Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium.

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).

Research in haemophilia B--approaching the request for high evidence levels in a rare disease.

Payers in European countries request studies with high levels of evidence for decision making also for rare diseases like haemophilia B (HB). The objective of the study was to determine the status quo of current studies in HB regarding the overall level of evidence generated. The methods used for performing the study were systematic literature research in EMBASE and MEDLINE, search terms 'HB' and 'factor IX' (FIX). The inclusion criteria were journal articles (JA), conference abstracts (CA), English language, published between January 2009 and March 2013, studies only; screening of titles, abstracts, full texts subsequently. ClinicalTrials.gov search: unpublished registered trials (RT) concerning HB or FIX. The analysis was performed on research topic, sponsor, recruitment status and study design. Screening of 1639 hits yielded 31 JA describing 35 studies, and 62 CA. FIX was subject of 21 studies (60.0%) and 29 CA (46.8%). Seven studies focused on various aspects of HB, six on haemophilia studies with separate HB data. Screening of 173 hits from ClinicalTrials.gov yielded 42 RT. Overall, 32 RT (76.2%) related to FIX. Measurement of health-related quality of life (HRQoL) was identified in none of these studies, four CA (6.5%), four RT (9.5%). Randomized study design was found in one study (2.9%), four RT (9.5%). Three studies (8.6%) and seven RT (16.7%) were prospective, observational and comparative. The majority of published clinical studies do not meet payers' expectations for evidence. Therefore, clinical investigation concepts addressing randomization, outcomes research including HRQoL and comparison of therapy options should be discussed. Refined statistical methods and exploitation of complementary real-life data sources may fill current evidence gaps concerning rare diseases.

Kreuth III: European consensus proposals for treatment of haemophilia with coagulation factor concentrates.

This report summarizes recommendations relating to haemophilia therapy arising from discussions among experts from 36 European countries during the Kreuth III meeting in April 2013. To optimize the organization of haemophilia care nationally, it is recommended that a formal body be established in each country to include the relevant clinicians, national haemophilia patient organization, health ministry, paying authority and (if appropriate) regulatory authorities. The minimum factor VIII consumption level in a country should be 3 I.U. per capita. Decisions on whether to adopt a new product should not be based solely on cost. Prophylaxis for children with severe haemophilia is already recognized as the optimum therapy. Ongoing prophylaxis for individual adults should also be provided when required based on clinical decision making by the clinician in consultation with the patient. Children with inhibitors who have failed, or who are not suitable for, immune tolerance therapy should be offered prophylaxis with bypassing agents. Single factor concentrates should be used as therapy wherever possible in patients with rare bleeding disorders. Orphan drug designation for a factor concentrate should not be used to hinder the development, licencing and marketing of other products for the same condition which have demonstrably different protein modification or enhancement.

A shared regulatory perspective on deferral from blood donation of men who have sex with men (MSM).

National Regulatory Authorities (NRAs) establish deferral criteria for donors with risk factors for transfusion transmissible infections (TTI). In most jurisdictions, epidemiological data show that men who have sex with men (MSM) have a significantly higher rate of TTI than the general population. Nevertheless, changes from an indefinite donor deferral for MSM have been considered in many countries in response to concerns over a perceived discrimination and questioning of the scientific need. Changes to MSM donor deferral criteria should be based on sound scientific evidence. Safety of transfusion recipients should be the first priority, and stakeholder input should be sought.

Reasoning about the implications of facial expressions: a behavioral and fMRI study on low and high social impact.

Inferring the cause of another person's emotional state is relevant for guiding behavior in social interactions. With respect to their potentially evoked behavioral reactions some emotional states like anger or happiness are considered to have high social impact while others such as fear and sadness have low social impact. We conducted a functional magnetic resonance imaging study to map the brain activation patterns related to reasoning about facial expressions of emotions with high or low social impact in twenty-six healthy volunteers with good emotional competence, self-reported empathy, and explicit facial affect recognition abilities. Our data show that empathic reasoning was faster and more accurate for high impact emotional states than for low impact emotional states. Activated brain areas involved brain circuits associated with basic and higher order empathy and decision-making in the dorsomedial and dorsolateral frontal cortex. However, activation in higher order areas was less during reasoning about emotional states of high social impact. Taken together, reasoning of high and low impact emotional states relied on similar empathy-related brain areas with reasoning about emotional states of low social impact being more erroneous and requiring more cognitive resources.

