EU Regulatory Framework for Biosimilars - Free PDF Download (2023)

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Drug Discovery Today, Volume 17, Digital, January 1/2, 2012

EU biosimilar regulatory framework Paola Minghetti1, Paolo Rocco1, Francesco Cilurzo1, Lucia Del Vecchio2 and Francesco Locatelli2 1 2

Faculty of Pharmaceutical Sciences "P. Pratesi”, Milan, via G. Colombo, 71–20133 Milan, Italy Department of Nephrology, Dialysis and Kidney Transplantation, A. Manzoni Hospital, Via dell'Eremo 9, 23900 Lecco, Italy

In the European Union (EU), the biosimilars regulatory policy allows various biosimilars to be placed on the market through a simplified application, which allows applicants to submit a simplified dossier. However, some producers of biologics that share certain characteristics with the replica have opted for complete presentations, thus increasing the number and scope of clinical trials required in such cases. Here we focus on the comparison of recombinant human erythropoietin pharmaceuticals. We analyze and discuss clinical trials submitted to the European Medicines Agency for biosimilars and biopharmaceuticals available for full documentation authorization. We also discuss interchangeability and substitution, as the EU allows each Member State to develop its own substitution policy.

Introduction The expiry of patents on some of the main biotech drugs (ie monoclonal antibodies and therapeutic proteins) has led to the production of replicas of the innovator's products. After the data protection period has expired, a marketing authorization (MAA) application for a duplicate may be considered as a summary application, with some data available and an acceptable simplified dossier. Therefore, there is a possibility that more copies will hit the market, thus promoting competition in the pharmaceutical industry. Copies of marketing authorizations (MAs) obtained in the European Union (EU) are defined as "similar biopharmaceuticals" or "biosimilars" for which a simplified dossier (described below) is attached to the marketing authorization. Unlike generic medicines, which contain the same active substance (small molecule) as the reference medicine and are bioequivalent through appropriate bioavailability studies, biosimilar medicines have been shown to be similar but not identical to their reference medicine. Its chemical properties are directly related to the manufacturing process and cannot be accurately reproduced due to

Author of correspondence: Minghetti, P. ([email protected]) 1359-6446/06/$ - see home page ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.drudis.2011.08.001

Its complex structure and close relationship between the manufacturing process and the properties of the final product [1]. Moreover, since analytical techniques cannot always detect or predict all biological and clinical properties of proteins, differences between biopharmaceuticals may go unnoticed, and even when detected, subtle differences are difficult to explain [2]. Therefore, the granting of a marketing authorization for biosimilars requires a different approach than that used in the case of original and generic drugs [3]. In Europe, the legal basis for biosimilar medicines is the EU Directive No. 1, which sets out the requirements for a marketing authorization based on the demonstration of similar properties of two biopharmaceuticals, which requires that the amount of clinical and non-clinical data be based on appropriate scientific guidance, as the case may be . Regulation of the European Parliament No. 726/2004 of 2004 establishes a Community procedure for the authorization and supervision of medicines, including biotechnological medicines, which require a centralized procedure. at the same time

1 Article 10 par. 4 and Section 4 of Part II of Annex I to Directive 2001/83/EC as amended by Directive 2007/27/EC.

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Today, biosimilar regulatory policy is largely managed by the European Medicines Agency (EMA) through general guidance on clinical, non-clinical and quality issues, and additional guidance for specific product categories. Here we look at the market in terms of available biosimilars and clinical trials of recombinant human erythropoietin submitted for EMA approval. Understanding the regulatory approach helps you expand your understanding of the drugs on the market and their similarities and differences.

Legal framework for biosimilars MAA In the European Union, technologically advanced drugs, e.g. developed in biotechnological processes (e.g. recombinant DNA technology), Regulation. The same provisions also provide for an alternative procedure whereby clinical data may be omitted in exceptional cases. In addition, centralized procedures may lead to conditional marketing authorizations under Regulation (EC) No. 507/2006. The application must be accompanied by a file containing the required data, presented in a standard format, which is a common technical document (DCT). The CTD consists of five modules: Module 1 contains specific administrative data; Module 2 includes clinical, non-clinical and qualitative summaries; Module 3 contains chemical, pharmaceutical and biological (i.e. quality) information; module 4 contains non-clinical (i.e. safety) reports; Module 5 contains clinical trial reports (i.e. efficacy). 3 MA holders can notify the competent authority of certain changes to the CTD, such as production methods or product specifications, and after a positive assessment, the application can generally be implemented. Where patent rights, SPCs and related data are protected for more than 10 years4 (or 11 years if "a new indication for an established substance has been applied for" if valid pre-clinical or clinical studies are relevant to the new indication"5), requiring other applicants to submit a complete dossier with copies of that particular drug seems unethical and wasteful. Therefore, the scope of the presented data varies. In the case of copies of small molecule chemical entities, the applicant is not required to submit the results of pre-clinical and clinical studies if it can be demonstrated,

2 Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down a Community procedure for the authorization and supervision of medicines for human and veterinary use and establishing a European Medicines Agency, as amended. 3 Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on Community codes relating to medicines for human use, as amended. 4 Article 10 par. 1 of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on Community rules on medicinal products for human use, as amended. 5 Article 10 par. 5 of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on Community codes relating to medicines for human use, as amended.

