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WHO EML 2016-2017 - Erythropoietin-stimulating agents December 2016

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WHO EML 2016-2017 - Application for erythropoietin-stimulating agents

(erythropoietin type blood factors)

Version 3, 23 December 2016

Report prepared by: Rita Banzi1 and Chiara Gerardi1 and revised by Vittorio Bertele’1, Silvio

Garattini,2 Arrigo Schieppati3,4

1Laboratory of Drug Regulatory Policies IRCCS- Istituto di Ricerche Farmacologiche "Mario

Negri", Milan, Italy.

2Directorate IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri"

3International Relations, Office of Rare Diseases IRCCS- Istituto di Ricerche Farmacologiche

"Mario Negri", Bergamo, Italy.

4Rare Disease Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy.

Executive Summary

Anemia is one of the several complications of chronic kidney disease, with an overall

prevalence of about 15% in the United States. More than 50% of patients with advanced

disease develop anemia. We advocate the inclusion of erythropoietin-stimulating agents in the

WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for

Children since they have been proved to reduce the need for transfusions in patients with

end-stage chronic kidney disease, thus avoiding the risks related to transfusions and the

necessary consumptions of blood units, the costs related to the facilities required, and those

related to the management of possible harms (viral, infections, hemosiderosis, etc.). The

application also includes biosimilars of epoetin alfa, that are currently licensed in several

countries worldwide. The cumulative clinical experience with biosimilars has confirmed that

their efficacy and safety profile is in line with that of the reference product. Their inclusion in

the drug market is expected to ensure cost-savings for health systems. The inclusion of

epoetins in the EML¸ with a square box indicating their therapeutic equivalence, could also

help lower their price by facilitating procurement mechanisms, such as tenders, so as to

facilitate their adoption also in disadvantaged settings where they would be hard to afford.


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Contents

Executive Summary .................................................................................................................................................... 1

1. Summary statement of the proposal for inclusion, change or deletion ............................................ 3

2. Name of the WHO technical department and focal point supporting the application ................ 3

3. Name of organization(s) consulted and/or supporting the application ........................................... 3

4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine .................................................................................................................................................. 3

INN ..................................................................................................................................................................... 3 ATC .................................................................................................................................................................... 3

5. Formulation(s) and strength(s) proposed for inclusion (adult and pediatric) .............................. 4

6. Whether listing is requested as an individual medicine or as representative of a class. ........... 6

7. Treatment details (requirements for diagnosis, treatment and monitoring) ................................ 6

Diagnosis ......................................................................................................................................................... 6 Treatment ....................................................................................................................................................... 8 Monitoring ...................................................................................................................................................... 9

8. Information supporting the public health relevance ............................................................................ 10

Epidemiological information on disease burden........................................................................... 10 Assessment of current use and target population ........................................................................ 11 Likely impact of treatment on the disease ....................................................................................... 11

9. Review of benefits: summary of comparative effectiveness in a variety of clinical settings . 12

Identification of clinical evidence ........................................................................................................ 12 Summary of available data ..................................................................................................................... 15

Adults ......................................................................................................................................................... 15 Children .................................................................................................................................................... 19

10. Review of harms and toxicity: summary of evidence on safety ...................................................... 21

11. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group. ................................................................................................ 22

12. Summary of regulatory status of the medicines ................................................................................... 28

13. Availability of pharmacopoeia standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia) ...................................... 31

14. References ........................................................................................................................................................... 32

15. Appendices .......................................................................................................................................................... 37

Appendix 1: Summary of findings tables .............................................................................................. 37

Appendix 2: List of RCTs and references* in the Summary of Findings tables ...................... 44


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1. Summary statement of the proposal for inclusion, change or deletion

Anemia is one of the most serious complications of chronic kidney disease and end-stage

renal disease. The current application requests the inclusion of erythropoietin-stimulating

agents (ESA) in the WHO Model List of Essential Medicines (EML) and Model List of Essential

Medicines for Children (EMLc) for the treatment of anemia in children, young people and

adult patients with end-stage renal disease requiring dialysis.

2. Name of the WHO technical department and focal point supporting the application

Management of non-communicable diseases. Dr. Cherian Varghese ([email protected])

3. Name of organization(s) consulted and/or supporting the application

IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", Italy.

4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical

(ATC) code of the medicine

INN

This application pertains to erythropoietin-type blood factors. The common stem for these

factors is -poetin. A Greek letter is used to differentiate compounds with the same amino acid

sequence but different glycosylation patterns (such as human erythropoietin). INNs with

different amino acid sequences are named using the -poetin stem and a random prefix.

Source: www.who.int/medicines/services/inn/BioRevforweb.pdf

ATC

In the ATC classification system, ESAs are classified as “Other antianemic preparations

(B03XA)”. This category contains four active substances:

B03XA01: erythropoietin

B03XA02: darbepoetin alfa

B03XA03: methoxy polyethylene glycol-epoetin beta

B03XA04: peginesatide (not included in this application, see Section 6)

Source: http://www.whocc.no/atc_ddd_index/


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5. Formulation(s) and strength(s) proposed for inclusion (adult and pediatric)

ESAs are available as a solution for intravenous or subcutaneous injection. The Kidney

Disease Improving Global Outcomes (KDIGO) group recommends either intravenous or

subcutaneous injection in patients undergoing hemodialysis and those on hemofiltration or

hemodiafiltration therapy. In the outpatient setting, subcutaneous injection is the only

routinely feasible route of administration for patients with CKD stage 3–5 or on peritoneal

dialysis.

Table 1 reports the dosing for treating anemia of chronic kidney disease in adults and

pediatric patients with end-stage renal disease undergoing dialysis. Correction phase refers to

the doses needed to reach a target hemoglobin (Hb) level of 11-12 g/dL (see also Section 7 for

Hb targets). Maintenance phase refers to the doses to keep the target Hb level stable (KDIGO

2012, KDIGO 2013).

WHO EML 2016-2017 - Erythropoietin-stimulating agents November 2016

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Table 1. Adapted from Dynamed Plus (DynaMed Plus 2016)

Drug Adult dosing Pediatric dosing Notes

Epoetin alfa and biosimilars

50 to 100 units/kg - three times per week 50 units/kg - three times per week Biosimilars include epoetin alfa and

zeta

Epoetin beta* Correction phase: 40 units/kg - three times per week Maintenance phase: half the previous dose

Correction phase: 40 units/kg - three times per week Maintenance phase: half the previous dose

Maximum dose: 720 units/kg per week

Epoetin theta*

Correction phase: 20 units/kg SC or 40 units/kg IV - three times per week Maintenance phase: 25% dose adjustments to maintain Hb target (10 - 12 g/dL)

Not established

Titration: may be increased to 40 units/kg SC or 80 units/kg IV three

times per week Maximum dose: 700 units/kg/week

Darbepoetin alfa

Epoetin alfa naive patients Correction phase: 0.45 mcg/kg IV (preferred route) or SC once weekly or 0.75 mcg/kg IV or SC once every two weeks as needed Switch from epoetin alfa Dose based on the weekly epoetin alfa dose (maintain the same route of administration) Refer to labeling information for conversion dosages

Epoetin alfa naive patients Initial: 0.45 mcg/kg IV (recommended) or SC once weekly Switch from epoetin alfa Dose based on the weekly epoetin alfa dose (maintain the same route of administration)

Titration: adjust dosage once every four weeks.

Methoxy polyethylene

glycol-epoetin beta

ESA naïve patients Correction phase: 0.6 mcg/kg as a single IV (preferred route) or SC injection once every two weeks Maintenance phase: double the dose used in the initial phase IV (preferred route) or SC once monthly Refer to labeling information for conversion dosages

Not established

Safety and efficacy not established in pediatric patients (European

pediatric investigation plan ongoing)

*not licensed in the United States. SC: subcutaneous; IV: intravenous; target Hb levels 11-12 g/dL in adults and 12 g/dL in pediatric patients (KDIGO 2013)


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6. Whether listing is requested as an individual medicine or as representative of a class.

This application covers erythropoietin-type blood factors, also called erythropoiesis-

stimulating agents (ESAs), including branded medicinal products and biosimilars. Specifically,

it refers to:

epoetin alfa and its biosimilars (epoetin alfa and zeta)

epoetin beta

epoetin theta

darbepoetin alfa

methoxy polyethylene glycol-epoetin beta (CERA)

All epoetins in clinical use have a similar amino acid sequence as endogenous erythropoietin

but differ in the glycosylation pattern. Glycosylation influences pharmacokinetics and may

affect efficacy and safety including immunogenicity. Currently, biosimilars of epoetin alfa are

licensed in several countries including Europe (Covic 2015). The patents on darbepoetin

(Aranesp) will expire in Europe in 2016 and in the US in 2024 (GaBI 2014).

This proposal does not include peginesatide because of the safety concerns reported post-

marketing, including serious hypersensitivity reactions such as anaphylaxis, which may be

life-threatening or fatal. In 2013, the FDA recalled all lots of injectable peginesatide (Omontys)

due to 19 reports of anaphylaxis after the first dose (including three deaths) in patients

receiving dialysis (FDA 2013).

7. Treatment details (requirements for diagnosis, treatment and monitoring)

Diagnosis

Chronic kidney disease is defined as the presence of kidney damage (usually detected as

urinary albumin excretion ≥30 mg/day, or equivalent) or reduced kidney function (defined as

estimated glomerular filtration rate [GFR] <60 mL/min/1.73 m2) for three or more months,

irrespective of the cause. The damage or reduced function must persist for at least three

months to distinguish chronic from acute kidney disease.

