Present and future challenges in the treatment of haemophilia: The patient's perspective

Abstract

Haemophilia is a rare bleeding disorder, caused by a mutation in the genes for factor VIII (Haemophilia A) and factor IX (Haemophilia B). Patients with severe haemophilia, with a factor plasma level of 1% or less, are affected by frequent episodes of spontaneous or excessive bleeding into joints and muscles. The current management of haemophilia is based on treatment with plasma-derived and recombinant factor VIII (FVIII) or factor IX products (FIX)1. Home treatment has shown to improve both life expectancy and quality of life of patients with haemophilia and other inherited coagulation disorders (PWH), with a reduction of musculoskeletal damage2.

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Blood Transfus 2013; 11 Suppl 4: s82-85 DOI 10.2450/2013.013s
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Present and future challenges in the treatment of haemophilia:
the patient's perspective
Romano Arcieri
1
, Angelo C. Molinari
2,3
,
Stefania Farace
1
, Giuseppe Mazza
1
, Alberto Garnero
1
, Gabriele
Calizzani
4
, Paola Giordano
2,5
, Emily Oliovecchio
6
, Lorenzo Mantovani
2,7
, Lamberto Manzoli
2,8
, Paul
Giangrande
2,9
1Italian Federation of Haemophilia Societies (FedEmo), Rome; 2Italian Federation of Haemophilia Societies Medical
Council, Rome; 3Thrombosis and Haemostasis Unit, Giannina Gaslini Children's Hospital, Genoa; 4Italian National
Blood Centre, National Institute of Health, Rome; 5Department of Biomedical Sciences and Human Oncology, Paediatric
Unit, University of Bari, Bari; 6Department of Internal Medicine, University of Perugia, Perugia; 7Department of Clinical
Medicine and Surgery Federico II University of Naples, Naples; 8Department of Medicine and Ageing Sciences, University
of Chieti, Chieti, Italy; 9Oxford Haemophilia and Thrombosis Centre, Oxford, United Kingdom
Haemophilia is a rare bleeding disorder, caused by
a mutation in the genes for factor VIII (Haemophilia
A) and factor IX (Haemophilia B). Patients with severe
haemophilia, with a factor plasma level of 1% or less,
are affected by frequent episodes of spontaneous or
excessive bleeding into joints and muscles. The current
management of haemophilia is based on treatment with
plasma-derived and recombinant factor VIII (FVIII)
or factor IX products (FIX)
1
. Home treatment has
shown to improve both life expectancy and quality of
life of patients with haemophilia and other inherited
coagulation disorders (PWH), with a reduction of
musculoskeletal damage
2
.
Several studies have demonstrated that primary
prophylaxis has a positive and significant impact on
the quality of life and on arthropathy prevention in
haemophiliac children
3,4
. Secondary prophylaxis has
been shown to reduce the number of haemarthroses and
the consequent joint disease and to improve the quality of
life in haemophiliac adults, who had already developed
arthropathy and disability
5
. However, prophylaxis costs
are high, ranging from €130,000-162,000 per year for
each person with haemophilia
6
.
The World Federation of Haemophilia has declared
that there should be "Treatment for All - closing the
gap in treatment" and call for "Closing the gap between
the amount of treatment products needed versus that
available"
7
. The Italian Federation of Haemophilia
Associations (FedEmo) has endorsed these statements,
launching at national level the campaign "100% Care
100% Rare" with the aim to improve both access to
treatment and quality of care for PWH.
But what does that mean for the haemophilia
community? Is treatment in Italy accessible, safe and
effective?
Taking the case of FVIII, according to the data
published by the Italian National Blood Centre,
a standardised national consumption of over 6,5
international units (I.U.) per capita has been achieved
which seems to be an adequate result in terms of supply
8
.
