Samantha Profili

The demand for human albumin in Italy.

Human albumin (HA) is a blood plasma protein produced in the liver. It constitutes about 60% of plasma proteins and is a physiological plasma-expander. However, its limited availability and high cost make it essential to define recommendations for its appropriate use, as an alternative to other therapeutic strategies including solutions of crystalloids and non-protein colloids. According to all official recommendations, the choice to use albumin rather than an artificial colloid strictly depends on the clinical situation of the patient1–6. HA is also used in all cases in which there is a contraindication to the use of non-protein colloids7. Based on clinical evidence, the 2009 guidance document of the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI)7 recommends the use of HA in acute conditions, which call for blood volume expansion and maintenance of adequate blood flow, as well as in some chronic conditions of low serum albumin levels. “There are some widely shared and fully agreed indications for the appropriate use of human albumin and indications that are occasionally appropriate, that is, when other criteria are fulfilled”7. In addition, in haemorrhagic shock HA should only be used as a second choice [i.e. when solutions of crystalloids or non-protein colloids (first choice treatment) have already been used at maximum doses without having produced a clinically adequate response] and in cases in which non-protein colloids are contraindicated7.

Clinical use and the Italian demand for prothrombin complex concentrates

Prothrombin complex concentrates (PCCs) are an important plasma-derived therapeutic option for the rapid correction of deficiency of vitamin-K dependent clotting factors1. PCCs are produced by ion-exchange chromatography from the cryoprecipitate supernatant of large plasma pools after removal of antithrombin and factor (F) XI2. Different processing techniques involving ion exchangers permit the production of either three- (i.e., FII, FIX and FX) or four-factor (i.e., FII, FVII, FIX and FX) concentrates with a final overall clotting factor concentration approximately 25 times higher than in normal plasma (Tables I and ​andIIII)3. To prevent activation of these factors, most PCCs contain heparin. In addition, they may also contain the physiological inhibitors of coagulation protein C and protein S. PCCs are standardised according to their FIX content and are subjected to viral inactivation processes, both by physical (vapour, heating) and chemical (solvent detergent treatment) methods. Table I Three-factors prothrombin complex concentrates brief fact sheet. Table II Four-factors prothrombin complex concentrates brief fact sheet. Various preparations are commercially available in Italy, as reported in Tables III4 and ​andIVIV4. Table III Products containing three-factors prothrombin complex concentrates currently available on the Italian market. Table IV Products containing four-factors prothrombin complex concentrates currently available on the Italian market. Clinical indications of prothrombin complex concentrates PCCs were originally developed for the treatment of haemophilia B patients; however, due to the availability in recent years of plasma-derived high purity FIX concentrates and, more recently, of a recombinant FIX product, they have progressively shifted from this clinical indication towards the replacement of vitamin K-dependent clotting factors. The current indications for the clinical use of PCCs are mostly based on retrospective or observational studies, as very few controlled randomised clinical trials have been conducted so far in this setting3. Therefore, PCCs are used for prophylaxis or treatment of bleeding in patients with a documented inherited deficiency of FII or FX; if PCCs are not available, fresh frozen plasma (FFP) can be used as an alternative. However, solvent/detergent plasma should be preferred in patients with inherited coagulation disorders who need replacement therapy when virus-inactivated single-factor concentrates are not available5. Similarly, in patients with congenital deficiency of FVII or FIX, PCCs can be used only when the specific clotting factor concentrate is not available. In patients