The prognosis of chronic kidney disease and the need for renal replacement therapy (either

dialysis or kidney transplant) depend on the following variables: 1) cause of chronic kidney


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disease; 2) GFR category; 3) albuminuria category; 4) other risk factors and comorbid

conditions (e.g. hypertension, hyperglycemia, dyslipidemia, smoking, obesity, history of

cardiovascular disease) (Figure 1). End-stage renal disease refers to people with stage 5

chronic kidney disease undergoing dialysis, and recipients of kidney transplant. The KDIGO

initiative recommends beginning dialysis as soon as life-threatening changes occur in fluid,

electrolyte, and acid-base balance. These usually happen when GFR is 5-10 mL/min/1.73 m2.

Specifically, starting dialysis is suggested when at least one of the following occurs:

signs or symptoms of renal failure, such as serositis, acid-base or electrolyte

abnormalities, pruritus;

inability to control volume status;

inability to control blood pressure;

malnutrition not responsive to dietary interventions;

cognitive impairment.

Figure 1. Prognosis of chronic kidney disease (CKD) by GFR and albuminuria category (from KDIGO 2012).

Anemia is one of the most serious complications of chronic kidney disease and end-stage

renal disease. Normochromic normocytic anemia is mainly due to erythropoietin deficiency

which itself is principally caused by reduced renal erythropoietin production, presumably

reflecting the reduction in the number of erythropoietin-producing cells in the kidneys. To a


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lesser degree, it is caused by the shortened red cell lifespan. Erythropoietin is the hormone

responsible for maintaining the proliferation and differentiation of erythroid progenitor cells

in the bone marrow. Renal anemia can thus be regarded as a hormone deficiency state.

Anemia can develop well before the appearance of uremic symptoms due to renal failure. It

usually starts when glomerular filtration falls to <60 mL/min/1.73 m2. If the estimated GFR is

≥ 60 mL/min/1.73 m2, anemia is likely to be due to other causes. To identify anemia in

people with GFR less than 30 mL/min/1.73 m2 (GFR categories G4-G5) Hb is usually

measured at least twice a year (NICE 2015, KDIGO 2012).

According to the World Health Organization anemia is to be diagnosed when Hb falls below

(WHO 2011):

13 g/dL (130 g/L) in men ≥ 15 years old;

12 g/dL (120 g/L) in nonpregnant women ≥ 15 years old or adolescents aged 12-14

years;

11.5 g/dL (115 g/L) in children aged 5-11 years;

11 g/dL (110 g/L) in pregnant women, or children aged 6-59 months.

If left untreated, anemia in chronic kidney disease may cause deterioration in cardiac

function, poor cognition and mental acuity, and fatigue. There are also associations with an

increased risk of morbidity and mortality, principally due to cardiac disease and stroke (NICE

2015).

Treatment

The initial evaluation of anemia is generally the same for chronic kidney disease patients as in

the general population and includes red blood cell count, reticulocyte count, serum iron, total

iron-binding capacity, percent transferrin saturation, serum ferritin, serum folate and vitamin

B12, and testing for occult blood in stool. Before starting ESA therapy all correctable causes of

anemia (including iron deficiency and inflammatory states) should be addressed.

ESA dosing

In the opinion of the Work Group KDOQI Clinical Practice Guidelines and Clinical Practice

Recommendations for Anemia in Chronic Kidney Disease (KDOQI 2006):


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the initial ESA dose and ESA dose adjustments should be based on the patient’s Hb level,

the target Hb, the observed rate of increase in Hb level, and clinical circumstances;

ESA doses should be reduced, but not necessarily withheld, when a downward

adjustment of Hb is needed;

scheduled ESA doses that have been missed should be replaced at the earliest possible

opportunity.

Below, we report the dosages recommended by the KDIGO Clinical Practice Guideline for

Anemia in Chronic Kidney Disease, Kidney International Supplements (KDIGO 2012).

Initiation

In adult patients with Stage 5 chronic kidney disease, ESA therapy is recommended to prevent

Hb falling below 9 g/dL (90 g/L). ESA therapy should be started when Hb is between 9-10

g/dL (90-100 g/L).

In children with chronic kidney disease, the decision to start ESA therapy needs to be

individualized, based on the balance of potential benefits (improvement in quality of life,

school attendance or performance, or avoiding transfusion) and potential harms.

Maintenance

In adults with chronic kidney disease, Hb should not exceed 11.5 g/dL (115 g/L) during ESA

therapy. Dose adjustment may be necessary as in some patients quality of life can only

improve at Hb levels higher than this. In any case, ESAs should not be used intentionally to

raise the Hb above 13 g/dL (130 g/L).

In pediatric chronic kidney disease patients receiving ESA therapy, the Hb target should be in

the range of 11.0 to 12.0 g/dL.

Monitoring

ESAs are critical components in managing anemia in chronic kidney disease. All those

currently available are effective in achieving and maintaining target Hb levels. Aspects of

administration may differ between short-acting and long-acting agents. Hb should be

monitored at least monthly in adults and pediatric patients treated with ESAs (KDOQI 2006).


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8. Information supporting the public health relevance

Epidemiological information on disease burden

Chronic kidney disease is a worldwide public health issue defined as abnormalities of kidney

structure or function, present for more than three months, with clinically relevant proteinuria,

hematuria, and/or structural kidney disease with or without estimated GFR <60

mL/min/1.73 m². It affects approximately 8-16% of the adult population worldwide (Jha

2013). The overall lifetime incidence of chronic kidney disease rises with age, with

approximately 50% of Stage 3a+ incidents occurred after age 70 years. The overall lifetime

incidence of end-stage renal disease has been estimated at 3.6% (Grams 2013). The incidence

and prevalence of chronic kidney disease seem remarkably consistent globally, though not

always well documented, whereas the distribution of those receiving renal replacement

therapies (dialysis and transplantation) varies by country. About 2.2 million people receive

dialysis globally, projected to be 5.4 million by 2030 (Global burden of CKD 2016).

Anemia is one of the several complications of chronic kidney disease. Its prevalence (from any

cause) in patients with renal failure is about 15% in the United States (Stauffer 2014). Table 2

shows the prevalence of anemia by stage of chronic kidney disease.

Table 2. Prevalence of anemia by stage of chronic kidney disease (CKD). Adapted from Stauffer 2014.

CKD Stage Prevalence of anemia (%)

Stage 1 8.4

Stage 2 12.2

Stage 3 17.4

Stage 4 50.3

Stage 5 53.4

The main impact of anemia on organ function is reduced oxygen delivery to tissues, leading to

debilitating symptoms such as fatigue, exercise intolerance, impaired cognitive function, sleep

disorder, altered hemostasis, and depressed immune function. Anemia in patients with

chronic kidney disease is associated with decreases in cardiac and renal functions, quality of

life, and poses a significant clinical and economic burden on healthcare systems. Anemia is

also associated with a high prevalence of cardiovascular diseases in renal patients, and their

consequent higher morbidity and mortality. Cardiovascular diseases are reported to account


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for more than 50% of deaths in these patients (Macdougall 2007). In children iron deficiency

and Hb lower than 11.8 g/dL (118 g/L) have also been associated with impairment in

cognition (Halterman 2001).

Assessment of current use and target population

The primary therapeutic options for anemia in chronic kidney disease include red blood cell

transfusions, ESAs, and, to a much lesser extent, androgens. Iron supplementation is another

important component of anemia management.

The first-generation ESAs were human recombinant erythropoietins (epoetin alfa and epoetin

beta) and have now been in clinical use for nearly 20 years. Although these agents have been

very effective, their frequent dosing regimen of up to three times per week pushed the

development of ESA agents with longer half-life, hence lower dosing frequency. This was done

by increasing either the receptor affinity of the erythropoietin molecule through changes in its

amino acid sequence (darbepoetin alfa) or the glycosylation pattern by addition of a pegylated

moiety (continuous erythropoietin receptor agonist [CERA]). The dosing schedules of once-

weekly or once every two weeks with darbepoetin and monthly dosing with CERA potentially

offer many advantages to both patients and caregivers (Bennet 2012). However, the impact of

this advantage should be considered in the light of the frequency of dialysis, which for most

patients is three times a week.

Likely impact of treatment on the disease

ESAs accelerate erythropoiesis, increase iron utilization and raise Hb, with clinical

improvement in signs and symptoms of anemia. ESA requirements are hard to predict in

individual patients, and may be higher in people with associated comorbidities including

cardiovascular diseases, diabetes and chronic inflammation. ESA requirements are generally

lower in patients not undergoing dialysis. ESA therapy aims to raise Hb levels slowly at a rate

of < 1-2 g/dL per month during the correction phase. This is done to avoid major side effects

including hypertension, vascular access thrombosis and cardiovascular events. A major issue

in ESA use relates to the Hb target. Recent systematic reviews have suggested that aiming at

Hb levels similar to those in healthy adults involves a significantly higher risk of all-cause

mortality (Palmer 2010, Hahn 2014).


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9. Review of benefits: summary of comparative effectiveness in a variety of clinical

settings

Identification of clinical evidence

In this application, we summarize the evidence on the effectiveness and safety of ESAs,

including branded medicinal products and biosimilars, for the treatment of anemia in end-

stage renal disease. Specifically, we sought evidence on adults and children with anemia due

to stage 5 chronic kidney disease undergoing dialysis.

We included up-to-date systematic reviews of randomized controlled trials (RCTs) and other

types of evidence syntheses (e.g. health technology assessment [HTA] reports, clinical

guidelines if developed following a systematic approach) and pharmacoeconomics analyses

comparing erythropoietins (epoetin alfa, beta, theta, zeta), darbepoetin alfa, and CERA to:

no intervention, placebo, standard care;

other ESAs;

other interventions (e.g., iron supplementation, androgen);

different dosages and administration schedules of the same ESA;

branded Vs. biosimilar products.