However, there is a wide regional variability in the
utilization of clotting factor. On the one hand, in seven
Regions and Autonomous Provinces -APs- (Abruzzo,
Aosta Valley, AP of Trento, Friuli-Venezia Giulia, Sicily,
Umbria and Veneto) the per capita utilisation, less than
or equal to 5 I.U., could be considered insufficient
to guarantee wide access to prophylaxis and immune
tolerance induction (ITI). On the other hand, the demand
for over 9 I.U. recorded in the Latium Region, if not
adequately justified by the number and case-mix of
patients, is unlikely to be associated with a significant
additional gain in terms of patient outcome, with respect
to the average value.
In 2011, approximately 92,000,000 I.U. of plasma
derived FVIII (pdFVIII), representing around 20%
of total FVIII demand
8
, were used for the clinical
management of PWH A. Currently, plasma sent to
fractionation by Italian Regions would be sufficient to
meet the demand for pdFVIII, yet only around 50% of the
demand is covered by pdFVIII from toll fractionation
9
supply. The reasons given for this discrepancy are the
specificity of pdFVIII from toll fractionation (e.g.
absence of indication for the treatment of von Willebrand
disease), continuity of care for patients already being
treated successfully with an alternative product, and the
prescribing practice of clinicians.
In Italy, an institutional accreditation scheme for
Haemophilia Centers (HCs) was approved by a formal
State-Regions Agreement in March 2013
10
. This provides
an organisational framework for Italian Regional Health
Authorities to optimise and standardise haemophilia
care on the basis of the latest scientific evidence and
international recommendations
11,12
. At the same time,
PWH should have equal access to treatment nationwide.
However, scientific debates continue on several
questions. Should personalised prophylactic treatment
in adults be considered
13,14
? What is the best immune
tolerance regimen for patients with inhibitor?
15
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Blood Transfus 2013; 11 Suppl 4: s82-85 DOI 10.2450/2013.013s
Challenges in haemophilia treatment: the patient’s view
These two clinical aspects are related to FVIII
product availability and type of pharmacologic approach
(plasma-derived versus recombinant products). Several
ongoing studies are trying to answer these questions.
They include the SPINART study (Trial to Evaluate
the Effect of Secondary Prophylaxis with Recombinant
FVIII Therapy in Severe Hemophilia Adult subjects
compared to That of Episodic Treatment)
16
, the POTTER
study (Prophylaxis vs On-demand Therapy Through
Economic Report)
17
and the SIPPET study (Study on
Inhibitors in Plasma-Products Exposed Toddlers)
18
.
The results of these studies are eagerly awaited as they
could lead to redefine both the guidelines on treatment
for haemophilia and the clinical use of FVIII products.
Another question to be answered concerns the future
trend in usage of clotting factor concentrates. "Will FVIII
demand be stable in Italy over time?" We believe that
it will increase over time, for three reasons. Firstly, the
longer life expectancy of PWH will generate an increase
of age-related comorbidities (orthopedic, oncological
and metabolic)
19
. Secondly, a higher amount of FVIII
will be necessary to maintain a good quality of life in
older haemophilia patients for secondary prophylaxis
5
.
Finally, a wider proportion of PWH will be adult, thus
increasing the consumption of FVIII via a simple and
direct weight-effect
20
.
The product provided by the fractionation of Italian
plasma could be an opportunity to ensure a valuable,
independent and effective stock of concentrates to
address any potential increase in demand. However,
the future availability of innovative products - such
as long-acting - could drastically change the context
and further shift away the demand for plasma-derived
products
21,22
. For this reason, we believe every effort
should be made to avoid any change in treatment that
might be driven more by "fashion" or "market" trends
than by the target of real gain in outcome or patient
quality of life. We would not consider it helpful to carry
on a general opposition between classes of products,
such as recombinant vs plasma-derived
23-27
. Instead, we
would envisage that treatment could be "tailored" -in
terms of product choice and posology- to the individual
patient's need, taking into consideration pharmacokinetic
response, efficacy, subjective perception of effectiveness,
inhibitor history, side effects, outcomes, patient's
preference and compliance
28,29
.
