WHO EML 2016-2017 - Erythropoietin-Stimulating Agents December 2016

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

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.

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

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

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

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/

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

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

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

Drug Adult dosing Pediatric dosing Notes Epoetin alfa Biosimilars include epoetin alfa and 50 to 100 units/kg - three times per week 50 units/kg - three times per week and biosimilars zeta

Correction phase: 40 units/kg - three Correction phase: 40 units/kg - three times per week Maximum dose: 720 units/kg per Epoetin beta* times per week Maintenance phase: half the previous dose week Maintenance phase: half the previous dose

Correction phase: 20 units/kg SC or 40 units/kg IV - three times Titration: may be increased to 40 per week units/kg SC or 80 units/kg IV three Epoetin theta* Not established Maintenance phase: 25% dose adjustments to maintain Hb times per week target (10 - 12 g/dL) Maximum dose: 700 units/kg/week

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

ESA naïve patients Methoxy Correction phase: 0.6 mcg/kg as a single IV (preferred route) or Safety and efficacy not established in polyethylene SC injection once every two weeks pediatric patients (European glycol-epoetin Maintenance phase: double the dose used in the initial phase IV Not established pediatric investigation plan ongoing) beta (preferred route) or SC once monthly Refer to labeling information for conversion dosages

*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)

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

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

WHO EML 2016-2017 - Erythropoietin-stimulating agents December 2016 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 7

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

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

. 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).

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

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

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

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

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.

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

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).

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

Records identified through Additional records identified database search through other sources (MedLine: 221; Embase: 54; (3) Cochrane Library: 101)

Records after duplicates removed (322)

Records screened Records excluded (322) (275)

Full-text articles excluded, Full-text articles with reasons (27) assessed for eligibility (47)  Narrative review (3)  Out of date/Included in more up-to-date reviews (11)  No data on patients on dialysis (3) Studies included in  No outcome of interest (1) qualitative synthesis (20)  No full text (2)  Other (7)  Systematic reviews (8)  Guidelines (3)  HTA reports (2)  Cost-analyses (5)  RCTs not included in systematic review (1)  Other (1)

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)

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

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,

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

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

WHO EML 2016-2017 - Erythropoietin-stimulating agents December 2016 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. 18

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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 19

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

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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 21

WHO EML 2016-2017 - Erythropoietin-stimulating agents December 2016 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). 22

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Table 4: Cost-utility analyses included in the review by Ferguson et al. (Adapted from Ferguson 2015). Author, Treatment Country Population Comparator ICER (cost/QALY) year target (g/dL) Adult (>16 Hb 9.0-10.9 Low: USD 107822/QALY Clement Canada years); CORR Hb 11.0-12.0 RBCT Intermediate: extended dominance 2010 and AKDN Hb >12.0 High: dominated

Glenngard SDDB and HD patients: USD 90455/QALY Sweden Hb 11.0-13.0 RBCT 2008 SRAU PD patients: USD 41025/QALY Germany: USD 193730 France: USD 173.271 Treatment Leese Spain: USD 677749 multiple multiple target not RBCT 1992 Italy: USD 224626 reported UK: USD 341722 (adverse events not included) Hb 10.0-12.0 Naci 2012 USA USRDS RBCT USD 931

Treatment Remake UK general UK target not RBCT USD 35343/QALY 2003 registry reported 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

WHO EML 2016-2017 - Erythropoietin-stimulating agents December 2016 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 -452,626 -475,258 -499,020 -523,971 -550,170 epoetin alfa (£) 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).

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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 Highest price 1.8440/vial ↓51% 4.3850/vial

Lowest price High/low ratio 1.0667/vial 4.11

Epoetin alfa, 4000 IU vial Source Package Package price (US Dollars) Unit price 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 Highest price 6.5629/vial ↓9% 17.0794/vial

Lowest price High/low Ratio 1.3250/vial 12.89

Epoetin beta, 50,000 IU vial Source Package Package price (US Dollars) Unit price 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).