To retrieve this evidence, we searched MedLine, EMBASE, and The Cochrane Library up to

November 2016, using the search strategies reported in Table 3. We also searched in the main

HTA body websites, such as The National Institute for Health and Care Excellence (NICE,

https://www.nice.org.uk/), Canadian Agency for Drugs and Technologies in Health (CADTH,

https://www.cadth.ca/), Agency for Healthcare Research & Quality (AHQR,

http://www.ahrq.gov/), Haute Autorité de Santé (HAS, http://www.has-

sante.fr/portail/jcms/r_1455081/en/home-page?portal=r_1455081), Institute for Quality

and Efficiency in Health Care IQWiG, https://www.iqwig.de/en/home.2724.html), New

Zealand Health Technology Assessment (NZHTA, http://nzhta.chmeds.ac.nz/). To retrieve

recent evidence not included in these evidence synthesis reports, we adapted the search

strategy reported in Table 3 to seek RCTs published in 2015 and 2016.


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Table 3: Search strategies applied to this review

Medline

((((erythropoietin OR epoetin alpha OR epoetin beta OR darbepoetin alpha OR EPO OR methoxy polyethylene glycol epoetin beta OR "Epoetin Alfa"[Mesh] OR "Erythropoietin"[Mesh] OR "epoetin beta"[Supplementary Concept]) OR "continuous erythropoietin receptor activator"[Supplementary Concept]) AND (end stage renal disease OR chronic renal failure OR "Renal Insufficiency, Chronic"[Mesh] OR "Renal Insufficiency, Chronic"))) Filters: Meta-Analysis; Systematic Reviews

Embase

((end-stage renal disease'/exp OR 'end-stage renal disease' OR 'chronic renal failure'/exp OR 'chronic renal failure' OR 'chronic kidney failure'/exp OR 'chronic kidney failure' OR 'renal insufficiency, chronic'/exp OR 'renal insufficiency, chronic') AND ('erythropoietin'/exp OR 'erythropoietin' OR 'epoetin alpha' OR 'epoetin beta'/exp OR 'epoetin beta' OR 'darbepoetin alpha'/exp OR 'darbepoetin alpha' OR epo OR 'methoxy polyethylene glycol epoetin beta'/exp OR 'methoxy polyethylene glycol epoetin beta' OR 'continuous erythropoietin receptor activator'/exp OR 'continuous erythropoietin receptor activator')) AND [embase]/lim ('meta-analysis'/de OR 'systematic review'/de)

The Cochrane Library

((MeSH descriptor: [Renal Insufficiency, Chronic] explode all trees)OR (chronic renal disease OR renal insufficiency OR kidney failure)) AND ((MeSH descriptor: [Erythropoietin] explode all trees) OR (erythropoietin OR darbepoetin OR methoxy polyethylene glycol-epoetin))

Our search strategies retrieved 319 publications, after discarding duplicates. We retrieved

three additional reports from websites. One author screened titles and abstracts to exclude

any clearly irrelevant records and selected 47 records for full-text review. This selection was

checked by a second reviewer to reduce the possibility of misclassification. After analysis of

the full texts by two reviewers, 20 reports were considered eligible. Any discrepancies were

resolved by discussion. At this stage, the papers excluded were narrative or out-of-date

(superseded) reviews, reviews not including patients on dialysis, or papers describing other

study designs (Figure 2).


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Figure 2. Flow chart of the studies included in the review. Date of last database searches November 22, 2016.

At the end of this process we included eight systematic reviews (Arlind 2016, Collister 2016,

Coronado Daza 2015, Hahn 2014, Palmer 2014-NM, Palmer 2014-darbe, Palmer 2010,

Wilhelm-Leen 2015), three clinical guidelines (KDIGO 2013, KDOQI 2006, NICE 2015), two

HTA reports (All Wales Medicines Strategy Group 2009, CADTH 2009), five cost-analyses

(described in section 11), one RCT published in 2015 not included in the evidence synthesis

reports (Al-Ali 2015) and one meta-regression study (Koulouridis 2013)

Records identified through database search

(MedLine: 221; Embase: 54; Cochrane Library: 101)

Additional records identified through other sources

(3)

Records after duplicates removed (322)

Records screened (322)

Records excluded (275)

Full-text articles assessed for

eligibility (47)

Full-text articles excluded, with reasons (27)

Narrative review (3) Out of date/Included in more

up-to-date reviews (11) No data on patients on

dialysis (3) No outcome of interest (1) No full text (2) Other (7)

Studies included in qualitative synthesis (20)

Systematic reviews (8) Guidelines (3) HTA reports (2) Cost-analyses (5) RCTs not included in

systematic review (1) Other (1)


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We focused our analyses on the following outcomes which comprise measures of possible

benefits and harms of the treatment.

All-cause mortality

Major adverse cardiovascular events (including fatal or nonfatal myocardial infarction,

stroke, vascular access thrombosis)

Quality of life

Blood transfusions

Hemoglobin levels

Hypertension

Vascular access thrombosis

Immunogenic potential (risk of developing anti-drug antibodies).

Summary of available data

Adults

In all, five systematic reviews provided useful information to support the possible benefits

and harms of the treatment of anemia in patients with end-stage renal disease (Palmer 2014-

NM, Palmer 2014-darbe, Hahn 2014, Wilhelm-Leen 2015, Collister 2016). We summarized the

main findings as well as the certainty of the evidence supporting them, in four Summary of

Findings (Appendix 1), prepared according to the GRADE approach for assessment of

evidence quality and strength of recommendations (GRADE 2016).

The main source of information was the network meta-analysis published in 2014 by Palmer

and co-workers, that summarizes 56 studies published between 1989 and 2013 for a total of

15,596 participants. This review compared the efficacy and safety of ESAs (epoetin alfa,

epoetin beta, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta, and biosimilar

ESAs, against each other, placebo, or no treatment) to treat anemia in adults with any stage of

chronic kidney disease. We therefore analyzed the studies included in this review and

selected those pertaining to participants undergoing dialysis (27). We also considered

additional studies from three other reviews (Wilhelm-Leen 2015, Palmer 2014-darbe, Hahn

2014). The RCT published in 2015 and not included in the evidence synthesis reports (Al-Ali

2015) was not combined with other studies as it reported only Hb levels (total 327 patients,


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no difference in Hb between the epoetin group, darbepoetin and CERA). Appendix 2 lists the

studies used to prepare the following Summary of Findings tables.

Epoetin alfa and beta Vs. placebo/no treatment/standard care (Summary of Findings 1)

The evidence collected suggests that there are no differences in all-cause mortality and major

cardiovascular events (stroke, myocardial infarction) presumably because of a paucity of data

on these outcomes. Epoetin alfa and beta consistently reduced the risk of requiring blood

transfusions. Epoetin alfa and beta do not appear to affect the risk of vascular access

thrombosis but increase the risk of hypertension. The quality of evidence was judged as low

for all-cause mortality, major cardiovascular events, and vascular access thrombosis because

of the unclear risk of selection bias and the imprecision of the estimates. The effect of epoetin

alfa and beta in reducing the number of blood transfusions and increasing risk of

hypertension was supported by high-quality evidence. However unclear, the risk of selection

bias appears negligible in the light of the magnitude of these effects. These results seem to be

consistent between industry-sponsored and other sponsorship trials (data not shown).

Darbepoetin Vs. other ESAs (epoetin alfa and beta, CERA) (Summary of Findings 2)

There is no evidence of a difference between darbepoetin and other ESAs (epoetin alfa, beta,

CERA) in terms of all-cause mortality, major cardiovascular events (stroke, myocardial

infarction), hypertension, vascular access thrombosis and Hb levels. The evidence collected

suggests that darbepoetin reduces the risk of requiring blood transfusions compared to

epoetin alfa but not to CERA. The quality of evidence was judged very low to moderate mainly

because of the unclear risk of selection bias, the imprecision of the estimates and the

suspicion of selective reporting of outcomes. Noteworthy, the benefit of darbepoetin in

reducing blood transfusions was supported by high-quality evidence. These results were

largely driven by industry-sponsored trials.

CERA Vs. epoetin alfa and beta (Summary of Findings 3)

CERA appears to be similar to epoetin alfa and beta in terms of all the outcomes evaluated.

However, the quality of evidence supporting these findings was judged very low and low

because of the unclear risk of selection bias, the imprecision of the estimates and the


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suspicion of selective reporting of outcomes. These results were largely driven by industry-

sponsored trials.

Originators (epoetin alfa) Vs. biosimilars (Summary of Findings 4)

We found no differences between the originator epoetin alfa and its biosimilars in terms of

all-cause mortality, major cardiovascular events (stroke, myocardial infarction), blood

transfusions, and vascular access thrombosis. The risk of hypertension seemed lower with

biosimilars. The quality of evidence was generally judged as low because of the unclear risk of

selection bias and the imprecision of the estimates, with the exception of the findings on

hypertension supported by evidence of moderate quality due to unclear risk of selection bias

only. These results appear to be consistent between industry-sponsored and other

sponsorship trials (data not shown).

Quality of life

Summary of Findings 1-4 do not include data on quality of life of patients treated with ESAs

because the systematic reviews described in the previous sections did not report this

outcome. A systematic review updated to November 2015 specifically assessed the effect of

achieving higher Hb targets on quality of life of patients with chronic kidney disease, including

those undergoing dialysis (Collister 2016). Of the 17 studies considered, 12 were in the

nondialysis population, four in the dialysis population, and one in a combined sample. In all,

the review showed that higher versus lower Hb targets resulted in only small and, in many

cases, non-significant changes in scores of several health-related quality of life tools, both in

the overall population and in the 2433 patients undergoing dialysis. In the latter subgroup,

differences in physical functioning, vitality, and social functioning measured as components of

SF-36 were 1.65 (95% CI −7.22 to 10.52), −1.73 (95% CI −13.95 to 10.49), and −0.70 (95% CI

−21.19 to 19.79) respectively. Differences were not statistically significant in the subgroup

analysis including only studies with low risk of bias.

