the very high development costs will limit biosimilar development to blockbuster biologicals, whereas costs for the &&
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multitude of niche biologicals will be maintained if not increased to compensate for lost income with products with biosimilar competition. At the same time, the healthcare market will be shouldered indirectly with the aggregate development costs of the many G-CSF biosimilars, whereas the makers of the originators will try to shift lost revenue from short-acting G-CSF to on-patent biologicals and ‘biobetters’. Whether the healthcare system, as a whole, will at the end of the day actually spend less on biologicals altogether remains to be seen. Without specific market regulating action by lawmakers, the authors of this article are certainly skeptical. The need for a comparative clinical trial to obtain a marketing authorization for a biosimilar was already briefly discussed, including these authors’ lack of confidence in their informational value. Technical and recruitment issues for such trials are to be expected [37–39] which regulators possibly failed to anticipate. The incentive for patients to participate in clinical trials is typically the expectation that the investigational treatment could potentially be better than the standard – if not for the participating individual, then for future patients. By definition, however, a biosimilar is at best equal to the originator; in other words, the only potential benefit is fiscal. What, therefore, would be the incentive for patients for participation in or for ethics committees for approval of biosimilar clinical trials is not immediately apparent. One conceivable tangible benefit from participation in such trials, access to otherwise unavailable treatments (originator or copy), does not apply in Germany and other countries with universal access, but – ethically questionable – could provide an incentive in countries with underfunded or otherwise limited access to healthcare. With respect to feasibility of trials, few biologicals offer rapid pharmacodynamic read-outs like insulin or G-CSF which vary relatively little and can be readily assessed in healthy volunteers (lowering of blood glucose levels or leukocytosis/stem cell mobilization, respectively), thus greatly facilitating the performance of comparative clinical trials. Biologicals with slower read-out, such as reduction of multiple sclerosis flares in patients on beta-interferon or glatiramer acetate or remissions in patients with B-cell malignancies on rituxan, will require large studies with very long follow-up. If regulators were convinced of the predictive power of the in-vitro comparability exercise, clinical trials would not be required, as with generics. The FDA’s recent decision to approve Sandoz’ version of the multiple sclerosis drug glatiramer acetate without a formal comparative trial, vainly challenged by the maker of the originator (ironically, themselves the world’s largest maker of Volume 23 Number 1 January 2016
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generics), suggests that regulators might share these authors’ skepticism about the added benefit of clinical trials. In summary, in the field of biosimilar G-CSF, no news is good news, and such is the case. Tedious studies and case series suggest that biosimilar G-CSF is just as (in)tolerable, effective and safe as originator G-CSF in all indications that were studied. No evidence of immunogenicity has emerged nor have seven years of copious use in Europe raised any other concerns about long-term safety, although universal long-term follow-up is missing for biosimilars as for originators. Clinical experience is currently restricted to postchemo/postauto-transplant neutropenia and autologous/allogeneic stem cell mobilization. Thus far, no data were reported on granulocyte mobilization for preparative apheresis [40] or on congenital and acquired neutropenias [41,42]. While several studies report financial benefits for the healthcare system, these focus on G-CSF costs and prescribing behavior. They mostly fail to address, however, the big picture, that is, total healthcare expenditure, by failing to include in the analyses the issues of ‘biobetters’ as impediments to market access of biosimilars and of potential compensatory price increases of competitor-free products. In countries with limited access to healthcare, price reductions brought on by biosimilars may induce more generous prescribing habits in the interest of previously undertreated patients. Acknowledgements None. Financial support and sponsorship H.B. is a member of LOEWE Cell and Gene Therapy Frankfurt faculty, funded by Hessian Ministry of Higher Education, Research and the Arts ref.no.: III L 4- 518/ 17.004 (2013). Conflicts of interest H.B. has received research funding and has served on the advisory board and speakers’ bureau of Sandoz-Hexal, makers of a biosimilar Filgrastim G-CSF, as well as research funding from Chugai, makers of Lenograstim G-CSF. M.S. has got no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Bonig H, Becker PS, Schwebig A, Turner M. Biosimilar granulocyte-colonystimulating factor for healthy donor stem cell mobilization: need we be afraid? Transfusion 2015; 55:430–439.