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With appropriate bioavailability studies, the replica (generic drug) is bioequivalent to the original drug. In the case of generic biopharmaceuticals, since the active substance is similar, but not identical, to the active substance of the originator product, the requirement for marketing authorization is based on demonstrating the similar properties of the two biologics through comparable studies, called 'comparability exercise'. Benchmarking is required to provide evidence that similar new biopharmaceuticals are similar in terms of quality, safety and efficacy to selected reference medicines authorized in the EU [4].

Comparative study The number and scope of comparative studies required for the granting of a marketing authorization are set out in guidelines published by the EMA's Committee for Medicinal Products for Human Use (CHMP). This guidance covers a variety of topics including manufacturing, demonstration of quality comparability (module 3), non-clinical (module 4) and clinical (module 5) reporting, physicochemical and biological analysis, and compliance requirements. as well as additional data. (i.e. toxicological data, other relevant clinical and non-clinical data), the relevance of which should be determined on a case-by-case basis due to the complexity and variety of products. The purpose of the comparison is to demonstrate the similarity of the biosimilar product and the reference product, thereby reducing the amount of data provided in Modules 4 and 5 of the CTD. The U.S. Food and Drug Administration (FDA) introduced the comparison to allow manufacturers of "well-characterized biopharmaceuticals" (i.e. proteins whose identity, purity, impurities, potency, and quantity can be determined and controlled) to make changes to the manufacturing process. . This includes changing the place of production or modifying cell and seed strains or fermentation and purification processes, in most cases without additional clinical trials demonstrating efficacy [5]. In 2000 [6] and 2002 [7] EMA issued two guidelines on the comparability of medicinal products containing biotechnology-derived proteins as active substances, addressing qualitative, non-clinical and clinical issues respectively. Although the title does not say so, these two guidelines clearly address the issue of changes in the production process. Subsequently, EMA expanded the range of products produced by different manufacturers, publishing in 2004 a generic guide to similar biopharmaceutical products [4] and two guides on quality [8] and non-clinical and clinical issues [9] on the scope of comparability. biopharmaceuticals. . Published in 2005 (EMA; http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000086.jsp&murl=menus/regulations/regulations.jsp∣=WC0b01ac 058002754a) . The 2000 and 2002 guidelines were updated in 2003 [10] and 2006 [11] respectively to explicitly refer only to changes in the production process. Additional product category guidelines have been developed for pre-clinical and clinical studies of various therapeutic proteins, providing guidance on relevant pharmacodynamic and toxicology studies (in the non-clinical segment), as well as pharmacodynamics, clinical pharmacokinetics, efficacy and safety (in the non-clinical segment).

clinical part). In the case of biosimilars containing recombinant human erythropoietin, the EMA guidelines [12] have recently been revised based on the experience gained in recent years with licensed products. Of course, the dossier for a biosimilar is more cumbersome than the dossier for a generic product. Both contain complete modules 1, 2 and 3, but for biosimilars, comparative exercises for modules 3, 4 and 5 are required, while for generics, module 4 is omitted and module 5 is replaced by a bioequivalence list. Replaces [13].

Production and sale of biosimilars in the EU For each biosimilar on the market, it is possible to identify: (i) the manufacturer of the biologically active substance; (ii) the manufacturer responsible for batch release; (iii) the marketing authorization holder. The practice of co-marketing is more widespread than in other areas of the pharmaceutical industry due to the complexity of developing and manufacturing biotechnological active ingredients. In fact, in many cases the first two manufacturers listed above are related to the same company for products sold under different brands. The 14 biosimilars currently sold in the EU are listed in Table 1 and discussed below. growth hormone. Omnitrope1 was the first biosimilar medicine in Europe, launched in 2006. It is manufactured and marketed by Sandoz, a unit of Novartis (Novartis was formed in 1996 from the merger of Ciba-Geigy and Sandoz). Valtropin is manufactured by LG Life Sciences and marketed by its partner Biopartners. epoetin. Three erythropoietin products with the same International Nonproprietary Name (INN) (recombinant human erythropoietin

