1. No category

CONSEJERÍA DE SALUD Y BIENESTAR SOCIAL
AGENCIA DE EVALUACIÓN
DE TECNOLOGÍAS SANITARIAS
DE ANDALUCÍA (AETSA)
Eculizumab (Soliris®)
Assessment of effectivity and safety
of the drug and economic analysis
of use in Paroxysmal Nocturnal
Haemoglobinuria therapy
2011
INFORME_5
CONSEJERÍA DE SALUD
Agencia de Evaluación de Tecnologías
Sanitarias de Andalucía (AETSA)
Report on drug assessment
Eculizumab (Soliris)
Assessment of effectivity and safety of the drug
and economic analysis of use in Paroxysmal
Nocturnal Haemoglobinuria therapy
Avda. Luis Montoto, 89. 4ª planta
41007 Sevilla-España (Spain)
Tlf.: 955 951 581 - Fax: 955 923 572
e-mail: [email protected]
2011
INFORME_5
Eculizumab (Soliris®)
Assessment of effectivity and safety of the drug and
economic analysis of use in Paroxysmal Nocturnal
Haemoglobinuria therapy
Agencia de Evaluación de Tecnologías Sanitarias de Andalucía
www.juntadeandalucia.es/salud/aetsa
Avda. Luis Montoto, 89. 4ª planta
41007 Sevilla
España – Spain
Authors
Laila Abdel-Kader Martín. AETSA Technician. María Auxiliadora Castillo Muñoz. AETSA
Technician. Emilio Jesús Alegre del Rey. Hospital Pharmacist. Hospital Universitario
Puerto Real (Cádiz). Nuria Muñoz Muñoz. Hospital Pharmacist. Hospital Universitario
Virgen Macarena (Sevilla). Juan Antonio Muñoz Muñoz. Haematologist. Haematology
Department. Hospital Universitario Puerta del Mar (Cádiz), on behalf of the working
group.
Conflict of interests
Authors declare no conflict of interest which could interfere with the primary interest
and main goals in this final appraisal report on eculizumab.
One of the authors has received honoraria in the past for his contribution to
symposiums organized by Alexion Pharma.
This report was finished in April 2010
Note to English translation:
Appendices to the original document have been not translated for the English version.
Please, if necessary, consult the Spanish version.
Direction: Sandra Flores Moreno. Director of AETSA.
The following people have participated in this study:
Coordination of workgroup
Carmen Beltrán Calvo. Head of HTA Service, Andalusian Agency for Health Technology
Assessment (AETSA).
José Antonio Navarro Caballero. Economist. AETSA Operations Management Area and
Health Economy Manager.
José María Recalde Manrique. Director of CADIME.
Workgroup
Belén Corbacho Martín. Economist of AETSA.
Jaime Espín Balbino. Economist. Professor of Escuela Andaluza de Salud Pública.
Sergio Márquez Peláez. Economist of AETSA.
Nieves Merino Kolly. Pharmacologist. Centro Andaluz de Farmacovigilancia.
Álvaro Urbano Ispizua. Haematologist. Hospital Clinic (Barcelona).
Documentation
María Teresa Nieto Rodríguez. Technician of CADIME.
Antonio Romero Tabares. Head of Servicio de Documentación e Información. AETSA.
External review
Ramiro Núñez Vázquez. Haematologist. Hospital Universitario Virgen del Rocío (Sevilla).
Nuria Paladio Durán. Agència d’Avaluació de Tecnologia i Recerca Mèdiques (AATRM).
José Luis Pinto Prades. Economist. Universidad Pablo de Olavide.
Bernardo Santos Ramos. Hospital Pharmacist. Hospital Universitario Virgen del Rocío
(Sevilla).
Organizations
Agencia de Evaluación de Tecnologías Sanitarias de Andalucía (AETSA)
http://www.juntadeandalucia.es/salud/aetsa
Centro Andaluz de Documentación e Información de Medicamentos (CADIME)
http://www.easp.es/web/cadime/index.asp?idSub=303&idSec=303&idCab=303
Centro Andaluz de Farmacovigilancia (CAFV)
http://www.cafv.es/
Asociación Andaluza de Hematología
http://www.aa-hh.org/fundacion.php
Sociedad Andaluza de Farmacéuticos de Hospital (SAFH)
http://www.safh.org
Contents
Abbreviations ...................................................................................................7
Executive summary .........................................................................................9
Introduction ....................................................................................................15
Description of paroxysmal nocturnal haemoglobinuria ..............................15
Justification ................................................................................................17
Main objectives ..........................................................................................19
Secondary objectives .................................................................................19
Metodology ....................................................................................................21
Systematic review of literature: efficacy and safety ...................................21
Systematic review of economic evaluation literature .................................22
Selection, evaluation of quality, and synthesis of literature of efficacy,
safety, and economics............................................................................................22
Results of efficacy and safety bibliographic search ...................................25
Description of the documents included in the systematic review of efficacy
and safety ...............................................................................................................26
Quality assessment of the studies .............................................................27
1. Baseline characteristics of patients included in the studies...................28
2. Intervention in the studies ......................................................................29
3. Main results of efficacy and safety.........................................................30
Economic evaluation results..........................................................................45
A. Review of the literature on economic aspects.......................................45
B. Critical analysis of information submitted by the company ...................47
C. Economic analysis de novo...................................................................48
Discussion .....................................................................................................53
1. Efficacy and safety systematic review discussion .................................53
2. Review of the economic analysis...........................................................56
Conclusions ...................................................................................................59
Recommendations.........................................................................................61
References ....................................................................................................63
Tables and figures
Table 1. Summary of characteristics of Eculizumab drug..................................... 17
Table 2. Baseline characteristics of patients included in the pilot study
(phase II), TRIUMPH and SHEPERD ................................................... 28
Tabla 3. Adverse events most frequently observed in the studies ....................... 34
Table 4. Summary of studies results..................................................................... 36
Table 5a. Phase II study, Hillmen et al. 2004 (14). Most relevant aspects of
Phase II study........................................................................................ 37
Table 5b. Phase II study, Hillmen et al. 2004 (14). Measured variables .............. 37
Table 6a. Extension study of phase II study, Hill et al. 2005 (15). Most
relevant aspects of Phase II study ........................................................ 38
Table 6b. Extension study of phase II study, Hill et al. 2005 (15). Variables........ 38
Table 7a. TRIUMPH randomised clinical trial (8;16). Most relevant aspects
of study.................................................................................................. 39
Table 7b. TRIUMPH randomised clinical trial (8;16). Variables............................ 40
Table 8a. SHEPHERD study (17). Most relevant aspects of study ...................... 41
Table 8b. SHEPHERD study (17). Variables ........................................................ 41
Table 9a. Extension study by Hillmen et al. 2007 (18). Most relevant
aspects of study .................................................................................... 42
Tablee 9b. Extension study by Hillmen et al. 2007 (18). Variables ...................... 43
Table 10. Cost per PRBN avoided according to the study TRIUMPH .................. 50
Table 11. Cost per PRBN avoided according to the study SHEPHERED ............ 50
Table 12. “Scenarios” of eculizumab use.............................................................. 51
Table 13. Number of cases and scenarios impact................................................ 51
Table 14. Annual savings for each scenario ......................................................... 52
Figure 1. Flowchart illustrating selection process of documents for the
systematic review .................................................................................. 25
Figure 2. Flowchart showing eculizumab studies undertaken in patients
with PNH .............................................................................................. 27
Eculizumab for treatment of PNH / AETSA 2011
Abbreviations
AAH
Andalusian Hematology Association
AATRM
Catalan Agency for Health Information, Assessment and Quality
ADIS
AdisInsight
AERS
Event Reporting System
AETSA
Agency for Health Technology Assessment
AEs
Adverse events
AUC
Area under Curve
BOJA
Official Journal of the Andalusian Regional Government
MAVE
Major vascular events
AWMSG
All Wales Medicines Strategy Group
CADIME
Andalusian Drug Documentation and Information Center
CADTH
Canadian Agency for Drugs and Technologies in Health
CAFV
Andalusian Pharmacovigilance Center
CASPe
Critical Appraisal Skills Programme (CASP)
CRD
Center for Reviews and Dissemination
EMA
European Medicines Agency
EORTC
European Organization for Research and Treatment of Cancer EPAR
European Public Assessment Report
FACIT
Functional Assessment of Chronic Illness Therapy
FDA
Food and Drug Administration
GENESIS
Assessment of new drug approvals, standardization and research in drug
selection Group
GPI
Glycosylphosphatidylinositol
Hb
Hemoglobin
HPP
Hospital Purchase Price
IDIS
Iowa Drug Information Service
IPA
International Pharmaceutical Abstracts Database
ITT
Intent to treat
LDH
Lactate dehydrogenase
MAVEs
Major adverse vascular events
NICE
National Institute for Clinical Excellence
<7
AETSA 2011 / Eculizumab for treatment of PNH
NNT
Number needed to treat
PMN
Polymorphonuclear
PNH
Paroxysmal Nocturnal Haemoglobinuria
PRBC
Packed Red Blood Cells
PRBCU
Packed Red Blood Cells Units
QALY
Quality-adjusted life year
QLQ-C30
Quality of Life Questionnaire Core 30
RCT
Randomised controlled trial
RPI
Retail Price Index
SAEs
Serious adverse events
SAFH
Andalusian Society of Hospital Pharmacists
SAS
Andalusian Health Service
SD
Standard Deviation
SEFH
Spanish Society of Hospital Pharmacy
SSPA
Andalusian Health Public System
ULN
Upper Limit of Normal
RUD
Rational Use of Drugs
VAT
Value-added Tax
8>
Eculizumab for treatment of PNH / AETSA 2011
Executive summary
Introduction
Paroxysmal Nocturnal Haemoglobinuria (PNH) is a rare, acquired disorder, which
affects pluripotential haematopoietic stem cells. Incidence rate has been reported in 0.13
cases per 100,000 inhabitants. Survival has been estimated as 10-15 years, with death
occurring primarily due to thromboses, besides infections and haemorrhages.
Primary goals
•
Evaluate clinical efficacy of eculizumab in the treatment of patients with PNH
in terms of survival, thromboembolic events, quality of life, packed red blood
cells (PRBC's) transfusions, hemoglobin levels, and haemolysis.
•
Evaluate efficacy and safety of eculizumab in patients with PNH.
•
Provide an economic analysis of eculizumab regarding cost effectiveness
ratios in patients suffering PNH.
Secondary goals
o
Evaluate safety of eculizumab treatment in patients with PNH de novo.
o
Evaluate efficacy and safety of eculizumab treatment in patients with PNH
who are under 18.
o
Evaluate efficacy and safety of eculizumab treatment in cases of patients
receiving again eculizumab treatment after withdrawal.
o
Evaluate efficacy and safety of eculizumab treatment in patients with PNH,
during pregnancy.
Methodology
A multidisciplinary work panel of experts was constitued in order to elaborate an
evaluation report on eculizumab.
To accomplish evidence-based response to effectiveness and safety objectives,
an exhaustive search of the published literature in referential data sources was
performed.
Papers included in the efficacy and safety systematic review were studies
regarding patients with PNH under eculizumab treatment. In these cases survival,
thromboembolic events, quality of life, packed red blood cells (PRBC's) transfusions,
hemoglobin levels, haemolysis, and safety were evaluated. Included studies were
metanalysis, systematic reviews, clinical trials (RCTs), EMA’s evaluation report, cohort
studies, and series of cases with a number of patients equal or superior to 10.
Articles included in the economic analysis literature review were economic reports
<9
AETSA 2011 / Eculizumab for treatment of PNH
and studies of health technology assessment.
Systematic reviews quality evaluation, RCTs, and economic studies quality
evaluations were performed by means of CASPe questionnaires of literature critical
reading. An specific questionnaire by panel methodologists was used for the critical
evaluation of non-randomised intervention studies.
Efficacy and safety evaluation results
In the systematic review the following documents were included: a systematic
review, eculizumab EMA’s European Public Assessment Report (EPAR), and five clinical
studies evaluating the efficacy and safety of eculizumab in a total number of 195 patients
with PNH [a pilot study in phase II and its extension, a randomised clinical trial (RCT) and
two non-randomised intervention studies]
The systematic review results are presented below:
There is no evidence that eculizumab treatment improves survival in patients with
PNH.
An uncontrolled intervention study evaluated the incidence of thromboembolic
events in patients with PNH under eculizumab treatment. The effect of thromboembolic
events minimized from 7.37 to 1.07 events/ 100 patients per year (p< 0.001).
Patient’s quality of life improvement was evaluated in the pilot study, its
extensions, the TRIUMPH RCT, and the SHEPHERD study. It was measured by the
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue instrument and the
European Organization for Research and Treatment of Cancer Quality of Life
Questionnaire (EORTC QLQ-C30). Only in the phase II study the baseline scores were
indicated in the EORTC QLQ-C30 scale.
In the TRIUMPH RCT, the 53.7% of patients of eculizumab group with respect to
the 20.5% of the placebo group showed a change on the FACIT-Fatigue scale of 4.0
points, minimum clinically important difference (p=0.0028).
In most items showed in EORTC QLQ-C30 scale, there were significant
differences both in the TRIUMPH RCT and the SHEPHERD study.
The median of PRBC's was equal to 0 in the group under eculizumab treatment
compared to 10 in the placebo group (p<0.001), according to TRIUMPH RCT. In the
same way, in the SHEPHERD study, the median of PRBC's before eculizumab treatment
was reduced from 8 to 0 PRBC's after 12 months of treatment (p< 0.001).
Patients of TRIUMPH RCT were stratified at randomisation in three levels (4-14,
15-25 and > 25 PRBC's), according to the PRBC's units transfused in the previous year.
After a 26-week treatment, differences among the median of PRBC's transfused in the
eculizumab group and the placebo group was of 6.8 and 15 PRBC's (p< 0.005),
respectively.
In the SHEPHERD study, patients were stratified according to the baseline LDH
levels (537-1,379, 1,380-2,050, 2,051-2,866 and 2,867-5,245 U/L). The difference
between PRBC's units transfused before and after the eculizumab treatment was: 8 (p=
0.143), 6.5 (p= 0.033), 9 (p<0.001) and 6.5 PRBC's (p=0.006), respectively.
51% of patients who received eculizumab, compared to 0% of the placebo group,
10 >
Eculizumab for treatment of PNH / AETSA 2011
in the TRIUMPH RCT, achieved transfusion independence over the 26 week-treatment
(p<0.001).
Reduction of haemolysis was evaluated by means of the LDH levels. These levels
decreased significantly after eculizumab treatment and remained stable during the study
(p< 0.001).
With regards to eculizumab safety, the most serious adverse event considered to
be treatment-related was meningococcal infection reported in 0.3% of eculizumab-treated
patients.
In the TRIUMPH RCT, no significant differences were reported in relation to the
frequency of adverse events between both treatment groups. In the SHEPHERD study,
percentage of patients with adverse effects was 7.2%.
