NDT Advance Access originally published online on September 18, 2008
Nephrology Dialysis Transplantation 2008 23(12):3731-3737; doi:10.1093/ndt/gfn519
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Biosimilars and biopharmaceuticals: what the nephrologists need to know—a position paper by the ERA-EDTA Council
1 Dialysis and Transplantation Center, Dr. C.I. Parhon University Hospital, Iasi, Romania 2 Bone and Mineral Research Unit, Universidad de Oviedo, Hospital Universitario Central de Asturias, Oviedo, Spain 3 Nephrology Department, Nephrology Institute, Brescia 4 Nephrology and Dialysis Department, Regina Margherita Hospital, Torino, Italy 5 Hospital S. João, Serviço de Nefrologia, Al. Hernâni Monteiro, 4200 Porto, Portugal 6 Department of Nephrology, Guy's & St. Thomas' Hospital, London, UK 7 Nephrology Department and INSERM Unit 702, Tenon Hospital, Paris, France 8 Department of Nephrology, Clinical Center Skopje, University of Skopje, F.Y.R. Macedonia 9 Department of Clinical Science, Technology and Intervention, Karolinska Institutet, Stockholm, Sweden 10 Department of Nephrology, Erciyes University Medical Faculty, Kayseri, Turkey 11 Department of Nephrology, Silesian School of Medicine, Katowice, Poland 12 CNR, Renal, Hypertension and Transplantation Unit, Ospedali Riuniti, Reggio Calabria, Italy 13 Department of Nephrology, Centre Hospitalier, Mahnes, Fleury, France
Correspondence and offprint requests to: Adrian Covic, Dialysis and Transplantation Center, Dr. C.I. Parhon University Hospital, Carol 1st Blvd. Nr. 50, Iasi 700503, Romania. Tel: +40-721-280246; Fax: +40-232-211752; E-mail: acovic{at}xnet.ro
Keywords: biopharmaceuticals; biosimilars; ERA-EDTA position paper; pharmacovigilance
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Introduction |
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Top
Introduction
Definition, history and...Since January 2008, four biosimilars have been approved by EMEA: two human growth hormone analogues and two erythropoiesis-simulating agents (ESAs) (in five different branding versions). The ESAs were approved despite some differences from the comparator product in potency and consistency. For example (as shown in the official EMEA document), epoetin zeta (SB309) ‘provided evidence that a difference of 35.3 IU/kg/week in epoetin dose (worst case scenario) was clinically not relevant in the investigated study population, whether this difference was calculated as absolute value or as percentage of the reference dose (21%)’ [1]. At the same time, a biosimilar interferon product was rejected because of concerns about stability, impurities, validation of the manufacturing process and differences in outcomes and adverse effects [2].
In response to a letter from European Biopharmaceutical Enterprises (EBE) and concerns from the renal community, the ERA-EDTA Council meeting decided in Porto, during the Autumn 2007 Council meeting, to form a working group that should analyse and debate the issue of ESA biosimilars. A draft document was prepared and submitted for Council debate; at the 2008 Spring Council meeting in London, a decision to elaborate a Position Statement was considered. The final draft was submitted for Council approval during the ERA-EDTA Stockholm Congress. Considering the objectivity and high scientific standards of the ERA-EDTA, the document was also sent for external peer reviewing. The final approved document was submitted to NDT. This document briefly summarizes what biopharmaceuticals and biosimilars are, why they exist and why their regulation and use is a subject of debate. It is intended to serve as a means for all interested stakeholders to learn more about a complex and important area of medicine, and one in which there is room for debate and discussion especially concerning regulatory frameworks and pharmacovigilance. We review the evidence supporting that any decision to employ biosimilar biopharmaceuticals should be taken with appropriate knowledge and understanding of this complex area, by the primary responsible physician, after a careful appraisal of the advantages and disadvantages of taking this course of action.
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Definition, history and implications of biosimilars |
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A biopharmaceutical, or biological medicine, is ‘a medicine whose active substance is made by or derived from a living organism’ [1], typically replacing or supplementing a natural protein produced by the body. Such agents are far more complex than traditional chemical drugs, in their structure, methods of production and modes of action.
Biopharmaceuticals are a major medical growth area. In addition to the 
120 existing agents, over 400 new biopharmaceuticals are under development, mostly in the fields of oncology, infectious and autoimmune diseases and respiratory disorders [3]. These medicines are extending physicians’ ability to fight diseases, including many previously thought to be incurable.