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alpha) is produced by Rentschler Biotechnologie (owned by Dr Rentschler Holding, which sold its subsidiary Rentschler Arzneimittel to Medice). These products are marketed by Sandoz as Binocrit, by its licensor Medice as Abseamed, and by Hexal as Epoetin alfa Hexal. Both epoetin zeta products are manufactured by Norbitec, a joint venture between Stada, Bioceutical and Normark, and jointly marketed by Stada and Hospira. Stada sells its products through a network of commercial companies under various names in Europe, such as Hemofarm (Bosnia-Herzegovina and Romania); Aliud Pharma (Czech Republic); PharmaCoDane (Denmark); EG (France); Responsible for branded products (Italy); Clonmel Healthcare (Ireland); Hemomont (Montenegro); Centerfarm (Netherlands); Ciclum Farma (Portugal); Nizhpharm (Ukraine); and Genus Pharmaceuticals (UK). Not all erythropoietin products manufactured after the first original are biosimilar. For example, Neorecormon is an epoetin beta licensed in 1997, manufactured and marketed by Roche. Biopoin and Eporatio are epoetins thetases that were authorized in 2009. They are manufactured by Merckle Biotec and marketed by CT Arzneimittel and Ratiopharm, respectively. Complete documentation is provided for these products. We then compare clinical trials conducted with biosimilars erythropoietin theta and erythropoietin. Filgrastim. All four filgrastim products are manufactured by Sicor Biotech, a subsidiary of the Teva Group. Two of them are sold by two other Teva subsidiaries: Ratiopharm and CT Arzneimittel. The manufacturer responsible for the launch of all three series of products was Mercle Biotec, a subsidiary of Ratiopharm, which produces biopharmaceutical active substances. Nivestim is manufactured by Hospira in its biopharmaceutical facility in Croatia, acquired in 2009 (with the rights to Nivestim)

table 1

Biosimilars sold in the US drugs

Posada

reference drug

master's degree holder

The manufacturer is responsible for batch release.

manufacturer of the active substance

MA data

powerful

growth hormone

gonadotropiny

Sandoz

Sandoz

Sandoz

4/2006

Vitropin

growth hormone

Humidity

biological partner

biological partner

LG Life Sciences

4/2006

to repeat

erythropoietin zeta

Eprex/Erypo

Hesheng

Herd of cattle

Nobitek

12/2007

Silapo

erythropoietin zeta

Eprex/Erypo

Herd of cattle

Herd of cattle

Nobitek

12/2007

sinking

recombinant human erythropoietin alfa

Eprex/Erypo

doctor

hexagon

Renchler biotechnology

8/2007

In pairs

recombinant human erythropoietin alpha

Eprex/Erypo

Sandoz

hexagon

Renchler biotechnology

8/2007

Epoetina Alfa Seis

recombinant human erythropoietin alpha

Eprex/Erypo

hexagon

hexagon

Renchler biotechnology

8/2007

Biograstim

Filgrastym

Nupsona

Light CT

Merck Biociencias

DRY Biotechnology

9/2008

Proportionate drug to filgrastim

Filgrastym

Nupsona

proportional drug

Merck Biociencias

DRY Biotechnology

9/2008

Thank you very much

Filgrastym

Nupsona

proportional drug

Merck Biociencias

DRY Biotechnology

9/2008

tivagrastim

Filgrastym

Nupsona

Generyki Teva

Teva Pharmaceuticals

DRY Biotechnology

9/2008

Nevistin

Filgrastym

Nupson.

Hesheng

Krakow Swimming

Hospira Zagreb

6/2010

Zatio

Filgrastym

Nupsona

Sandoz

Sandoz

Sandoz

2/2009

Hexagonal filgrastim

Filgrastym

Nupsona

hexagon

Sandoz

Sandoz

2/2009

A

In addition to marketing authorization holders, manufacturers of bioactive substances and finished products are listed to highlight cases of joint marketing. www.drugdiscoverytoday.com

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Drug Discovery Today, Volume 17, Digital, January 1/2, 2012

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Drug Discovery Today, Volume 17, Digital, January 1/2, 2012

From Pliva, Hospira's former filgrastim partner, now part of the Teva Group. The other two are manufactured by Sandoz, either Sandoz or Hexal.

Clinical trials of biosimilars and original products: Epoetin

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Here we compare the clinical trials of erythropoietin biosimilars (HX575, SB309) and the newest parent drugs (Epoetin theta such as Biopoin and/or Eporatio). The case of epoetin is particularly important because the regulatory requirements are stricter than for other recombinant proteins, reflecting its clinical history, in particular the case of pure red cell aplasia (PRCA) reported in 2002 [2]. In particular, similar clinical efficacy should be demonstrated in at least two randomized, preferably double-blind, parallel-group studies, and not in one double-blind study as was the case with somatropin biosimilars and filgrastim. Data should be provided for the intravenous (i.v.) and subcutaneous (s.c.) routes of administration (separate clinical trials for both routes or one clinical trial for one route plus appropriate bridging data for the other [12,14]).

