[Hemorrhagic congenital diseases: What can be the future of plasma-derived products against recombinants?]. / Maladies hémorragiques congénitales: quel avenir pour les dérivés plasmatiques par rapport aux recombinants et aux produits sanguins labiles ?

Until 1990, congenital hemorrhagic disorders were treated by plasma-derived concentrates. The first recombinant drug, recombinant factor VIII was available after this date and few years later recombinant factor IX could also be proposed to patients. The evolution of market share in France was different between these two drugs: while recombinant factor VIII took a large place in hemophilia A treatment (85%), plasma-derived factor IX represent 50% of the French market. In the next years, the arrival of long-acting antihemophilic factors may lead to the dramatically reduce the amount of plasma-derived antihemophilic factors used to treat hemophilia. For rare bleeding coagulation disorders, plasma-derived concentrates are still widely used, while they are the only concentrates available in most diseases. This situation is unlikely to evolve significantly in the next years.

Public expenditure for plasma-derived and recombinant medicinal products in Italy.

BACKGROUND: In Italy, the supply of plasma-derived medicinal products funded by the National Health Service can be through public healthcare facilities, accredited pharmacies or toll fractionation agreements between Regions and the manufacturer. Pharmaceutical public expenditure includes the supply related to the first two channels and costs can significantly vary because of channel-specific price reductions. This paper describes 2011 public expenditure for plasma-derived medicinal products purchased on the market, as well as the cost analysis per active substance. MATERIALS AND METHODS: Analysis of the usage of plasma-derived medicinal products and of the related expenditure in public facilities has been carried out using medicinal product traceability data. The analysis related to the accredited pharmacies channel has been carried out using quantities for every medicinal package recorded by Pharmacy Associations and applying reference prices in force on March 1(st), 2012 as well as discounts for the accredited pharmaceutical expenditure imposed by law. RESULTS: At national and regional level, total and total per capita expenditures on plasma-derived medicinal products by market channel and funded by the National Health Service are shown. Analysis was conducted considering the active substances in three groups: substances included in toll fractionation agreements, recombinant coagulation factors, and other substances not included in toll fractionation agreements. In 2011, the national expenditure estimate for plasma-derived and recombinant medicinal product acquisition on the market was about € 535 million. DISCUSSION: The purchased volumes and mean purchased prices per unit of each substance have a significant influence on the observed regional variability of the pharmaceutical public expenditure. A strategy of regional comparison aimed at both sharing a national range of reference for purchase prices and evaluating modalities for centralised purchasing is desirable.

Resultados de operación acceso y del Programa Nacional de Hemostasia y Trombosis / The results of operation access and the National Hemostasis and Thrombosis Program

En el decenio que va desde 1996 hasta 2006, se establecieron en Chile las políticas sanitarias programáticas que se hicieron cargo de la dramática situación que vivían hasta ese momento las personas afectadas de hemofilia. En dicho período fue fundamental la implementación de la Operación Acceso y del Programa Nacional de Hemostasia y Trombosis, ambos a cargo del Ministerio de Salud con el apoyo de la Sociedad Chilena de la Hemofilia y de la Facultad de Medicina de la Universidad de Chile. Este proceso trajo aparejado además la sistematización en cuanto a registro de casos, un avance cualitativo y cuantitativo en cuanto al acceso a tratamientos, así como a medicamentos seguros, efectivos y oportunos para la comunidad hemofílica del país con independencia de su sistema previsional. El artículo anterior de esta serie describe los programas, y este los resultados en el mencionado período.

During the time span going from 1996 to 2006 the healthcare policies that address hemophilic patient’s dramatic needs were set up in Chile. Operation Access and the National Hemostasis and Thrombosis Program were implemented, both in charge of the Ministry of Health, with the support of the Chilean Society of Hemophilia and the School of Medicine of the University of Chile. The process was coupled with the systematization of case registries, a qualitative and quantitative advance in access to treatment options, including timely access to safe and effective medications, regardless of the health insurance system to which patients belonged. The previous article of this series describes both programs, while the present article describes the results in that the ten-year period.