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Table 7. ESA prices (2015-2016)

Active Commercial Dosage Price per unit Country Unit Notes substance name (IU*) in USD Binocrit Italy 4000 PFS 35.6 Ex-factory price

Eprex Italy 4000 PFS 34.5 Ex-factory price DPMQ - price for dispensing the maximum quantity of a product 53 Not stated Australia 4000 Vial 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

Epoetin alfa Epokine Jordan 4000 Vial 29.3 Pre-Tax Hospital Unit Price 39.2 Eprex Jordan 4000 PFS Pre-Tax Hospital Unit Price

Eprex Portugal 4000 PFS 15.3 Max retail price at pharmacy

38.4 Retail Unit Price in USD Binocrit Sweden 4000 PFS 36.8 Wholesale Unit Price

South Eprex 4000 PFS 66.6 Retail Unit Price in USD Africa

Eporatio Italy 4000 PFS 35.6 Ex-factory price Epoetin theta 19.9 Retail Unit Price in USD Eporatio Sweden 4000 PFS 18.6 Wholesale Unit Price

Epoetin zeta Retacrit Italy 4000 PFS 35.6 Ex-factory price

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105.27 Retail Unit Price in USD Retacrit Sweden 4000 PFS 101 Wholesale Unit Price in USD 4000 NeoRecormon Italy PFS 32.4 Ex-factory price

DPMQ - price for dispensing the maximum quantity of a product Not stated Australia 4000 Not stated 50.5 incorporating ex-manufacturer price, all fees, mark-ups and patient contributions 42.4 Retail Unit Price in USD Epoetin beta NeoRecormon Sweden 4000 PFS 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 South Recormon 4000 PFS 26.6 Retail Unit Price in USD Africa 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

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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.

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

European Union United Active substance Australia Canada Pediatric indication (EU) States Eprex Biosimilar- Eprex epoetin alfa: Epogen, 1 month and older on Biosimilar- Abseamed, Binocrit, Procrit dialysis (FDA) Epoetin alfa and epoetin Eprex Epoetin alfa Hexal pediatric population biosimilars lambda: Biosimilar-epoetin (EU, Canada, Novicrit zeta: Retacrit, Australia) Silapo, Epobel Pediatric population Not Not Epoetin beta NeoRecormon NeoRecormon including premature approved approved infants (EU) Not Biopoin, Eporatio, Not Not approved in Epoetin theta Not approved approved EpoTheta Teva approved pediatrics (EU) 1 month and older on dialysis (FDA) Darbepoetin alfa Aranesp Aranesp Aranesp Aranesp pediatric population (EU) Methoxy polyethylene Not approved in Mircera Mircera Mircera Mircera glycol-epoetin pediatrics beta 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

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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

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

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14. References . Al-Ali FS, El-Sayed Abdelfattah M, Fawzy AA, Hamdy AF, Abdulla AE. Erythropoietin-stimulating agents in the management of anemia of end-stage renal disease patients on regular hemodialysis: a prospective randomized comparative study from Qatar. Hemodial Int. 2015;19(1):33-43.

. All Wales Medicines Strategy Group Final Appraisal Report Methoxy polyethylene glycol-epoetin beta (Mircera) – October 2009.

. Arnlind MH Fryklund L, Vitols S, Bertilsson G Biosimilar erythropoiesis-stimulating agents and the risk of developing anti-drug antibodies-a systematic review. Eur J Clin Pharmacol 2016;72:1161–69.

. Bennet A, Spiegel DM, Macdougall IC, et al Review of Safety, Efficacy, and Utilization of Erythropoietin, Darbepoetin, and Peginesatide for Patients with Cancer or Chronic Kidney Disease: A Report from the Southern Network on Adverse Reactions (SONAR) Semin Thromb Hemost. 2012;38(8):783–96.

. Brandt JR, Avner ED, Hickman RO, Watkins SL. Safety and efficacy of erythropoietin in children with chronic renal failure. Pediatr Nephrol. 1999;13:143-7.

. Burke JR Low-dose subcutaneous recombinant erythropoietin in children with chronic renal failure. Australian and New Zealand Paediatric Nephrology Association. Pediatr Nephrol 1995;9:558-61.

. Canadian Agency for Drugs and Technology in Health (CADTH). Erythropoiesis-stimulating agents for anemia of chronic kidney disease: systematic review and economic evaluation. 2009 www.cadth.ca/media/pdf/H0468_Erythropoiesis-stimulating_agents_tr_e.pdf.

. Clement FM, Klarenbach S, Tonelli M, Wiebe N, Hemmelgarn B, Manns BJ. An economic evaluation of erythropoiesis-stimulating agents in CKD. Am J Kidney Dis. 2010;56(6):1050-61.