Immunogenic potential (risk of developing anti-drug antibodies)

As shown in Summary of Findings 4 biosimilars appear substantially equivalent to epoetin

alfa in terms of Hb response and requirements for blood transfusion. The quality of evidence


18

supporting these findings is generally low. There are some concerns about the different

potential risk for developing drug-associated antibodies, especially regarding the

interchangeability and switching from originators to biosimilars. These concerns were

addressed in a comprehensive systematic review by the Swedish Council of Health

Technology Assessment of immunological reactions induced by treatment with biosimilar

ESAs in patients with chronic kidney disease (Arnlind 2016). The primary questions in the

systematic review were:

how great is the risk of developing drug-associated antibodies?

what are the clinical implications of the development of drug-associated antibodies

(e.g. aplasia—pure red cell aplasia, PRCA)? Is PRCA reversible?

how often does drug-associated antibodies against ESA lead to therapy resistance?

what are the immunological and clinical consequences when switching between

products?

are there any known risk factors for drug-associated antibodies in the use of ESA?

is antibody development more common for subcutaneous than intravenous injection?

are there differences in Hb response and the need for blood transfusion between the

original ESA preparations and biosimilars?

does the presence of drug-associated antibodies and neutralizing antibodies inhibit the

biological effect of the drug?

The review included 14 RCTs and seven observational studies. Fourteen studies involved

patients with end-stage renal disease undergoing dialysis. None of these studies indicated any

important difference in efficacy between the original product and its biosimilar. Drug-

associated antibodies were found in six of the 14 RCTs and six of the seven observational

studies. However, the authors noted that inadequate and non-validated analytical methods

were applied. No data were available on the clinical implications and reversibility of drug-

associated antibodies and induction of resistance, and no data could demonstrate

immunological and clinical consequences when switching between products.

In conclusion, ESAs are effective in correcting the anemia of end-stage renal disease in

patients on dialysis especially in terms of reducing the number of blood transfusions. All ESAs,

including biosimilars, appears to have similar benefit/harm profiles.


19

Although the benefits of ESA for dialysis patients have been demonstrated, it remains unclear

whether the new, longer-acting ESAs given less frequently offer the same efficacy and safety

as older ESAs. A Cochrane systematic review updated in 2013 (Hahn 2014) sought to

establish the optimal frequency of ESA administration in terms of:

1. effectiveness (correction of anemia, and freedom from adverse events);

2. efficiency (optimal resource use) of different ESA dose regimens.

The review included 33 studies involving 5526 participants and concluded that longer-acting

ESA (darbepoetin and CERA) given at one to four-week intervals were non-inferior to ESA

given one to three times/week in terms of achieving Hb targets, without any significant

differences in adverse events in hemodialysis patients.

It is generally known that targeting higher Hb levels in chronic kidney disease raises the risks

for stroke, hypertension, and vascular access thrombosis and probably increases the risks of

death, serious cardiovascular events, and end-stage renal disease (Palmer 2010). A systematic

review with meta-regression of RCTs of ESAs in patients with chronic kidney disease

examined whether a gradient of doses was associated with these potential harms, adjusting

for the target or achieved Hb level (Koulouridis 2013). The authors identified an association

between the first three month and total study period mean ESA dose and all-cause mortality,

both in unadjusted models and models adjusting for target Hb. When restricting the analyses

to dialysis patients, the association persisted in both the unadjusted and adjusted analyses.

The lack of adjustment for other factors such as comorbidities and inflammatory markers, as

well as inadequate control for treatment-by-indication bias and ecological fallacy are to be

acknowledged as limitations of this meta-regression analysis. In any case, these findings

support the widely accepted use of more conservative dosing regimens for the treatment of

patients with chronic kidney disease.

A Cochrane systematic review found no evidence to assess the benefits and harms of early

versus delayed ESAs for the treatment of anemia in end-stage renal disease (Coronado-Daza

2015).

Children

Although children, from birth through adolescence, differ substantially from adults, providers

caring for adult and pediatric patients with chronic kidney disease largely share the same

concerns regarding the diagnosis and management of anemia. As generally the evidence in


20

children is scarce and of low quality, one has unavoidably to generalize from evidence in

adults. The review by Palmer et al. of 2010 identified two RCTs in children with end-stage

renal disease (Morris 1993, Brandt 1999) and one additional study was included in the review

by Palmer et al. 2014 on darbepoetin (Warady 2006). Brandt reported a RCT comparing

different dosages of epoetins in 44 pre-dialysis and dialysis children aged 4 months to 21

years. Transfusion requirements and panel-reactive antibody levels decreased during the 12-

week study period. Iron deficiency and/or hypertension occurred in 30% of children. Morris

compared ESA therapy (target Hb >10 g/dL) or placebo in a blinded crossover trial of 11

children aged between 2.3 and 12.3 years, undergoing peritoneal or hemodialysis. ESA

therapy was associated with partial correction of an elevated cardiac index by six months and

a significant reduction in left ventricular mass by 12 months.

Additional information can be found in the Clinical Practice Guidelines and Clinical Practice

Recommendations for Anemia in Chronic Kidney Disease issued by the National Kidney

Foundation, which include non-randomized studies and data from registries (KDOQI 2006).

The most robust evidence for using ESA products in children is related to erythropoietin alfa

and beta, with some preliminary data on darbepoetin. In children with chronic kidney disease

stages 4 and 5, darbepoetin alfa compared to epoetin had uncertain effects on the need for

blood transfusion and risk of progression to renal replacement therapy, all-cause mortality,

hypertension, dialysis vascular access thrombosis, exceeding Hb target level and injection site

pain, as well as Hb levels during treatment (Palmer 2014-darbe).

Children in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)

database from 1992 to 2001 with Hb lower than 9.9 g/dL compared with those with Hb more

than 9.9 g/dL had a high risk for mortality (adjusted relative risk, 1.52; 95% confidence

interval [CI], 1.03 to 2.26). Patients with more severe anemia also had an increased risk of

hospitalization.

In a multicenter single-arm interventional trial evaluating 22 children with chronic kidney

disease (4 months to 16 years) treatment of anemia with recombinant erythropoietin was

associated with a significant increase in intelligence quotient, although the relative increase in

Hb levels was small (Hb baseline, 9.2 ± 1.6 versus final, 9.7 ± 1.7 g/dL) (Burke 1995 and

KDOQI 2006).


21

10. Review of harms and toxicity: summary of evidence on safety

The main data on the cardiovascular safety of ESAs in patients with chronic kidney disease are

summarized in Section 9, where the benefit/harm profile is estimated and discussed. The

main safety concern linked to the use of ESAs in patients with chronic kidney disease is

increases in the risk of death, myocardial infarction, stroke, and other serious cardiovascular

events. This is related to ESA doses targeting Hb of 11 g/dL and above. No trial has identified a

Hb target level, ESA dose, or dosing strategy that does not raise these risks. Therefore, the

lowest effective dose is recommended (FDA 2007).

All proprietary ESAs raised the odds of hypertension compared to placebo, while the effect of

biosimilar ESAs on hypertension was less certain (Palmer 2014-NM). In dialysis patients there

might be a risk of adverse events due to access thrombosis. Thus, anticoagulation with

heparin may be required to prevent clotting in the extracorporeal circuit during hemodialysis.

Other safety concerns

Since 2000, cases of PRCA and severe anemia, with or without cytopenia, associated with

neutralizing antibodies to erythropoietin, were reported in Europe and in the United States,

primarily in patients with chronic kidney disease given the drug by subcutaneous injection.

This was probably due to the interaction of polysorbate 80 (that substituted the human serum

albumin as stabilizing agent) with the uncoated rubber stopper of the pre-filled syringes. In

2002 authorities in Europe, Australia, Singapore, and Canada mandated the intravenous route

in hemodialysis patients and the manufacturers added teflon coating to prefilled syringes of

epoetin alfa (Eprex) that led to a decrease in the number of PRCA cases (McKoy 2008). By

2003 180 Eprex associated PRCAs were identified in Europe, Canada, Australia, and Asia,

despite improvements in handling. Since 2002 FDA safety databases include information on

59 new cases of antibody-associated PRCA. These findings prompted the FDA to issue a

warning in all the proprietary ESAs (Aranesp, Epogen and Procrit) (FDA 2005). A large

multinational, non-interventional, immunogenicity surveillance registry funded by Janssen

and Johnson & Johnson collected data on more than 15,000 adults with chronic kidney disease

receiving or about to initiate subcutaneous Eprex, epoetin beta (NeoRecormon) or

darbepoetin (Aranesp) for anemia and followed for up to three years (Macdougall 2015).

Unexplained loss or lack of effect was reported in 23 patients, five of whom with confirmed

PRCA. Based on time of exposure, PRCA incidence was 35.8/100000 patient-years (95% CI 7.4


22

to 104.7) for Eprex, 14.0/100 000 patient-years (95% CI 1.7 to 50.6) for NeoRecormon and

Aranesp. No cases of PRCA emerged from the clinical development of Retacrit and Binocrit,

two biosimilars of epoetin alfa. However, sudden loss of efficacy and confirmed cases of PRCA

were reported in a cluster of 23 Thai patients receiving regionally manufactured

subcutaneous epoetin not approved in Europe (Wish 2014, Praditpornsilpa 2011).

High doses of erythropoietin may be associated with nephrogenic fibrosing dermopathy

(Swaminathan 2006).

The cumulative clinical experience with biosimilars has confirmed that their safety profile is

in line with that of the reference products in terms of cardiovascular and thromboembolic

events and immunogenicity data. In general, the known safety profile of ESAs as a class can be

extended to biosimilars (Covic 2015).

11. Summary of available data on comparative cost and cost-effectiveness within the

pharmacological class or therapeutic group.