2. Weise M, Kurki P, Wolff-Holz E, et al. Biosimilars: the science of extrapolation. Blood 2014; 124:3191–3196. Very insightful review article into regulatory issues of biosimilar licensing. 3. Farfan-Portet MI, Gerkens S, Lepage-Nefkens I, et al. Are biosimilars the next tool to guarantee cost-containment for pharmaceutical expenditures? Eur J Health Econ 2014; 15:223–228. 4. FDA approves first biosimilar product Zarxio. http://www.fda.gov/News Events/Newsroom/PressAnnouncements/ucm436648.htm. [Accessed 11 October 2015] 5. Ledford H. First biosimilar drug set to enter US market. Nature 2015; 517:253–254. 6. Traynor K. FDA advisers recommend approval of biosimilar filgrastim. Am J Health Syst Pharm 2015; 72:262; 264. 7. Crobu D, Spinetti G, Schrepfer R, et al. Preclinical and clinical phase I studies of a new recombinant Filgrastim (BK0023) in comparison with Neupogen. BMC Pharmacol Toxicol 2014; 15:7. 8. Ebbers HC. Biosimilars: in support of extrapolation of indications. J Crohns Colitis 2014; 8:431–435. 9. Barosi G, Bosi A, Abbracchio MP, et al. Key concepts and critical issues on epoetin and filgrastim biosimilars. A position paper from the Italian Society of Hematology, Italian Society of Experimental Hematology, and Italian Group for Bone Marrow Transplantation. Haematologica 2011; 96:937–942. 10. European Group for Blood and Marrow Transplantation(EBMT). Position statement: biosimilar granulocyte-colony stimulating factor (G-CSF) for stem cell mobilization in related and unrelated donors. http://www.worldmarrow.org/fileadmin/Committees/CLWG/Biosimilars/Biosimilars_9Jan09.pdf. 2009. [Accessed 8 July 2015] 11. Shaw BE, Confer DL, Hwang WY, et al. Concerns about the use of biosimilar granulocyte colony-stimulating factors for the mobilization of stem cells in normal donors: position of the World Marrow Donor Association. Haematologica 2011; 96:942–947. 12. Cortes J, Curigliano G, Dieras V. Expert perspectives on biosimilar monoclonal antibodies in breast cancer. Breast Cancer Res Treat 2014; 144:233–239. 13. Sourgens H, Lefrere F. A systematic review of available clinical evidence: filgrastim compared with lenograstim. Int J Clin Pharmacol Ther 2011; 49:510–518. 14. Bonig H, Silbermann S, Weller S, et al. Glycosylated vs nonglycosylated granulocyte colony-stimulating factor (G-CSF)–results of a prospective randomised monocentre study. Bone Marrow Transplant 2001; 28:259–264. 15. Cesaro S, Tridello G, Prete A, et al. Biosimilar granulocyte-colony-stimulating factor for mobilization of autologous peripheral blood stem cells in pediatric hematology-oncology patients. Transfusion 2015; 55:246–252. 16. Uddin S, Russell P, Farrell M, et al. Use of biosimilar filgrastim compared with lenograstim in autologous haematopoietic stem-cell transplant and in sibling allogeneic transplant. Ther Adv Hematol 2015; 6:53–60. 17. Schmitt M, Publicover A, Orchard KH, et al. Biosimilar G-CSF based mobilization of peripheral blood hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Theranostics 2014; 4:280–289. 18. Remenyi P, Gopcsa L, Marton I, et al. Peripheral blood stem cell mobilization and engraftment after autologous stem cell transplantation with biosimilar rhG-CSF. Adv Ther 2014; 31:451–460. 