. Collister D, Komenda P, Hiebert B, et al The Effect of Erythropoietin-Stimulating Agents on Health-Related Quality of Life in Anemia of Chronic Kidney Disease A Systematic Review and Meta-analysis Ann Intern Med. 2016;164:472-8.

. Coronado Daza J, Martí-Carvajal AJ, Ariza García A, Rodelo Ceballos J, Yomayusa González N, Páez-Canro C, Loza Munárriz C, Urrútia G. Early versus delayed erythropoietin for the anaemia of end-stage kidney disease. Cochrane Database of Systematic Reviews 2015, Issue 12. Art. No.: CD011122.

. Covic A, Abraham I. State of the art biosimilar erythropoietins in the management of renal anemia: lessons learned from Europe and implications for US nephrologists Int Urol Nephrol 2015;47:1529–39.

. D’Amore C, Da Cas R, Rossi M, Traversa G Switching Between Epoetins: A Practice in Support of Biosimilar Use BioDrugs 2016;30:27–32.

. DynaMed Plus 2016. Ipswich (MA): EBSCO Information Services. 1995. Record No.905401, Anemia of chronic kidney disease. Available from www.dynamed.com/login.aspx?direct=true&site=DynaMed&id=905401 Registration and login required.

. Ebbers HC, Muenzberg M, Schellekens H. The safety of switching between therapeutic proteins. Expert Opin Biol Ther. 2012;12:1473–85.

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. European Commission 2013. Project Group on Market Access and Uptake of Biosimilars: What you need to know about biosimilar medicinal products. A consensus information document. European Commission, Brussels, 2013. www.medicinesforeurope.com/wp-content/uploads/2016/03/biosimilars_report_en.pdf

. European Medicines Agency 2005. Guidelines on similar biological medicinal products, 2005 www.ema.europa.eu/docs/en GB/document library/Scientificguideline/2009/09 /WC500003517.pdf

. European Medicines Agency, 2012. Concept paper on extrapolation of efficacy and safety in medicine development. EMA/129698/2012, www.ema.europa.eu/ema/pages/includes/document/opendocument.jsp?webContentId=WC500142358

. European Medicines Agency 2014. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, 2014 www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf

. Farfan-Portet MI, Gerkens S, Lepage-Nefkens I, Vinck I, Hulstaert F. Are biosimilars the next tool to guarantee cost-containment for pharmaceutical expenditures? Eur J Health Econ. 2014;15(3):223-8.

. FDA 2013 Omontys (peginesatide) Injection by Affymax and Takeda: Recall of All Lots - Serious Hypersensitivity Reactions www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm340895.htm

. FDA 2007 FDA Press Release 2007 Nov 8 For Patients with Chronic Kidney Failure www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109024.htm

. FDA 2005 FDA Safety Information and Adverse Event Reporting Program www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150646.htm

. FDA 2009 U.S. Food and Drug Administration: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. www.fda.gov/downloads/Drugs/Guidances/UCM273001.pdf

. FDA 2012a U.S. Food and Drug Administration: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ UCM291128.pdf

. FDA 2012b U.S. Food and Drug Administration: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product. 2012. www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/ Guidances/UCM291134.pdf.

. Ferguson T, Xu Y, Gunasekara R, Lerner B, et al The cost effectiveness of erythropoietin-stimulating agents for treating anemia in patients on dialysis: a systematic review.Am J Nephrol. 2015;41(2):89-97.

. GaBI Online 2014 - Generics and Biosimilars Initiative. US$67 billion worth of biosimilar patents expiring before 2020. www.gabionline.net/Biosimilars/General/US-67-billion-worth-of-biosimilar-patents-expiring- before-2020

. Glenngård AH, Persson U, Schön S. Cost-effectiveness analysis of treatment with epoietin-alpha for patients with anaemia due to renal failure: the case of Sweden. Scand. J Urol Nephrol. 2008;42(1):66-73.

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. Global burden of CKD: a call for serious action 2016 www.theisn.org/news/item/2896-the-global-burden-of- ckd-a-call-for-serious-action

. GRADE 2016 The Grading of Recommendations Assessment, Development and Evaluation http://gradeworkinggroup.org/

. Grams ME, Chow EK, Segev DL, Coresh J. Lifetime incidence of CKD stages 3-5 in the United States Am J Kidney Dis 2013;62(2):245.