HX575 HX575 (Abseamed1, Binocrit1, epoetin alfa Hexal) was studied in five pharmacokinetic/pharmacodynamic studies in healthy volunteers using intravenous single and multiple dose regimens. or South Carolina (Table 2). These studies showed a similar pharmacokinetic profile to intravenous HX575. and Sc and Eprex1/Erypo1 under steady state conditions. The pharmacodynamic effects of HX575 were investigated in a pharmacokinetic study as recommended in the Guideline for similar biopharmaceuticals containing recombinant erythropoietin. The same intravenous or subcutaneous doses of HX575 and Eprex/Erypo produce similar increases in hemoglobin (Hb) levels in healthy volunteers. A multicenter, double-blind, randomized, parallel-group study (INJ-9) [15] compared intravenous HX575. (n = 314) compared to Eprex/Erypo (n = 164) in hemodialysis patients with anemia secondary to chronic kidney disease (CKD). Confidence Interval (CI) for Mean Change in Intent-to-Treat (ITT) and Per Protocol (PP) Populations

The Hb in the HX575 and Erypo groups was within the established range of 0.5 g/dL. The proportion of patients with Hb in the target range or with dose adjustments during the study was also similar between the two groups. The mean weekly dose of erythropoietin decreased in both treatment groups from baseline to the evaluation period, but more for Eripo than for HX575 [739 IU/week (8.9%) versus 314 IU/week (2.2%) ]. However, this is not sufficient to confirm therapeutic equivalence (safety data are comparable) between Eprex/Erypo and HX575. During the HX575 MAA, epoetin alfa was not administered subcutaneously. Due to the risk of PRCA in CKD patients, it is not possible to conduct a comparative study using this route of administration in CKD patients. Such studies were conducted several years after MA but were discontinued after 1 case of PRCA and 1 positive result of anti-erythropoietin antibodies [16]. The company also presented the results of a non-comparative, controlled study (INJ-11) of 114 cancer patients receiving chemotherapy (40 patients were assigned to Eprex/Erypo as a measure of internal validity)[12]. Response to treatment (defined as an increase in Hb of 2.0 g/dL from baseline) was greater in the HX575 group than in the Eprex/Erypo group, but the study design did not allow for a reliable comparison. Due to the small sample size, therapeutic equivalence between HX 575 and Erypo could not be established by subcutaneous administration, but was considered possible. After these studies, the therapeutic indications for HX575 may overlap with those for Eprex.

SB309 The pharmacokinetics of SB309 (Retacrit1, Silapo1) and the reference product Eripo were compared in two single subcutaneous pharmacokinetic studies in healthy volunteers. and IV administration (Table 3). Preliminary analysis showed less availability of SB309 compared to Eripo; however, this was not confirmed when correcting serum erythropoietin concentrations for total protein content in individual lots. No specific pharmacodynamic studies have been conducted with SB309. In fact, the pharmacodynamics of erythropoietin is known and

Table 2

Pharmacokinetic/pharmacodynamic and clinical studies of the biosimilar product HX 575 (recombinant human erythropoietin alfa), marketed under the study identification codes Abseamed, Binocrit or Epoetin Alfa Hexal

Case number (registered)

reference drug

ruta

main variable

INJ-4 (first stage)

6

Eprex/Erypo

sc/iv

–

INJ-5 (first stage)

76

Eprex/Erypo

iv

–

INJ-6 (first stage)

72

New Raymond

South Carolina

–

INJ-7 (first stage)

6

–

South Carolina

–

INJ-12 (first stage)

74

Eprex/Erypo

South Carolina

–

2003-29-INJ-9 (Basic Phase III)

tests: 314; References: 164

Eripo

iv

Therapeutic equivalency: Mean absolute change in Hb levels between screening and/or baseline and evaluation period in CKD patients on hemodialysis

2003-31-INJ-11 (Support Phase III)

tests: 74; References: 40

Eripo

South Carolina

Absolute Hb increase of 2.0 g/dL between screening and/or baseline and assessment periods in the absence of a red cell transfusion in the last 4 weeks

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Table 3

research identification

Case number (registered)

reference drug

ruta

main variable

411-54-05-05-0000 (Phase 1)

24

Eprex/Erypo

iv 1 dose

–

411-54-03-09-0001 (Phase 1)