with acquired deficiencies of factors of the prothrombin complex (due to severe liver disease, blood loss or dilution), PCCs could be administered, as a second choice alternative to FFP, taking into account that the potential utility of PCCs in (bleeding) patients not being treated with vitamin K antagonist (VKA) is only based on limited evidence from retrospective studies involving few patients6 and that the risk of thrombosis is higher with PCC than with plasma7–10. Thus, the current clinical indications for PCC use include: - patients on VKA therapy requiring emergency reversal in case of bleeding or need for urgent surgery (grade of recommendation: 1B)7,9,11–19. PCCs are able to completely reverse the warfarin-induced anticoagulation within 10 minutes but the infused clotting factors have a finite half-life. Therefore, intravenous vitamin K (10 mg) should be given with the PCC. The recently published ACCP (American College of Chest Physicians) guidelines suggest, for patients with VKA-associated major bleeding, rapid reversal of anticoagulation with four-factor PCCs, due to the presence of FVII (Grade of recommendation: 2C)19; - prophylaxis or treatment of bleeding in patients with a documented inherited deficiency of FII or FX (grade of recommendation: 2C)7,9,20,21; - prophylaxis or treatment of bleeding in patients with congenital deficiency of FVII or FIX if the specific clotting factor concentrate is not available (grade of recommendation: 2C)7,9,20,21; - patients with acquired deficiencies of factors of the PCCs and limitations to the use of FFP, such as those at a risk of circulatory overload or with the need for urgent restoration of normal haemostasis (grade of recommendation: 2C)6,7,9,22. Quantification and characterisation of the three-factors prothrombin complex concentrates demand Tables V and ​andVIVI show both the absolute and standardised demand (expressed in I.U. and per capita I.U., respectively) for three-factors PCCs in the period 2007–2011, at the national and regional level, according to medicinal products traceability data23. Table V Quantification of total (public and private) demand for three-factors prothrombin complex concentrates (expressed in international units) in Italy and Italian regions, from 2007 to 2011. Table VI Quantification of total (public and private) standardised demand for three-factors prothrombin complex concentrates (expressed in per capita international units) in Italy and Italian regions, from 2007 to 2011. The three-factors PCCs national demand showed an increase of about 65%, from 15,645,100 I.U. in 2007 to 25,782,200 I.U. in 2011 (Table V), with a per capita consumption of 0.4 I.U. in 2011 (Table VI). Regions with the highest per capita demand are Aosta Valley and Emilia-Romagna, as well as the Autonomous Province (AP) of Bolzano with about 2 and 1 I.U., respectively (Figure 1), with a percentage change from the national mean demand of +313%, +84%, and +156%, respectively (Figure 2). Figure 1 Quantification of total (public and private) standardised demand for three-factors prothrombin complex concentrates (in per capita international units), in Italy and Italian regions, year 2011. Figure 2 Percentage change from the national mean value of standardised regional demand of prothrombin complex concentrates (per capita international units) in 2011. Regions with the lowest observed demand are Calabria, Latium and Abruzzo with 0.1, 0.2, and 0.3 per capita I.U., with a percentage departure of −71%, −46%, and −42% from the national mean value (Figure 2). The distribution of PCCs takes place almost exclusively through the public health facilities distribution channel23. Aosta Valley, the AP of Bolzano and Emilia-Romagna have the largest demand through this channel, i.e. about 2 per capita I.U. for the first Region and about 1 I.U. for the latter two, respectively (Figure 3). Figure 3 Demand for three-factors prothrombin complex concentrates (per capita international units), in Italy and Italian regions, by public health facilities channel, year 2011. It is also necessary to underline the use of the pharmacies open to the public channel in Latium and Campania, which represents on average of about 6% of the total demand of both Regions (data reported elsewhere)24.