The search strategy described in section 9 identified five cost-analyses. Four of them

(Ferguson 2015, Thaweethamcharoen 2014, Jordan 2012, Schmid 2014) and two HTA reports

(All Wales Medicines Strategy Group 2009, CADTH 2009) form the basis of the evidence

reported below.

A fairly recent systematic review summarizes the studies aimed at evaluating the cost-

effectiveness of ESAs in patients with kidney failure on dialysis (up to June 2013). The

primary endpoint was the incremental cost–effectiveness ratio (ICER) of ESA dosages for

different hemoglobin targets compared with either red blood cell transfusion (RBCT), lower

hemoglobin targets or no ESA therapy. The ICER was calculated as cost per quality-adjusted

life-year (QALY), price referred to US dollars (2012). The review included seven cost-utility

analyses employing a Markov process, four conducted in North America, three in Europe. All

adopted the health care payer perspective and included efficacy data mainly from registries

and databases. ICERs varied across the studies; substantial variability was evident in the

estimates of the cost-effectiveness of using ESAs in the dialysis population.

Three studies evaluated different Hb targets and showed that reaching higher Hb is not a cost-

effective strategy, with mortality, hospitalization, and utility estimates as major drivers of

costs. Reported cost/QALY ratios ranged from US dollars 931 to 677,749/QALY across five

studies comparing ESAs to red blood cell transfusions (Table 4).


23

Table 4: Cost-utility analyses included in the review by Ferguson et al. (Adapted from Ferguson 2015).

Author, year

Country Population Treatment

target (g/dL) Comparator ICER (cost/QALY)

Clement 2010

Canada Adult (>16

years); CORR and AKDN

Hb 9.0-10.9 Hb 11.0-12.0

Hb >12.0 RBCT

Low: USD 107822/QALY Intermediate: extended dominance

High: dominated

Glenngard 2008 Sweden

SDDB and SRAU Hb 11.0-13.0 RBCT

HD patients: USD 90455/QALY PD patients: USD 41025/QALY

Leese 1992

multiple multiple Treatment target not reported

RBCT

Germany: USD 193730 France: USD 173.271 Spain: USD 677749 Italy: USD 224626

UK: USD 341722 (adverse events not included)

Naci 2012 USA USRDS Hb 10.0-12.0

RBCT USD 931

Remake 2003 UK

UK general registry

Treatment target not reported

RBCT USD 35343/QALY

AKDN: Alberta Kidney Disease Network; COOR: Canadian Organ Replacement Register; HD: hemodialysis; PD: peritoneal

dialyisis; RBCT: Renal Blood Cell Transfusion; SDDB: Swedish Dialysis DataBase; SRAU: Swedish Register for Active Uremia

care USRDS: United States Renal Data System.

One cost-utility analysis evaluated the cost-effectiveness of epoetins for different Hb targets in

end-stage renal disease patients in Thailand (Thaweethamcharoen 2014). This study applied

a Markov model and adopted a societal perspective. Efficacy data were collected from

systematic reviews and costs estimated from in-hospital reference prices and as income lost

because of sick leave or hospital visits. The results were in line with the findings from

Ferguson et al. When the initial Hb levels in hemodialysis patients were lower than 9 g/dL,

providing epoetins in order to reach Hb 10 to 11g/dL was less costly and more effective than

higher or lower Hb levels. Epoetin targeting Hb higher than 10 to 11 g/dL yielded an

incremental cost per QALY of about US dollars 18,800. A Canadian health technology

assessment found similar results. A Hb target of 11 g/dL gave the largest QALY benefit

(incremental cost of Canadian dollars 25,000) compared with lower target Hb (CADTH 2009).

One retrospective study conducted in Canadian dialysis centers on the relative utilization and

cost of ESAs in patients switched from epoetin to darbepoetin showed that the median dose-

conversion ratio for each hemodialysis center ranged from 288:1 to 400:1 and the average

annual per-patient saving ranged from US dollars 2140 to 4711. The authors concluded that

switching patients from epoetin to darbepoetin maintained clinical benefits while


24

considerably reducing costs. The study was conducted by independent researchers with an

unrestricted grant from the darbepoetin producer (Jordan 2012).

Another systematic review examined whether once-monthly CERA gave better cost-

effectiveness or even cost saving compared to other ESAs. The review included 18 studies and

findings were contradictory, some demonstrating an increase of costs associated with CERA

and others a cost reduction (Schmid 2014). An HTA report from Wales also assessed the

cost/benefit ratio of CERA in three separate patient groups: dialysis patients switched from an

alternative ESA, ESA-naïve dialysis patients, and ESA-naïve non-dialysis patients. In each

group, the overall costs of treatment with intravenous CERA were lower than with other ESAs.

In dialysis patients, CERA was estimated to be less expensive in terms of both drug

administration costs and drug acquisition costs, with the exception of intravenous epoetin alfa

which had a lower drug acquisition cost than CERA in dialysis patients switched from an

alternative ESA (switch/dialysis patients). It is uncertain to what extent these analyses

adequately reflect the use of ESAs in peritoneal or hemodialysis patients in whom the

subcutaneous route is preferred. Table 5 reports estimates of budget impact for CERA instead

of epoetin alfa in dialysis patients (All Wales Medicines Strategy Group 2009).

Table 5. Adapted from All Wales Medicines Strategy Group 2009

Year 2009 2010 2011 2012 2013 No. dialysis patients 1,192 1,252 1,314 1,380 1,449

Drug cost versus epoetin alfa (£) +373,144 +391,801 +411,391 +431,960 +453,558

Administration costs versus epoetin alfa (£)

-452,626 -475,258 -499,020 -523,971 -550,170

Net cost impact (£) -79,483 -83,457 -87,630 -92,011 -96,612

Additional data on prices of ESAs were retrieved from Management Sciences for Health (MSH)

International Drug Price Indicator Guide 2015 classification (Table 6).


25

Table 6. Erythropoietin Buyer Prices 2014

Epoetin alfa, 2000 IU vial

Source Package Package price (US Dollars) Unit price

OECS/PPS 6 syringe (1 VIAL) 6.40 1.0667/vial

PERU 1 vial 1.15 1.1479/vial

SICA 1 vial 2.54 2.5400/vial

SAFRICA 1 vial 4.39 4.3850/vial

Median price 1.8440/vial ↓51% Highest price 4.3850/vial

Lowest price 1.0667/vial High/low ratio 4.11

Epoetin alfa, 4000 IU vial


OECS/PPS 6 syringe (1 vial) 7.95 1.3250/vial

DOMREPUB 1 syringe (1 vial) 2.96 2.9600 /vial

SAFRICA 1 vial 6.56 6.5629 /vial

PERU 1 vial 7.06 7.0640 /vial

SUDANNHIF 1 vial 17.08 17.0794 /vial

Median price 6.5629/vial ↓9% Highest price 17.0794/vial

Lowest price 1.3250/vial High/low Ratio 12.89

Epoetin beta, 50,000 IU vial


CRSS 1 vial 149.60 149.6000 /vial

The median percentage price difference is compared to the previous year. OECS/PPS: Organisation of Eastern Caribbean

States; SICA: The System of Central American Integration; CRSS: Caja Costarricense de Seguro Social; DOMREPUB:

PROMESE/CAL, Dominican Republic; SUDANNHIF: The National Health Insurance Fund of Sudan, SAFRICA: South Africa

Department of Health

Source: http://erc.msh.org/mainpage.cfm?file=1.0.htm&module=DMP&language=English

We also report examples of prices of ESAs in different countries. For Italy, data were retrieved

from CODIFA (www.codifa.it, subscription required); for the other countries (Australia,

Jordan, Indonesia, Portugal, Sweden, South Africa) data were provided by WHO (Table 7).


26

Table 7. ESA prices (2015-2016)

Active substance

Commercial name

Country Dosage

(IU*) Unit

Price per unit in USD

Notes

Epoetin alfa

Binocrit Italy 4000 PFS 35.6 Ex-factory price

Eprex Italy 4000 PFS 34.5 Ex-factory price

Not stated Australia 4000 Vial 53

DPMQ - price for dispensing the maximum quantity of a product incorporating ex-manufacturer price, all fees, mark-ups and

patient contributions

Hemapo 3000 Indonesia 3000 PFS 9.6 Procurement price for the DKI Jakarta province

Binocrit Jordan 4000 PFS

31.8

Pre-Tax Hospital Unit Price

Epokine Jordan 4000 Vial 29.3 Pre-Tax Hospital Unit Price

Eprex Jordan 4000 PFS 39.2

Pre-Tax Hospital Unit Price

Eprex Portugal 4000 PFS 15.3 Max retail price at pharmacy

Binocrit Sweden 4000 PFS 38.4 Retail Unit Price in USD

36.8 Wholesale Unit Price

Eprex South Africa

4000 PFS 66.6

Retail Unit Price in USD

Epoetin theta

Eporatio Italy 4000 PFS 35.6 Ex-factory price

Eporatio Sweden 4000 PFS 19.9 Retail Unit Price in USD

18.6 Wholesale Unit Price

Epoetin zeta Retacrit Italy 4000 PFS 35.6 Ex-factory price


27

Retacrit Sweden 4000 PFS 105.27 Retail Unit Price in USD

101 Wholesale Unit Price in USD

Epoetin beta

NeoRecormon Italy 4000

PFS 32.4 Ex-factory price

Not stated Australia 4000 Not stated 50.5 DPMQ - price for dispensing the maximum quantity of a product

incorporating ex-manufacturer price, all fees, mark-ups and patient contributions

NeoRecormon Sweden 4000 PFS 42.4 Retail Unit Price in USD

40.6 Wholesale Unit Price in USD

Recormon Indonesia 2000 PFS 10.4 Procurement Unit Price

Recormon Jordan 5000 Vial 84.6 Pre-Tax Hospital Unit Price

Recormon South Africa

4000 PFS 26.6 Retail Unit Price in USD

Darbepoetin Aranesp Italy 40 PFS 81.7 Ex-factory price

CERA Mircera Italy 100 PFS 212.5 Ex-factory price

CERA: Methoxy polyethylene glycol-epoetin beta, *Darbepoetin and CERA dosages are expressed in mcg, PFS: Pre-filled syringe. USD: United States dollar


28

It is expected that the introduction of biosimilars of epoetin has an impact on prices and drug

market. Price differences between biosimilars and originators has been broadly estimated

between 10 and 34%, although current evidence is limited (Farfan-Portet 2014).