The replacement therapy is based on infusions of
plasma-derived and recombinant products. In 2011, the
National Health Service (NHS) expenditure for just FVIII
and FIX products was estimated to be around 272 million
euros, without considering products manufactured from
plasma collected by the Italian Transfusion Service
10
.
As replacement therapy is believed to be "costly",
the questions that need to be addressed are: "Will the
treatment that offers the higher ratio of benefit versus
side effects be available for all patients in the future?
Will the continuity of care still be an affordable principle
of haemophilia treatment
25
? Might the economic crisis
and the healthcare budget reductions lead to a restriction
of the replacement therapy?" National organisations
of patients, such as FedEmo, have expressed concern
regarding this latter possibility, as well as concern
that the financial restrictions might interfere with the
development of centres. It is worth considering that,
following policies adopted and actions put in place by
previous Italian governments, the total pharmaceutical
expenditure through the channel of pharmacies open
to the public has dropped from 204 Euro per capita,
in 2011, to 142 in 2012, allowing a saving of around
3,680,000,000 Euro
30
. In this context, the expense for
haemophilia replacement treatment - for which the
efficacy and economic evaluation are supported by
strong and plentiful evidence, in contrast to many other
diseases or technologies, should not be penalised.
FedEmo promotes actions to support a sustainable
national care programme for achieving a framework of
services that will guarantee a comprehensive care and
the best pharmacologic regimen for PWH.
However, in order to implement an efficient network
of Haemophilia Centres of Expertise
10,11,31-34
, the issue
of a dedicated funding system should be adequately
addressed. Further studies aimed at assessing the
sustainability and the costs of haemophilia care in
Italy would also be required. Given the current limited
resources, and in the absence of feasible alternative
options, a possibility could be to shift part of the funding
from the pharmaceutical budget to the overall budget
for the Haemophilia Centres. But how can this be done
without impacting negatively on patients' needs and
outcomes? And how can it be achieved in a silo-based
organisational system?
These challenges can be addressed by assessing,
and where possible improving, the appropriateness of
prescriptions; providing Regions with a wider portfolio,
in terms of typology and quality, of medicinal products
from toll fractionation by opening the market to new
fractionators, as a consequence of the implementation
of the new regulatory framework on plasma and plasma
products
35
; promoting access to new recombinant
products in order to provide more treatment options and
reduce costs; centralising and making the procurement
of medicinal product more efficient. National tendering
proved to be successful, at least in the short term, in
restraining the cost of replacement treatment
36
. However,
risks associated with product switching cannot be
excluded with certainty
36-39
. Therefore, until more
definitive evidence is produced, a more patient-centered
approach and a more efficient procurement mechanism,
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Arcieri R et al
Blood Transfus 2013; 11 Suppl 4: s82-85 DOI 10.2450/2013.013s
such as pay for performance or risk sharing
40,41
, could
be studied and eventually implemented. Meanwhile,
national recommendations on procurement are envisaged
in order to prevent differences between Regions in the
basic level of care.
In conclusion, as the experience of the Institutional
Accreditation Model demonstrated
10
, we believe that the
participation of non-governmental organisations, such as
national or regional haemophilia patients' organisations,
can bring an added value to the policy making process,
including product procurement. Similarly, an early
involvement of PWH representatives in the discussion
of any clinical or organisational guidelines, as well
of any associated health care programme, should be
systematically pursued in line with the fourth principle
of the European Principles of Haemophilia Care
11
.
Keywords: haemophilia treatment, factor VIII demand,
comprehensive care, sustainability.
Conflict of interest disclosure
Lorenzo Mantovani declares the following conflict of
interest: Advisory boards for Pfizer; consulting fees
from Bayer (not in the field of haemophilia), Research
Grants from Grifols and Pfizer.
The other Authors declare no conflicts of interest.
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Correspondence: Romano Arcieri
Italian Federation of Haemophilia Associations (FedEmo)
Via Lorenzo il Magnifico 148
00162 Rome, Italy
E-mail address: romano.arcieri@fedemo.it
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