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

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.

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 disability⁵. However, prophylaxis costs are high, ranging from €130,000–162,000 per year for each person with haemophilia⁶.

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 supply⁸. 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 demand⁸, 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 fractionation⁹ 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 2013¹⁰. 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

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 prophylaxis⁵. Finally, a wider proportion of PWH will be adult, thus increasing the consumption of FVIII via a simple and direct weight-effect²⁰.

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 Service¹⁰. 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 treatment²⁵? 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 Euro³⁰. 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 products³⁵; 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 treatment³⁶. 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, 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 demonstrated¹⁰, 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 Care¹¹.