An estimate of biosimilar-related savings from 2007 to 2020 in eight European countries

(Germany, France, UK, Italy, Spain, Sweden, Poland and Romania) was provided by Haustein

et al in a report supported by Sandoz Pharmaceuticals (Haustein 2012). On the basis of the

data provided by IMS Health, this paper evaluated how biosimilars can help reducing

healthcare expenditure over the long term, through the increased use of biosimilars rather

than originators. The analysis applied a multi-step process to evaluate the cost savings

through different scenarios. The first step was aimed to estimate the future consumption of

each drug in each country in daily defined dosage (DDD) until the year 2020. Two approaches

were applied: the first one was based on the theoretical medical requirement for the

respective country estimated from the existing epidemiological literature (‘top-down’); the

second implied an update of the current volume development using growth rates over the

observed time period (‘bottom-up’). The second step was the modelling of mean

reimbursement prices for each drug adopting the manufacturers’ selling prices (data from

IMS Health), and other information about the healthcare systems in each country. The

estimated cumulative saving for biosimilar epoietins was 9.4 to 11.2 billion of Euro, subject to

the expected market share trend. The expected savings amount to 21.4 to 25.5% of the 43.8

billion Euro estimated expenditure without the market entry of biosimilars.

Cost-saving should be weighted and evaluated considering the different penetration of

biosimilars in different countries. IMS Data up to 2011 showed the overall biosimilar sales are

still a relatively small segment of the European market, but have a strong annual growth.

Considering epoetins, the highest uptake was reported in Germany, Greece and Sweden

(European Commission 2013).

12. Summary of regulatory status of the medicines

ESAs are licensed globally with the following indication: “Treatment of symptomatic anemia

associated with chronic kidney disease”. Table 8 reports the regulatory status in Australia,

Canada, European Union and US with specific information on the pediatric indication.


29

Table 8: Regulatory status in Australia, Canada, European Union and United States

Active substance Australia Canada European Union

(EU) United States

Pediatric indication

Epoetin alfa and biosimilars

Eprex Biosimilar-

epoetin lambda: Novicrit

Eprex

Eprex Biosimilar-epoetin alfa:

Abseamed, Binocrit, Epoetin alfa Hexal Biosimilar-epoetin

zeta: Retacrit, Silapo, Epobel

Epogen, Procrit

1 month and older on dialysis (FDA)

pediatric population (EU, Canada,

Australia)

Epoetin beta NeoRecormon Not

approved NeoRecormon

Not approved

Pediatric population including premature

infants (EU)

Epoetin theta Not approved Not

approved Biopoin, Eporatio,

EpoTheta Teva Not

approved Not approved in pediatrics (EU)

Darbepoetin alfa Aranesp Aranesp Aranesp Aranesp

1 month and older on dialysis (FDA)

pediatric population (EU)

Methoxy polyethylene

glycol-epoetin beta

Mircera Mircera Mircera Mircera Not approved in

pediatrics

Source: European Medicines Agency (www.ema.europa.eu); Food and Drug Administration

(http://www.accessdata.fda.gov), Health Canada http://www.hc-sc.gc.ca/dhp

mps/prodpharma/databasdon/index-eng.php), Therapeutic Goods Administration (https://www.tga.gov.au/),

Drugs.com (www.drugs.com)

With the expiry of patent protection for epoetin alfa in Europe in 2007, biosimilar

erythropoietins (e.g. epoetin alfa [Binocrit, Abseamed, Epoetin alfa Hexal], epoetin zeta

[Retacrit], [Silapo]) were introduced on the market (Covic 2015). Darbepoetin alfa ‘similar

biologic’ drugs (Actorise, Cresp, Darbatitor) are available in India (GaBI 2014). It has to be

noted that they have been approved following regulatory processes that are considered not as

stringent as those of the European Union and United States. To be licensed in the latter

countries, a new epoetin claimed to be similar to a reference marketed product needs to

undergo a proper comparability exercise, i.e. the head-to-head comparison to establish

similarity in quality, safety, and efficacy (World Health Organization 2009). Biosimilarity is to

be demonstrated along a drug development pipeline that involves comparisons in terms of

physicochemical, biological and immunological properties, pharmacokinetics and

pharmacodynamics, preclinical and confirmatory clinical data. General guidelines for the

approval of biosimilars have been developed or drafted in several countries (Heinemann


30

2015). The first set of guidelines on biosimilars were published in 2005 and revised in 2014

by the European Medicines Agency (European Medicines Agency 2005 and 2014). In 2010 the

European agency issued a specific guideline on the non-clinical and clinical data requirements

for demonstration of comparability of two epoetin-containing medicinal products (European

Medicines Agency 2010). The clinical program should include pharmacokinetic studies for

each route of administration, usually in healthy volunteers, assessing also pharmacodynamics

parameters and comparative clinical efficacy studies. These are preferably double-blind trials

in patients with renal anemia and without major complications, aimed to establish clinical

equivalence in terms of ‘Hb responder (or maintenance) rate’ (proportion of patients

achieving or maintaining a pre-specified Hb target) or ‘change in Hb level’. If change from

baseline in Hb is used as the primary endpoint, an equivalence margin of ± 0.5 g/dL is

recommended. Transfusion requirements should be included as an important secondary

endpoint. Comparative safety data from the efficacy trials are usually sufficient to provide an

adequate premarketing safety database. Comparative immunogenicity data will always be

required for subcutaneous use, if applied for. The risk management plan should particularly

focus on rare serious adverse events such as immune mediated PRCA and tumor-promoting

potential. Besides the provision of direct evidence, the approval of biosimilars also relies on

extrapolation of information and conclusions available from studies in one or more subgroups

of the patient population (source population), or in related conditions or on related medicinal

products, to make inferences for another subgroup of the population (target population),

condition or product (European Medicines Agency 2012).

In the US, guidance on biosimilar product development were developed later than in Europe.

However, a similar regulatory framework, defined by three FDA guidance documents (FDA

2009, FDA 2012a, FDA 2012b), applies. In 2015 the Chinese FDA also established regulatory

pathway for the development of copies of biological drugs

(www.cde.org.cn/zdyz.do?method=largePage&id=212).

The stringent regulatory criteria and the need for providing a comprehensive data package

have often been claimed as putting an unnecessary burden (and cost) on the development and

licensing, thus leading to delay in the access to biosimilars. On the other hand, these criteria

are meant to provide a sufficient level of evidence and extrapolation to reduce patients and

health care professionals’ concerns about the use of biosimilars. Still, the adoption of such


31

criteria is matter of debate in clinical practice, with particular regard to the acceptability of

switching from a reference drug to its biosimilars. However, pre-marketing trials and, above

all, post-marketing drug-utilization data helped consolidating not only the therapeutic

equivalence of the two products, but also the safety of switching from reference to biosimilar

products (D’Amore 2016, Ebbers 2012, Wiecek 2010).

13. Availability of pharmacopoeia standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia)

The medicinal products included in the present application are mentioned in the following

pharmacopoeia:

The British Pharmacopoeia: Erythropoietin concentrated solution, Erythropoietin for

injection (Edition 2015)

The United States Pharmacopoeia: Erythropoietin bioassay (Edition 2015)

The European Pharmacopoeia: Erythropoietin concentrated solution (8th Edition 2014)

ESAs are not mentioned in the International Pharmacopoeia - Fifth Edition, 2015

http://apps.who.int/phint/alt/index.html#search


32

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developing anti-drug antibodies-a systematic review. Eur J Clin Pharmacol 2016;72:1161–69.

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37

15. Appendices

Appendix 1: Summary of findings tables

GRADE Working Group grades of evidence

High quality: We are very confident that the true effect lies close to that of the estimate of the effect

Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but

there is a possibility that it is substantially different

Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect

Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the

estimate of effect


38

Summary of findings 1: Epoetin alfa or beta compared to placebo/no treatment/standard care for the anaemia of end-stage kidney disease in dialysis patients

Patient or population: dialysis patients with anaemia of end-stage kidney disease Intervention: epoetin alfa or beta Comparison: placebo/no treatment/standard care

Outcomes Anticipated absolute effects* (95% CI) Relative effect (95% CI)

No. of participants (studies)

Quality of the evidence (GRADE)

Comments

Risk with placebo/no treatment/standard care

Risk with Epoetin alfa or beta

All-cause mortality 61 per 1000

48 per 1000 (26 to 87)

OR 0.78 (0.41 to 1.48)

774 (4 RCTs)

⨁⨁◯◯ LOW a,b

Major cardiovascular events 19 per 1000

6 per 1000 (0 to 136)

OR 0.33 (0.01 to 8.21)

106 (1 RCT)


Blood transfusions 437 per 1000

30 per 1000 (8 to 104)

OR 0.04 (0.01 to 0.15)

329 (3 RCTs)

⨁⨁⨁⨁ HIGH a,c

Vascular access thrombosis 58 per 1000

121 per 1000 (24 to 443)

OR 2.23 (0.39 to 12.88)

217 (2 RCTs)


Hypertension 83 per 1000 245 per 1000 (171 to 338)

OR 3.59 (2.29 to 5.64)

843 (5 RCTs)

⨁⨁⨁⨁ HIGH a,c

Final/Change in Hb level

The mean final/change in Hb level was 0

The mean final/change in Hb level in the intervention group was 0 (0 to 0 )