A ‘biosimilar’ (Europe) or ‘follow-on biologic’ (USA) is ‘a medicine which is similar to a biological medicine that has already been authorized’ [1] and whose patent has typically expired. The term arises from the difficulty in comparing two versions of a biopharmaceutical agent. While it is possible to assess measures such as molecular mass, in vitro activity, physicochemical integrity and stability, none of these will guarantee equivalent efficacy and safety in the relevant patient population, issues that may take long time frames to resolve in full. Since the structure of large proteins cannot yet be unequivocally determined [4], the requirements for marketing authorization of replacement biopharmaceutical products cannot be the same as for low-molecular-mass generic drugs [5]. Such products are therefore brought to market on the basis that they are similar, rather than identical, to the original agents. Regulatory authorities have yet to offer a definition of what ‘similar’ means in practice, and it is possible that it may differ by a class of drug or by indication.
Biopharmaceuticals are relatively expensive compared to chemical agents, due to their complex manufacture and clinical development and the costs of handling and distribution, delivery systems, etc. They currently account for approximately $30 billion of the US healthcare budget, a figure expected to rise to about $60 billion by 2010 (of a total projected health budget of $3 trillion). In Europe, in 2008, the cost of biopharmaceutical agents is around Euro 60 000 000 000, which is 9% of the global market (both the projected costs and the proportion of the global market which Europe represents will rise significantly over the next decade). The driving force behind the development of biosimilars is thus primarily financial: the idea is to produce cost savings analogous to those arising from generic versions of branded drugs although given the different economics of biopharmaceuticals, the potential size of such savings is unclear. It is also theoretically possible that biosimilars may be better than the original products since often new drugs are developed and produced with more advanced technologies than the original products. Furthermore, the advent of biosimilars will have an impact on the innovation cycle, stimulating the research and development of second-generation products. Nevertheless, the current prevailing reason for using a biosimilar, at this moment, is related to costs because it is cheaper, not because it is better or safer. In certain parts of the world with a lower per capita income, using a cheaper biosimilar may be the only way into receiving complex new treatments.
Finally, to complete the perspective, it is important to mention that although the issue of biosimilars is a relatively recent development, the issue of comparing drugs within classes is certainly not. The scenario of introducing ‘Me too’ drugs, claiming equivalence based upon weak data, with no improved outcome demonstrated (defined as either an increased benefit or a reduction in harm), usually on the grounds of cost minimization for national reimbursement purposes, has been very common. Specific problems have included [6–8]
- lack of regulatory clarity about what is meant by a class effect;
- lack of FDA/EMEA requirement for comparative RCTs (indirect comparison against a common placebo comparison) and
- the quality of the data supporting equivalence (power, surrogate outcomes only, indirect comparisons).
There are significant examples (e.g., cerivastatin, rofecoxib) where this process has raised numerous medical and finally regulatory problems. The paper by McAlister et al. [9] provides an excellent summary of a hierarchy of what constitutes best evidence for a claim of equivalence. The new development is that biosimilars have forced EMEA to develop more explicit criteria for equivalence (see the Pharmacovigilance in the EU section).
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Challenges in pharmaceutical manufacturing with biological drugs |
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The manufacturer of any drug faces significant challenges. To guarantee that a product is safe and efficacious, it must be consistent in composition, and stable when stored correctly. To this end, starting materials must be pure and standardized, equipment and facilities must be continuously checked, manufacturing processes must fall within defined ranges of temperature, pH, etc., and packaging, storage, and distribution must all be monitored for variation. The final product must also be quantifiably free of contaminants such as starting materials, solvents and products of side-reactions. A battery of well-validated quality control and analysis systems checks these parameters at every stage and is itself subject to measurement and control [10–14]. During the substantial periods over which many of these drugs have been produced, a wealth of knowledge has accrued about potential sources of problems, and standards have been established as to what level of batch-to-batch variability is acceptable. These challenges are all increased in biopharmaceutical manufacturing.
Biopharmaceuticals are by definition produced by a living system, making standardization (the central plank of quality control) more difficult. Their manufacture is generally more complex: genetic sequences must be inserted into a suitable expression vector; a host cell expression system must be generated and scaled up for large-scale production; the desired protein must be isolated and purified and the purified product must be correctly handled and transported. These processes are often highly sensitive to minor changes, both during production and beyond, making it more difficult to specify what level of variation is acceptable. Contamination is also a major concern, not simply because it can compromise the purity of the final product, but also because it may subtly alter its three-dimensional or aggregative properties (see the EMEA Guidelines section). Lastly, these products are comparatively new; thus, the background of experience described above is still in the process of being established.