Economic evaluation results
Three reports have been included: two of them for the National Health Service
(NHS), and one for the Andalusian Public Health System (SSPA). In all the cases no
evidence was found to estimate cost-effectiveness in terms of quality adjusted life year
(QALY), and when analytic models were build to calculate the estimation, the incremental
cost per QALY gained is considered too superior compared with regular costeffectiveness according to public health systems.
The economic analysis undertaken has evaluated the cost-effectiveness ratios of
the effectiveness, making different assumptions. Cost-effectiveness ratios obtained are:
the annual cost to improve patients’ quality of life after six months, measured by FACITFatigue scale (1,500,000€/year); the annual cost for averting thrombosis in the course of
a year (over 6,000,000€ minimum); and the cost of averted PRBC units within the range
13,125 to 19,669€, depending of the PRBC units previously required by each patient.
The SSPA (Andalusian Public Health System) annual cost estimation for
provision of the drug, according to the number of patients, would be around 2,263,092
and 17,350,372€, with a reduction of budget impact estimated in 7,978.79 to 67,967.44€,
due to reduced costs associated with a reduction in the transfusion of PRBC units.
Conclusions:
ƒ
There is no evidence that eculizumab improves survival in PNH patients.
ƒ
Evidence of eculizumab is not of sufficient quality. As a result of this, it is
impossible to arrive at definite conclusions about the reduction of thromboembolic
events in PNH patients. It is necessary to develop high quality studies contributing
to solid evidence regarding this matter.
ƒ
Half of PNH patients receiving eculizumab treatment show FACIT-Fatigue scores
increased (improved) by four points in this instrument scale, especially when
related to fatigue grade (minimum clinically important difference in quality of life).
ƒ
Eculizumab treatment in PNH patients reduced the number of PRBC units
transfused compared with placebo. Patients requiring less PRBC transfusions are
< 11
AETSA 2011 / Eculizumab for treatment of PNH
the more severely affected patients or the moderate affected (depending on pretreatment transfusion requirements and haemolysis).
ƒ
Eculizumab treatment in PNH patients diminishes haemolysis (measured by LDH
levels). The reduction in LDH levels with eculizumab commenced within one month
and levels remain constant during the treatment period.
ƒ
Eculizumab treatment is generally well tolerated.
ƒ
Patients following therapy with eculizumab show a higher incidence of N.
meningitidis compared with general population. In consequence, must be
vaccinated when receiving eculizumab. However, the vaccine is not effective
against serogroup B of Neisseria meningitidis, being this the most prevalent
serogroup in Spain, and the one producing more infections.
ƒ
There is no evidence of long-term safety of eculizumab in PNH patients.
ƒ
There is no evidence regarding efficacy and safety when resuming eculizumab
treatment after withdrawal in PNH patients.
ƒ
There is no quality evidence allowing recommendations for eculizumab usage in
PNH patients during pregnancy.
ƒ
There is no evidence of efficacy and safety regarding eculizumab treatment in PNH
patients under 18.
ƒ
No evidence was found for the use of eculizumab in patients with PNH de novo
(patients without previous transfusions).
ƒ
Lack of information related to drug effectiveness means implementation of a full
economic assessment for estimation of cost-effectiveness and/or cost-utility is
impractical at this time.
ƒ
The budget impact for the SSPA varies according to the different scenarios of
cases for treatment and was estimated between 0.07% and 0.5% of total hospital
expenditure.
ƒ
As there is no scientific evidence regarding survival of treated patients, but just
improvement in surrogate endpoints, it is not possible to calculate a model for
estimation of cost in terms of QALY. According to a theoretical exercie based on
significant assumptions, a cost per LYG will exceed between two and six times the
highest estimations for ultra-orphan drugs as advised by NICE.
ƒ
Cost-efficacy ratios estimated for surrogate endpoints of major clinical relevance
show very high values (exceeding the highest estimations advised by NICE for this
type of drug in terms of the incremental cost per QALY, which could serve as
reference).
Recommendations:
■
12 >
The use of eculizumab in PNH patients when there is no clinical evidence should
be considered as experimental. These situations include at this moment: patients
without a history of transfusions, patients under 18, pregnant patients, and cases of
Eculizumab for treatment of PNH / AETSA 2011
patients who recommence eculizumab treatment after withdrawal.
ƒ
Given that there is only solid evidence of eculizumab efficacy in surrogated
endpoints, transfused PRBC units, and LDH levels, these outcomes should guide
the criteria that define those patients who would qualify for eculizumab treatment.
There is solid evidence that only patients with a greater history of transfusions in
the previous year and higher LDH baseline levels, show major clinical benefit and
better relation cost-efficacy. In consequence, those should be the criteria to select
subgroups which potentially will obtain more benefit from treatment. For the rest of
patients supportive treatment and monitoring are recommended.
ƒ
In areas where there is uncertainty about eculizumab efficacy, being it measured in
terms of health-related outcomes (f. e. efficacy in rates of thrombosis), it is
recommended to establish an agreement based on shared risks with the
manufacturing laboratory.
ƒ
It is necessary for all patients who enroll for eculizumab treatment to accomplish
the Risk Management Plan designed by the EMA for this drug.
ƒ
It is recommended to undertake an evaluation of efficacy and safety after 3 months
of treatment. In this initial evaluation, LDH levels will indicate eculizumab efficacy.
In those patients in which eculizumab is not effective and/or safe, it is
recommended to withdraw treatment.
ƒ
Patients in whom treatment seems to be effective after the three first months
should continue periodic monitorisation every six months. The following
parameters should be registered: thrombotic events (type and location), number of
RBC units transfused, biochemical parameters (LDH and creatinine), hemograma,
infections (type and location), disease evolving towards other haematologic
pathologies (aplastic anemia, leukaemia or myelodysplasic syndromes), adverse
events, and spontaneus remission. Patients for whom eculizumab is not effective
and/or safe are recommended to withdraw from treatment.
ƒ
It is recommendable that the SSPA creates a group for the granting of centralised
authorisation for this treatment. The group should apply the resolution established
by the SAS management, individually, to each potential case. In the same way this
group will be responsible for management of patients’ monitoring.
ƒ
In addition, it is recommended the foundation of a PNH registry in Andalusia.
< 13
Eculizumab for treatment of PNH / AETSA 2011
Introduction
Description of paroxysmal nocturnal haemoglobinuria
Epidemiology of PNH
Paroxysmal Nocturnal Haemoglubinuria (PNH) is a rare disease, genetically
acquired, which affects pluripotent hematopoietic cells. Incidence is estimated in
0.13/100,000 inhabitants (1). PNH is a chronic illness affecting mainly young adults of
both sexes (2).
In Andalusia, real prevalence of this disease is unknown. Notwithstanding,
according to information provided by clinical consultants, there are 32 patients diagnosed
with PNH, and 25 of them show a polymorphonuclear neutrophils (PMN) PNH clone
greater than 30%.
PNH etiopathogeny
Disease development is due to the following factors (2):
a) A somatic mutation of the PIG-A gene in a bone marrow stem cell. Due to this
mutation,
affected
cells
show
deficiency
or
absence
of
glycosilphosphatidylinositol cell protein (GPI) [molecule essential for plasma
membrane anchored proteins]. As a result, red blood cells are susceptible to
lytic membrane attack complex.
b) Bone marrow failure contributes to the PNH clone proliferation with respect to
normal cells.
PNH diagnosis and clinical significance
In PNH patients, three types of RBC or PMN can be detected: normal cells (Type
I), cells which are partially deficient in GPI proteins (Type II), and cells completely lacking
GPI proteins (Type III) (1).
Transfusions or hemolysis may alter the quatification of GPI-anchored protein
deficient erythrocytes in PNH. As a result, the PMN clone quantification provides more
information that the analysis of erythrocytes clone in PNH. Nowadays, flow cytometry is
the method used in PNH diagnosis (2;3).
From a clinical point of view, the International Paroxysmal Nocturnal
Haemoglobinuria Interest Group has established three PNH subcategories (2;3):
1. Classic PNH. Characterized by the evidence of florid intravascular hemolysis
(macroscopic hemoglobinuria is frequent or persistent), with a PMN
deficiency in GPI greater than 50%, and a predominance of red blood cells
type III. Patients show no bone marrow related illness.
2. PNH related to other hemopathies, such as aplastic anemia or
myelodysplastic syndrome. Rate of intravascular hemolysis is mild to
< 15
AETSA 2011 / Eculizumab for treatment of PNH
moderate (macroscopic hemoglobinuria is intermittent or absent). Percentage
of GPI-deficient PMNs in these patients varies, but normally it is under 30%.
3. Subclinical PNH. There is no clinical or biochemical evidence of hemolysis,
but small populations of GPI-deficient hematopoietic cells may be detected.
PNH PMNs percentage analysed by flow cytometry is under 1%.
PNH spontaneous remission has been described in approximately 15-25% of the
patients (1). This spontaneous remission is not related with illness severity or
complications, as it even occurs in patients with high transfusion requirements who also
suffered thrombotic events. Spontaneous remission usually occurs in 10 to 20 years after
diagnosis. A possible explanation for this spontaneous remission could be that affected
clones have a limited life span, such as somatic cells. Recovery may depend on the
presence of normal cells capable of repopulate the bone marrow (4).
Classic PNH is characterized by triad of haemolytic anaemia, thrombophilia
(affecting 12-40% of patients), and bone marrow failure (5). Median survival following
diagnosis of PNH has been estimated as 10-15 years (1). Thrombosis is the main cause
of morbidity, followed by infections and haemorrhage. Development of acute myeloid
leukaemia is not frequent (less than 5% of the cases) (2;6).
When the quantity of PNH red blood cells type III is greater than 20%, patients
usually show signs of intravascular haemolysis.
Presence of PNH granulocytes type II or III clones higher than 50% is associated
to additional risk factors for thrombosis (7).
Also, PNH is characterized by the presence of anemia, asthenia, esophageal
spasms, erectile dysfunction, recurrent abdominal pain, pulmonary hypertension, chronic
renal failure, and worsening of health-related quality of life (1).
PNH treatment
Allogeneic haematopoietic stem cell transplantation is currently considered the
only potentially curative option for PNH. Management of PNH is mainly supportive, a
mean of controlling its clinical manifestations. Hence, treatment consists in red blood cells
transfusions (RBC) in patients with serious haemolysis, corticosteroids treatment, and
prophylactic anticoagulation.
Description of Eculizumab drug
Eculizumab (Soliris®) is a recombinant humanized monoclonal antibody. It
belongs to the pharmacotherapeutic group of immunomodulators, ATC code: L04AA25.
Eculizumab is an orphan drug of hospital clinical use.
At first, eculizumab treatment was researched in patients with rheumatoid
arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, and idiopathic
membranous glomerulonephritis (6;8).
Mechanism of action
Eculizumab specifically binds with high affinity complement factor (C5) protein,
16 >
Eculizumab for treatment of PNH / AETSA 2011
Inhibiting and thereby blocking its cleavage into active forms. As a result, it avoids
the activation of C5b-9 terminal complement complex. Eculizumab blocks the red blood
cells lysis in patients with PNH, in dose-dependent manner. It preserves the first
components in the complex activation which are essential for the opsonization of
microorganisms and to eliminate immune complexes (8).
EMA approval
Eculizumab is indicated for the treatment of patients with PNH. Evidence of
eculizumab efficacy and safety in the treatment of PNH patients is limited to patients with
history of transfusions of RBC (8).
Special warnings and precautions according to summary of
product characteristics
Due to its mechanism of action, the use of eculizumab increases the risk of a
Neisseria meningitidis infection. However, there is the risk of an illness caused by the
less common serogroups (Y, W135, and X, specifically), though meningitis may be
caused by any serogroup.
In order to reduce the risk of Neisseria meningitidis infection, all patients must be
vaccinated at least two weeks before starting eculizumab treatment (9).
Table 1. Summary of characteristics of Eculizumab drug (9)
Presentation
Concentrate for solution for infusion of 300 mg eculizumab singleuse vial each containing 30 ml (10 mg/ml).
Dosage
• Initial phase: 600 mg weekly for four weeks, followed by 900 mg in
the fifth week.
• Maintenance phase: 900 mg each 14 ± 2 days
Characteristics
Intravenous infusion
Unit price (HPP
+VAT)
4,628€ (10)
Justification
This report was commissioned by the SAS Management, in accordance with
Resolution SC 0369/09, from August 7th, established for the Harmonised Criteria for
Drug Use in all SAS centres.
< 17
Eculizumab for treatment of PNH / AETSA 2011
Objectives
Main objectives
•
Evaluate clinical efficacy of eculizumab in the treatment of patients with PNH
in terms of increase of survival, reduction of the incidence of thromboembolic
events, improvement of quality of life, diminishing packed red blood cells
(PRBC's) transfusions, increase in hemoglobin levels, and diminishing
haemolysis.
•
Evaluate safety of eculizumab in patients with PNH.
•
Provide an economic analysis of eculizumab in with PNH.
Secondary objectives
o
Evaluate efficacy and safety of eculizumab treatment in patients with PNH de
novo (without a history of transfusions).
o
Evaluate efficacy and safety of eculizumab treatment in PNH patients under
18.
o
Evaluate efficacy and safety of eculizumab treatment in patients with PNH
receiving again eculizumab treatment after withdrawal.
o
Evaluate efficacy and safety of eculizumab treatment in patients with PNH,
during pregnancy.
< 19
Eculizumab for treatment of PNH / AETSA 2011
Metodology
A multidisciplinary work panel of experts, coordinated and managed by the
Andalusian Agency for Health Technology Assessment (AETSA), was constitued in order
to elaborate an assessment report on eculizumab.
This work team was constitued by four methodologists, two technicians experts in
drug documentation and information, two haematologists, a clinical pharmacologist, two
clinical pharmacists, and four health-specialized economists.
External review was accomplished by a haematologist, a clinical pharmacist, an
economist expert in pharmaceutical politics, and the Catalan Agency for Health
Information Assessment and Quality (AATRM).
Systematic review of literature: efficacy and safety
To accomplish evidence-based response to efficacy and safety objectives it was
performed an exhaustive research of the published literature in referential data sources
until 12th February 2010.
Data base consulted for systematic review included the Cochrane Library, dat
abase from the Center for Reviews and Dissemination (CRD), MEDLINE, EMBASE,
ECRI and Hayes Inc. Besides, other information systems were consulted, such as Web of
Knowledge and different web pages of drug and health technology assessment agencies
(complete list in Appendix I).
In addition, the International Pharmaceutical Abstracts Database (IPA),
AdisInsight (ADIS), Iowa Drug Information Service (IDIS) and Adverse Event Reporting
System (AERS) from Food and Drug Administration (FDA) were consulted.
Appendix I also includes search strategies used in main data bases. In the rest of
the data bases, searching was accomplished by means of keywords or using specific
terms of each searching data base. No restriction by language was applied.