- (0 studies) -

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio; MD: Mean difference

a. unclear risk of selection bias b. small number of events, 95% CI includes 1 c. large magnitude of effect


39

Summary of findings 2: Darbepoetin compared to other ESAs for the anaemia of end-stage kidney disease in dialysis patients

Patient or population: dialysis patients with anaemia of end-stage kidney disease Intervention: darbepoetin Comparison: other ESAs




Comments

Risk with other ESAs Risk with Darbepoetin

All-cause mortality - Darbepoetin vs Epoetin alfa or beta

54 per 1000 69 per 1000 (50 to 93)

OR 1.29 (0.93 to 1.80)

2639 (12 RCTs)

⨁◯◯◯ VERY LOW a,b,c

All-cause mortality - Darbepoetin vs CERA 68 per 1000

65 per 1000 (38 to 108)

OR 0.95 (0.55 to 1.67)

798 (2 RCTs)

⨁⨁⨁◯ MODERATE b

Major cardiovascular events - Darbepoetin vs Epoetin alfa

37 per 1000 20 per 1000 (9 to 46)

OR 0.53 (0.23 to 1.24)

1023 (2 RCTs)

⨁◯◯◯ VERY LOW a,b,d

Major cardiovascular events - Darbepoetin vs CERA

not pooled not pooled not pooled (0 studies) -

Blood transfusions - Darbepoetin vs Epoetin alfa

83 per 1000 32 per 1000 (20 to 55)

OR 0.37 (0.22 to 0.64)

1269 (3 RCTs)

⨁⨁⨁⨁ HIGH a,e

Blood transfusions - Darbepoetin vs CERA 135 per 1000

128 per 1000 (88 to 180)

OR 0.94 (0.62 to 1.41)

802 (2 RCTs)


Vascular access thrombosis - Darbepoetin vs Epoetin alfa or beta

112 per 1000 109 per 1000 (78 to 150)

OR 0.97 (0.67 to 1.40)

1432 (3 RCTs)


Vascular access thrombosis - Darbepoetin vs CERA

90 per 1000 70 per 1000 (37 to 127)

OR 0.76 (0.39 to 1.47)

489 (1 RCT)



40

Summary of findings 2: Darbepoetin compared to other ESAs for the anaemia of end-stage kidney disease in dialysis patients

Patient or population: dialysis patients with anaemia of end-stage kidney disease Intervention: darbepoetin Comparison: other ESAs




Comments

Risk with other ESAs Risk with Darbepoetin

Hypertension - Darbepoetin vs Epoetin alfa or beta

199 per 1000 205 per 1000 (166 to 249)

OR 1.04 (0.80 to 1.34)

1591 (4 RCTs)


Hypertension - Darbepoetin vs CERA 123 per 1000

95 per 1000 (63 to 141)

OR 0.75 (0.48 to 1.17)

798 (2 RCTs)


Final/change in Hb level - Darbepoetin vs Epoetin alfa

The mean final/change in Hb level - Darbepoetin vs Epoetin alfa was 0

The mean final/change in Hb level - Darbepoetin vs Epoetin alfa in the intervention group was 0,02 higher (0.09 lower to 0.12 higher)

- 1245 (6 RCTs)

⨁⨁◯◯ LOW a,f

Final/change in Hb level - Darbepoetin vs CERA

The mean final/change in Hb level - Darbepoetin vs CERA was 0

The mean final/change in Hb level - Darbepoetin vs CERA in the intervention group was 0,3 lower (0,55 lower to 0,05 lower)

- 249 (1 RCT)

⨁⨁⨁◯ MODERATE g


a. unclear risk of selection bias b. small number of events, 95% CI includes 1 c. high risk of selective reporting bias (8 out of 12 studies) d. all studies at high risk of selective reporting bias e. large magnitude of effect f. 95% CI includes zero g. sample size less than 400


41

Summary of findings 3: CERA compared to other ESAs for the anemia of end-stage kidney disease in dialysis patients

Patient or population: dialysis patients with anemia of end-stage kidney disease Intervention: methoxy polyethylene glycol-epoetin beta (CERA) Comparison: other ESAs




Comments

Risk with other ESAs Risk with CERA

All-cause mortality - CERA every 2 weeks vs EPO 62 per 1000

64 per 1000 (41 to 97)

OR 1.03 (0.65 to 1.62)

1341 (4 RCTs)


All-cause mortality - CERA every 4 weeks vs EPO 59 per 1000

68 per 1000 (42 to 107)

OR 1.16 (0.70 to 1.92)

1108 (3 RCTs)


Blood transfusions - CERA every 2 weeks vs epoetins 90 per 1000

83 per 1000 (58 to 118)

OR 0.91 (0.62 to 1.35)

1341 (4 RCTs)


Blood transfusions - CERA every 4 weeks vs epoetins 87 per 1000

87 per 1000 (55 to 134)

OR 1.01 (0.62 to 1.64)

827 (2 RCTs)

⨁⨁◯◯ LOW b,e

Vascular access thrombosis - CERA vs epoetin beta 87 per 1000

51 per 1000 (15 to 164)

OR 0.57 (0.16 to 2.06)

181 (1 RCT)


Hypertension - CERA vs epoetin beta 239 per 1000

185 per 1000 (91 to 337)

OR 0.72 (0.32 to 1.62)

181 (1 RCT)

⨁⨁◯◯ LOW a,f

Final/change in Hb level - CERA every 2 weeks vs epoetins

The mean final/change in Hb level - CERA every 2 weeks vs EPO was 0

The mean final/change in Hb level - CERA every 2 weeks vs EPO in the intervention group was 0,08 higher (0,04 lower to 0,21 higher)

- 1126 (4 RCTs)

⨁◯◯◯ VERY LOW a,c,g


42

Summary of findings 3: CERA compared to other ESAs for the anemia of end-stage kidney disease in dialysis patients

Patient or population: dialysis patients with anemia of end-stage kidney disease Intervention: methoxy polyethylene glycol-epoetin beta (CERA) Comparison: other ESAs




Comments

Risk with other ESAs Risk with CERA

Final/change in Hb level - CERA every 4 weeks vs EPO

The mean final/change in Hb level - CERA every 4 weeks vs EPO was 0

The mean final/change in Hb level - CERA every 4 weeks vs EPO in the intervention group was 0.03 lower (0.17 lower to 0.12 higher)

- 672 (2 RCTs)

⨁◯◯◯ VERY LOW a,e,g


a. unclear risk of selection bias b. small number of events, 95% CI includes 1 c. three out of four studies reported ITT data only graphically d. two out of three studies reported ITT data only graphically e. all studies reported ITT data only graphically f. sample size less than 400, 95% CI includes 1 g. 95% CI includes zero


43

Summary of findings 4: Biosimilars compared to epoetin alfa for the anemia of end-stage kidney disease in dialysis patients

Patient or population: dialysis patients with anemia of end-stage kidney disease Intervention: biosimilars Comparison: epoetin alfa




Comments

Risk with epoetin alfa Risk with biosimilars

All-cause mortality 37 per 1000

48 per 1000 (31 to 74)

OR 1.32 (0.83 to 2.09)

1883 (6 RCTs)


Major cardiovascular events 69 per 1000

80 per 1000 (48 to 132)

OR 1.17 (0.67 to 2.04)

718 (3 RCTs)


Blood transfusions 29 per 1000

40 per 1000 (24 to 66)

OR 1.41 (0.83 to 2.38)

1823 (3 RCTs)


Hypertension 69 per 1000

39 per 1000 (23 to 66)

OR 0.55 (0.32 to 0.95)

1464 (4 RCTs)

⨁⨁⨁◯ MODERATE a

Vascular access thrombosis 35 per 1000

24 per 1000 (10 to 58)

OR 0.69 (0.28 to 1.70)

823 (2 RCTs)


Final/Change in Hb level The mean final/change in Hb level was 0

The mean final/change in Hb level in the intervention group was 0

- (0 studies) - Outcome not reported in the analysed reviews


a. unclear risk of selection bias b. small number of events, 95% CI includes 1


44

Appendix 2: List of RCTs and references* in the Summary of Findings tables Sources of trials:

Palmer SC, Saglimbene V, Mavridis D, Salanti G, Craig JC, Tonelli M, Wiebe N, Strippoli GFM. Erythropoiesis-stimulating agents for anemia in

adults with chronic kidney disease: a network meta-analysis. Cochrane Database of Systematic Reviews 2014, Issue12. Art.No:CD010590.

Palmer SC, Saglimbene V, Craig JC, Navaneethan SD, Strippoli GFM. Darbepoetin for the anemia of chronic kidney disease. Cochrane Database of

Systematic Reviews 2014, Issue 3. Art. No.: CD009297. DOI: 10.1002/14651858.CD009297.pub2.

Hahn D, Cody JD, Hodson EM. Frequency of administration of erythropoiesis-stimulating agents for the anemia of end-stage kidney disease in

dialysis patients. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD003895.

Wilhelm-Leen ER, Winkelmayer WC Mortality Risk of Darbepoetin Alfa versus Epoetin Alfa in Patients with Chronic Kidney Disease: Systematic

Review and Meta-Analysis Am J Kidney Dis. 2015; 66(1): 69–74.

1 Allon 2002 Allon M, Kleinman K, Walczyk M, et al. Pharmacokinetics and pharmacodynamics of darbepoetin alfa and epoetin in patients

undergoing dialysis. Clin Pharmacol Ther. 2002; 72:546–555.