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Theoretical concerns with biosimilars |
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The two chief issues with biosimilar agents include variable potency/response and immunogenicity and are thought to be due to one of three mechanisms: glycosylation, contamination and changes to 3D structure. Immunogenicity is generally the primary safety concern, but the variation in potency can also raise safety issues in the case of substitution of the original molecule with biosimilars, e.g. variability in haemoglobin values seen with original epoetin [15,16] and its possible association with increased mortality in dialysis patients [17]. The issues of safety and efficacy can seldom be entirely separated: binding of an agent by immune system molecules will often decrease its clinical effect, and changes to the shape or structure of a protein can alter its binding to immune system receptors as well as to its physiological target. Therefore, some biopharmaceuticals may induce immune responses, often with no clinically relevant consequences, but sometimes with severe and potentially lethal results [18]. The most dramatic side effects occur when neutralizing antibodies cross-react with an endogenous factor that has an essential biological function. The antibodies induced by some epoetin alpha formulations have led to cases of life-threatening pure red-cell aplasia (PRCA) [19].
Glycosylation
The glycosylation of recombinant proteins can influence their degradation, their exposure of antigenic sites and their solubility, as well as their immunogenicity [13]. Changes in degradation can produce novel antigenic epitopes not found in the parent molecule, with potentially increased immunogenicity [20] and biological activity and metabolic half-life may also be affected [21]. The degree of glycosylation depends primarily on the host cell expression system. For example, recombinant G-CSF expressed in Escherichia coli is non-glycosylated, whereas that expressed in Chinese hamster ovary cells is glycosylated [22]. Similarly, proteins manufactured in yeast cells contain high levels of mannose sugar groups, rendering them more prone to degradation and thereby decreasing their half-life [23]. However, the conditions under which host cells are cultivated can also affect the glycosylation of the protein expressed [24]. Variable sialylation of protein molecules can have similar effects; the serum half-life of epoetin alpha is dependent on four sialylated N-glycans [25].
Contamination
Impurities in biopharmaceuticals may derive from chemicals or antibiotics used during manufacture, or may result from microbial or viral contamination. A contaminant can make a significant difference to the immunogenicity of a biopharmaceutical even at very low levels, if it has adjuvant activity. Impurities such as endotoxins or denatured proteins, for example, may give a ‘danger’ signal to T cells, which may then send activating signals to B cells, leading to an immune response to the drug [14]. Interest has recently focused on the possibility that impurities with adjuvant activity could be leached or extracted from container closure systems [26]. Although there are reasonable theoretical grounds for this hypothesis, experimental evidence suggesting that this factor has actually been the cause of problems such as PRCA is not currently conclusive.
Changes to three-dimensional structure
Alterations to the three-dimensional structure of a protein can have major affect on its degradation, with the implications described above. Important sources of such changes include protein aggregation, oxidation and deamidation.
- Protein aggregation typically involves denatured protein molecules, thus solvents, temperature, handling, surface interactions and freeze-drying may all have an effect [27].
- Protein oxidation can occur both in solution and during freeze-drying and is often due to contamination with oxidants or from exposure to light during storage [28].
- Protein deamidation can also occur during manufacture, but comparatively little is understood about its role in immunogenicity [29].
Of these three mechanisms, aggregation is of particular concern, because it may lead to the immune system recognizing the protein as non-self and mounting a response [30,31]. This is probably because the repeating structure of protein aggregates more closely resembles the microbial structures that the immune system is primed to act against [29]. The process by which the body becomes reactive to the protein can be very slow: antibodies to products such as interferon (IFN) and erythropoietin may be detected for more than a year after treatment cessation [32]. Aggregation has been suggested as an explanation for the PRCA epidemic (as a consequence of the change in stabilizer) although this remains unproven [33].
Other causes
Many other factors can be affected by the manufacturing process, including side chains (carbamylation, GSH-adducts), other post-translational processing (methylation, acetylation) and the tertiary and quaternary structures of the protein product. These factors have received less attention to date, but may nonetheless be important [34,35].
Clearly, therefore, with these significant challenges facing doctors and patients, it has been incumbent on regulators to attempt to scope and define the principal issues of operational principles that should be adopted. In the next section, we focus on the EMEA response to this challenge, as we are commenting predominantly from a European perspective.