48 lat

Eprex/Erypo

SC and 1 IV dose

–

411-54-04-05-0000 (correction phase)

Sample: 305; Reference: 304

Eripo

iv

Weekly dose of epoetin per kg of body weight and Hb concentration during the last 4 weeks of treatment

411-54-04-04-0000 (maintenance phase)

402

Eripo

iv

Intra-individual variation in mean weekly dose per kg body weight and Hb levels for each product during double-blind treatment (reference test)

411-54-04-14-0000 (Additional Maintenance Therapy Study)

745 (patients who have completed the adjustment or maintenance phase of the study)

not applicable

iv

Uncontrolled safety study with focus on erythropoietin antibody formation

441-54-04-46-0000

216

not applicable

South Carolina

An uncontrolled trial of safety in patients with cancer and chemotherapy-induced anemia

literature. Guidelines for similar recombinant erythropoietin drugs recommended that pharmacodynamic studies be mandatory, but these were not available at the time [17]. Intravenous SB309 was compared with the reference medicine in two large studies involving 922 anemic patients on haemodialysis. The first study (411-54-04-05-0000) compared SB309 (n=305) and Eprex/Erypo (n=304) for the treatment of anemia in 609 patients over 24 weeks. During the evaluation period, Hb levels and the proportion of patients successfully treated were comparable in the two groups, but the dose of SB309 was approximately 10% higher than the reference product. The second study (411-54-04-040000) compared SB309 to Eprex/Erypo in maintaining a 1:1 Hb ratio (402 patients). The dose was increased by approximately 10-15% after switching from the reference drug to the study drug and by approximately 10-15% after switching from the study drug to the reference drug. The company also presented the results of a study on the effects of subcutaneous administration of SB309 in 216 cancer patients receiving chemotherapy (411-54-04-46-0000). Renal anemia patients who completed any of the above efficacy studies were eligible to receive SB309 in an uncontrolled safety study that specifically focused on the development of anti-erythropoietin antibodies (411-54-04-14-0000), a total of 745 patients. saved [17]. After this study, in February 2010, EMA approved SB309 for patients with chronic kidney disease via the subcutaneous route, so the indications for treatment can almost coincide with those of Eprex.

Biopoin/Eporatio Unlike HX575 and SB309, Biopoin and Eporatio are not biosimilars but have been authorized with a full application. Marketing authorization holders must submit complete Modules 4 and 5. For Biopoin/Eporatio (epoetin theta), the company was granted a marketing authorization in 2009, provided six phase I pharmacodynamic/pharmacokinetic studies (Table 4), six phase II/III studies supporting the study

Indication of anemia in patients with chronic kidney disease and three phase III studies supporting the indication for the treatment of anemia in patients with cancer. For CKD, four independent studies involving 841 patients were conducted to demonstrate the efficacy and safety of subcutaneously administered epoetin theta. and intravenous administration in the corrective and maintenance phases. The first was to demonstrate a dose-dependent mean weekly increase in Hb using a constant dose. As expected, changes in Hb were significantly greater in the group with the highest amount of epoetin theta (120 IU/kg) than in the group with the lowest amount (20 IU/kg). In the maintenance phase study comparing epoetin theta to epoetin beta, mean Hb values ​​over the evaluation period remained similar in the two treatment arms and within the acceptable range of the selected delta, indicating non-inferiority of epoetin theta to epoetin. beta Three phase III trials were also conducted with 586 cancer patients receiving chemotherapy [18]. Based on the data presented, the approved therapeutic indications are limited to adult patients and for the treatment of: (i) symptomatic anemia in adult patients with chronic renal failure; (ii) symptomatic anemia in adult patients with non-myeloid cancer receiving chemotherapy.

Clinical experience with epoetin and epoetin theta biosimilars Perhaps the main reason for prescribing biosimilars today is their lower price. In fact, these molecules should have similar efficacy and safety profiles as their inventors, but without the potential advantages of the newer molecules (i.e. less frequent dosing and dose equivalency between the subcutaneous and intravenous route of administration). second or third generation erythropoiesis stimulating agents [ESA; such as darbepoetin alfa or continuous erythropoietin receptor activators (CERA)] may be relevant to the hemodialysis patient as patients regularly attend treatment 3 times a week. However, from the point of view of nurses, some benefits are appreciated, such as reducing their burden and increasing the frequency of injections (risk management), avoiding possible s.c. www.drugdiscoverytoday.com

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Pharmacokinetic/pharmacodynamic and clinical studies of the biosimilar SB 309 (Epoetin zeta) marketed as Retacrit or Silapo

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Drug Discovery Today, Volume 17, Digital, January 1/2, 2012