[Indications and use of prothrombin complex in cardiac surgery]. / Indicaciones y usos del complejo protrombínico en cirugía cardiaca.

On of the most common, and serious, complications in cardiac surgery is postoperative bleeding. According to the majority of studies, between 10% and 92% of patients subjected to elective surgery require transfusions of blood products and blood derivatives. Transfusions and reinterventions are associated with longer stays in critical care units and a decrease in survival rates. There have been some important changes in the treatment of changes in haemostasis and post-surgical bleeding in the last few years, particularly with the introduction into clinical practice of working procedures backed up by clinical guidelines, as well as the appearance of new drugs. The aim of this work is to describe the main characteristics and update the use of prothrombin complexes that are currently available in Spain, with special emphasis on their use in cardiac surgery.

[Report on notifications pursuant to Section 21 of the German Transfusion Act for the years 2008 and 2009]. / Bericht zur Meldung nach § 21 TFG für die Jahre 2008 und 2009.

This report contains the data collected in 2008 and 2009, pursuant to Section 21 of the German Transfusion Act (Transfusionsgesetz), as well as an overview of the supply situation during the last 10 years. In 2009, blood donation services reported a total of 7.5 million donations--the largest amount since 2000. At the same time, more than 4.7 million red blood cell concentrates and more than 500,000 platelet concentrates were available. The number of therapeutic single plasma units decreased to 1.1 million units in 2009. The loss rate for red blood cell concentrates is still between 3% and 4% for the users, while for the manufacturers, it has decreased slightly to 1.4%. The loss rate, for platelet concentrates, on the other hand, increased in 2009, and--what is noteworthy--especially for manufacturers of pooled platelet concentrates. The loss rate for apheresis platelet concentrates accounted for 5.2% compared to 17.5% for pooled platelet concentrates. As far as the users were concerned, loss rates for platelet concentrates largely remained unchanged with rates between 5% and 6%. Based on the data collected, the supply of blood components for transfusion can be regarded as assured. Nearly 2.9 million liters of plasma for fractionation were collected in Germany in 2009. According to reports from the pharmaceutical industry, of these, 2.6 million liters remained on the German market, of which only 56% were fractionated in this country; no statement can be made on the use of the remaining amount. Many plasma derivatives are not manufactured in Germany, despite the large amount of plasma collected. The supply with these products, however, is assured by imports. Overall, 16,409 autologous and 9,435 allogeneic hematopoietic stem cell preparations were manufactured in 2009, of which 3,382 allogeneic preparations were exported. A total of 3,181 autologous and 2,374 allogeneic preparations were transplanted; 187 of these products from imports. The large number of exported stem cells and the small number of imported stem cells suggest that no serious shortages are to be expected for the supply with these products.

[Report on notifications pursuant to Section 21 German Transfusion Act for 2007]. / Bericht zur Meldung nach section sign 21 TFG für das Jahr 2007.