A manual cross-file searching was accomplished from bibliographical references
in the selected papers.
Efficacy and safety searchings were accomplished separately by two AETSA and
CADIME technicians specialized in drug documentation and information, in
complementary databases, in order to find the maximum available information.
Selection criteria for systematic review of efficacy and safety
Inclusion criteria
•
Population: PNH patients.
•
Intervention: eculizumab treatment.
•
Comparator: supportive care and/or placebo.
•
Outcomes: survival, thrombotic events, quality of life, transfusions needs
< 21
AETSA 2011 / Eculizumab for treatment of PNH
(packed red blood cells), haemoglobin levels, haemolysis or adverse events.
•
Procedure: meta-analysis, systematic reviews, clinical trials, EMA evaluation
report, cohort studies, and before and after studies in at least 10 patients.
Exclusion criteria
•
Studies performed with the following designs: narrative reviews, case series
studies of less than 10 patients, clinical cases and editorials.
Systematic review of economic evaluation literature
In order to attain the economic goals, an exhaustive search of the published
literature in referential data sources until 12th February 2010 was accomplished.
Consulted data bases for the review of the economic evaluation literature were
NHS Economic Evaluation Database (NHS EED), EMBASE, MEDLINE and EuronHEED.
In addition, other researchings were accomplished in various web pages of agencies for
health technology assessment, and in the database of the evaluation group GENESIS of
the Spanish Society of Hospital Pharmacy (SEFH) (complete list in Appendix I).
Appendix I details the search strategy of economic search in MEDLINE. Other
searches were accomplished by means of keywords or using specific terms of each
searching database.
Bibliographic search on economic aspects was undertaken by AETSA
Documentation Service.
Selection criteria of the economic literature review
Inclusion criteria
•
Population: PNH patients.
•
Intervention: eculizumab treatment.
•
Comparator: supportive care and/or placebo.
•
Outcomes: economic information.
•
Procedure: economic studies and healthcare technology assessment reports.
Selection, evaluation of quality, and synthesis of literature
of efficacy, safety, and economics
22 >
•
To elaborate a systematic review, papers were chosen by title and abstract.
After a complete reading, all documents not meeting inclusion criteria were
excluded.
•
The evaluation of the quality of clinical trials, systematic reviews, and
economic analysis were attained using specific evaluation scales from the
Critical Appraisal Skills Programme (CASP), adapted by CASP Spain
Eculizumab for treatment of PNH / AETSA 2011
(CASPe) (11-13). Work team methodologists used a specific questionnaire to
provide a critical evaluation on the quality of non-controlled intervention
studies.
•
Selection, critical reading, and qualitative synthesis of the evaluated studies
were independently undertaken by two pairs of researchers (two
methodologists and two clinical pharmacists). Discrepancies were solved in
each pair by means of a discussion.
•
Evaluation of safety was accomplished by the Andalusian Center of
Pharmacovigilance (CAFV) and summarized by the methodologists.
•
Two PNH clinical experts acted as consultants for the methodologists during
the elaboration of this report.
•
Economic evaluation and budget impact study in different scenarios were
accomplished by the economists.
•
Preliminary evaluation report was reviewed by all panel members.
< 23
Eculizumab for treatment of PNH / AETSA 2011
Results
Results of efficacy and safety bibliographic search
In the bibliographic search of efficacy and safety on eculizumab treatment in
patients with PNH, a total amount of 153 documents were found in different databases
(70 in MEDLINE, 30 in EMBASE, 11 in the Cochrane Library, and 42 in the rest of
databases). Figure 1 shows the flow diagram of the documents selection process during
the systematic review. Complete text was obtained from 34 documents, seven of which
met inclusion criteria.
Reasons for exclusion of the rest of studies are indicated in Appendix II.
Figure 1. Flowchart illustrating selection process of documents for the systematic review
Documents identified during search
(n = 153)
Documents after clearing duplicates
(n = 85)
Excluded full papers
(n = 27)
Papers excluded by title and
abstract
(n = 51)
Included documents
(n = 7)
< 25
AETSA 2011 / Eculizumab for treatment of PNH
Description of the documents included in the systematic
review of efficacy and safety
The following documents were included: a systematic review (1), EMA’s
eculizumab European Public Assessment Report (EPAR) (8), besides five clinical studies
evaluating efficacy and safety of eculizumab treatment in patients with PNH: a phase II
pilot study (14), a phase II extension study II (15), a randomised clinical trial (RCT)
(TRIUMPH pivotal study) (16), and two interventional non-controlled studies [SHEPHERD
study (17), and extension study including all patients (18)].
Eculizumab studies undertaken in patients with PNH (Figure 2):
ƒ
ƒ
26 >
Phase II studies:
o
Descriptive pilot study (C02-001) with 11 patients, evaluated after 12
week treatment with eculizumab (14).
o
Descriptive extension study of the previous study. Patients were
evaluated 64 week after starting eculizumab treatment (E02-001) (15).
Besides, an extension of the pilot study was undertaken during 104
weeks (X03-001). This study has not been published and its results are
not included in the EMA EPAR.
Phase III studies:
o
TRIUMPH: eculizumab RCT pivotal trial versus placebo (C04-001) (16).
A 26-week study including 87 patients with PNH.
o
SHEPHERD: uncontrolled study (C04-002) (17). This 52-week treatment
study included 97 patients with PNH. Results of pre-treatment and after
eculizumab treatment were analysed.
o
Extension study: interventional non-controlled study (E05-001), including
the 195 patients of the studies previously undertaken (phase II,
TRIUMPH and SHEPHERD) (18). Ongoing study after the publication of
the data.
Eculizumab for treatment of PNH / AETSA 2011
Figure 2. Flowchart showing eculizumab studies undertaken in patients with PNH
Hillmen et al. 2004 (14)
Phase II, 12 week treatment,
11 patients
Hill et al. 2005 (15)
Phase II, 52 week treatment,
11 patients
Phase II, 104 week treatment,
11 patients
Hillmen et al. 2006 (TRIUMPH) (16)
Phase III, 26 week treatment,
87 patients
Hillmen et al. 2007 (Extension
study) (18)
Phase III, 102 week treatment,
195 patients
Brodsky et al. 2008 (SHEPHERD) (17)
Phase III, 52 week treatment,
97 patients
Quality assessment of the studies
The TRIUMPH RCT (16) quality was low. Of 9 questions in the CASPe scale (11),
5 answers were negative (3 related to internal validity, and 2 related to external validity).
Main endpoints in the RCT were surrogate endpoints.
Quality of the systematic review was good according to CASPe (12) scale. Of 8
questions of the scale, one answer related to external validity was negative.
Uncontrolled intervention studies [phase II study (14) and its extension (15),
SHEPHERD study (17), and Hillmen et al. extension study (18)] are not valid designs to
evaluate drug efficacy, given the possible biases associated to these type of designs.
However, taking all this into account, these studies were accurate in the description of
populations, patients baseline characteristics, inclusion criteria, and missing data during
the follow-up.
RCT and systematic review quality evaluation results, according to CASPe scale,
are indicated in Appendix III.
< 27
AETSA 2011 / Eculizumab for treatment of PNH
1. Baseline characteristics of patients included in the
studies
Main baseline characteristics of patients included in the studies are described in
the following table:
Table 2. Baseline characteristics of patients included in the pilot study (phase II), TRIUMPH
and SHEPERD
FASE II (14)
Patients
Main baseline characteristics
pre-treatment
thrombotic event incidence (%)
PRBC units-transfused the
previous 12 months (median,
range)
LDH levels
(median) (U/L)
Percentage of PNH
granulocytes(median, range)
Age (years) (median/mean,
range)
Time from diagnosis (years)
(median, range):
Patients with history of aplasic
anemia or mielodisplasic
syndrome (%)
Patients with anticoagulant
treatment (%)
TRIUMPH (16)
SHEPHERD(17)
Eculizumab
n= 11
Eculizumab
n= 43
Placebo
n= 44
Eculizumab
n= 97
27%
21%
18%
43%
(12-55)
18
17
8
(0-66)
2.032
2.234
3,111
(mean)
97.0
(47.8-99.8)
48 (meanna)
(21-67)
8.7 (1.7-37.9)
73%
95.3
†
(82.6-99.5)
41 (mean)
35 (mean)
(20-85)
(18-78)
4.3
9.2
(0.9- 29.8)
(0.5-38.5)
18.7%
*
55.8%
27.3%
*
&
61%
#
-
† Data of 31 patients with baseline determinations (18)
‡ Data of 94 patients with baseline determinations (18)
& Data published by Hillmen et al. 2007 (18)
* Data from EMA’s eculizumab EPAR (8)
# Data published by Hillmen et al. 2006 (16)
28 >
&
32%
45.5%
55%
Patients with erythropoietin
treatment (%)
2,051
(537-5.245)
96.0
(1.1-99.9)‡
41 (meanna)
(18-78)
4.9
(0.1-31.4)
#
49%
25 %
7%
0%
-
Eculizumab for treatment of PNH / AETSA 2011
In relation to patients baseline characteristics:
•
Incidence of pre-treatment thrombotic events, in patients of the SHEPHERD
study (17), doubled the one found in patients of TRIUMPH study (16).
•
In the previous 12 months before eculizumab treatment, patients incluided in
TRIUMPH RCT (16) had received more than double of PRBC units than
patients included in the SHEPHERD study(17).
•
In all studies (14;16;17), lactate dehydrogenase (LDH) baseline levels
exceeded (almost nine times) the upper limit of normal (ULN).
•
Patients age average in the different studies was similar.
TRIUMPH RCT (16) showed no differences among the baseline characteristics of
both groups except duration of illness, aplasic anemia history, and patients treated with
anticoagulants or with erythropoietin. Hillmen et al. (16) stated that these differences were
not statistically significant, however, significance values of baseline characteristics
differences were not indicated.
Major differences regarding inclusion criteria of patients in the
studies
Major differences regarding inclusion criteria of patients in the studies were the
number of PRBC transfused prior to eculizumab treatment and baseline platelets levels.
•
Patients incluided in the SHEPHERD study (17) received less PRBC before
starting treatment [≥1 PRBC units in the previous 24 months vs. ≥4 PRBC
units in the previous 12 months before starting the phase II study (14) and
the TRIUMPH RCT (16)].
•
In the TRIUMPH RCT (16), patients included showed a baseline platelet
count superior to 100,000/mm3 vs. superior to 30,000/mm3 in the
SHEPHERD study (17).
2. Intervention in the studies
In all studies(14-18), during the induction phase, eculizumab was given to all
patients with PNH, at one 600 mg dose weekly for four weeks followed by a 900 mg dose
in the fifth week. Then, in the maintenance phase, 900 mg every two weeks.
In two patients of the phase II extension study (15), a patient of the TRIUMPH
RCT (16), and eight patients of the SHEPHERD study (17), it was necessary to modify
the dosage regime during the maintenance phase, due to an increment in the haemolysis
in the last two days of the interval dosing. These patients received eculizumab every 12
days. Haemolysis was reduced in the two patients involved in the extension study (15)
and six of the SHEPHERD patients whose dosage regime was adjusted (17).
< 29
AETSA 2011 / Eculizumab for treatment of PNH
3. Main results of efficacy and safety
Results from the systematic review are displayed following the clinical relevance
order given by the evaluated endpoints (survival, thrombotic events, quality of life, PRBC
transfusions requirements, and haemoglobin and haemolysis levels).
Survival
No studies evaluating survival in PNH patients under eculizumab treatment were
reported. The extension study including 195 patients had the longest monitoring period
(102 weeks ) (18).
Incidence of thrombotic events
The only study which evaluated the incidence of thrombotic events in patients
with PNH under eculizumab treatment was the extension study by Hillmen et al. (1;18).
This study included the patients participating in the pilot, TRIUMPH, and SHEPHERD
studies.
Main endpoint of the extension study was the rate of major adverse vascular
events (MAVE) or thrombotic events. Pre-treatment MAVEs were evaluated through a
retrospective analysis of the patients’ medical history. Of all pre-treatment MAVEs
considered in the study, only 73% of them had diagnostic confirmation.
MAVEs included thrombophlebitis, deep vein thrombosis, pulmonary embolus,
cerebrovascular accident, amputation, myocardial infarction, transient ischemic attack,
unstable angina, renal vein thrombosis, mesenteric vein thrombosis, portal vein
thrombosis, gangrene, acute peripheral vascular occlusion, sudden death, and other
events.
Incidence of thrombotic events in patients with PNH decreased from 7.37
events/100 patients-year (124 events) before eculizumab treatment to 1.07 events/100
patients-year (3 events) after treatment (p< 0.001).
Within the subgroup of patients who received antithrombotic therapy before the
study, thrombotic events rate decreased from 10.61 events/100 patients-year before
eculizumab treatment to 0.62 events/100 patients- year after treatment (p< 0.001).
In the study, similar time periods before eculizumab were also compared. When
considering the same time period of pre-treatment and post-treatment with eculizumab,
the number of thrombotic events was 39 and 3, respectively (p< 0.001).
The paper of the extension study (18) also showed thrombotic events results after
26 weeks in the TRIUMPH RCT. One patient from the placebo group developed a
thrombotic event vs. 0 in the eculizumab group. The proportion of anticoagulated patients
in the RCT was of 45.5% in the placebo group vs. 55.8% in the eculizumab group,
according to the EPAR (8). Nevertheless, according to Hillmen et al. paper (16),
proportion of anticoagulated patients in the RCT was 25% in the placebo group vs. 49%
in the eculizumab group.
30 >
Eculizumab for treatment of PNH / AETSA 2011
Quality of life
Quality of life was evaluated as secondary endpoint in the pilot study (14) and its
extension (15), TRIUMPH (16) and SHEPHERD (1;17). It was assessed by means of the
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale and the
European Organisation for Research and Treatment of Cancer Quality of Life
Questionnaire Core 30 (EORTC QLQ-C30). Appendices IV and V show both scales and a
brief description of each.
Baseline score of patients quality of life obtained in both scales was not indicated
in the TRIUMPH or SHEPHERD studies. Baseline score obtained in the EORTC QLQC30 scale was only indicated in the phase II study.
In the SHEPHERD study, patients’ quality of life, measured in both scales before
and after eculizumab treatment, showed a major improvement over patients who received
eculizumab in the TRIUMPH RCT. It is necessary to bear in mind that patients in the RCT
received a transfusion prior to quality of life analysis, while in the SHEPHERD study, they
did not received it.
FACIT-Fatigue scale
TRIUMPH RCT (16) showed that in patients treated with eculizumab, the mean
score in the FACIT-Fatigue scale increased 6.4 ± 1.2 points, while in patients who
received placebo, median score decreased 4.0 ± 1.7 points (p< 0.001). 53.7% of
eculizumab group patients showed a change in the FACIT-Fatigue scale ≥ 4 points
(minimal clinically important difference) with respect to a 20.5% of patients in the placebo
group (p=0.0028) (see Table 7) (8).