Table 4

Pharmacokinetic/Pharmacodynamic and clinical trial identification codes supporting the therapeutic indications of the breakthrough product Biopoin/Eporatio (epoetin theta)

Diagnosis and item numbers

ruta

design and control

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XM01-12 (Phase I)

healthy (18)

South Carolina 3 doses

Open, random, 3-way crossover

XM01-20 (Phase I)

healthy (40)

South Carolina 1 dose

Parallel, randomized, double-blind, placebo-controlled group

XM01-01 (Phase I)

End-stage renal failure (18)

iv 1 dose; 2 doses subcutaneously

open, sequential

XM01-11 (Phase I)

End-stage renal failure (14)

iv 7 doses in 2 weeks

open single

XM01-10 (Phase I)

Chronic renal failure (14)

South Carolina 7 doses in 2 weeks

open single

XM01-24 (Phase I)

Non-myeloid cancers (14)

South Carolina 3 doses over 3 weeks

open single

XM01-04 (Phase II), calibration phase study

Anemia associated with chronic renal failure not on dialysis (133)

South Carolina

Multicenter, randomized, controlled, double-blind, multinational, parallel group; five XM01-05 titration arms and one epoetin beta arm

XM01-05 (Phase II), calibration phase study

Anemia associated with chronic renal failure on hemodialysis (150)

iv

Multinational, multicenter, randomized, controlled, double-blind, parallel group; four XM01-05 titration arms and one epoetin beta arm

XM01-06 (Phase III), maintenance phase study

Anemia associated with chronic renal failure not yet on dialysis (240; 159 Epoetin theta and 81 Epoetin beta)

South Carolina

Multinational, Multicenter, Randomized, Controlled, Double-Blind, Comparative, Parallel Groups, 2:1 Randomization Ratio

XM01-07 (Phase III), maintenance phase study

Anemia associated with chronic renal failure on hemodialysis (224; 150 epoetin theta and 74 epoetin beta)

iv

Multinational, Multicenter, Randomized, Controlled, Double-Blind, Comparative, Parallel Groups, 2:1 Randomization Ratio

XM01-08 (Phase III)

Anemia associated with chronic renal failure not yet on dialysis (289)

South Carolina

Open-label, multinational, multicenter, randomized, parallel group, follow-up XM01-04 and XM01-06

XM01-09 (Phase III)

Anemia associated with chronic renal failure on hemodialysis (124)

iv

Open, supranational, multicenter, continuation of XM01-05

XM01-21 (Phase III)

Solid tumor patients receiving platinum-based chemotherapy with an Hb level of 11 g/dL (223)

South Carolina

Multinational, Multicenter, Randomized, Placebo-Controlled, Active, Double-Blind, Parallel Group Study

XM01-22 (Phase III)

Patients with solid tumors or non-myeloid haematological malignancies receiving non-platinum chemotherapy with Hb 11 g/dl (186)

South Carolina

Multicenter, randomized, placebo-controlled, double-blind, multinational, parallel-group study

XM01-23 (Phase III)

Patients with low-grade non-Hodgkin's lymphoma, chronic lymphocytic leukemia or multiple myeloma with endogenous erythropoietin deficiency and receiving anticancer therapy with Hb 10 g/dl (corrected to 11 g/dl) (177)

South Carolina

Multicenter, randomized, placebo-controlled, double-blind, multinational, parallel-group study

For economic reasons and from the hospital's perspective, the organizational burden (e.g. rescheduling, need for large refrigeration space, etc.) should be reduced to manage the potential risk of contamination. These benefits become even more important in patients with chronic kidney disease who are not on dialysis, patients on peritoneal dialysis or transplant recipients who are self-administered by subcutaneous injection. routes are more likely. In these patients, less frequent treatment may be a real advantage, reducing the perception of disease, possibly increasing safety, and reducing the possibility of breaking the cold chain of ESA maintenance, thereby preserving 68

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ESA stability, especially after subcutaneous administration In fact, second- and third-generation ESAs are more stable at room temperature than short-acting ESAs. These aspects should reduce the likelihood that biosimilars (and short-acting erythropoietin in general) will be prescribed to these patients in the future (of course, price differences can play an important role in decision-making). Considering the use of the sc route of administration, these patients are at higher risk of immunogenicity after ESA administration. Even SB309 can be administered intravenously at the same time. and South Carolina, only large post-marketing studies can fully reassure clinicians about the safety of biosimilars in relation to the risk of developing PRCA.