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EMEA guidelines |
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While in the USA the FDA has taken the position that new legislation is needed to address the problem of biosimilars, in Europe the EMEA has taken a global lead in establishing guidelines for their approval [36,37]. These guidelines include both clinical and non-clinical issues of biosimilars [36], including manufacturing processes and quality control [37], and guidance specific to particular classes of biosimilars such as human growth hormone, insulin and erythropoietin. The guidelines call for far more rigorous testing than would be needed for a chemical generic product or for approval of a change in production process by the originator company, stating that in most cases, ‘comparative clinical trials will be necessary to demonstrate clinical comparability between the similar biological and the reference medicinal product’ [36]. They also emphasize the importance of the production process, advising applicants to ‘generate the required clinical data for the comparability study with product manufactured with the final manufacturing process and therefore representing the quality profile of the batches to be commercialized’. EMEA guidelines do however permit the possibility of extrapolation of data from one therapeutic indication to another, allowing for the use of a biosimilar in indications where it has not been formally studied, on a case-by-case basis.
The EMEA-recommended studies for any new similar biological erythropoietin are reproduced here.
Pharmacodynamics studies
In vitro studies
In order to assess any alterations in reactivity between the similar biological medicinal and the reference medicinal product, data from a number of comparative bioassays should be provided.
In vivo animal studies
The erythrogenic effects of the similar biological medicinal product and the reference medicinal product should be quantitatively compared in an appropriate animal assay (e.g. the European Pharmacopoeia polycythaemic and/or normocythaemic mouse assay). Additional information on the erythrogenic activity may be obtained from the described repeat-dose toxicity study.
Toxicological studies
Data from at least one repeat-dose toxicity study in a relevant species (e.g. rat) should be provided. The study duration should be at least 4 weeks. The study should be performed in accordance with the requirements of the ‘Note for guidance on repeated dose toxicity’ (CPMP/SWP/1042/99) and include appropriate toxicokinetic measurements in accordance with the ‘Note for guidance on toxicokinetics: A Guidance for assessing systemic exposure in toxicological studies’ (CPMP/ICH/384/95). In this context, special emphasis should be laid on the determining of immune responses. Data on local tolerance in at least one species should be provided in accordance with the ‘Note for guidance on non-clinical local tolerance testing of medicinal products’ (CPMP/SWP/2145/00). If feasible, local tolerance testing can be performed as part of the described repeat-dose toxicity study. Safety pharmacology, reproduction toxicology, mutagenicity and carcinogenicity studies are not routine requirements for non-clinical testing of similar biological medicinal products containing EPO as an active substance.
Clinical studies
Pharmacokinetic studies
The relative pharmacokinetic properties of the similar biological medicinal product and the reference product should be determined in single-dose crossover studies using subcutaneous and intravenous administration. The selected dose should be in the sensitive part of the dose–response curve. The primary pharmacokinetic parameter is AUC and the secondary pharmacokinetic parameters are Cmax and T1/2 or CL/F. Equivalence margins have to be defined a priori and appropriately justified. Differences in T1/2 for the IV and the SC route of administration and the dose dependence of clearance of epoetin should be taken into account when designing the studies.
Pharmacodynamic studies
Pharmacodynamics should preferably be evaluated as part of the comparative pharmacokinetic studies. The selected dose should be in the linear ascending part of the dose–response curve. In single-dose studies, the reticulocyte count is the most relevant and, therefore, recommended pharmacodynamic marker for the assessment of the activity of epoetin. On the other hand, the reticulocyte count is not an established surrogate marker for the efficacy of epoetin and therefore there is no suitable endpoint in clinical trials.
Clinical efficacy studies
A comparable clinical efficacy between the similar and the reference product should be demonstrated in at least two adequately powered, randomized, parallel group clinical trials. Confirmatory studies should be blind (for investigators and patients) to avoid bias. If this is not possible, at minimum the person(s) involved in decision making (e.g. dose adjustment) should be effectively masked to treatment allocation. Ideally, the outcome assessor should also be blinded.
Patients with renal anaemia are therefore recommended as the target study population as this would provide the most sensitive model. Other reasons for anaemia should be excluded. The clinical trials should include a ‘correction phase’ study during anaemia correction and a ‘maintenance phase’ study in patients on epoetin maintenance therapy.