In the SHEPHERD study (17), median score of FACIT-Fatigue scale in PNH
patients increased 12.2 points (p<0.001).
EORTC QLQ-C30 scale
At the beginning of the pilot study, median score of overall health status in the
eleven patients who received eculizumab was of 56.1. It was observed a change of 13.7
points after 12 weeks of treatment (p=0.02), and a change of 13.8 points after 64 weeks
with eculizumab (p<0.009) (14;15) (see Tables 5 and 6).
En el RCT TRIUMPH (16), there were statistically significant differences among
both treatment groups in all EORTC QLQ-C30 scale items, except those of nausea and
vomits, financial difficulties, constipation, and diarrhea. In the SHEPHERD study (17)
there were also observed statistically significant differences before and after eculizumab
treatment, in the same items of the EORTC QLQ-C30 scale (see Tables 7 and 8).
Transfusions of Packed Red Blood Cells
The number of PRBC units transfused to each patient was evaluated as main
efficacy endpoint in TRIUMPH (16) and SHEPHERD (17) studies. Besides, the same
endpoint was evaluated in the phase II study en (14) and its extension (15). In the
< 31
AETSA 2011 / Eculizumab for treatment of PNH
TRIUMPH RCT (16) it was evaluated the number of PRBC units transfused per patient
was evaluated contrasting the eculizumab group vs. the placebo group. In both phase II
studies (14;15), and in the SHEPHERD study (17), the number of PRBC transfused per
patient, was evaluated before and after eculizumab treatment. Also, both TRIUMPH RCT
and SHEPHERD study evaluated the proportion of patients achieving transfusion
independence during eculizumab treatment (1;16;17).
In the TRIUMPH RCT (16), the median of PRBC units transfused was of 10
(range 2-21) in the placebo group versus 0 (range 0-16) in the eculizumab group (p<
0.001). Likewise, in the SHEPHERD study (17), the median of transfused PRBC units in
the 12 months pre-treatment was of 8 versus 0 (p< 0.001) in the following 12 months.
Patients of TRIUMPH RCT were randomized into three groups, according to the
number of PRBC units who received during the 12 months prior to enrolling in the study
(4-14, 15-25 and > 25 PRBC units). When groups results are individually analysed, the
difference in the median of required PRBC units was of 6 (p< 0.005), 8 (p< 0.005), and
15 (p< 0.005), respectively (8) (see Table 7).
In the SHEPHERD study (17), patients were stratified into four groups, according
to baseline level of LDH: 537-1,379; 1,380-2,050; 2,051-2,866; and 2,867-5,245 U/L. In
patients with a baseline level of LDH among 537 and 1,379 U/L, the reduction of
transfused PRBC units before and after eculizumab treatment was not statistically
significant. However, patients with baseline levels of LDH superior to 1,380 U/L,
reductions of transfused PRBC units before and after eculizumab treatment were
statistically significant.
Differences observed before and after the median in each of the four groups were
of 8 PRBC units (p= 0.143), 6.5 PRBC units (p= 0.033), 9 PRBC units (p<0.001), and
6.5 PRBC units (p=0.006), respectively (see Table 8).
On the other hand, phase II study (14) and its extension study(15), showed that
the median of transfused PRBC units patient/months decreased from 1.8 to 0 (p= 0.003)
and to 0.3, after 12 weeks and 64 weeks of eculizumab treatment, respectively (see
Tables 5 and 6).
51% of the patients who received eculizumab, according to TRIUMPH RCT,
required no transfusions during the 26 week-treatment; while all patients in the placebo
group required transfusions (p<0.001) (16). Same percentage of patients in the
SHEPHERD study (51%) achieve transfusion independence during the 52-week
treatment with eculizumab (p =0.001) (17).
Haemoglobin levels
Percentage of patients with stable haemoglobin levels was only evaluated in the
TRIUMPH RCT (primary efficacy endpoint) (1;16). 48.8% of patients treated with
eculizumab showed stable haemoglobin levels vs. 0% of patients in the placebo group
(p<0.001) (16).
When analysing stratification, depending on the number of PRBC received during
the 12 months prior to the study (4-14, 15-25 and > 25 PRBC units), it was observed that
eculizumab group patients showed stable haemoglobin levels in 80% (p<0.001), 29.4%
(p=0.02), and 36.4% (p=0.09) of the cases, respectively (8).
32 >
Eculizumab for treatment of PNH / AETSA 2011
Haemolysis
Haemolysis was evaluated through LDH level, area under curve (AUC) of LDH,
and percentage of PNH type III erythrocyte population (1).
In the TRIUMPH RCT (16), after 26 weeks of treatment, LDH levels were
reduced from 2,199.7 ± 157.7 to 327.3 ± 67.6 U/L in patients who were treated with
eculizumab. In patients who received placebo, LDH levels remained high, ranging from
2,258.0 ± 154.8 to 2,418.9 ± 140.3 U/L (p< 0.001).
Both in TRIUMPH RCT (16) and SHEPHERD study (17), in patients under
eculizumab treatment, LDH levels were significantly reduced towards normal range (103223 U/L) after the first month of treatment, and they were closer to normal range during
monitoring (p< 0.001).
In the TRIUMPH RCT (16), patients of placebo group showed a constant
percentage of PNH type III erythrocyte population (35.7 ± 2.8% before starting the RCT
and 35.5 ± 2.8% after 26 weeks). Reduction of intravascular haemolysis within
eculizumab patients generated an increase of PNH type III erythrocyte population (from
28.1% ± 2.0% to 56.9% ± 3.6%) (p<0.001). Similarly, in the SHERPHED study (17), there
was an increment of PNH type III erythrocyte population (from 38.7 ±2.17% to 55.4 ±
2.85%) after 52 weeks of eculizumab treatment.
Adverse events
Eculizumab is a new treatment for PNH of recent commercialization, so there is
no evidence of long-term safety.
Clinical trials data
Safety was evaluated in the phase II pilot study (14), in the extension study of the
phase II study (15), in the TRIUMPH RCT (16), and in the SHEPHERD uncontrolled
intervention study (17).
Meningococcal infection was the most serious adverse event (AE) observed
related to eculizumab treatment. Out of 195 patients with PNH and other 716 patients
with other pathologies, all treated with eculizumab, there were 3 cases of meningitis (one
of them in a non-vaccinated patient without PNH, and two cases in vaccinated PNH
patients). Therefore, 0.3% of patients under eculizumab treatment developed
meningococcal infection (8).
TRIUMPH RCT (16), reported no significant differences in the frequency of
adverse events among patients treated with eculizumab and the placebo group. In the
SHEPHERD study (17), the percentage of patients with serious adverse events (SAES)
during the 52 weeks of treatment was 7.2%.
91.8% of patients included in the SHEPHERD study suffered from one or more
infections (one infection: 15.5% of patients; two infections: 33% of patients; three or more
infections: 43.3% of patients). 74.7% of infections were mild, 24.2% moderate, and 1.1%
< 33
AETSA 2011 / Eculizumab for treatment of PNH
severe. 29.9% of patients under eculizumab treatment showed an upper respiratory tract
infection and the 13.4 % an urinary tract infection (17).
Most frequent AE are described in the following table:
Tabla 3. Adverse events most frequently observed in the studies
Most frequent AE
(>10% in some
groups)
Cephalea
Nasopharyngitis
Upper respiratory
tract infection
Nausea
Pyrexia
Back pain
Myalgia
Fatigue
TRIUMPH (16)
SHEPHERD (17)
Datos combinados
TRIUMPH/SHEPHERD (8)
26 weeks
52 weeks
26 weeks
Eculizumab
Placebo
Eculizumab
Eculizumab
n= 43
n= 44
n= 97
n=140
44%
27%
53%
50%
23%
18%
32%
25%
14%
23%
30%
-
16%
11%
21%
17%
-
5%
20%
14%
19%
9%
15%
-
-
-
10%
8%
12%
2%
-
8%
One patient of each treatment groups in the TRIUMPH RCT (16) showed low
antibody levels against eculizumab. The antibodies of the patient who received
eculizumab did not affect complement inhibition. In the SHEPHERD study (17), 2.1% of
patients developed neutralising antibodies after 52 weeks of treatment with eculizumab.
Safety data from secondary sources
In the FDA Adverse Event Reporting System (19) (AERS) database, 31
notifications have been found containing a total amount of 91 adverse events associated
with eculizumab treatment. 18.7% of these events is associated to infusion-related
reactions and general disorders, and 12.1%, with infections.
The EMA (8;20) established a risk management plan which specified activities
related to pharmacovigilance and risk minimization, regarding the following safety
aspects:
34 >
•
Meningococcal infection (identified risk).
•
General infections (potential risk).
•
Serious haemolysis after treatment withdrawal (potential risk).
Eculizumab for treatment of PNH / AETSA 2011
•
Cephalea (identified risk).
•
Infusion reactions (potential risk).
•
Immunogenicity (potential risk).
•
Hematologic Malignancies (potential risk).
•
Pregnancy and lactation (no information available).
•
Experience in children (no information available).
•
Renal impairment (no information available).
•
Hepatic impairment (no information available).
Other clinical situations
Efficacy and safety of eculizumab treatment in patients with PNH de novo
No studies were found that accomplished the inclusion criteria of the systematic
review, and which also evaluated efficacy and safety of eculizumab treatment in patients
de novo.
In the SHEPHERD study (17) there were included patients who did not receive
RBC transfusions in the 12 months prior to beginning of treatment. Notwithstanding, they
were no patients de novo, as they had received at least one PRBC transfusion during the
24 months prior to beginning of study.
Efficacy and safety of eculizumab treatment in PNH patients under 18
No studies were found that evaluated efficacy and safety of eculizumab treatment
in PNH patients aged ≤ 18 years.
Reintroduction of eculizumab treatment
No studies were found that evaluated efficacy and safety of reintroduction of
eculizumab, after withdrawal from treatment, in patients with PNH.
Eficacia y seguridad del tratamiento con eculizumab durante el embarazo
No se localizaron estudios que cumplieran los criterios de inclusión de la revisión
sistemática y que evaluaran la eficacia y seguridad del tratamiento con eculizumab
durante el embarazo, en pacientes con HPN.
Efficacy and safety of eculizumab treatment during pregnancy
No studies were found that accomplished the inclusion criteria of the systematic
review and that evaluated efficacy and safety of eculizumab treatment during pregnancy
in patients with HPN.
< 35
AETSA 2011 / Eculizumab for treatment of PNH
Table 4. Summary of studies results
Study
PHASE II
Phase II
extension
Phase II
extension
Type of
Study
n
Intervention
Group
Control
Group
descriptive
11
Eculizumab
descriptive
11
Eculizumab
-
descriptive
11
Eculizumab
-
PRBC units transfused/ patient/month
Hb levels
LDH levels
Hemoglobinuria (days/patient/month)
Quality of life
Primary
endpoints
analysis
Time of
treatment
ITT
12 weeks
ITT
12 + 52
weeks
ITT
104 weeks
% of patients avoiding
transfusions
AUC and LDH levels
Quality of life
ITT
26 weeks
-
% of patients with serious
adverse events
PRBC units transfused/patient
% of patients avoiding
transfusions
Quality of life
ITT
52 weeks
-
Thrombotic events rate (nº per 100 patients-year)
ITT
102 weeks
87
Eculizumab
Placebo
SHEPHERD
descriptive
97
Eculizumab
EXTENSION
descriptive
195
Eculizumab
36 >
Secondary endpoints
% of patients with stable Hb levels
PRBC units transfused/patient
RCT and
DB
TRIUMPH
Primary endpoints
Eculizumab for treatment of PNH / AETSA 2011
Table 5a. Phase II study, Hillmen et al. 2004 (14). Most relevant aspects of Phase II study
SAMPLE SIZE
11 patients with PNH.
PATIENTS’
LOSSES
0 patients.
DESIGN
TREATMENT
OTHER DATA OF
INTEREST REGARDING
TREATMENT AND
STUDY
INCLUSION CRITERIA
TYPE OF ANALYSIS
Phase II, descriptive pilot study, accomplished in two hospitals in the
United Kingdom.
Eculizumab 600 mg i.v. weekly (4 dose), followed by a 900 mg dose in
th
the 5 week. Then, 900 mg every 2 weeks.
concomitant immunosuppressant therapy (f.e. cyclosporine), warfarin,
and iron supplements were allowed.
2 of 11 patients had a history of thrombosis.
6 of 11 patients were treated with warfarin before and during treatment.
8 of 11 patients had a history of aplastic anemia.
Patients ≥ 18 years.
PNH diagnosed using flow cytometric analysis, at least 6 months
before beginning of study.
≥ 4 transfusions in the previous12 months before beginning of study.
Negative throat culture for Neisseria meningitidis and N. gonorrhoeae.
ITT, Alexion Pharmaceuticals reviewed the manuscript and provided
feedback.
Table 5b. Phase II study, Hillmen et al. 2004 (14). Measured variables
ENDPOINT EVALUATED IN
THE STUDY
PRBC
units/patient/month
(mean)
PRBC units/patient/
month (median)
Before eculizumab
treatment (n= 11)
After 12 weeks of eculizumab
treatment (n= 11)
P
2.1
0.6
0.003
1.8
0.0
0.003
3,111 ± 598
594 ± 32
0.002
2.9
0.12
0.001
Median baseline
score
56.1
70.9
70.5
77.3
47.5
39.4
30.3
Change in the scores
LDH (median ± DE) IU/L
Incidence of
hemoglobinuria (mean)
(days/patient/ month)
Quality of life
EORTC QLQ-C30
Global health
Physical status
Emotional status
Cognitive status
Fatigue
Dyspnea
Insomnia
13.7
13.0
12,7
11.8
-15.3
-12.4
-10.8
0.02
<0.001
<0.001
0.002
<0.001
0.002
0.049
LDH (normal range): 150-480 U/L
< 37
AETSA 2011 / Eculizumab for treatment of PNH
Table 6a. Extension study of phase II study, Hill et al. 2005 (15). Most relevant aspects of
Phase II study
SAMPLE SIZE
11 patients with PNH.
PATIENTS’
0 patients.
LOSSES
DESIGN
Descriptive study.
TREATMENT
Eculizumab maintenance regimen during 52 weeks, 900mg every two
weeks.
TYPE OF ANALYSIS
ITT, Alexion Pharmaceuticals reviewed the manuscript and provided
feedback.