The demand for polyvalent immunoglobulins in Italy.

Polyvalent immunoglobulins (IG) for subcutaneous administration (SCIG) and for intravascular administration (IVIG) are used in the replacement therapy of the immunodeficiencies and in the treatment of autoimmune pathologies or systemic inflammatory processes (Tables I and ​andIIII)1,2. However, in the clinical practice IGs are often used more extensively than what the authorised indications allow (“off-label” use) even if, in this case, the use is not always supported by available scientific evidence1–4. Table I Polyvalent immunoglobulins, for subcutaneous administration, brief fact sheet. Table II Polyvalent immunoglobulins, for intravascular administration, brief fact sheet IGs are isolated from pooled plasma that has been donated by 1,000–100,000 people. With such large pools of donors, the entire spectrum of antibodies produced by the population is represented in the final product. IVIG contains 8–15 g/dL of protein, of which >90% is IgG. IVIG is further purified to remove or inactivate infectious agents and prevent aggregates1,3–5.

Clinical use and the Italian demand for antithrombin

Antithrombin (AT) is a single-stranded glycoprotein synthesised in the liver with a plasma concentration of approximately 150 μg/mL and a molecular weight of approximately 59,000 Da1. It is a complex molecule with multiple biologically important properties. It is a serine protease inhibitor (serpin) that inactivates many enzymes in the coagulation cascade2,3. Indeed, it is the key inhibitor of the coagulation system and is estimated to provide 80% of the inhibitory activity against thrombin but it also inhibits activated factors X, IX, VII, XI, and XII. AT has a great affinity for thrombin and is also known as heparin cofactor as it is responsible for the anticoagulant effect of heparin. Heparins markedly accelerate the rate of complex formation between AT and the serine proteases thus increasing AT inhibitory activity 5,000–40,000-fold4. AT also has remarkable anti-inflammatory properties, several of which result from its actions in the coagulation cascade. Other anti-inflammatory properties of AT involve direct interactions with endothelial cells, leading to the release of prostacyclin, which also mediates its anti-platelet effect3. In addition, recent evidence of interactions of the endothelial cell growth factors bFGF (basic fibroblast growth factor) and VEGF (vascular endothelial cell growth factor) with a heparin-like molecule in matrix provide the rationale for further investigation into the possible role of AT as a potent anti-angiogenic factor5. Normal values of AT activity in the plasma range from 80% to 120%. In normal conditions, its biological half-life is 1.5–2.5 days. In conditions of acquired deficiency and in the presence of heparin, the half-life of AT can be notably shorter, being reduced to only a few hours6.

Improving access to haemophilia therapies-Beyond humanitarian aid

than a study able to demonstrate the correlation between blood group and bleeding phenotype. In conclusion, the results of our study identify a significant association between O blood group type and the bleeding risk in patients with mild rare bleeding disorders. The significantly higher vWF plasma levels that we observed in non bleeders are more likely than not a protecting mechanism against haemorrhagic episodes in non‐O blood type patients. Further pro‐ spective studies are needed to confirm our data and to thoroughly investigate VWF’s role on the bleeding phenotype in a much larger population.

Definition of an organisational model for the prevention and reduction of health and social impacts of inherited bleeding disorders.

INTRODUCTION Due to the increase in life expectancy, patients with haemophilia and other inherited bleeding disorders are experiencing age-related comorbidities that present new challenges. In order to meet current and emerging needs, a model for healthcare pathways was developed through a project funded by the Italian Ministry of Health. The project aimed to prevent or reduce the social-health burden of the disease and its complications. MATERIAL AND METHODS The National Blood Centre appointed a panel of experts comprising clinicians, patients, National and Regional Health Authority representatives. Following an analysis of the scientific and regulatory references, the panel drafted a technical proposal containing recommendations for Regional Health Authorities, which has been formally submitted to the Ministry of Health. Finally, a set of indicators to monitor haemophilia care provision has been defined. RESULTS In the technical document, the panel of experts proposed the adoption of health policy recommendations summarised in areas, such as: multidisciplinary integrated approach for optimal healthcare provision; networking and protocols for emergency care; home therapy; registries/databases; replacement therapy supply and distribution; recruitment and training of experts in bleeding disorders. The recommendations became the content of proposal of agreement between the Government and the Regions. Monitoring and evaluation of haemophilia care through the set of established indicators was partially performed due to limited available data. CONCLUSIONS The project provided recommendations for the clinical and organisational management of patient with haemophilia. A particular concern was given to those areas that play a critical role in the comorbidities and complications prevention. Recommendations are expected to harmonise healthcare care delivery across regional networks and building the foundation for the national haemophilia network.

The evolution of the regulatory framework for the plasma and plasma-derived medicinal products system in Italy.