19. Marchesi F, Cerchiara E, Dessanti ML, et al. Comparison between biosimilar filgrastim vs other granulocyte-colony stimulating factor formulations (originator filgrastim, peg-filgrastim and lenograstim) after autologous stem cell transplantation: a retrospective survey from the Rome Transplant Network. Br J Haematol 2015; 169:293–296. 20. Cioch M, Jawniak D, Kotwica K, et al. Biosimilar granulocyte colony-stimulating factor is effective in reducing the duration of neutropenia after autologous peripheral blood stem cell transplantation. Transplant Proc 2014; 46:2882– 2884. 21. Bassi S, Stroppa EM, Moroni CF, et al. Safety and efficacy of granulocyte colony-stimulating factor biosimilars in engraftment after autologous stem cell transplantation for haematological malignancies: a 4-year, single institute experience with different conditioning regimens. Blood Transfus 2015; 13:478–483. 22. Tesch H, Ulshofer T, Vehling-Kaiser U, et al. Prevention and treatment of chemotherapy-induced neutropenia with the biosimilar filgrastim: a non-interventional observational study of clinical practice patterns. Oncol Res Treat 2015; 38:146–152. 23. Manko J, Walter-Croneck A, Jawniak D, et al. A clinical comparison of the & efficacy and safety of biosimilar G-CSF and originator G-CSF in haematopoietic stem cell mobilization. Pharmacol Rep 2014; 66:239–242. Albeit small, one of the rare controlled trials of originator vs. biosimilar G-CSF. 24. Matsuguma K, Matsuki S, Sakamoto K, et al. A comparative pharmacokinetic and pharmacodynamic study of FSK0808 versus reference filgrastim after repeated subcutaneous administration in healthy Japanese men. Clin Pharmacol Drug Dev 2015; 4:99–104. 25. Schmitt M, Xu X, Hilgendorf I, et al. Mobilization of PBSC for allogeneic transplantation by the use of the G-CSF biosimilar XM02 in healthy donors. Bone Marrow Transplant 2013; 48:922–925. 26. Becker PS, Brauninger S, Bialleck H, et al. Use of biosimilar G-CSF for hematopoietic stem cell mobilization in healthy unrelated donors: interim results of a 10-year follow-up study [abstract]. Bone Marrow Transplant 2015; 50:328.
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35. Haustein R, deMillas D, Ho¨er A, Ha¨ussler B. Saving money in the European healthcare systems with biosimilars. GaBi J 2011; 1:120–126. 36. Ha¨ussler B, Thiede M. Die Rolle der Biosimilars im Wettbewerb auf dem GKVArzneimittelmarkt [The role of biosimilars as competitors in the health insurance market]. Berlin, Germany: IGES Institute; 2008. 37. Garattini L, Curto A, van de Vooren K. Western European markets for biosimilar and generic drugs: worth differentiating. Eur J Health Econ 2015; 16:683–687. 38. Bui LA, Taylor C. Developing clinical trials for biosimilars. Semin Oncol 2014; 41 (Suppl 1):S15–S25. 39. Guillon-Munos A, Daguet A, Watier H. Antibody biosimilars: fears or opportunities?: First LabEx MAbImprove industrial workshop, May 28, 2013; Tours, France. MAbs 2014; 6:805–809. 40. Thorausch K, Schulz M, Bialleck H, et al. Granulocyte collections: comparison of two apheresis systems. Transfusion 2013; 53:3262–3268. 41. Sicre de FF, Moignet A, Beaupain B, et al. Severe chronic primary neutropenia in adults: report on a series 108 patients. Blood 2015; 126:1643–1650. 42. Boxer LA, Bolyard AA, Kelley ML, et al. Use of granulocyte colony-stimulating factor during pregnancy in women with chronic neutropenia. Obstet Gynecol 2015; 125:197–203.
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