An update on sargramostim for treatment of acute radiation syndrome.

The potential use by terrorists of an improvised nuclear device, a radiological dispersal device, or an unintended nuclear/radiological accident in heavily populated areas is a national security threat of major consequences. Although this type of security threat is considered to be low-risk, it would have a devastating impact. Health issues would be a major concern; medical care would be necessary for all those who received considerable radiation exposure (> 1 Gy) leading to hematopoietic acute radiation syndrome (ARS). In the past few years, the U.S. Food and Drug Administration (FDA) has approved for such radiation exposure contingencies recombinant human granulocyte colony-stimulating factor (rhG-CSF, filgrastim, Neupogen), PEGylated rhG-CSF (PEGylated filgrastim, Neulasta) and granulocyte-macrophage colony-stimulating factor (rhGM-CSF, sargramostim, Leukine) following the FDA's Animal Rule guidance. In this article, we have briefly reviewed the consequences of exposure to acute, potentially lethal doses of radiation and its pathologic sequelae, as well as ARS and the latest of the FDA-approved recombinant growth factors, namely sargramostim (Leukine), as a new treatment option for the subclinical, hematopoietic syndrome component of ARS. The nature of the recombinant and the preclinical and clinical research that preceded approval by the FDA are presented, as well as its use in the treatment of victims of radiation accidents.

Innovation in Cell Banking, Expansion, and Production Culture.

Cell culture-based production processes enable the development and commercial supply of recombinant protein products. Such processes consist of the following elements: thaw and initiation of culture, seed expansion, and production culture. A robust cell source storage system in the form of a cell bank is developed and cells are thawed to initiate the cell culture process. Seed culture expansion generates sufficient cell mass to initiate the production culture. The production culture provides an environment where the cells can synthesize the product and is optimized to deliver the highest possible product concentration with acceptable product quality. This chapter describes the significant innovations made in these process elements and the resulting improvements in the overall efficiency, robustness, and safety of the processes and products.

Treatment outcomes, quality of life, and impact of hemophilia on young adults (aged 18-30 years) with hemophilia.

The Hemophilia Experiences, Results and Opportunities (HERO) initiative assessed psychosocial issues reported by people with moderate to severe hemophilia and was led by a multidisciplinary international advisory board. This analysis reports data from young adult respondents (aged 18-30 years), including both US and overall global (including US respondents) results, and investigates treatment outcomes, quality of life, and impacts of hemophilia on relationships. More young adults in HERO received prophylaxis than on-demand treatment, although a majority reported not using factor products exactly as prescribed, and 50% of global respondents and 26% of US respondents reported issues with access to factor replacement therapy in the previous 5 years. Many young adults with hemophilia reported comorbidities, including bone/skeletal arthritis, chronic pain, and viral infections, and nearly half of young adults reported anxiety/depression. Most reported pain interference with daily activities in the past 4 weeks, although a majority reported participating in lower-risk activities and approximately half in intermediate-risk activities. Most young adults were very or quite satisfied with the support of partners/spouses, family, and friends, although roughly one-third reported that hemophilia affected their ability to develop close relationships with a partner. A majority of young adults reported that hemophilia has had a negative impact on employment, and 62% of global respondents and 78% of US respondents were employed at least part-time. Together these data highlight the psychosocial issues experienced by young adults with hemophilia and suggest that increased focus on these issues may improve comprehensive care during the transition to adulthood.

[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.

Seeds as a production system for molecular pharming applications: status and prospects.

The production of recombinant proteins in seeds is achieved by driving transgene expression using promoters and protein targeting sequences derived from genes encoding abundant seed storage proteins. This approach is advantageous because high yields, stability and containment are conferred by the accumulation of recombinant proteins in specialized storage compartments such as protein bodies and protein storage vacuoles. Seeds are particularly suitable for the production of pharmaceutical proteins in developing country settings because they reduce the costs of production and distribution by avoiding the need for fermenter-based production capacity and a cold chain for storage and distribution, thus increasing access to critical medicines for the poor in rural areas. Seeds are also ideal for the production of oral vaccine antigens, because encapsulation within the seed provides protection that prolongs exposure to the gastric immune system and thus increases the potency of the immune response. In this review we discuss the current state of the art in seed-based molecular pharming and the future potential of production platforms based on seeds.

Techniques for improving efficiency in the emergency department for patients with acute ischemic stroke.

The past 15 years have witnessed significant strides in the management of acute stroke. The most significant advance, reperfusion therapy, has changed relatively little, but the integrated healthcare systems-stroke systems-established to effectively and safely administer stroke treatments have evolved greatly. Driving change is the understanding that "time is brain." Data are compelling that the likelihood of improvement is directly tied to time of reperfusion. Regional stroke systems of care ensure patients arrive at the most appropriate stroke-capable hospital in which intrahospital systems have been created to process the potential stroke patient as quickly as possible. The hospital-based systems are comprised of prehospital care providers, emergency department physicians and nurses, stroke team members, and critical ancillary services such as neuroimaging and laboratory. Given their complexity, these systems of care require maintenance. Through teamwork and ownership of the process, more patients will be saved from potential death and long-term disability.

Pharmaceutical protein production by yeast: towards production of human blood proteins by microbial fermentation.

Since the approval of recombinant insulin from Escherichia coli for its clinical use in the early 1980s, the amount of recombinant pharmaceutical proteins obtained by microbial fermentations has significantly increased. The recent advances in genomics together with high throughput analysis techniques (the so-called-omics approaches) and integrative approaches (systems biology) allow the development of novel microbial cell factories as valuable platforms for large scale production of therapeutic proteins. This review summarizes the main achievements and the current situation in the field of recombinant therapeutics using yeast Saccharomyces cerevisiae as a model platform, and discusses the future potential of this platform for production of blood proteins and substitutes.