In Italy, the plasma system is a part of the Blood System (BS) that is run under a thoroughly public governance scheme. The Italian National Blood Centre (NBC) (Centro Nazionale Sangue, http://www.centronazionalesangue.it) is designated as the Italian blood and blood product competent authority operating on behalf of the Ministry of Health (Ministero della Salute, MoH, http://www.salute.gov.it). It coordinates and supervises the 21 Regional Blood Transfusion Centres, with the aim of guaranteeing homogeneous standards of quality and safety across the 310 blood establishments (BEs) and 352 donor association collection units (with 1,867 collection points) (source: Italian Blood Information System, SISTRA database1). In 2012, the number of voluntary non-remunerated donors of whole blood and blood components amounted to approximately 1,739,712. The BS relied on 1,739,712 voluntary non-remunerated donors of whole blood and blood components: 1,443,770 (83%) repeat donors and 295,942 first-time donors2. Based on a national definition, 666,479 of the repeated donors are considered “frequent donors” that means they donated at least once a year, every year, in the previous 5 years. There were 240,218 apheresis donors (13.8% of total). In the same year, 3,191,026 donations (53.7 donations per 1,000 population) were collected. Of the 7,224,409 blood components produced in 2012, 2,666,726 were red blood cell units (44.9 units per 1,000 population). Those transfused were 2,529,803 (42.6 units per 1,000 population). Every day, 8,719 blood components were transfused involving totally approximately 650.000 recipients (source: Italian Blood Information System, SISTRA database). In 2012, the volume of plasma sent to industry for fractionation was approximately 772,590 kilograms (source: Kedrion Biopharma SpA). In February 2011, the MoH convened a panel of experts from the national competent authorities in the field of blood and blood products: the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA, http://www.agenziafarmaco.gov.it), the National Institute of Health (Istituto Superiore di Sanita, ISS, http://www.iss.it), the NBC and the MoH. The mission of the panel was to review and implement the current legislation and define proposals for regulations to comply with European directives and guidelines. Furthermore, efforts had to be put into the harmonisation of existing legislation, particularly for those aspects which were lacking and/or were not implemented: the production of plasma-derived medicinal products (PMPs) from Italian plasma, the opening up of the toll fractionation market to other contractors and the import/export of plasma and its products. The proposals, after approval of the State-Regions Conference, upon advice of the National Blood Technical Board and auditing of the Plasma Fractionators Association (Gruppo Emoderivati di Farmindustria), were signed by the Minister of Health on April 12th, 20123–6. The aim of this paper is to describe the main features of the Italian regulatory framework of the plasma system in the light of the recent changes of legislation, in particular related to the opening up of the toll fractionation market.

Plasma and plasma-derived medicinal product self-sufficiency: the Italian case

According to the World Health Organization, “self-sufficiency in safe blood and blood products based on voluntary non-remunerated blood donation (VNRBD) means that the national needs of patients for safe blood and blood products, as assessed within the framework of the National Health Service (NHS), are met in a timely manner, that patients have equitable access to transfusion services and blood products, and that these products are obtained from VNRBD of national, and where needed, of regional origin, such as from neighbouring countries”1. In Italy, the achievement of self-sufficiency of plasma-derived medicinal products (PMPs), as well as blood components, is a goal of the blood system “aimed at guaranteeing equal conditions of quality and safety of transfusion therapy to all citizens”, as set out by the main regulatory reference2. Self-sufficiency is recognised as a role of “national, supra-regional, supra-local indivisible interest of the National Health Service” whose achievement is entrusted to the contributions of the regional health authorities. In order to attain this strategic goal, the Ministry of Health is responsible for defining an annual national programme for self-sufficiency aimed at identifying historical usages, real demand, necessary production levels, resources, funding system criteria, interregional PMP exchanges, import and export levels3–5. Moreover, according to current legislative provisions6,7, a special decree must be adopted for defining the “program for the development of plasma collection in blood services and blood collection units, as well as the promotion of an appropriate and rational use of plasma-derived medicinal products”. In addition, national plasma derives from voluntary, periodic, responsible, anonymous and non-remunerated donations2. Regions and Autonomous Provinces (APs) (henceforth referred to as “Regions”), individually or in association, send the plasma collected by blood establishments (BE) to Kedrion Biopharma (Kedrion SpA, Castelvecchio Pascoli, Lucca, Italy), which, at the moment, is the only manufacturer authorised under a toll fractionation agreement. The latter has the capacity to produce at least the following PMPs: human albumin solution (albumin), polyvalent immunoglobulin (for intravascular administration, IVIG), plasma-derived factor VIII concentrates (pdFVIII), plasma-derived factor IX concentrates (pdFIX), prothrombin complex concentrates (PCCs), and antithrombin (AT). However, Regions remain owners of the plasma sent for fractionation, as well as of PMPs manufactured and of the residual raw material, including discards. Therefore, self-sufficiency strongly depends on the capacity of regional health systems and the national blood system to ensure the satisfaction of patients’ needs using all products obtained by the manufacturing of national plasma within the toll fractionation agreements between Regions and fractionators thus reducing supplies from the pharmaceutical market8–10. However, also the appropriate clinical use of plasma11 and of PMPs plays a key role in self-sufficiency. The aim of the present paper is to address the issue of PMPs self-sufficiency in Italy in 2011.