It is recommended that the comparative phase be 6 months in order to establish comparable clinical efficacy of the test and the study duration should be justified. The study design for a maintenance phase study should minimize the carry-over effects of previous treatments. Patients included in a maintenance phase study should be optimally titrated on the reference product (stable haemoglobin in the target range on stable epoetin dose and regimen without transfusions) for 3 months. Thereafter, study subjects should be randomized to the similar or the reference product and followed up for at least 3 and ideally 6 months to avoid carry-over effects. In the course of both studies, epoetin doses should be closely titrated to achieve (correction phase study) or maintain (maintenance phase study) target haemoglobin concentrations. The protocol should clearly pre-define the dose adjustment algorithm. The haemoglobin target range and titration schedule should be in accordance with current clinical practice. In the correction phase study ‘haemoglobin responder rate’ (proportion of patients achieving a pre-specified haemoglobin target) or ‘change in haemoglobin’ is the preferred primary endpoint. In the maintenance phase study ‘haemoglobin maintenance rate’ (proportion of patients maintaining haemoglobin levels within a pre-specified range without transfusion) or ‘change in haemoglobin’ is the preferred primary endpoint. An epoetin dosage should be a co-primary endpoint in both studies. The fact that epoetin dose is titrated to achieve the desired response reduces the sensitivity of the haemoglobin-related endpoints to detect possible differences in the efficacy of the treatment arms. Equivalence margins for both co-primary endpoints have to be pre-specified and appropriately justified and serve as the basis for powering the studies. Transfusion requirements should be included as an important secondary endpoint. Since epoetin doses necessary to achieve target haemoglobin levels differ in pre-dialysis and dialysis patients, these two populations should not be mixed in the same study. Clinical comparability has to be demonstrated for both routes of administration. This is best achieved by performing separate studies, e.g. a correction phase study in a pre-dialysis population using SC epoetin and a maintenance phase study in a haemodialysis population using IV epoetin.
Clinical safety data
Comparative safety data from the efficacy trials are sufficient to provide an adequate pre-marketing safety database. The applicant should provide at least 12-month comparative immunogenicity data pre-authorization. Retention samples for both correction phase and maintenance phase studies are recommended. For the detection of anti-epoetin antibodies, a validated, highly sensitive assay should be used.
Within the authorization procedure the applicant should present a risk management programme/pharmacovigilance plan in accordance with current EU legislation and pharmacovigilance guidelines. In order to further study the safety profile of the similar biological medicinal product, particularly rare serious adverse events such as immune-mediated PRCA, safety data should be collected from a cohort of patients representing all approved therapeutic indications.
To summarize, difficulties in establishing equivalence of biopharmaceutical agents have meant that the EMEA approval process is based on ‘comparability’: the demonstration of comparable efficacy and safety to a reference product in a relevant patient population [38]. The question of what exactly is to be considered ‘comparable’ is not defined a priori, and the approval process is likely to vary between products according to the nature and quantity of data available. In the end, one has to point out that a change in haemoglobin should not be assumed as a validated surrogate, within the context of an RCT (i.e. there are no RCT to show that a change in haemoglobin is associated with a change in hard clinical endpoint such as death or cardiovascular event). In particular cases, if there is uncertainty regarding the full range of mechanism of action for a biosimilar, then an end-point trial should be required/optimal.
The main challenges therefore faced by physicians, pharmacists and patients are those around patient safety, and these concerns were of course at the heart of the proposals put forward by the EMEA (see above). Concerns remain however about ensuring
- that pharmacovigilance programmes attain uniform excellence across Europe and apply to all new/biopharmaceutical products;
- that physicians, pharmacists and patients are clearly informed about the benefits, responsibilities for users and potential safety and efficacy issues around the use of any biosimilar agent (with special reference to pharmacovigilance) and
- that, to improve pharmacovogilence, the substitution of an existing established epoetin by a biosimilar agent should only be decided by the physician after receiving the informed consent from the patient.
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Pharmacovigilance in the EU |
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Biopharmaceuticals are infrequently associated with serious adverse events such as PRCA; therefore, the EMEA guidelines require immunogenicity testing and pharmacovigilance programmes to monitor the efficacy and safety of biosimilar products post-approval. As noted above, some adverse effects may take more than a year to appear [32] and even very small changes in manufacturing can have major consequences for a product's adverse effects [19,33]. Pharmacovigilance is thus likely to be a long-term project for any biosimilar agent. Routine pharmacovigilance is recommended for products where no special concerns have arisen, whereas additional pharmacovigilance activities and action plans will be required for medicinal products with important established risks, potential risks or missing information.
Concern has been expressed, however, that the approval decision will be partly based on convincing the EMEA that a suitable pharmacovigilance plan will be implemented and that data representative of all approved patient groups will be collected [37], rather than actual evidence of long-term safety [39].