. Hahn D, Cody JD, Hodson EM. Frequency of administration of erythropoiesis-stimulating agents for the anaemia of end-stage kidney disease in dialysis patients. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD003895.

. Halterman JS, Kaczorowski JM, Aligne CA, Auinger P, Szilagyi PG Iron deficiency and cognitive achievement among school-aged children and adolescents in the United States. Pediatrics 2001;107:1381-6.

. Haustein R, de Millas C, Hoer A, Häussler H Saving money in the European healthcare systems with biosimilars. GaBi J. 2011;1(3–4): 120-6. . Heinemann L, Khatami H, McKinnon R, Home P An overview of current regulatory requirements for approval of biosimilar insulins Diabetes Technology&Therapeutics 2015;17(7): 510-26.

. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al Chronic kidney disease: global dimension and perspectives Lancet 2013; 382: 260–72.

. Jordan J, Breckles J, Leung V, Hopkins M, Battistella M Conversion from epoetin alfa to darbepoetin alfa: effects on patients' hemoglobin and costs to canadian dialysis centres. Can J Hosp Pharm. 2012;65(6):443-9.

. KDIGO 2013, Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 1–150.

. KDIGO 2012, KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease Kidney International Supplements (2012) 2, 283–287.

. KDOQI National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease Am J Kidney Dis 2006;47:S1-S146.

. Koulouridis I, Alfayez M, Trikalinos TA, Balk EM, Jaber BL. Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a meta-regression analysis. Am J Kidney Dis. 2013;61(1): 44–56.

. Leese B, Hutton J, Maynard A. A comparison of the costs and benefits of recombinant human erythropoietin (epoetin) in the treatment of chronic renal failure in 5 European countries. Pharmacoeconomics. 1992;1(5):346-56.

. Macdougall IC. Anaemia of chronic kidney disease. Medicine 2007; 35(8): 457-60.

. Macdougall IC, Casadevall N, Locatelli F, Combe C, London GM, Di Paolo S, et al Incidence of erythropoietin antibody-mediated pure red cell aplasia: the Prospective Immunogenicity Surveillance Registry (PRIMS) Nephrol Dial Transplant 2015;30: 460–6.

. McKoy JM, Stonecash RE, Cournoyer D, Rossert J, Nissenson AR, Raisch DW, et al Epoetin-associated pure red cell aplasia: past, present, and future considerations Transfusion. 2008;48(8):1754–62. 34

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. Morris KP, Skinner JR, Hunter S, Coulthard MG. Short term correction of anaemia with recombinant human erythropoietin and reduction of cardiac output in end stage renal failure. Arch Dis Child. 1993;68:644-8.

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. NICE 2015 - National Institute for Health and Care Excellence (NICE) guideline on chronic kidney disease: managing anaemia. www.nice.org.uk/guidance/ng8.

. Palmer SC, Saglimbene V, Mavridis D, Salanti G, Craig JC, Tonelli M, Wiebe N, Strippoli GFM. Erythropoiesis- stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database of Systematic Reviews 2014, Issue12. Art.No:CD010590. (Palmer 2014-NM).

. Palmer SC, Saglimbene V, Craig JC, Navaneethan SD, Strippoli GFM. Darbepoetin for the anaemia of chronic kidney disease. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD009297. DOI: 10.1002/14651858.CD009297.pub2. (Palmer 2014-darbe).

. Palmer SC, Navaneethan SD, Craig JC, et al Meta-analysis: Erythropoiesis-Stimulating Agents in Patients With Chronic Kidney Disease. Ann Intern Med. 2010;153:23-3.