[Consequences of the judicialization of health policies: the cost of medicines for mucopolysaccharidosis]. / Consequências da judicialização das políticas de saúde: custos de medicamentos para as mucopolissacaridoses.

This study analyzes expenditures backed by court rulings to ensure the public provision of medicines for treatment of mucopolysaccharidosis (MPS), a rare disease that requires high-cost drugs not covered by the Brazilian government's policy for pharmaceutical care and which have disputed clinical efficacy. The methodology included a review of files from 196 court rulings ordering the Brazilian Ministry of Health to provide the medicines, in addition to Ministry of Health administrative records. According to the analysis, the "judicialization" of the health system subjected the Brazilian government to a monopoly in the distribution of medicines and consequently the loss of its capacity to manage drug purchases. The study also indicates that the imposition of immediate, individualized purchases prevents obtaining economies of scale with planned procurement of larger amounts of the medication, besides causing logistic difficulties in controlling the amounts consumed and stored. In conclusion, litigation results from the lack of a clear policy in the health system for rare diseases in general, thereby leading to excessive expenditures for MPS treatment.

Consequências da judicialização das políticas de saúde: custos de medicamentos para as mucopolissacaridoses / Consequences of the judicialization of health policies: the cost of medicines for mucopolysaccharidosis

O estudo analisa os gastos da judicialização de medicamentos para a mucopolissacaridose (MPS), uma doença rara, de alto custo, fora da política de assistência farmacêutica e com benefício clínico. O levantamento de dados foi realizado nos arquivos de 196 dossiês que determinou que o Ministério da Saúde fornecesse medicamentos no período entre 2006 e 2010, e nos registros administrativos e contábeis do Ministério da Saúde. A análise identifica sujeição do governo brasileiro a monopólios de distribuição de medicamentos e, consequentemente, perda de sua capacidade de administrar compras. Também identifica que a imposição da aquisição imediata e individualizada impede a obtenção de economias de escala com a compra planejada de maiores quantidades de medicamento, e impõe dificuldades logísticas para o controle das quantidades consumidas e estocadas. Conclui-se que a judicialização decorre da ausência de uma política clara do sistema de saúde para doenças raras em geral, e tem como consequência gastos acima do necessário para o tratamento.

This study analyzes expenditures backed by court rulings to ensure the public provision of medicines for treatment of mucopolysaccharidosis (MPS), a rare disease that requires high-cost drugs not covered by the Brazilian government's policy for pharmaceutical care and which have disputed clinical efficacy. The methodology included a review of files from 196 court rulings ordering the Brazilian Ministry of Health to provide the medicines, in addition to Ministry of Health administrative records. According to the analysis, the "judicialization" of the health system subjected the Brazilian government to a monopoly in the distribution of medicines and consequently the loss of its capacity to manage drug purchases. The study also indicates that the imposition of immediate, individualized purchases prevents obtaining economies of scale with planned procurement of larger amounts of the medication, besides causing logistic difficulties in controlling the amounts consumed and stored. In conclusion, litigation results from the lack of a clear policy in the health system for rare diseases in general, thereby leading to excessive expenditures for MPS treatment.

Benefits associated with a broad selection of dosage strengths for recombinant factor VIII products.

Factor VIII (FVIII) concentrates for haemophilia A patients are dosed according to body weight. This results in a continuous range of prescribed doses, which challenges pharmacies to find dosage strengths closest to the prescribed dose while utilizing the least number of vials. This study was conducted to determine whether a broader selection of FVIII dosage strengths results in improved dispensing accuracy and an increased number of single-vial users. This research retrospectively analyzed a US pharmacy database of prescriptions filled in 2008. Recombinant FVIII (rFVIII) therapies were classified by the range of dosage strengths offered in 2008: Group 1 had three dosage strengths; Group 2 had four dosage strengths; and Group 3 had six dosage strengths. A total of 76,584 dispensed doses of rFVIII for 1,244 patients were included in this analysis. Dispensing accuracy (calculated as both the absolute and relative difference between dispensed and prescribed dose) was significantly better for Group 3 (23.2 IU, 1.2%) than Groups 1 (33.5 IU, 1.6%) and 2 (50.2 IU, 2.4%) (both P < 0.01). In addition, the average number of unique actual rFVIII potencies dispensed per month was highly correlated (-0.977) with dispensing accuracy for each dosage strength group. Among Groups 1, 2 and 3, 23.0%, 44.9% and 73.4% of patients, respectively, had at least one single vial option dispensed (P < 0.0001). A broader selection of rFVIII dosage strengths and more actual rFVIII potencies were associated with improved dispensing accuracy and more single-vial users. This may translate into less waste, cost savings, increased convenience and improved adherence to physician-prescribed regimens.

[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.

Force majeure: therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease.

Gaucher disease is the first lysosomal disorder for which clinically effective enzyme replacement therapy has been introduced. Lifelong treatment with imiglucerase, the recombinant glucocerebrosidase manufactured by the Genzyme Corporation (MA, USA), is administered intravenously - usually at biweekly intervals. An acute shortage of imiglucerase (to 20% of prior global supply) has occurred as a result of viral contamination of the production facility; production was halted, and a full supply of imiglucerase is not anticipated until January 2010. An urgent meeting of physicians, researchers, and patients was convened through the agency of the European Working Group for Gaucher Disease; this was instigated by patients internationally represented by the European Gaucher Alliance. Here we present a position statement based on the findings of the group, with key recommendations about identification and monitoring of at-risk patients threatened by the abrupt withdrawal of treatment, the equitable distribution of residual imiglucerase - and access to alternative treatments including those that have completed phase III clinical trials but have not yet been licensed.

[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.