The present report contains the data collected in 2007, pursuant to Section 21 Transfusionsgesetz (German Transfusion Act), and an analysis of the supply situation over the past eight years. The recording of the data by online reporting is in the meantime well established and generally accepted. As in previous years, all blood donation centers located in Germany transmitted data on the collection, manufacture, import and export of blood components for transfusion, so that meaningful data are available. According to these data, a total of 6.7 million blood collections were performed in 2007. The number of whole blood donations was at the level of previous years, with 4.7 million, whereas the number of apheresis donations rose again, to 1.9 million. The portion of autologous blood collections accounts for only 1.1% and thus continues to decline. Since 2003, the number of red blood cell concentrates prepared has been a constant 4.5 million transfusion units. The decrease in the portion of decay of red blood cell concentrates on the user side is particularly good news. In 2000, it accounted for 5% and in 2007, it was just above 3%, referred to the total quantity of data reported as transfused and decayed. The manufacture of platelet concentrates rose from 366,000 to 480,000 transfusion units between 2003 and 2007. The production of therapeutic single plasmas also markedly increased in 2007 compared with previous years, accounting for 1.2 million transfusion units. In 2007, 2.2 million liters of plasma for fractionation were collected in Germany. This trend went hand in hand with the increasing number of apheresis donations that year. In addition, 1.0 million liters were imported, and, at the same time, 1.8 million liters were exported. The quantity available in Germany from a pure arithmetic point of view of 1.4 million liters was almost entirely allocated to basic fractionation, so that a sufficient plasma supply can be assumed. The assessment of the degree of self-sufficiency is made difficult because of the influence of imports and exports; however, the results show no deficit for plasma derivatives. Due to the fact that manufacturing capacities are still lacking in Germany, recombinant factors need to be imported in their entirety. Since 2003, Germany has by far been the leader in Europe with more than 20 liters of fractionation plasma collected per 1,000 inhabitants. Furthermore, regarding the manufacturing figures of red blood cell concentrates, platelet concentrates, and therapeutic single plasma, Germany is in the top third for all these products compared with other European countries. The manufacture of allogeneic stem cell products for hematopoietic reconstitution, obtained by apheresis, has continuously risen to 4,700 in the reporting year. A large portion of this, 1,810 transplants could be exported while only a small number, 179 preparations, had to be imported. The manufacture of autologous stem cell preparations from cord blood also rose drastically compared with 2006, to more than 10,000 in 2007. It must be emphasized that these products were entirely placed into stock; none were transplanted in the reporting year. The interest in the figures collected in compliance with Section 21, Transfusion Act remains high both in Germany and at the international level. Reliable data are available thanks to the evaluations of trends over years, above all on the availability of blood components for transfusion. In addition, the Paul Ehrlich Institute will continue to strive to meet the demands for high-quality information on the supply situation in the future.

[Report on notifications pursuant to Section 21 German Transfusion Act for 2005 and 2006]. / Bericht zur Meldung nach SS 21 TFG für die Jahre 2005 und 2006.

In 2007, for the first time since the introduction of reporting pursuant to Section 21 of the German Transfusion Act, a timely report including data collected concerning the previous year can be published. In this report on the years 2005 and 2006, a trend analysis over the 7 years since 2000 can be presented. Thereby the favourable result is confirmed that, thanks to sustained reliable reporting on collection, manufacture, import and export of blood and blood products, interesting and meaningful data on the amount of available medicinal products are provided. The amount of heterologous donations increased in 2006 again up to 6.4 million, after a decrease observed since 2003. The share of whole blood donations during the past three years was constantly about 4.7 million, out of which ca. 4.5 million erythrocyte concentrates are manufactured. While in 2005 with 1.8 million Litres plasma for fractionation the lowest amount since 2002 had been collected, the figure increased again in 2006 up to 2.1 million Litres, as a consequence of enhanced apheresis donations. About 40 % thereof are exported. On average, 1.75 million Litres are available on the German market; up to 1.4 million Litres are used for basis fractionation in Germany. After introduction of on-line submission as the obligatory way of reporting, the response rate concerning collection of blood and blood components from allergenic donors, and manufacture, import and export as well is 95 %. In contrast, in 2006 only 64 % of consuming institutions reported; this means 8 % less than in 2005. Hence, with regard to the collection of data on the usage of blood products, an unacceptably high rate of missing report from the side of health care facilities persists. Therefore, regrettably even after 7 years, it was not possible to generate a solid basis for the assessment of the demand to be met and thus the supply situation. As a potential approach to a tentative judgement of the supply situation concerning plasma derivatives, a query on the sales figures was performed. A comparison with the reported figures on consumption, however, was of little relevance in many cases. The reported number of haemophilia patients has to be regarded as considerably too low. With the upcoming introduction of a German Haemophilia Register, an improvement of the data base is intended.