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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

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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 No. of participants Quality of the Comments (95% CI) (studies) evidence Risk with placebo/no Risk with Epoetin (GRADE) treatment/standard care alfa or beta

All-cause mortality 48 per 1000 OR 0.78 774 ⨁⨁◯◯ 61 per 1000 (26 to 87) (0.41 to 1.48) (4 RCTs) LOW a,b

Major cardiovascular 6 per 1000 OR 0.33 106 ⨁⨁◯◯ 19 per 1000 events (0 to 136) (0.01 to 8.21) (1 RCT) LOW a,b

Blood transfusions 30 per 1000 OR 0.04 329 ⨁⨁⨁⨁ 437 per 1000 (8 to 104) (0.01 to 0.15) (3 RCTs) HIGH a,c

Vascular access 121 per 1000 OR 2.23 217 ⨁⨁◯◯ 58 per 1000 thrombosis (24 to 443) (0.39 to 12.88) (2 RCTs) LOW a,b

Hypertension 245 per 1000 OR 3.59 843 ⨁⨁⨁⨁ 83 per 1000 (171 to 338) (2.29 to 5.64) (5 RCTs) HIGH a,c

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

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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

Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of Quality of the Comments (95% CI) participants evidence Risk with other ESAs Risk with Darbepoetin (studies) (GRADE)

All-cause mortality - 69 per 1000 OR 1.29 2639 ⨁◯◯◯ Darbepoetin vs Epoetin 54 per 1000 (50 to 93) (0.93 to 1.80) (12 RCTs) VERY LOW a,b,c alfa or beta

All-cause mortality - 65 per 1000 OR 0.95 798 ⨁⨁⨁◯ 68 per 1000 Darbepoetin vs CERA (38 to 108) (0.55 to 1.67) (2 RCTs) MODERATE b

Major cardiovascular 20 per 1000 OR 0.53 1023 ⨁◯◯◯ events - Darbepoetin vs 37 per 1000 (9 to 46) (0.23 to 1.24) (2 RCTs) VERY LOW a,b,d Epoetin alfa

Major cardiovascular not pooled not pooled (0 studies) - events - Darbepoetin vs not pooled CERA

Blood transfusions - 32 per 1000 OR 0.37 1269 ⨁⨁⨁⨁ Darbepoetin vs Epoetin 83 per 1000 (20 to 55) (0.22 to 0.64) (3 RCTs) HIGH a,e alfa

Blood transfusions - 128 per 1000 OR 0.94 802 ⨁⨁⨁◯ 135 per 1000 Darbepoetin vs CERA (88 to 180) (0.62 to 1.41) (2 RCTs) MODERATE b

Vascular access 109 per 1000 OR 0.97 1432 ⨁◯◯◯ thrombosis - Darbepoetin 112 per 1000 (78 to 150) (0.67 to 1.40) (3 RCTs) VERY LOW a,b,d vs Epoetin alfa or beta

Vascular access 70 per 1000 OR 0.76 489 ⨁⨁⨁◯ thrombosis - Darbepoetin 90 per 1000 (37 to 127) (0.39 to 1.47) (1 RCT) MODERATE b vs CERA 39

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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

Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of Quality of the Comments (95% CI) participants evidence Risk with other ESAs Risk with Darbepoetin (studies) (GRADE)

Hypertension - 205 per 1000 OR 1.04 1591 ⨁◯◯◯ Darbepoetin vs Epoetin 199 per 1000 (166 to 249) (0.80 to 1.34) (4 RCTs) VERY LOW a,b,d alfa or beta

Hypertension - 95 per 1000 OR 0.75 798 ⨁⨁⨁◯ 123 per 1000 Darbepoetin vs CERA (63 to 141) (0.48 to 1.17) (2 RCTs) MODERATE b

Final/change in Hb level - The mean The mean final/change in - 1245 ⨁⨁◯◯ Darbepoetin vs Epoetin final/change in Hb Hb level - Darbepoetin vs (6 RCTs) LOW a,f alfa level - Darbepoetin vs Epoetin alfa in the Epoetin alfa was 0 intervention group was 0,02 higher (0.09 lower to 0.12 higher)

Final/change in Hb level - The mean The mean final/change in - 249 ⨁⨁⨁◯ Darbepoetin vs CERA final/change in Hb Hb level - Darbepoetin vs (1 RCT) MODERATE g level - Darbepoetin vs CERA in the intervention CERA was 0 group was 0,3 lower (0,55 lower to 0,05 lower)

*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. 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 40

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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

Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of participants Quality of the Comments (95% CI) (studies) evidence Risk with other ESAs Risk with CERA (GRADE)

All-cause mortality - CERA 64 per 1000 OR 1.03 1341 ⨁◯◯◯ 62 per 1000 every 2 weeks vs EPO (41 to 97) (0.65 to 1.62) (4 RCTs) VERY LOW a,b,c