Depending on the country, biosimilar epoetins may have an economic advantage over their originals. The situation is similar with epoetin theta, although it has not undergone the simplified registration process for biosimilars, but has been submitted to the EMA with complete documentation as the originator (hence higher expenditure on clinical development). However, companies selling epoetin alfa and beta have lowered their prices to stay competitive with biosimilars. The same thing happened with darbepoetin alfa and CERA. Also, when a single large organization (such as a hospital or local healthcare organization) buys a large quantity of drugs after a tender, official prices can vary significantly. The equivalence of drug potency should also be taken into account. Just because a biosimilar drug was found to be comparable to the parent drug in a small study conducted for the EMA registry does not necessarily mean that exactly the same dose will produce a similar effect. In practice, the acceptable range of therapeutic equivalence is wide (Hb 0.5-0.6 g/dl; dose 14 IU/kg/week). Small differences in doses between patients can translate into large differences in costs on a large scale. In one dialysis center, 18 patients treated with various ESAs were switched to epoetin zeta [19]. After a 6-month follow-up, no significant changes in Hb concentration were observed (11.72 ± 0.64 g/dl vs. 11.62 ± 0.70 g/dl; p = 0.64). Similarly, the change in the mean weekly ESA dose was not statistically significant (from 5890 ± 4740 IU to 6890 ± 5312 IU; p = 0.56). However, this percentage dose increase of almost 20% can become statistically significant in larger samples and can be economically significant. Considering the negative trend also in Hb values, the erythropoietin resistance index (i.e. ESA dose to Hb ratio) may be statistically significant, but unfortunately this information was missing in this study. In turn, Brinks et al. [20] recently compared the quality of four different erythropoietins, two parent products: alpha-erythropoietin (Eprex1) and delta erythropoietin, and two biosimilars: HX575 and erythropoietin zeta. They found that the biosimilars were of the same or even better quality than the original drug. Surprisingly, epoetin alfa (Eprex) was 129% more potent than stated on the package label. Taken together, these considerations make it difficult to economically assess the potential cost savings from biosimilar products entering the EU market, in addition to the obvious positive impact of lowering the price of all EEE available on the market. Despite potentially lower prices, the distribution of biosimilars on the EU market remains limited. There may be several explanations for this hesitation. The first is the possible risk of inducing PRCA with molecules that have not been used on a large scale. Secondly, the lower cost will be balanced against the potential advantages of second or third generation ESAs. For the first time in the field of anemia, nephrologists are faced with the problem of having new drugs with the same properties as those introduced into clinical practice more than 20 years ago. Finally, transferring patients from one ESA to another may increase immunogenicity and reduce the likelihood of identifying the culprit of the immune response. This is the main reason why the automatic substitution of branded drugs with biosimilars is widely considered unacceptable. Public administrations can introduce automatic substitution at the issuing level

Comment

Based on interchangeability and related to administrative procedures that may be implemented differently in different Member States. Rather, interchangeability is due to therapeutic equivalence and is related to the intrinsic properties of the drug. The parent drug and its biosimilar (or a biosimilar from another manufacturer) are not interchangeable because bioequivalence cannot be used to demonstrate therapeutic equivalence and the active ingredients are similar but not identical in both products. Same as [13]. Historically, clinicians have mainly prescribed erythropoietin biosimilars only to hemodialysis patients who have not previously undergone ESA. In order to expand the use of biosimilars and reduce the cost of treating patients with chronic kidney disease, many Italian hospitals and local health organizations have adopted policies that make all types of ESAs available by internal prescription, but require doctors to prescribe biosimilars in all cases. patients who require medical treatment with ESAnaive Generic. Others buy and prescribe only biosimilars. However, this approach is problematic as physicians should be responsible for prescribing drugs to their patients and therefore should be responsible for assessing the cost-benefit ratio for each patient.

Conclusion Biosimilars are the status quo on the EU pharmaceutical market. The situation is complicated by the evolution of regulatory policy, mainly based on guidance issued by the EMA and updated periodically to reflect lessons learned. In addition, pharmaceutical companies can submit a specific molecule with biosimilar properties as a new application (providing complete documentation) or as an abbreviated application, further complicating the concept of "biosimilarity". Of course, in the latter case, the authorization procedure requires less time and is more financially burdensome for the applicant as it requires fewer clinical trials. A comparison of the number and extent of studies required for the various erythropoietin MAAs clearly shows the shift from a short to a full application. Companies applying for Biopoin/Eporatio have to provide more studies, although when it comes to sponsors, the number of subjects involved in one study is usually smaller because no comparison is made. Biopoin/Eporatio conducted six phase I studies in healthy volunteers and patients, and for two biosimilars, five (HX575) or two (SB309) phase I studies in healthy volunteers. The sponsor conducted nine Phase II/III studies in conjunction with two comparator studies HX575 and four comparator studies SB309 (including two uncontrolled safety studies). It is therefore clear that a biosimilar approach can save a lot of time where appropriate. Manufacturers of reference and biosimilar medicines often make changes to the manufacturing process not only during development but also after approval. These changes may cause the quality profile to evolve over the product's life cycle, so that the conclusions of a benchmarking exercise at a given point in time may not be applicable to the entire life cycle [21]. The practical impact of these changes on products on the market needs to be assessed and new comparative tests may be required when biotech active ingredients show significant changes. www.drugdiscoverytoday.com