Table 6b. Extension study of phase II study, Hill et al. 2005 (15). Variables
ENDPOINT EVALUATED
THE STUDY
IN
PRBC UNITS /patient/month
(mean)
PRBC UNITS /patient/month
(median)
LDH (mean ± SD) IU/L
Haemoglobin (g/dL)
Platelets x 109/L
PNH Erythrocyte type III (%)
Hemoglobinuria incidence
(mean) (days/patient/month)
Quality of life
EORTC QLQ-C30
Before eculizumab
treatment ( n= 11)
After 64 weeks of
eculizumab treatment
(n= 11)
p
2.1
0.5
---
1.8
0.3
0.001
3,111 ± 598
10.0 ± 0.4
183.0 ± 35.3
36.7 ± 5.9
622.4 ± 41.1
10.4 ± 0.4
180.8 ± 35.8
58.4 ± 8.5
0.002
NS
NS
0.005
2.9
0.2
0.001
Median baseline score
Change in the scores
56.1
13.8
0.009
70.9
14.3
<0.001
70.5
12.5
<0.001
66.7
14.5
0.003
77.3
10.3
0.001
-17.8
47.5
Fatigue
<0,001
-16.6
39.4
<0.001
Dyspnea
-8.2
30.3
Insomnia
0.031
-8.2
21.2
0.023
Pain
4.1
3.0
Constipation
<0.001
Haptoglobine, bilirubin, and reticulocytes levels did not change significantly when patients were
treated with eculizumab.
Global health
Physical status
Emotional status
Psychological status
Cognitive status
Normal range for a platelet count: 150-400 x 109/L.
38 >
Eculizumab for treatment of PNH / AETSA 2011
Table 7a. TRIUMPH randomised clinical trial (8;16). Most relevant aspects of study
SAMPLE SIZE
PATIENTS’
LOSSES
DESIGN
87 patients with PNH.
85 patients completed treatment period in the study.
2 patients of eculizumab group did not complete the RTC, one of them due
to problems in accesing the study centre, the other due patient due to
pregnancy.
10 patients of placebo group discontinued infusions. However, monitoring
continued until study completion.
Phase III, RCT, DB and multicenter (34 centres in USA, Canada, Europe,
and Australia).
Stratified randomization according to the number of PRBC units required in
the previous 12 months before study began. Three groups:
‰
between 4 and 14 of PRBC units.
‰
between 15 and 25 of PRBC units.
‰
> of 25 of PRBC units.
2 weeks of population screening + 3 months of monotorization + 26 weeks
of treatment.
Active group: Eculizumab 600 mg i.v. weekly (4 doses), followed by 1
dose of 900mg in the 5th week; then 900mg every 2 weeks.
TREATMENT
Control group: Placebo i.v. weekly (5 doses), then every 2 weeks.
OTHER INTEREST
DATA IN RELATION
TO TREATMENT
INCLUSION CRITERIA
EXCLUSION CRITERIA
TYPE OF ANALYSIS
concomitant therapy allowed: erythropoietin, immunosuppressants,
anticoagulants, iron supplements, and folic acid. Concomitant theraphy,
steady doses, from 26 weeks before starting treatment and during
treatment.
Patients aged ≥ 18.
Erythrocytes PNH type III percentage ≥ 10%, confirmed by flow cytometry.
≥ 4 transfusions in the 12 months prior to beginning of study, and one
transfusion at least during the 13-week monitoring period.
Platelets count > 100.000/mm3.
LDH ≥ 1,5 x ULN.
Neutrophils count ≤ 500/μL.
Patients with hereditary complement deficiency, active bacterial infection
or meningococcal disease history; patients who received an allogeneic
hematopoietic cell transplantation.
ITT analysis was only accomplished in major endpoints.
Data were analyzed by Alexion laboratory.
< 39
AETSA 2011 / Eculizumab for treatment of PNH
Table 7b. TRIUMPH randomised clinical trial (8;16). Variables
ENDPOINT EVALUATED
IN THE STUDY
Eculizumab
Placebo
ARR
n= 43
n= 44
(IC 95%)
Results of major endpoints
p
NNT
Pacientes en los que se
48,8 % (33,93
estabilizan los niveles de
48,8 %
0,0%
< 0,001
63,8%)
(2-3)
Hb
Patients who stabilized their Hb levels (%), towards the end of the study. Stratified data according to the number
of transfusion received in the 12 months prior to study
4 -14 PRBC units
80.0%
2
80.0%
0.0%
< 0.001
(ne=15, np=15)
(59.8-100.2%)
(1-2)
15 and 25
29.4%
4
29.4%
0.0%
0.02
PRBC units (ne=17,
(7.8-51.1%)
(2-13)
np=18)
> 25 PRBC units
36.4%
3
36.4%
0.0%
0,09
(ne=11, np=11)
(7.9-64.8%)
(2-13)
PRBC units
10
0 (0-16)
< 0.001
transfused/patient
(2-21)
(median, range)
PRBC units transfused per patient. Stratified data according to the number of transfusion received in the 12
months prior to study
4 -14 PRBC units
6
(20 (0-4)
< 0.001
(ne=15, np=15)
12)
15-25 PRBC units (ne=17,
10
(22 (0-15)
< 0.001
np=18)
21)
> 25 PRBC units (ne=11,
18
3 (0-16)
< 0.001
np=11)
(10-20)
Secondary endpoints results
Patients with transfusion
51.0%
2
51.0%
0%
< 0.001
independence
(36.1-65.9%)
(2-3)
LDH level towards the
end of study (median,
239
2,167
< 0.001
U/L)
Mean change in quality
6.4 ± 1.2
- 4.0 ± 1.7
< 0.001
of life (FACIT-Fatigue)
Patients with changes in
quality of life FACIT33.1%
4
Fatigue scale ≥ 4
53.7%
20.5%
0.002
(13.3-53.0%)
(2-8)
(minimal relevant
difference)
Quality of life with EORTC
QLQ-C30
Global health status
10.9
-8.5
<0.001
Role status
17.9
-6.9
<0.001
Social skills
16.7
2.0
0.003
Cognitive status
7.9
-6.1
0.002
Physical status
9.4
-3.5
<0.001
Emotional status
7.5
-3.7
0.008
Fatigue
-16.9
10.0
<0.001
Pain
-12.3
5.3
0.002
Nausea and vomits
-0.4
2.8
0.06
Dyspnea
-7.9
8.9
<0.001
Lack of appetite
-10.3
3.3
<0.001
Insomnia
-7.9
4.9
0.01
Economic difficulties
-10.3
0.0
0.19
Constipation
-6.3
0.0
0.20
Diarrhea
4.8
5.7
0.15
Safety results
11.2%
9
Serious adverse events
9.3 %
20.5 %
(-3.6-25.9%)
(4-28)
40 >
Eculizumab for treatment of PNH / AETSA 2011
Table 8a. SHEPHERD study (17). Most relevant aspects of study
POPULATION
97 patients with PNH.
96 patients completed the 52-week study.
PATIENTS’
LOSSES
DESIGN
One patient did not finish study period due to an AE not related to the
study drug.
Phase III, multicenter descriptive study (USA, Canada, Europe, and
Australia).
2 weeks of screening + 52 weeks of treatment.
TREATMENT
Eculizumab 600mg i.v. weekly (4 doses), followed by one 900mg dose in
the 5th week; then 900mg every 2 weeks.
INCLUSION
CRITERIA
Patients ≥ 18 years.
Percentage of RBC type III ≥ 10% confirmed by flow cytometry.
≥1 transfusion in the previous 24 months prior to study.
Platelets count > 30 x 109/L.
LDH ≥ 1.5 x ULN.
EXCLUSION CRITERIA
Neutrophils count ≤ 500/μL (= 0.5 x 109/L).
Patients with hereditary complement deficiency, active bacterial infection
or meningococcal disease history; patients who received an allogeneic
hematopoietic cell transplantation.
TYPE OF ANALYSIS
ITT
Table 8b. SHEPHERD study (17). Variables
ENDPOINT EVALUATED IN
THE STUDY
% patients with serious adverse
events *
% patients experiencing one or
more infections **
% patients developing antibodies
Before eculizumab
treatment
n= 97
Safety results
After 52 weeks of
eculizumab treatment
n= 97
-
7.2
-
91.8
-
2.1
p
Efficacy results
PNH erythrocytes type III (%)
55.7
33.5
< 0.001
(median)
PNH erythrocytes type III (%)
38.7 ± 2.17
55.4 ± 2.85
(mean ± SD)
% patients who avoided
51
< 0.001
transfusion
Stratification results. in four groups. according to baseline LDH value. in relation to the percentage of
patients achieving transfusions independence (%).
LDH between 537-1.379 U/L
60
< 0.001
(n=25)
LDH between 1.380-2.050 U/L
50
0.021
(n=24)
LDH between 2.051-2.866 U/L
50
< 0.001
(n=24)
LDH between 2.867- 5.245 U/L
42
0.021
(n=24)
Number of transfused PRBC
8.0 (12.3 ± 1.25)
0.0 (5.9 ± 1.06)
< 0.001
/patient [median (mean ± SD)]
previous 12 months
following 12 months
Stratification results. in four groups. according to baseline LDH values. in relation to the number of
< 41
AETSA 2011 / Eculizumab for treatment of PNH
Table 8b. SHEPHERD study (17). Variables
Before eculizumab
After 52 weeks of
treatment
eculizumab treatment
n= 97
n= 97
transfused PRBC/ patient [median (mean ± SD)].
ENDPOINT EVALUATED IN
THE STUDY
p
LDH between 537-1.379 U/L
8.0 (11.3 ± 2.21)
0.0 (7.6 ± 2.41)
0.143
(n=25)
LDH between 1.380-2.050 U/L
7.5 (11.3 ± 2.38)
1.0 (7.9 ± 2.77)
0.033
(n=24)
LDH between 2.051-2.866 U/L
9.5 (14.3 ± 3.15)
0.5 (2.6 ± 0.91)
< 0.001
(n=24)
LDH between 2.867-5.245 U/L
8.5 (12.3 ± 2.27)
2.0 (5.4 ± 1.82)
0.006
(n=24)
Quality of life change (FACIT12.2 ± 1.1
<0.001
Fatigue) [mean ± SD] (n=95)
Quality of life change (FACIT10.0
Fatigue) [median] (n=95)
Stratification results. in four groups. according to baseline LDH values. in relation to quality of life
change (FACIT-Fatigue) [median]
LDH entre 537-1.379 U/L (n=23)
8.0
LDH entre 1.380-2.050 U/L (n=24)
9.0
LDH entre 2.051-2.866 U/L (n=24)
-
10.5
LDH entre 2.867- 5.245 U/L (n=24)
15.5
Quality of life EORTC QLQ-C30
(change mean after 52 weeks of treatment ± SD).
Global health
19.7 (2.05)
< 0.001
Role status
20.4 (2.67)
< 0.001
Social skills
17.4 (2.84)
< 0.001
Cognitive status
8.6 (2.26)
< 0.001
Physical status
14.8 (1.63)
< 0.001
Emotional status
15.6 (2.26)
< 0.001
Fatigue
27.5 (2.32)
< 0.001
Pain
8.1 (2.61)
<0.001
Nausea and vomits
2.5 (1.54)
0.002
Dyspnea
7.9 (2.11)
< 0.001
Lack of appetite
11.6 (2.77)
< 0.001
Insomnia
1.8 (1.96)
< 0.001
Economic difficulties
0.7 (2.78)
0.768
Constipation
0.4 (2.03)
0.4 (2.03)
* Serious adverse events were: pyrexia (2.1%). headache (1%). abdominal distension (1%). viral infection (1%).
anxiety (1%). and renal failure (1%).
**74.7% of infections were of mild intensity. and 24.2% of moderate intensity.
Table 9a. Extension study by Hillmen et al. 2007 (18). Most relevant aspects of study
SAMPLE SIZE
195 patients with PNH.
DESIGN
Intervention descriptive multicenter before/after study.
TREATMENT
Patients previously treated with eculizumab, continued receiving 900mg
eculizumab every 2 weeks, during 102 weeks.
Patients formely included in the placebo group in the TRIUMPH study
received eculizumab 600 mg i.v. weekly (4 doses), followed by 1 dose of
th
900mg in the 5 week; then 900mg every 2 weeks.
OTHER DATA OF INTEREST
REGARDING TREATMENT
concomitant immunosuppressant therapy, anticoagulants, and iron
supplements were allowed. Doses could be modified by clinician.
•
INCLUSION CRITERIA
EXCLUSION
CRITERIA
ANALYSIS TYPE
42 >
•
•
ITT
Patients who completed all previous studies (Phase II and its
extensions, TRIUMPH, and SHEPHERD).
Patients included in the TRIUMPH study who withdraw eculizumab
therapy before last study-stage due to lack of efficacy or exacerbation
of PNH symptoms, and who completed all monthly safety and efficacy
evaluations.
Patients who finished early extension studies of Phase II study,
SHEPHERD, and TRIUMPH due to adverse events.
Eculizumab for treatment of PNH / AETSA 2011
Tablee 9b. Extension study by Hillmen et al. 2007 (18). Variables
ENDPOINTS EVALUATED IN THE
STUDY
Thrombotic events (n)
Thrombotic events rate (nº per 100
patients-year) *
Thrombotic events (n) comparing
same period of time before and
after eculizumab treatment
Thrombotic events in patients who
received antithrombotic therapy
(n=103)
Thrombotic events rate in patients
who received antithrombotic therapy
(nº per 100 patients-year)
Before eculizumab
treatment
n= 195
After eculizumab
treatment
n= 195
124
3
7.37
1.07
< 0.001
39
3
< 0.001
40
1
< 0.001
10.61
0.62
< 0.001
p
< 43
Eculizumab for treatment of PNH / AETSA 2011
Economic evaluation results
This section includes:
A. A review of the literature on economic aspects.
B. A critical analysis on the information provided by the industry.
C. An economic analysis de novo.
A. Review of the literature on economic aspects
Four documents which included economic information regarding eculizumab
treatment for patients with PNH were taken into account. One of them was excluded from
consideration, as it was a letter to the director. The other three studies included were: two
reports of health technologies assessment (1;21) and a report evaluation of medicinal
products by the Pharmacotherapeutic Guide of Andalusian Hospitals (22). The first two
are related to the United Kingdom Health System and the third is related to the SSPA.
Evaluation results of the quality of the economic reports, according to CASPe
scale are indicated in Appendix III.
Description
The report by The West Midlands Health Technology Assessment Collaboration
(WMHTAC) reviewed evidence about natural history, prevalence, and prognosis of PNH,
as well as clinical efficacy and cost-efficacy of eculizumab treatment (1). In addition, three
economic analysis were undertaken with the aim of calculating the incremental costeffectiveness ratio.
The report accomplished by All Wales Medicines Strategy Group presented a
critical review and analysis on the evaluations of the report by the WMHTAG, and the
comments on it submitted by the company (21). For this reason, a conjoint analysis of
both reports have been attained.