All-cause mortality - CERA 68 per 1000 OR 1.16 1108 ⨁◯◯◯ 59 per 1000 every 4 weeks vs EPO (42 to 107) (0.70 to 1.92) (3 RCTs) VERY LOW a,b,d

Blood transfusions - CERA 83 per 1000 OR 0.91 1341 ⨁◯◯◯ 90 per 1000 every 2 weeks vs epoetins (58 to 118) (0.62 to 1.35) (4 RCTs) VERY LOW a,b,c

Blood transfusions - CERA 87 per 1000 OR 1.01 827 ⨁⨁◯◯ 87 per 1000 every 4 weeks vs epoetins (55 to 134) (0.62 to 1.64) (2 RCTs) LOW b,e

Vascular access thrombosis - 51 per 1000 OR 0.57 181 ⨁⨁◯◯ 87 per 1000 CERA vs epoetin beta (15 to 164) (0.16 to 2.06) (1 RCT) LOW a,b

Hypertension - CERA vs 185 per 1000 OR 0.72 181 ⨁⨁◯◯ 239 per 1000 epoetin beta (91 to 337) (0.32 to 1.62) (1 RCT) LOW a,f

Final/change in Hb level - The mean The mean final/change in - 1126 ⨁◯◯◯ CERA every 2 weeks vs final/change in Hb Hb level - CERA every 2 (4 RCTs) VERY LOW a,c,g epoetins level - CERA every 2 weeks vs EPO in the weeks vs EPO was 0 intervention group was 0,08 higher (0,04 lower to 0,21 higher)

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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

Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of participants Quality of the Comments (95% CI) (studies) evidence Risk with other ESAs Risk with CERA (GRADE)

Final/change in Hb level - The mean The mean final/change in - 672 ⨁◯◯◯ CERA every 4 weeks vs EPO final/change in Hb Hb level - CERA every 4 (2 RCTs) VERY LOW a,e,g level - CERA every 4 weeks vs EPO in the weeks vs EPO was 0 intervention group was 0.03 lower (0.17 lower to 0.12 higher)

*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. 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

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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

Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of Quality of the Comments (95% CI) participants evidence Risk with epoetin alfa Risk with biosimilars (studies) (GRADE)

All-cause mortality 48 per 1000 OR 1.32 1883 ⨁⨁◯◯ 37 per 1000 (31 to 74) (0.83 to 2.09) (6 RCTs) LOW a,b

Major cardiovascular events 80 per 1000 OR 1.17 718 ⨁⨁◯◯ 69 per 1000 (48 to 132) (0.67 to 2.04) (3 RCTs) LOW a,b

Blood transfusions 40 per 1000 OR 1.41 1823 ⨁⨁◯◯ 29 per 1000 (24 to 66) (0.83 to 2.38) (3 RCTs) LOW a,b

Hypertension 39 per 1000 OR 0.55 1464 ⨁⨁⨁◯ 69 per 1000 (23 to 66) (0.32 to 0.95) (4 RCTs) MODERATE a

Vascular access thrombosis 24 per 1000 OR 0.69 823 ⨁⨁◯◯ 35 per 1000 (10 to 58) (0.28 to 1.70) (2 RCTs) LOW a,b

Final/Change in Hb level The mean final/change in The mean final/change in Hb - (0 studies) - Outcome not reported Hb level was 0 level in the intervention group in the analysed was 0 reviews

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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 Anonymous. [1/25/2010] A Randomized, Double-blind Study Comparing Aranesp (darbepoetin alfa) and Recombinant Human 200010125 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 Klinger M, Arias M, Vargemezis V, Besarab A, Sulowicz W, Gerntholtz T, et al. Efficacy of intravenous methoxy 2007 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 Keown PA, Churchill DN, Poulin-Costello M, Lei L, Gantotti S, Agodoa I, et al. Dialysis patients treated with Epoetin alfa show improved Study 1990 anemia symptoms: A new analysis of the Canadian Erythropoietin Study Group trial. Hemodialysis International 2010;14(2):168–73.

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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 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 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 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. 2010 Nephrology Dialysis Transplantation 2010;25(12):4009–17. 20 PROTOS STUDY 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 2007 Journal of the American Society of Nephrology 2007;2(4):637–46.

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21 RUBRA STUDY 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. 2008 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 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 2008 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 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. 2002 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.