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Moreover, different products may cause different adverse events, especially those related to immunogenicity, which requires specific pharmacovigilance rules. For example, a large post-marketing observational study of HX575 in hemodialysis patients was recently planned [22]. The final theme is substitution and interchangeability, where the term "substitution" refers to automatic substitution at the dispensing level without affecting the freedom of physicians to change the prescription according to their knowledge and clinical experience.

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Data itself. Substitution should not be allowed without the knowledge of doctors and patients because, in addition to clinical concerns, it can lead to difficulties in controlling the safety of products that threaten pharmacovigilance programmes.

Conflict of Interest FL is on the advisory boards of the security committees of Affymax, Amgen-Dompe, Jansen, GSK, Roche, Takeda and Sandoz.

References 1 Genazzani, A.A. et al. (2007) Biosimilars: Concerns and Opportunities. BioDrugs 21, 351–356 2 Schellekens, H. (2009) Biosimilars: what should we consider? NDTPlus. (Suppl 1), i27–i36 3 Minghetti, P. (1996) Regulatory status of medicines for human use in the European Union and the role of generic medicines. Pharmacodynamics. tank. 34, 3-7 4 European Medicines Agency. (2005) Guidelines for similar biomedical products, EMA (CHMP/437/04) 5 US Food and Drug Administration (1996). Demonstration of the comparability of biologics for humans, including therapeutic biotechnological derivatives. FDA 6 European Medicines Agency. (2001) Comparability Guidelines for Medicinal Products Containing Biotechnologically Derived Proteins as Active Substances: Quality Issues, EMA (CPMP/BWP/3207/00) 7 European Medicines Agency. (2003) Guidelines on the comparability of medicinal products containing proteins of biotechnology origin as active substances: clinical and non-clinical considerations, EMA (CPMP/3097/02) 8 European Medicines Agency. (2006) Guidelines for similar biopharmaceutical products containing proteins of biotech origin as active ingredients. Quality issues, EMA (CHMP/BWP/49348/05) 9 European Medicines Agency. (2006) Guidelines for similar biopharmaceutical products containing proteins of biotech origin as active ingredients. Non-clinical and clinical considerations, EMA (CHMP/BMWP/42832/05) 10 European Medicines Agency (2004). Comparability of biotech/biological products with regard to quality changes during manufacture, EMA (CPMP/ICH/5721/03) 11 European Medicines Agency (2006). Guidelines for the comparability of medicines derived from biotechnology after manufacturing changes

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Process: non-clinical and clinical questions. EMA (CHMP/BMWP/101695/2006) European Medicines Agency (2008). Guidelines for the clinical and non-clinical development of similar biopharmaceutical products containing recombinant erythropoietin. EMA (EMEA/CHMP/BWMP/301636/2008) Minghetti, P. et al. (2010) Biosimilar Products and Regulatory Agencies. clinical nephron. practice. 117, C1–C7 Schellekens, H. (2009) The case of Retacrit1. drug discovery. Today 14, 495–499 European Medicines Agency (2007) Abseamed, Binocrit, Epoetin alfa Hexal, European Public Assessment Report Schellekens, H. (2009) Biosimilars: the long and winding road to clinical equivalence. Hospital. medicine. EUR. European Medicines Agency. (2008) Retacrit, Silapo. European Public Assessment Report European Medicines Agency. (2009) Biopoin, Eporatio, European Public Assessment Report Lonnemann, G. and Wrenger, E. (2011) Biosimilar epoetin zeta in nephrology: a single-dialysis center experience. Clinical. Adrenalin. 75, 59–62 Brinks, V. et al. (2011), Quality of original and biosimilar products containing epoetin. medicine. tank. 28, 386–389 European Medicines Agency, (2010) Concept paper for the revision of the guidelines for similar biomedical products containing proteins of biotechnology origin as active substances: quality issues. EMA (EMA/CHMP/BWP/617111/2010) Gesualdo, L. et al. (2011) A pharmacoepidemiological study of multilevel determinants, predictors and clinical outcomes of treatment with biosimilar epoetin alfa in the treatment of renal anemia in hemodialysis patients: background and methods of the MONITORCKD5 study. internal. To appear. medicine. 10.1007/s11739-011-0622-7