The accomplished analyses are presented below:
1. Cost per life year gained with eculizumab treatment
European cohort studies which evaluated PNH natural history showed that
patients with more than 25 years of disease, worsen their life expectancy in 4.5 and 10.2
years in relation to general population. Though there is no evidence of drug impact in
terms of mortality, authors considered that survival after eculizumab treatment equaled
survival of general population, due to the reduction of thrombotic events rate achieved
with treatment. In this case, over a 25 year time horizon, the cost of eculizumab per life
year gained was estimated to be between £0.6 million and £1 million, with a discount rate
of 3.5%. The same analysis was done taking into account the saving from the use of
eculizumab. As there are no published estimates for the costs, authors assumed it to be
between £1,000 and £100,000 per patient. Treatment with eculizumab would save
< 45
AETSA 2011 / Eculizumab for treatment of PNH
between 50% and 90% of the cost of life support treatment. With these assumptions,
incremental cost per life year gained ranged from £0.5 million to £1.4 million (1;21).
The company submission states that incremental cost of £1.4 million uses an
excessively low estimate of life year gained with treatment (4.5 years). The statement
was not taken into account and authors pointed out that in any case, even in more in
more favourable circumstances for this drug, cost-efficacy ratios were still quite high
(lowest ratio was of 0.6 millions) (1;21).
2. Cost per year gained for averting thrombotic events thrombotic after
treatment with eculizumab
Cost per life year gained was estimated as result of thrombotic events averted
due to eculizumab treatment. Costs of thrombotic events were not considered due to lack
of data. A time horizon of 10-15 years (based on reported median survival data of media
en patients with PNH) was used together with a discount rate of 3.5%. Thrombotic events
before/after antes- eculizumab treatment were 7.37-1.07 events/100 patients- year.
Mortality rates of 52% for patients with thrombotic events, and 15% for patients without
thrombosis were used. In light of the aforementioned premises, incremental cost-efficacy
was ranged from £1.2 million to £1.4 million per life year gained, for a estimated median
survival of 10-15 years, respectively (1;21).
It was included a sensitivity analysis varying rate of thrombotic events of 4.22 per
100 patient-years for patients without use of eculizumab. It was considered that after
treatment, thrombotic events rate diminished to 0.61 per 100 person-years. Incremental
cost-efficacy in this case was estimated as £2.8 million £3.2 million per life year gained,
assuming a survival period of 15 and 10 years, respectively (1;21).
3. Cost of haemoglobin and LDH levels stabilization with eculizumab
treatment
This analysis calculated cost-efficacy ratios based on TRIUMPH RCT efficacy
data. The first year of treatment was estimated in £252,000, so the cost of the 26 weekRCT was of £126,000. Incremental cost-efficacy ratio estimated to stabilize haemoglobin
levels with eculizumab treatment was of £257,142 and the cost of stabilizing LDH levels
was of £340,541 (1;21).
When it was considered the cost of lowering LDH levels to a level which provided
clinical benefit to patient, incremental cost- effectiveness ratio decreased to £132,492
(1;21).
Laboratory company claimed that those sums could be revised downwards if
costs of clinical practice savings were included, savings resulting from clinical benefit
obtained with the use of eculizumab. The response was that those costs are unknown
(1;21).
In the same way it was accomplished a critical review of budget impact submitted
by the company. They considered that in order to establish net budget impact of drug
financing, saving costs for health system due to eculizumab clinical benefits must be
contemplated. Expenditure of normal clinical practice resulting of PNH treatment includes
varied interventions (from PRBC transfusions to analgesics or anticoagulants) and the
study did not assess estimation and valuation of those costs. This was the major
limitation of the analysis. As alternative, a saving range between £1,000 and £200,000
was estimated, but it was too broad and unrealistic, as there is a two-hundred times
46 >
Eculizumab for treatment of PNH / AETSA 2011
difference in pounds among the two extremes (1;21).
Authors concluded that:
•
Economic evidence is too limited at present, and
•
One limitation of the report is that cost- effectiveness was calculated by
inadequate result measures and incomplete cost estimations.
Finally, eculizumab evaluation report accomplished for the Pharmacotherapeutic
Guide of Andalusian Hospitals (22) estimated the incremental cost- efficacy for the major
endpoint in the TRIUMPH RCT. The cost for a patient to be transfusion-independent
during a year was of 698,900€. This estimation took into account the saving due to
reduction of the amount of PRBC units required. Cost of PRBC unit used in the estimation
was of 750€. This is a much superior cost that the one provided by the BOJA 210, 27th
Octubre 2005, which stipulates public prices for the health care services provided by
centers dependant of the Andalusian Public Health System. The autonomous agency
establishes a price of 68.09 €.
This report also estimated the incremental cost of eculizumab treatment con
eculizumab regarding allogeneic haematopoietic stem cell transplantation. Starting from a
cost estimation of this transplantation provided by Alexion Pharma, incremental cost was
of 316,141.22€. It should be taken into account that allogeneic haematopoietic stem cell
transplantation is the less frequent alternative in PNH patients (22).
B. Critical analysis of information submitted by the
company
Economic information submitted by the company did not include
pharmacoeconomic evaluation of treatment with eculizumab nor the detailed budget
impact for Andalusia. Information provided included:
•
Estimation of annual cost of the treatment in terms of retail price, under the
assumption that total cost would consist of HPP + VAT. It was stated that
budget impact would amount to 0.51% regarding the total health, but this
particular datum was not warranted. In the same way, the existence of
potential saving was mentioned, both in direct and indirect costs derived from
drug use, but remained unquantified.
•
Survival analysis. For this analysis two assumptions were made, as there is
no evidence was presented to suggest that eculizumab will provide survival
results. The first assumption presumed a median survival from diagnosis
between 10 and 22 years. In the second case, median survival was
estimated between 22 and 30 years. In both cases it was also assumed a
constant mortality rate through time. From these data, the company
established 4 different scenarios (best and worst scenario for eculizumab in a
combined manner) in which better survival after 20 years ranged from 0%50%.
•
From a methodological point of view, survival analysis accomplished, though
interesting, it lacks limitations derived from the assumptions made, that
reduce the degree of validity of the results given. Firstly, median survival from
diagnosis of 10-22 years is excessively optimistic, as best quality available
< 47
AETSA 2011 / Eculizumab for treatment of PNH
bibliography places it
between 10-14.6 years (1). Mortality rate is not
maintained constant through time: in the first ten years after diagnosis, rate is
significantly greater (4).
•
Analysis of the necessary number of patients to treat (NNT) to obtain different
clinical results.
For the reduction of thrombotic events, company concluded that NNT was of 2
(absolute risk reduction 62%). However, it must be taken into account that data
were based on a non-controlled intervention study, in which patients enrolled
through different stages in time. In the different studies, time period elapsed from
diagnosis of PNH to starting treatment varied from a median of 4.9 and 8.7 years.
While the mean period after starting treatment was just of 1.4 years. This means
that number of thrombotic events were compared among quite irregular temporal
periods. Thus, to estimate the NNT, it is necessary to use the thrombotic events
rate, instead the number of thrombotic events.
In the case of absence of PRBC transfusions requirements, information provided
(NNT=3) was not correct, as risk was reduced in a 51 % (NNT=2).
To attain haemoglobin levels stabilization, NNT provided by the company was
inferior to real (2 vs. 3).
In the case of NNT, to achieve relevant differences in the quality of life measured
by FACIT-Fatigue scale, NNT was of 4, what coincides with the one subsequently
calculated in this report.
C. Economic analysis de novo
There are different estimations of cost-efficacy ratios for clinically significant
markers evaluated in the studies. These estimations were accomplished using the results
of the efficacy and safety systematic review.
In the same way, estimations of the budget impact for the SSPA have been made
according to the number of PNH patients who would be treated with in different scenarios.
Information base
•
Population in Andalusia: 8,389,271 inhabitants (23).
•
Prevalence of PNH: 0,55 cases/ 100,000 inhabitants (24)
•
Cost of treatment with eculizumab (HPP + VAT) (10):
•
-
First year:
-
Second year and subsequent:
377,182.00 €
360,984.00 €
Cost of each PRBC: SAS pricing: 73.88€ (25). Figure updated on February
2010 (general variation on the RPI 8.5%).
Cost-efficacy ratios
Cost of life year gained
There is no evidence about the impact of eculizumab treatment on survival
48 >
Eculizumab for treatment of PNH / AETSA 2011
improvement in patients with PNH. In consequence, it is not possible at present to
estimate life years gained with treatment.
Cost of thrombotic events reduction
Efficacy results in terms of reduction of thrombotic events rate belong to a poor
quality study, so it is impossible to estimate the real magnitude of that reduction. When
considering data from the extension study, despite its poor quality, it is observed that
reduction of thrombotic events would be around 7.37/100 patients/year to 1.07/100
patients/year. This would be an absolute reduction of 6.30 events per 100 patients/year,
that is, 16 patients should be treated in a year in order to avoid one thrombotic event
during that year.
Annual cost to avoid one thrombotic event in a year:
16 ° 377,182.00€ = 6,034,912.00 €
Corresponding annual cost of eculizumab drug in the first year of treatment.
Coste para mejorar la calidad de vida
In TRIUMPH RCT, 53.7% of patients in eculizumab group showed a shift in the FACITFatigue scale ≥ 4 scores (minimal clinically important difference) with respect to 20.5% of
patients in the placebo group (p=0.0028) (8). This means a NNT of 4 (IC 95%: 2-8). In
consequence, it is necessary to treat 4 patients to achieve a clinically relevant
improvement of quality of life (measured FACIT-Fatigue scale) in one of them.
Cost of quality of life improvement in one patient after six months:
1,508,728 € (754,364 – 3,017,456 €).
It must be taken into account that patients’ baseline scoring data in the scale were
not indicated, and the marker was not an intention to treat analysis.
Cost per each PRBC unit avoided
Las UCH evitadas por el tratamiento con eculizumab se obtuvieron a partir de los
estudios TRIUMPH y SHEPHERD. Se utilizaron las medianas de UCH al no seguir esta
variable una distribución normal.
PRBC units avoided due to eculizumab treatment were estimated from TRIUMPH
and SHEPHERD studies. Medians of PRBC units were used, as this marker does not
follow a normal distribution.
TRIUMPH RCT
Median of transfused PRBC units in the placebo group was 10 vs. 0 in the
eculizumab group, after 6 months.
Cost of each PRBC unit avoided in 6 months = 19,669.00 €
It must be taken into account that this cost is applied when a patient receives 9
PRBC units instead of 10 PRBC units, during 6 months (1.7 vs.1.5 PRBC units
< 49
AETSA 2011 / Eculizumab for treatment of PNH
transfused/month).
Considering patients stratification according to transfused PRBC units in the
previous 12 months before treatment, median differences of PRBC units among placebo
and eculizumab groups, after 6 months treatment, were calculated.
Table 10. Cost per PRBN avoided according to the study TRIUMPH
PRBC units
prior to
Median PRBC
Median PRBC
units transfused units transfused
Cost per averted
Difference
prbc unit after 6
after 6 months
after 6 months
ECULIZUMAB
PLACEBO
4 - 14
0
6
6
32,781.67 €
15 - 25
2
10
8
24,586.25 €
> 25
3
18
15
13,112.67 €
treatment
months
SHEPHERD study
According to results provided by this study, the median of transfused PRBC units
diminished from 8 to 0 after 52 weeks of eculizumab treatment. Patients of this study
required less amount of previous PRBC units transfusions than patients in the TRIUMPH
RCT.
Cost of each PRBC unit avoided in 1 year = 47,147.75 €
Considering patients stratification according to LDH levels when starting
eculizumab treatment, median differences of PRBC units after 12 months treatment were
calculated.
Table 11. Cost per PRBN avoided according to the study SHEPHERED
PRBC units
PRBC units
transfused prior to
transfused after
treatment (median)
treatment (median)
537 - 1379
8.00
0.00
8.00
47,147.75 €
1380 - 2050
7.50
1.00
6.50
58,028.00 €
2051-2866
9.50
0.50
9.00
41,909.11 €
2867 - 5245
8.50
2.00
6.50
58,028.00 €
Previous LDH
levels (U/L)
50 >
Reduction
Cost per PRBC
unit averted
Eculizumab for treatment of PNH / AETSA 2011
Annual cost for a patient to avoid transfusions during six months
In the TRIUMPH RCT, 51% of patients in the eculizumab group was transfusionindependent during 6 months against 0% in the placebo group. Thus, the NNT is 2 (IC
95%: 2-3), that is, it is necessary to treat 2 patients for one of them to avoid transfusions.
Annual cost for a patient to be transfusion-independent during six months =
754,364.00€ (754,364.00€ -1,131,546.00 €)
Annual cost applied correspond to the first year of treatment.
Budgetary impact for SSPA
Estimate of budget impact has been limited to a time horizon of one year, as there
are no efficacy date of eculizumab treatment in longer periods of time.
Different scenarios have been considered, accordingly to the different estimates
of cases that would be treated.
Table 12. “Scenarios” of eculizumab use
Scenario
A
B and C
D
E
Description
All patients accomplishing indication criteria approved in the technical data
sheet would be treated.
To calculate the number of cases it is estimated a prevalence of 0.55
cases/100,000 inhabitants (24)
Between 16% and 33% of patients with PNH (1) could be treated, according
to international experts .
To calculate the number of cases it is estimated a prevalence of 0.55
cases/100,000 inhabitants (24)
According to region experts’ opinion, in Andalusia, 25 patients with PNH
could be candidates to be treated with eculizumab.
Patients in which treatment is more cost-effective.
Table 13. Number of cases and scenarios impact
Scenarios
Cases/ year
Annual cost
A. Technical data
46
17,350,372.00 €
B. 16% patients with PNH
7
2,640,274.00 €
C. 33% patients with PNH
D. Clinical experts opinion
E. According TRIUMPH RCT
E.1 4-14 PRBC required
E.2 15-25 PRBC required
E.3 >25 PRBC required
15
5,657,730.00 €
25
9,429,550.00 €
25
9
10
6
3,394,638.00 €
3,771,820.00 €
2,263,092.00 €
Health expenditure reflected in the 2006 SAS Report (26) increased to
2,976,446,295.52 € (3,134,197,949€, updated in 2010, general variation on RPI rate
< 51
AETSA 2011 / Eculizumab for treatment of PNH
5.3%). From this datum the budget impact of health expenditure may be calculated, and
would range between 0.07% and 0.55%, depending on the scenarios with less or more
treated patients, respectively.
In TRIUMPH RCT, the median of transfused PRBC units in the placebo group
was of 10 vs. 0 of the eculizumab group, after 6 months. It was estimated the annual cost
of averted PRBC units transfused in the different scenarios taken into account
accordingly to cases susceptible of treatment. Thus, it was assumed that reduction of
PRBC units transfused median differences remain steady for a year.
Table 14. Annual savings for each scenario
Scenario according to cases susceptible of
being treated in Andalusia
Annual saving due to reduction of
PRBC units transfused
A. Technical data
67,967.44 €
B. 16% patients with PNH
10,342.87 €
C. 33% patients with PNH
22,163.30 €
D. Clinical experts opinion
36,938.83 €
E. According TRIUMPH RCT
E.1 4-14 PRBC required
7,978.79€
E.2 15-25 PRBC required
11,820.42€
E.3 >25 PRBC required
13,297.98€
52 >
Eculizumab for treatment of PNH / AETSA 2011
Discussion
1. Efficacy and safety systematic review discussion
Evidence available on eculizumab is still very limited in terms of clinical endpoints
measured in trials, monitoring follow-up, and number of patients. However, it must be
taken into account that the recent commercialization of this drug, as well as the fact of
being an ultra-rare disease treatment, justify these limitations.