European principles of haemophilia care.

As the management of haemophilia is complex, it is essential that those with the disorder should have ready access to a range of services provided by a multidisciplinary team of specialists. This document sets out the principles of comprehensive haemophilia care in Europe. Within each country there should be a national organization which oversees the provision of specialist Comprehensive Care Centres that provide the entire spectrum of clinical and laboratory services. Depending upon the size and geographical distribution of the population, a network of smaller haemophilia centres may also be necessary. There should be arrangements for the supply of safe clotting factor concentrates which can also be used in home treatment and prophylaxis programmes. A national register of patients is recommended along with collection of treatment statistics. As comprehensive haemophilia care is multidisciplinary by nature, the need for education and research programmes for all staff members is emphasized: Members of the Interdisciplinary Working Group not represented in the list of authors are mentioned in Section 4 of this document.

Clinical uses of plasma and plasma fractions: plasma-derived products for hemophilias A and B, and for von Willebrand disease.

The use of plasma-derived factor products to treat hemophilia A, hemophilia B, and von Willebrand disease (vWD) has changed since the start of the human immunodeficiency virus (HIV) epidemic. The use of plasma-derived factor concentrates for hemophilias A and B has decreased in developed countries because of the availability of recombinant products. However, in developing countries, which encompass most of the world's hemophilia community, plasma-product-based therapy remains the backbone of treatment because of economic constraints. Viral attenuation strategies have resulted in a much safer product profile. vWD product selection is less complicated than for hemophilas A and B because plasma-derived products are the only choice for patients who are unresponsive or who cannot receive pharmacologic therapy. As the majority of patients in the world with hemophilias A, B and vWD are treated with plasma-derived clotting factors, the need for these safe and efficacious therapies will continue in the future. This chapter discusses safety strategies for plasma-derived clotting factor, its availability, economics, efficacy, and inhibitor formation.

Emerging and receding risks of therapeutic regimens for haemophilia.

During the past two decades, the improvement of therapeutic agents for the management of haemophilia has created the opportunity for individuals with haemophilia to live normal lives. However, in some instances, the progress made has been accompanied by emergence of unexpected risks and other new complications. A number of viruses have either emerged, or become greater risks to people with haemophilia. In addition, the drive of many countries towards self-sufficiency in blood products may in fact be endangering people with haemophilia by restricting blood donation to a pool of donors with high infection risk, discouraging commercial interests from developing safer products, and discouraging use of 'foreign' products even where that may be the safer option. Gene therapy for haemophilia, although an encouraging new treatment, has brought with it a number of adverse events, including risk of virus infection and development of carcinomas. The risk of inhibitors is still the most important problem for people with haemophilia, and a recent report showed that the type of factor concentrate does not impact significantly on this risk. Despite the advent of new and promising treatments for haemophilia, heathcare providers must be alert to new risks posed by them.

Product delivery in the developing world: options, opportunities and threats.

While many developed countries are moving to recombinant coagulation factors as their preferred modality for delivering haemophilia care, the cost of these products currently impedes their access by developing countries. A number of options are available to these countries for the provision of plasma-derived therapeutic products. The decreasing market for plasma-derived coagulation factors in the developed world is leading to the generation of a surplus of these products and an ability to offer them outside their traditional markets if prices are affordable. Current indications are that the commercial fractionation industry of the developed world has an excess capacity in both available plasma and fractionation plants. It would seem that accessing this capacity might have attractions for the developing world. Countries wedded to achieving self-sufficiency in haemophilia products may elect to develop a strategy for fractionating domestically sourced plasma. This may be achieved by the generation of a capacity to fractionate within the country or by contracting the fractionation to an external agency overseas. However, reliance on domestic plasma should not be allowed to impede access to sufficient and safe coagulation products. Irrespective of the route chosen, products need to attain satisfactory compliance to standards for safety, quality and efficacy. This is best done through alignment of the products with the requirements of credible regulatory agencies. While the approval of the mainstream regulators of the developed world affords considerable assurance regarding product quality, the increasing efforts made by fractionation agencies in the developing world to attain best practice is commendable and augurs well for the enhancement of haemophilia care in these countries.