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Automatic substitution and INN |
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In the case of generic drugs, substitution often occurs without the knowledge of the prescribing physician, either because the pharmacist overrides the original prescription of a branded drug or because the original prescription specifies only the WHO International Non-proprietary Name (INN) and not a manufacturer. Regulations in some EU countries allow pharmacists to substitute any drug for another that has the same INN. Given the difficulties with equivalence of biosimilar products, however, this approach seems unlikely to be used with biopharmaceuticals. In addition to the possibility of clinical consequences, such automatic substitutions would also affect pharmacovigilance efforts, making it more difficult to know when greater vigilance levels were justified and to trace back reported adverse events to the correct brand or manufacturer [40]. Several European countries, including France, Germany and Spain, have already explicitly forbidden automatic substitution for biosimilars and Italy is set to do in 2008.
While it may be desirable for the reason cited above for different biosimilars to have different INNs, as recommended by the EBE and EFPIA [41], this would require a change in approach from WHO regarding the purpose and function of INNs. It is currently unclear how the WHO intends to approach this issue; in the executive summary of the 46th Consultation on INN for Pharmaceutical Substances (April 2008), the uncertainty concerning the definitions for EPOs was not yet solved; it was agreed that the INN Secretariat should pursue a definition for a glycoprotein, but this would need to be assessed by the INN Expert Group before publication [42]. It becomes thus mandatory that the levels of ‘responsibility’ in allowing and using biosimilars should be defined (regulatory bodies, physicians, pharmacists). We should promote efforts for a common ‘European’ way to face this problem, by avoiding/minimizing differences among the different countries.
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Conclusions |
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Biosimilar biopharmaceutical therapeutic agents may offer considerable advantages to hard-pressed health-care economies, as the costs of providing effective therapies in a variety of new and existing disease areas increase progressively. However, a decision to permit their use clinically should be balanced by a clear mandate to ensure, as with all biopharmaceutical agents, that patients, physicians and pharmacists truly understand the complex arguments and decisions which apply to this new and challenging area. In particular, pharmacovigilance is a responsibility that is shared between the pharmaceutical industry, pharmacists and physicians, with appropriately informed and educated patients. Ease of tracing and identification of new/substituted agents especially when dealing with patients who may be exposed to injected therapies for many years is a pivotal requirement and one where new input into nomenclature decisions and systems is now urgently needed. Any decision to employ biosimilar biopharmaceuticals should be taken with appropriate knowledge and understanding of this complex area by the primary responsible physician, after a careful appraisal of the advantages and disadvantages of taking this course of action, and with appropriate systems for pharmacovigilance in place.
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Acknowledgments |
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Among the authors, A. Wiecek is a member of the EBPG Working Group, which formulated the 2004 update of the EBPG anaemia guidelines. A Covic, J Cannata-Andia, G. Spassovski, A Wiecek, C. Zoccali are members of the ERBP Advisory Board. This document has been independently fully reviewed and approved by J. Craig who is a member of KDIGO and COCHRANE. The position paper has been revised by all members of the ERA-EDTA council. The position paper was approved by the ERA-EDTA council.
Conflict of interest statements. Andrzej Wiecek has received financial gratitude for congress participation, lectures and clinical trials from: Janssen-Cilag, Roche, Amgen and Affimax. Giovanni Cancarini has received lecture fees by Roche, Amgen and Genzyme and a research grant by Roche. Peter Stenvinkel is in the scientific advisory board of Gambro. He has research support from Amgen and has given (or will give) lectures at meetings organized by Genzyme, Amgen, Gambro, Roche, Cilag, Shire and Baxter. Gérard London serves as a consultant for Genzyme, Shire, Abbott and Roche. Pierre Ronco has no conflict of interest related to this topic. Jorge B. Cannata-Andía received funds for Research, Boards or Conferences from Shire, Abbott and Amgen. Adrian Covic is a scientific consultant for Fresenius Medical Care and has received speaker and advisory fees from Amgen, Roche and Affymax. David Goldsmith has received speaker and advisory fees from Johnson & Johnson, Amgen, Roche, Shire. Goce Spasovski has no conflict of interest. Carmine Zoccali has no conflict of interest related to this topic. Rosanna Coppo has no conflict of interest related to this topic. João M. Frazão has received consultancy and lecture fees from Amgen and Genzyme. He is also an advisory board member for Amgen and Genzyme. Cengiz Utas has no conflict of interest.
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Accepted in revised form: 22. 8.08
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