Survival
Until end date of this systematic review no evidence was found that treatment
with eculizumab improves survival in PNH patients.
Thrombotic events
Risk reduction of thrombotic events is, after an improvement in survival, one of
the most relevant clinical endpoints in patients with PNH, as thrombotic events are the
leading cause of death. In Hillmen et al. extension study(18), incidence of thrombotic
events rate prior to eculizumab treatment almost doubled the incidence rate published in
the systematic review of the natural history of PNH by Connock et al, in patients who had
not received treatment with eculizumab (1). This difference between incidence rates of
thrombotic events may be due to the fact that only 73% thrombotic events, in Hillmen et
al. study, could be objectively identified, therefore assuming that this rate could be
overvalued.
In the same study (18), when thrombotic events incidence rate is evaluated in
patients receiving previous antithrombotic treatment, it increases considerably. This is
almost certainly due to the fact that patients with prophylactic treatment were the most
severe cases and also the ones with higher baseline risk of suffering this type of events.
Major limitation of Hillmen et al. study is the absence of a control group, which
makes impossible to assess whether the effect on the reduction of thrombotic events is
due to eculizumab, or to other interventions such as concomitant anticoagulation therapy,
or non-controlled factors. In this sense, Hall et al. (27) data suggest that prophylactic
antithrombotic therapy is effective in the prevention of events in PNH patients. The
cumulative incidence rate of thrombotic events was 0 events/100 patients-year in patients
treated with prophylactic antithrombotic therapy vs. 3.7 events/100 patients-year in
treatments without prophylaxis.
Monitoring period of TRIUMPH RCT (26 weeks), is not sufficient to obtain
conclusions on eculizumab efficacy in the prevention of thrombotic events.
In short, there is no clear evidence that eculizumab reduces the number of
thrombotic events. It is necessary to attain good quality studies, in order to evaluate
eculizumab efficacy in the incidence of thrombotic events, with an accurate monitoring
period, and bring solid evidence to this aspect.
< 53
AETSA 2011 / Eculizumab for treatment of PNH
Quality of life
Quality of life improvement is a fundamental parameter in the evaluation of
treatments of disabling diseases such as PNH. However, quality of life gaining is a
subjective endpoint which is also dependant on the scale used. Likewise, taking into
account that quality of life in closely related to other markers such as RBC administration,
anemia, etc, which can be evaluated in an objective manner, it could be possible to
determine which marker is most clinically significant.
In the TRIUMPH RCT (16), the mean change in the scoring of the FACIT-Fatigue
scale in quality of life was greater than in eculizumab patients. However, within more
frequent adverse events in patients of TRIUMPH RCT, it was observed that 12% of
patients treated with eculizumab showed fatigue versus 2% of patients treated with
placebo. In the SHEPHERD study (17), mean scoring of FACIT-Fatigue scale also
improved significantly after eculizumab treatment. Notwithstanding, as baseline scoring in
the patients’ quality of life questionnaires was unknown, both in TRIUPMH and
SHEPHERD studies, it is not possible to compare improvement in quality of life of
eculizumab treatment with the general population [(mean scoring of FACIT-Fatigue scale
in general population is 40.1 ± 10.4 (28)].
In relation to global health status in the different studies, there were
improvements in scoring shifts in most of evaluated items. However, only EORTC QLQC30 baseline scoring of pilot study (14;15) are available. Mean baseline scoring was
56.1, and shift after 64 weeks of treatment was 13.8(p=0,009)(15). That is, patients with
PNH improve scoring in global health status, but they do not achieve mean scores of
general population[76, approximately (29;30)].
In relation to fatigue, patients in pilot study extension showed a mean baseline
scoring of 47.5 and shift after eculizumab treatment was of -17.8 (p<0,001) (15) (better
results imply low scoring, so, the closer to 0 less fatigue). For all this, patients with PNH
achieve improvement in fatigue scores, but they do not reach the mean scorings of
general population[16 (Sweden) (29) y 20 (Germany) (30)].
Transfusions requirements
TRIUMPH RCT provides best evidence that eculizumab treatment significantly
reduces need for RBC transfusions in patients with PNH, with very similar results to that
of the SHEPHERD study. However, despite reduction in the median of number of
transfused PRBC are statistically significant, almost half of the patients (49%) under
eculizumab treatment still require transfusions, both in TRIUMPH RCT and SHEPHERD
study (16;17). Besides, in SHEPHERD study(17), the percentage of patients free of
PRBC transfusions could be overvalued, as there were patients who did not received
transfusions in the previous 12 months before the study (see Table 2).
In the stratified analysis of TRIUMPH RCT, patients treated with eculizumab vs.
placebo achieved significant reduction of PRBC units transfused (8). However, in groups
with greater transfusions requirements before study, patients achieved major reductions
in PRBC requirements.
In the stratified analysis of SHEPHERD study (17), according to baseline levels of
LDH, only patients with levels of LDH superior to 1,380 U/L, could reduce significantly the
number of transfused PRBC units.
54 >
Eculizumab for treatment of PNH / AETSA 2011
In conclusion, treatment with eculizumab reduces PRBC units transfusion
requirements versus placebo, being patients with moderate to severe type of disease
(according to transfusion requirements and haemolysis) the ones obtaining more benefits.
Safety
Eculizumab treatment is generally well tolerated by patients with PNH.
Incidence of meningitis is higher in patients treated with eculizumab than in
normal population. It is important to highlight that, despite vaccination before eculizumab
treatment is recommended, N. meningitidis serogroup more prevalent in Spain is
serogroup B, which has no vaccine at present. In Spain, incidence of N. meningitidis B
within general population was of 1.19 cases/100,000 inhabitants during the years 20042005 (31); while estimated incidence of meningitis in patients with eculizumab treatment
is of 500 cases/100,000 patients (32).
In relation to the risk of haemolysis crisis upon withdrawal of eculizumab
treatment, both TRIUMPH RCT and SHERPHED study show an increase of PNH
erythrocytes type III (16;17). These results indicate a reduction of haemolysis in patients
treated with eculizumab, and provide a biological plausibility of considering a potential risk
of serious haemolytic episode if eculizumab treatment is interrupted. Notwithstanding,
published data show that 16 patients withdraw from treatment during the studies (3;8;33).
This patients were monitored during 8 weeks at least after withdrawal from eculizumab
treatment, and no haemolytic episodes were observed (3;33).
Nevertheless, eculizumab has recent comercialization, so there is no long-term
evidence of safety in its administration.
Restarting of eculizumab treatment
There is no evidence of efficacy and safety of restarting eculizumab treatment
upon withdrawal, in PNH patients.
Efficacy and safety during pregnancy
In general, IgG may pass through the placenta, though IgG2 structucture is more
problematic to pass through it. Eculizumab is a formulation which is a recombinant
humanized monoclonal IgG2/4 kappa immunoglobulin, so crossing the placenta is
improbable. However, in animal testing it has been observed that eculizumab can cross
the placenta. Due to the absence of quality studies in pregnant patients with en PNH,
eculizumab has been included in pregnancy category C C (34).
Published evidence regarding pregnant women is limited to a series of 6 patients.
One of the patients underwent an elective abortion, one patient received eculizumab
during the whole pregnancy, one started treatment in 27th week of pregnancy, and three
patients received eculizumab from the beginning and until 4-16 weeks of gestation. The
latter three interrupted treatment, as trial excluded pregnant women.
Any of the pregnant women suffered adverse events, though one of them
< 55
AETSA 2011 / Eculizumab for treatment of PNH
required an adjustment of the posological interval (from 14 to 12 days), as a result of an
increase of haemoglobinuria and abdominal pain. All babies were healthy (34-36).
In short, evidence of eculizumab usage in PNH patients during pregnancy is of
poor quality.
Efficacy and safety in patients under 18
No evidence was found of efficacy and safety of eculizumab treatment in patients
under 18.
Efficacy and safety in patients de novo (who did not received
previous transfusions)
No evidence was found of efficacy and safety of eculizumab treatment in patients
de novo.
Sytematic review results in comparison with other systematic
reviews
The results of this sytematic review are consistent with the results published by
Connock et al. (1). These authors declared that, in general terms, eculizumab treatment
reduced haemolysis, PRBC requirements, and anemia. Besides, quality of life also
improved after treatment with eculizumab, mainly in relation to fatigue.
Connock et al. (1) concluded that eculizumab treatment reduced the thrombotic
events rate in patients with PNH. In contrast, authors of this systematic review, after the
evaluation of the literature and its quality, consider that evidence related to eculizumab
efficacy on thrombotic events reduction, has not enough quality as to claim that
eculizumab reduces the thrombotic events rate in patients with PNH.
Limitation of the systematic review of efficacy and safety
A systematic review of efficacy and safety of eculizumab in the PNH, has been
accomplished based on the best evidence available. Nevertheless, only a RCT estimating
eculizumab efficacy and safety in PNH patients was found in the literature.
2. Review of the economic analysis
Some international organisms establish parameters from which a certain clinical
technology is not cost-effective. In Spain, that limit is around 30,000€ and 50,000€ per
adjusted life year gained (QALY) (37). Above that amount it is considered that technology
is economically unsustainable by the public health system. In the case of ultra-orphan
drugs, quite above budget thresholds, QALYs had been reconsidered in order to obtain a
final cost per QALY similar to normal thresholds. The National Institute for Clinical
Excellence (NICE) (38) suggested that decision on incorporation of ultr-orphan drugs to
health systems, must be based on cost-effectiveness ratios of those ultra-orphan drugs
56 >
Eculizumab for treatment of PNH / AETSA 2011
that are already commercialized. In this sense, the NICE establishes the range £200,000
and £300,000 per QALY.
Up to the present, however, scientific evidence does not prove that eculizumab
improves survival in treated patients, but only that surrogate endpoints are improved, so it
is not possible to estimate a cost per QALY, even less the aforementioned discussion.
Even if considering those thresholds as estimates applicable to cost-efficacy ratios
(correspondant to those surrogate endpoints), these are too superior. Thus, the annual
cost of improving the quality of life (measured by FACIT-Fatigue scale) of a patient after
6 six months is approximately of 1,500,000€/ year. In the case of reduction of thrombotic
events (most clinically relevant surrogate endpoint) annual cost to avoid one event in a
year, in the best-case scenario, it is above 6,000,000€ (120 times the higher threshold to
increase life expectancy by a year; and 20 times over the maximum figure established by
the NICE for ultra-orphan drugs).
In a theoretical exercise considering the best scenario for eculizumab, the
following premises are assumed for this drug:
•
That survival levels of all treated patients equal the general population.
•
That suffering PNH for 25 years reduces life expectancy in 10.2 and 4.5
years.
•
That all patients under treatment are young.
•
That drug works well in all patients.
Cost per life year gained would range from 884,000€ and 2,000,467€, what
increases between 2 and 6 times the economic previsions established by the NICE for
ultra-orphan drugs. The Canadian Agency for Drugs and Technologies in Health
(CADTH) estimates an incremental cost per QALY of 2.4 million dollars which,
considering benefits in the long run, could be reduced, but never under 500,000$. That is
why this Agency does not recommend that eculizumab should be included in their health
system (39).
It is necessary to point out that the minimum incremental cost-efficacy obtained
for this drug is of 19,669€, which is also the cost of avoiding one PRBC unit after 6
months (the sum for a patient to receive 9 PRBC units instead of 10 PRBC units, after 6
months). This ratio improves when there is a greater number of transfused PRBC units
the 12 months prior to treatment: it decreases until 13,112€ per avoided PRBC unit in
those patients whose previous transfusion requirements surpassed 25 PRBC units.
In the case of thrombotic events, the annual cost for avoiding one death due to
thrombosis would be superior to 13,000,000€, according to the information submitted by
the industry, establishing that half of the patients die as a consequence of these events,
and assuming that 1 out of every two thrombosis was mortal (worst scenario).
There is still no estimation of budget impact in a time horizon superior to a year,
as there are no efficacy data of eculizumab for longer periods of time.
The annual cost of treatment with eculizumab for the SSPA, in different scenarios
according to various estimates of the number of cases to be treated with eculizumab, has
been calculated. The aforementioned costs range from 2,263,092€, in the scenario with
less amount of cases, to 17,350,372€ in the most populated scenario. Savings related to
costs averted by la reduction of transfused PRBC units would range from 13,298€ to
< 57
AETSA 2011 / Eculizumab for treatment of PNH
67,967€, respectively.
From this perspective, budget impact of treatment with eculizumab would range
between 0.55% and 0.07% of SSPA total health expenditure, depending on cases
treated: all patients (0.000006% of Andalusian population) or just patients in which drug
has better cost-effectiveness (0.000003% of Andalusian population), respectively.
Limitations of the economic analysis
Among major limitations to the economic analysis provided, the following are
highlighted:
58 >
•
Surrogate endpoints have been used.
•
There is no exact data available in Andalusia for the number of cases that
could be treated with eculizumab, as there is no an appropriate register.
Estimates regarding published data in the scientific literature have been
accomplished, and those estimates have been considered by expert
clinicians in Andalusia, obtaining similar results than the estimates of
prevalence at national level.
•
It is assumed that duration of drug efficacy is sustained through time
(TRIUMPH RCT provides results of 26 weeks, and best results are
extrapolated to 52 weeks).
•
Possible social and health benefits derived from reduction in rates of
thrombosis had not been considered.
Eculizumab for treatment of PNH / AETSA 2011
Conclusions
1. There is no evidence that treatment with eculizumab increases survival in PNH
patients.
2. Evidence of eculizumab in diminishing the probability of thromboembolic events is not
of sufficient quality. As a result of this, it is not possible to arrive at definite
conclusions about the reduction of thromboembolic events in PNH patients. It is
necessary to develop high quality studies contributing to solid evidence regarding this
matter.
3. Half of PNH patients receiving eculizumab treatment show FACIT-Fatigue scores
increased by four points in this instrument scale, especially when related to fatigue
grade (minimum clinically important difference in quality of life).
4. Eculizumab treatment in PNH patients reduces the number of PRBC transfusions
requirements when compared with placebo. Patients avoiding more PRBC
transfusions are the more severely affected patients or the moderate affected
(depending on pre-treatment transfusion requirements and haemolysis).
5. Eculizumab treatment in PNH patients diminishes haemolysis (measured through
LDH levels). The reduction in LDH levels with eculizumab commenced within one
month and levels remained constant during the treatment period.
6. Eculizumab treatment is generally well tolerated.
7. Patients with eculizumab therapy show a higher incidence of N. meningitidis
compared with general population. In consequence, patients must be vaccinated
when receiving eculizumab. However, the vaccine is not effective against serogroup
B of N. meningitidis, being this the most prevalent serogroup in Spain, and the one
producing more infections.