2 AMGEN 200010125

Anonymous. [1/25/2010] A Randomized, Double-blind Study Comparing Aranesp (darbepoetin alfa) and Recombinant Human Erythropoietin (rHuEPO) in the Treatment of Anemia in African-American Subjects With Chronic Renal Failure (CRF) Receiving Hemodialysis. http://download.veritasmedicine.com/REGFILES/amgen/08D_FDAMA_113_Posting_Summary_33_NESP_20010125.pdf

3 AMICUS Study 2007

Klinger M, Arias M, Vargemezis V, Besarab A, Sulowicz W, Gerntholtz T, et al. Efficacy of intravenous methoxy polyethylene glycol-epoetin beta administered every 2 weeks compared with epoetin administered 3 times weekly in patients treated by hemodialysis or peritoneal dialysis: a randomized trial. American Journal of Kidney Diseases 2007; 50(6):989–1000.

4 Bahlmann 1991 Bahlmann J, Schöter KH, Scigalla P, Gurland HJ, Hilfenhaus M, Koch KM, et al. Morbidity and mortality in hemodialysis patients with and without erythropoietin treatment: a controlled study. Contributions to Nephrology 1991;88:90–106.

5 Bennett 1991 Bennett WM. A multicenter clinical trial of epoetin beta for anemia of end-stage renal disease. Journal of the American Society of Nephrology 1991;1(7):990–8.

6 Bernieh 2014 _WL Bernieh B, Abouchacra S, Boobes Y, et al. Comparison between short- and long-acting erythropoiesis-stimulating agents in hemodialysis patients: target hemoglobin, variability, and outcome. Int Urol Nephrol. 2014; 46:453–459.

7 Canadian EPO Study 1990

Keown PA, Churchill DN, Poulin-Costello M, Lei L, Gantotti S, Agodoa I, et al. Dialysis patients treated with Epoetin alfa show improved anemia symptoms: A new analysis of the Canadian Erythropoietin Study Group trial. Hemodialysis International 2010;14(2):168–73.


45

8 Chen 2012 Chen N, Qian JQ, Mei CL, Zhang AH, Xing CY, Wang L, et al. The efficacy and safety of continuous erythropoietin receptor activator in dialytic patients with chronic renal anemia: an open, randomized, controlled, multi-center trial. Chung-Hua Nei Ko Tsa Chih [Chinese Journal of Internal Medicine] 2012;51(7):502–7.

9 Carrera 2003 Carrera F, Anunciada AI, Nogueira C, Silva JG. Comparison of HB levels in dialysis patients receiving three-times weekly rHuepo switched to once-weekly darbepoetin alfa: results of a randomized study [abstract]. Nephrology Dialysis Transplantation 2003;18(Suppl 4):164.

10 Coyne 2000 Coyne DW, Ling BN, Toto R, McDermott-Vitak AD, Trotman ML, Jackson L. Novel erythropoiesis stimulating protein (NESP) corrects anemia in dialysis patients when administered at reduced dose frequency compared with recombinant-human erythropoietin (r-huEPO) [abstract no: 1380]. Journal of the American Society of Nephrology 2000;11(Sept):263A

11 Coyne 2006a Coyne D, Zeig R, Benz R, Berns J, Varma N, Nakanishi A, et al. A randomized, double-blind study comparing darbepoetin alfa and recombinant human erythropoietin (rHuEPO) in the treatment of anemia in African-American (AA) subjects with chronic kidney disease (CKD) receiving hemodialysis (HD) [abstract no: TH-PO365]. Journal of the American Society of Nephrology 2006;17(Abstracts): 184A.

12 Hori 2004 Hori K, Tsujimoto Y, Ohmori H, Nakamura H, Suga A, Iwasaki M, et al. Randomized, double-blind, comparative study of intravenous KRN321 (darbepoetin alfa) compared to intravenous recombinant human erythropoietin (rHuEPO) for treatment of anemia in subjects with chronic renal failure (CRF) receiving hemodialysis in Japan [abstract no: F-PO502]. Journal of the American Society of Nephrology 2004;15(Oct):177A.

13 Klinkmann 1992 Klinkmann H, Wieczorek L, Scigalla P. Adverse events of subcutaneous recombinant human erythropoietin therapy: results of a controlled multicenter European study. Artificial Organs 1993;17(4):219–25.

14 Li 2008 Li WY, Chu TS, Huang JW,Wu MS,Wu KD. Randomized study of darbepoetin alfa and recombinant human erythropoietin for treatment of renal anemia in chronic renal failure patients receiving peritoneal dialysis. Journal of the Formosan Medical Association 2008;107(11):843–50.

15 Locatelli 2001 Locatelli F, Olivares J, Walker R, Wilkie M, Jenkins B, Dewey C, et al. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney International 2001;60(2):741–7.

16 Maxima study

2007

Levin NW, Fishbane S, Canedo FV, Zeig S, Nassar GM, Moran JE, et al. Intravenous methoxy polyethylene glycolepoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA). Lancet 2007;370(9596): 1415–21.

17 Nissenson 1995 Nissenson AR, Korbet S, Faber M, Burkart J, Gentile D, Hamburger R, et al. Multicenter trial of erythropoietin in patients on peritoneal dialysis. Journal of the American Society of Nephrology 1995;5(7):1517–29.

18 Nissenson 2002 Nissenson AR, Swan SK, Lindberg JS, Soroka SD, Beatey R, Wang C, et al. Randomized, controlled trial of darbepoetin alfa for the treatment of anemia in hemodialysis patients. American Journal of Kidney Diseases 2002;40(1): 110–8.

19 PATRONUS Study

2010

Carrera F, Lok CE, de Francisco A, Locatelli F, Mann JF, Canaud B, et al. Maintenance treatment of renal anaemia in haemodialysis patients with methoxy polyethylene glycolepoetin beta versus darbepoetin alfa administered monthly: a randomized comparative trial. Nephrology Dialysis Transplantation 2010;25(12):4009–17.

20 PROTOS STUDY

2007

Sulowicz W, Locatelli F, Ryckelynck JP, Balla J, Csiky B, Harris K, et al. Once-monthly subcutaneous C.E.R.A. maintains stable hemoglobin control in patients with chronic kidney disease on dialysis and converted directly from epoetin one to three times weekly. Clinical Journal of the American Society of Nephrology 2007;2(4):637–46.


46

21 RUBRA STUDY

2008

Spinowitz B, Coyne DW, Lok CE, Fraticelli M, Azer M, Dalal S, et al. C.E.R.A. maintains stable control of hemoglobin in patients with chronic kidney disease on dialysis when administered once every two weeks. American Journal of Nephrology 2008;28(2):280–9.

22 Smyth 2004 Smyth M, Pratt RD. Epoetin delta, erythropoietin produced in a human cell line, is as effective as epoetin alfa in the treatment of anemia [abstract no: 1296]. Blood 2006;108 (11):380a.

23 STRIATA Study

2008

Canaud B, Mingardi G, Braun J, Aljama P, Kerr PG, Locatelli F, et al. Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA, a randomized phase III study. Nephrology Dialysis Transplantation 2008; 23(11):3654–61.

24 Tessitore 2008 Tessitore N, Mantovani W, Bedogna V, Loss R, Melilli E, Poli A, et al. Cost analysis of switching from epoetin alfa to darbepoetin alfa in chronic hemodialysis patients (HD Pts): a long-term, randomized, open-label, cross-over, pilot study [abstract no: SA-PO2645]. Journal of the American Society of Nephrology 2008;19(Abstracts Issue):706A

25 Tolman 2005 Tolman C, Richardson D, Bartlett C, Will E. Structured conversion from thrice weekly to weekly erythropoietic regimens using a computerized decision-support system: a randomized clinical study. Journal of the American Society of Nephrology 2005;16(5):1463–70.

26 Vanrenterghem

2002

Vanrenterghem Y, Barany P, Mann JF, Kerr PG, Wilson J, Baker NF, et al. Randomized trial of darbepoetin alfa for treatment of renal anemia at a reduced dose frequency compared with rHuEPO in dialysis patients. Kidney International 2002;62(6):2167–75.

Biosimilars 27 Goh 2007 Goh BL, Ong LM, Sivanandam S, Lim TO, Morad Z, Biogeneric EPO Study Group. Randomized trial on the therapeutic equivalence

between Eprex and GerEPO in patients on haemodialysis. Nephrology 2007;12(5):431–6. 28 Haag-Weber 2009 Haag-Weber M, Vetter A, Thyroff-Friesinger U, INJStudy Group. Therapeutic equivalence, long-term efficacy and safety of HX575 in the

treatment of anemia in chronic renal failure patients receiving hemodialysis. Clinical Nephrology 2009;72(5):380–90. 29 Krivoshiev 2008 Krivoshiev S, Todorov VV, Manitius J, Czekalski S, Scigalla P, Koytchev R, et al. Comparison of the therapeutic effects of epoetin zeta and

epoetin alpha in the correction of renal anaemia. Current Medical Research & Opinion 2008; 24(5):1407–15. 30 Krivoshiev 2010 Krivoshiev S, Wizemann V, Czekalski S, Schiller A, Pljesa S, Wolf-Pflugmann M, et al. Therapeutic equivalence of epoetin zeta and alfa,

administered subcutaneously, for maintenance treatment of renal anemia. Advances in Therapy 2010;27(2):105–17. 31 Martin 2007 Martin KJ, Epoetin Delta 3001 Study Group. Epoetin delta in the management of renal anaemia: results of a 6-month study. Nephrology

Dialysis Transplantation 2007;22 (10):3052–4. 32 Milutinovic 2006 Milutinovic S, Plavljani E, Trkulja V. Comparison of two epoetin brands in anemic hemodialysis patients: results of two efficacy trials

and a single-dose pharmacokinetic study. Fundamental & Clinical Pharmacology 2006;20(5): 493–502. 33 Spinowitz 2006 Spinowitz BS, Pratt RD, Epoetin Delta 2002 Study Group. Epoetin delta is effective for the management of anaemia associated with

chronic kidney disease. Current Medical Research & Opinion 2006;22(12):2507–13. *In case of multiple publications for the same trial, we reported only the main reference.

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