Regulatory challenges to global harmonization and expanded access to concentrates: how will regulators balance the increasing cost of new safety requirements with the desire to increase the availability of affordable product?

The provision of concentrates of the deficient coagulation factors is an essential component of the provision of comprehensive haemophilia care. Their safety, quality and efficacy need to be assured independently of the measures dictated by the market and the individual manufacturers. Over the past 20 years, this assurance has become the role of regulatory authorities, which in the developed world have generated a framework that assesses haemophilia products as medicines in the highest category of risk relative to other therapeutic agents. Systems of official regulation mandating standards and other measures are now coupled with voluntary standards adopted by industry bodies as additional features of a comprehensive nexus of arrangements contributing to product quality and risk minimization. Currently, the regulation of products for haemophilia in less developed economies relies on reference to decisions in the first-world authorities. This may not always result in optimal outcomes as most of the haemophilia care in the developing world is through local plasma and cryoprecipitate, which are not subject to the oversight of mainstream regulators. Furthermore, the emergence of companies based outside the developed world and seeking to supply the emerging economies of the developing world with haemophilia concentrates has necessitated new strategies for regulation that are independent of the established frameworks. Overall, the principles used by mainstream agencies may be applied in all environments seeking to assure the quality of haemophilia care. Applied properly, they can contribute to maintaining the delivery of a form of therapy that is nowadays amongst the safest in therapeutic practice. A rigid interpretation can seriously impede access to treatment, and therefore the development of independent expertise and appropriate strategies in assuring product safety and quality in the developing world is essential if patient safety and access to products can be assured.

Towards the goal of prophylaxis: experience and treatment strategies from Sweden, France and Hungary.

The only form of haemophilia treatment that is able to prevent arthropathy and other consequences of bleeding symptoms in patients with severe haemophilia is prophylaxis started at an early age (primary prophylaxis). It is also highly beneficial for the psychological and social wellbeing of patients and their families. Scientific institutions and international organizations such as WHO, the World Federation of Hemophilia (WFH) and the National Haemophilia Foundation (NHF) have recommended that prophylaxis be considered optimum therapy. This paper discusses the barriers to prophylaxis, such as the perceived need, costs and availability, and difficulty of venous access, and describes the authors' experiences with the therapy.

Safety and supply of haemophilia products: worldwide perspectives.

The survival and well-being of people with haemophilia depends on the supply of safe therapeutic products. Safety and supply are entirely intertwined principles; in the absence of adequate amounts of coagulation products, safety measures may be compromised in order to enhance supply, leading to risks which may result in morbidity and mortality. As haemophilia therapy has emerged through the development of blood transfusion and plasma fractionation, the safety of the blood supply in general has had a strong effect on haemophilia care. Despite the gradual detachment of haemophilia care from blood transfusion through the use of recombinant products, the majority of the world's population with haemophilia in the developing world will be reliant on blood products for the foreseeable future. It is, therefore, important to continue efforts for a safe and sufficient blood supply worldwide. As such a blood supply develops, possibly in tandem with an independent plasma fractionation industry, the level of haemophilia care should improve with the gradual introduction of concentrates for the ultimate goal of covering all aspects of care. Constant vigilance for the threat of blood-borne pathogens should be linked to considerations of how these products are to be manufactured. This should be governed entirely by considerations of safety and pharmaceutical competence. Of equal importance is a governmental capacity to oversee the entry and maintenance of these products on the market. While it is not possible for all countries to have a regulatory authority of the same status as that of the developed countries, it is perfectly feasible to develop a set of basic principles which allow an assessment of basic product safety, quality and efficacy to be made.