8. There is no evidence for long-term safety of eculizumab in PNH patients.
9. There is no evidence regarding efficacy and safety when PNH patients resume
eculizumab treatment after withdrawal.
10. There is no quality evidence allowing recommendations for eculizumab usage in PNH
patients during pregnancy.
11. There is no evidence of efficacy and safety of eculizumab treatment in patients with
PNH who are under 18.
12. No evidence was found for the use of eculizumab in patients with PNH de novo
(patients without previous transfusions).
13. Lack of information related to drug effectiveness means that implementation of a full
economic assessment for estimation of cost-effectiveness and/or cost-utility is
impractical at this time.
14. The budget impact for the SSPA varies according to the different scenarios of cases
eligible for eculizimab treatment and was estimated between 0.07% and 0.5% of total
hospital expenditure.
15. As there is no scientific evidence regarding survival of treated patients, but just
improvement of surrogate endpoints, it is not possible to calculate a model for
< 59
AETSA 2011 / Eculizumab for treatment of PNH
estimation of cost in terms of QALY. According to a theoretical exercise based on
significant assumptions, a cost per LYG will exceed between two and six times the
highest estimations for ultra-orphan drugs as advised by NICE.
16. Cost-effectiveness ratios estimated for surrogate endpoints of major clinical
relevance show very high values (exceeding the highest estimations advised by NICE
for this type of drug in terms of the incremental cost per QALY, which could serve as
reference).
60 >
Eculizumab for treatment of PNH / AETSA 2011
Recommendations
•
The use of eculizumab in PNH patients when there is no evidence should be
considered as experimental. These situations include at this moment: patients without
a history of transfusions, patients under 18, pregnant patients, and patients who
recommence eculizumab treatment after withdrawal.
•
Given that there is only solid evidence of eculizumab effectiveness for the surrogate
endpoints, transfused PRBC units, and LDH levels, these outcomes should guide the
criteria that define those patients who would qualify for eculizumab treatment. There
is solid evidence that only patients with a greater history of transfusions in the
previous year and higher LDH baseline levels, show major clinical benefit and better
relation cost-effectiveness. In consequence, those should be the criteria to select
subgroups which potentially will obtain more benefit from treatment. For the rest of
patients supportive measures and monitoring are recommended.
•
In areas where there is uncertainty about eculizumab efficacy being it measured in
terms of health-related outcomes (f. e. reduction of thrombosis rates) it is
recommended to establish an agreement based on shared risks with the
manufacturing laboratory.
•
It is necessary for all patients who enroll for eculizumab treatment to accomplish the
Risk Management Plan designed by the EMA for this drug.
•
It is recommended to undertake an evaluation of effectiveness and safety after 3
months of treatment. In this initial evaluation, LDH levels will indicate eculizumab
effectiveness. In those patients in which eculizumab is not effective and/or safe, it is
recommended to withdraw treatment.
•
Patients in whom treatment seems to be effective after the three first months should
continue periodic monitorisation every six months. The following parameters should
be registered: thrombotic events (type and location), number of RBC units transfused,
biochemical parameters (LDH and creatinine), haemogram, infections (type and
location), disease evolving towards other haematologic pathologies (aplastic anemia,
leukaemia or myelodysplasic syndromes), adverse events, and spontaneus
remission. Patients in whom eculizumab is not effective and/or safe are
recommended to withdraw from treatment.
•
It is recommendable that the SSPA creates a group, for the granting of centralised
authorisation for this treatment. The group should apply the resolution established by
the SAS management, individually, to each potential case. In the same way this
group will be responsible for management of patients’ monitoring.
•
In addition, it is recommended the foundation of a PNH registry in Andalusia.
Eculizumab for treatment of PNH / AETSA 2011
References
(1)
Connock M, Wang D, Fry-Smith A, Moore D. Prevalence and prognosis of
paroxysmal nocturnal haemoglobinurea and the clinical and cost-effectiveness of
eculizumab. Birmingham: West Midlands Health Technology Assessment
Collaboration, 2008.
(2)
Hernandez-Campo PM, Almeida J, Orfao A. Hemoglobinuria paroxística nocturna.
Med Clin (Barc). 2008;131(16):617-30.
(3)
Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet.
2009;373(9665):759-67.
(4)
Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of
paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995;333(19):1253-8.
(5)
Young NS, Meyers G, Schrezenmeier H, Hillmen P, Hill A. The management of
paroxysmal nocturnal hemoglobinuria: recent advances in diagnosis and treatment
and new hope for patients. Semin Hematol. 2009;46(1 Suppl 1):S1-S16.
(6)
Risitano AM, Rotoli B. Paroxysmal nocturnal hemoglobinuria: pathophysiology,
natural history and treatment options in the era of biological agents. Biologics.
2008;2(2):205-22.
(7)
Richards SJ, Barnett D. The role of flow cytometry in the diagnosis of paroxysmal
nocturnal hemoglobinuria in the clinical laboratory. Clin Lab Med. 2007;27(3):57790.
(8)
Scientific Discussion Soliris®. European Public Assessment Report. European
Agency for the Evaluation of Medicinal Products. 2007. Disponible en:
http://www.ema.europa.eu/humandocs/PDFs/EPAR/soliris/H-791-en6.pdf. [citado
24 Mar 2010]. Archivado por WebCite® en: http://www.webcitation.
org/5oSpsvOSe.
(9)
Ficha técnica Soliris®. European Agency for the Evaluation of Medicinal Products.
2010.
Disponible
en:
http://www.ema.europa.eu/humandocs/PDFs/
EPAR/soliris/emea-combined-h791-es.pdf. [citado 24 Mar 2010]. Archivado por
WebCite® en: http://www.webcitation.org/5oSq3Q3Dy.
(10)
Nuevos principios activos autorizados en 2007 (con acuerdo de precio en EneroDiciembre 2007). Ministerio de Sanidad y Consumo. 2008. Disponible en:
http://www.msc.es/profesionales/farmacia/informaMedicamentos/pdf/ppiosActivos2
007.pdf.
[citado
29
Abr
2010].
Archivado
por
WebCite®
en:
http://www.webcitation.org/5pLpCBQ1R.
(11)
Guía CASPe de Lectura Crítica de la Literatura para la evaluación de ensayos
clínicos. 2009. Disponible en: http://www.redcaspe.org/herramientas/lectura/
11ensayo.pdf. [citado 28 Oct 2008]. Archivado por WebCite® en:
http://www.webcitation.org/5buEb9m6J.
(12)
Guía CASPe de Lectura Crítica de la Literatura para la evaluación de revisiones
sistemáticas. 2009. Disponible en: http://www.redcaspe.org/herramientas/lectura/
10revision.pdf. [citado 28 Oct 2008]. Archivado por WebCite® en:
http://www.webcitation.org/5buE1UJMZ.
AETSA 2011 / Eculizumab for treatment of PNH
(13)
Guía CASPe de Lectura Crítica de la Literatura para evaluaciones económicas.
2009. Disponible en: http://www.redcaspe.org/que-hacemos/herramientas/. [citado
29 Abr 2010]. Archivado por WebCite® en http://www.webcitation.org/5pLpTA8Gg.
(14)
Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, et al. Effect of
eculizumab on hemolysis and transfusion requirements in patients with paroxysmal
nocturnal hemoglobinuria. N Engl J Med. 2004;350(6):552-9.
(15)
Hill A, Hillmen P, Richards SJ, Elebute D, Marsh JC, Chan J, et al. Sustained
response and long-term safety of eculizumab in paroxysmal nocturnal
hemoglobinuria. Blood. 2005;106(7):2559-65.
(16)
Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, et al. The
complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J
Med. 2006;355(12):1233-43.
(17)
Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, et
al. Multicenter phase 3 study of the complement inhibitor eculizumab for the
treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood.
2008;111(4):1840-7.
(18)
Hillmen P, Muus P, Duhrsen U, Risitano AM, Schubert J, Luzzatto L, et al. Effect of
the complement inhibitor eculizumab on thromboembolism in patients with
paroxysmal nocturnal hemoglobinuria. Blood. 2007;110(12):4123-8.
(19)
Adverse Event Reporting System. Food and Drug Administration. 2009. Disponible
en:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/
Surveillance/AdverseDrugEffects/default.htm. [citado 18 Mar 2010]. Archivado por
WebCite® en: http://www.webcitation.org/5oJw3fWPE.
(20)
Anexo IV. Condiciones o restricciones en relación con la utilización segura y eficaz
del medicamento a implementar por los estados miembros. Conditions imposed on
member states for safe and effective use. European Agency for the Evaluation of
Medicinal
Products.
2009.
Disponible
en:
http://www.ema.europa.eu/
humandocs/PDFs/EPAR/soliris/H-791-Annex-es.pdf. [citado 24 Mar 2010].
Archivado por WebCite® en: http://www.webcitation.org/5oSqk9H2W.
(21) All Wales Medicines Strategy Group Final Appraisal Report. Eculizumab (Soliris®).
2009.
Disponible
en:
http://www.wales.nhs.uk/sites3/Documents/371/
Eculizumab%20%20%28Soliris%29%20FAR%20website.pdf. [citado 29 Abr 2010].
Archivado por WebCite® en: http://www.webcitation.org/5pLq0Va1O.
(22)
Santos B, Muñoz C, Muñoz N. Eculizumab en hemoglobinuria paroxística
nocturna. Informe para la Guía Farmacoterapéutica de Hospitales de Andalucía.
2008.
Disponible
en:
http://www.sas.junta-andalucia.es/contenidos/
publicaciones/datos/102/html/Eculizumab%20en%20hemoglobinuria%20parox%C
3%ADstica%20nocturna.pdf. [citado 30 Abr 2010].
(23)
Instituto de Estadística de Andalucía. Proyección de la población 2006-2070.
Disponible en: http://www.iea.junta-andalucia.es/proyecc/tablas/index.htm. [citado
8 Abr 2010].
(24) Prevalencia de las enfermedades raras: Datos bibliográficos. 2009. Disponible
en:http://www.orpha.net/orphacom/cahiers/docs/ES/Prevalencia_de_las_enfermed
ades_raras_por_orden_alfabetico.pdf. [citado 8 Abr 2010]. Archivado por
WebCite® en: http://www.webcitation.org/5opXaUPPO,
64 >
Eculizumab for treatment of PNH / AETSA 2011
(25)
Orden de 14 de octubre de 2005, por la que se fijan los precios públicos de los
servicios sanitarios prestados por Centros dependientes del Sistema Sanitario
Público de Andalucía. boletín Oficial de la Junta de Andalucía. 2005. Disponible
en: http://juntadeandalucia.es/boja/boletines/2005/210/d/updf/d28.pdf. [citado 8 Abr
2010].
(26)
Memoria 2006. Servicio Andaluz de Salud. 2007. Disponible en:
http://www.sas.junta-andalucia.es/library/plantillas/externa.asp?pag=../../
publicaciones/datos/286/pdf/MemoSalud2006_mod_pag9.pdf. [citado 8 Abr 2010].
(27)
Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents
thrombosis
in
paroxysmal
nocturnal
hemoglobinuria
(PNH).
Blood.
2003;102(10):3587-91.
(28)
Webster K, Cella D, Yost K. The Functional Assessment of Chronic Illness Therapy
(FACIT) Measurement System: properties, applications, and interpretation. Health
Qual Life Outcomes. 2003;1:79.
(29)
Michelson H, Bolund C, Nilsson B, Brandberg Y. Health-related quality of life
measured by the EORTC QLQ-C30-reference values from a large sample of
Swedish population. Acta Oncol. 2000;39(4):477-84.
(30)
Schwarz R, Hinz A. Reference data for the quality of life questionnaire EORTC
QLQ-C30 in the general German population. Eur J Cancer. 2001;37(11):1345-51.
(31) Grupo de Trabajo de Enfermedad Meningocócica. Situación actual de la
enfermedad meningocócica en España. Modificación de la pauta de vacunación
frente a menningitis C. 2005. Disponible en: http://www.sp.san.gva.es/
rvn/docs/MenC_MARZO_2006.pdf. [citado 30 Abr 2010].
(32)
Hillmen P. The role of complement inhibition in PNH. Hematology Am Soc Hematol
Educ Program. 2008;116-23.
(33)
Davis J. Eculizumab. Am J Health Syst Pharm. 2008;65(17):1609-15.
(34)
Danilov AV, Brodsky RA, Craigo S, Smith H, Miller KB. Managing a pregnant
patient with paroxysmal nocturnal hemoglobinuria in the era of eculizumab. Leuk
Res. 2010;34(5):566-71.
(35)
Kelly R., Arnold L.M., Richards S.J., Hill C., Bomken C., Hanley J. Successful
pregnancy outcome in paroxysmal nocturnal haemoglobinuria on long term
eculizumab. Haematologica. 2009; 94 (Suppl. 2): 452 abs. 1114a.
(36)
Danilov AV, Smith H, Craigo S, Feeney DM, Relias V, Miller KB. Paroxysmal
nocturnal hemoglobinuria (PNH) and pregnancy in the era of eculizumab. Leuk
Res. 2009;33(6):e4-e5.
(37)
De Cock E, Miravitlles M, González-Juanatey JR. Valor umbral del coste por año
de vida ganado para recomendar la adopción de tecnologías sanitarias en España:
evidencias procedentes de una revisión de literatura. Pharmacoeconomics. Span
Res Artic. 2007; 4(3): 97-107.
(38)
Appraising Orphan Drugs. National Institute for Health and Clinical Excellence.
Disponible en: http://www.nice.org.uk/niceMedia/pdf/smt/120705item4.pdf. [citado
8 Abr 2010]. Archivado por WebCite® en http://www.webcitation.org/5opvydg4J.
(39)
Eculizumab. Indication: Paroxysmal Nocturnal Hemoglobinuria. 2010. Disponible
AETSA 2011 / Eculizumab for treatment of PNH
en:http://www.cadth.ca/media/cdr/complete/cdr_complete_Soliris_February_18_20
10.pdf.
[citado
9
Abr
2010].
Archivado
por
WebCite®
en
http://www.webcitation.org/5orH1fOl2.
(40)
66 >
Cuestionario
EORTC
QLQ-C30
(versión
3).
Disponible
en:
http://www.eortc.be/home/qol/downloads/f/C30/QLQ-C30%20Spanish_neutral.pdf.
[citado
6
Abr
2010].
Archivado
por
WebCite®
en
http://www.webcitation.org/5onA0d7X7.
AGENCIA DE EVALUACIÓN DE TECNOLOGÍAS
SANITARIAS DE ANDALUCÍA (AETSA)
Avda. Luis Montoto, 89. 4ª planta
41007 Sevilla. España (Spain)
Tlf. +34 955 921 581 / Fax +34 955 923 572
www.juntadeandalucia.es/salud/AETSA