[Official experimental testing of biomedical products. Regulatory frame and importance of for quality, safety and efficacy]. / Staatliche experimentelle Produktprüfung von biomedizinischen Arzneimitteln. Regulatorischer Rahmen und Bedeutung für die Qualität, Sicherheit und Wirksamkeit.

The official experimental testing of biomedicinal products provides a very significant contribution to ensuring quality, safety and efficacy of these indispensable medicines. Already in the prelicensing phase or to elucidate clusters of increased adverse effects, official medicinal control laboratories are committed to perform experimental testing. The official batch release can be seen as external quality control of the manufacturer's release testing. For proficient performance in these tasks, scientific research is required, in particular on the development and refinement of test methods, and considering the continuous development of innovative biomedicinal products. This article is aimed at introducing the present thematic issue and in particular the regulatory basis of experimental product testing, and illustrates by means of several examples its great importance for the sake of the patients.

[The EDQM Biological Standardisation Programme for the development of methods and reference preparations]. / Das Biological Standardisation Programme des EDQM zur Entwicklung von Methoden und Referenzpräparaten.

The Biological Standardisation Programme (BSP) of the European Directorate for the Quality of Medicines & HealthCare (EDQM) was founded in 1992 with the objective to provide the necessary tools for the quality controls prescribed by the European Pharmacopoeia (Ph. Eur.). The BSP accomplishes this task by establishing reference standards and materials, as well as standardised control methods. A key aspect of BSP's work on development of methods is the validation of methods which can replace Ph. Eur. tests involving animals. The current area of work includes vaccines (for human and animal use), medicines produced from human plasma, hormones, cytokines, allergens, as well as reference materials and methods for determination of impurities and contaminations. BSP closely collaborates with the World Health Organization (WHO) and national authorities; many reference standards are established in joint projects with WHO. Participants of studies for establishing of reference materials and methods are mainly national control laboratories and manufacturers. BSP has to date run 131 projects, whereby 121 reference materials were established. Method development was the objective of 38 projects, with 21 thereof aiming at replacement of animal tests. BSP is funded by the EDQM (Council of Europe) and by the European Commission. With its activities BSP makes a significant contribution to quality, safety and efficacy of biological medicinal products in Europe and beyond, and serves thereby health and well-being of human beings and animals.

A functional magnetic resonance imaging study of visuomotor processing in a virtual reality-based paradigm: Rehabilitation Gaming System.

The Rehabilitation Gaming System (RGS) has been designed as a flexible, virtual-reality (VR)-based device for rehabilitation of neurological patients. Recently, training of visuomotor processing with the RGS was shown to effectively improve arm function in acute and chronic stroke patients. It is assumed that the VR-based training protocol related to RGS creates conditions that aid recovery by virtue of the human mirror neuron system. Here, we provide evidence for this assumption by identifying the brain areas involved in controlling the catching of approaching colored balls in the virtual environment of the RGS. We used functional magnetic resonance imaging of 18 right-handed healthy subjects (24 ± 3 years) in both active and imagination conditions. We observed that the imagery of target catching was related to activation of frontal, parietal, temporal, cingulate and cerebellar regions. We interpret these activations in relation to object processing, attention, mirror mechanisms, and motor intention. Active catching followed an anticipatory mode, and resulted in significantly less activity in the motor control areas. Our results provide preliminary support for the hypothesis underlying RGS that this novel neurorehabilitation approach engages human mirror mechanisms that can be employed for visuomotor training.

Peripheral blood levels of matrix metalloproteinase-9 predict lesion volume in acute stroke.

Matrix metalloproteinases (MMPs) have been implicated to play an important role in the destruction of the extracellular matrix in diseases of the central nervous system. This study investigated whether the expression of one of these proteases, MMP-9 in blood, is related to the size of human brain infarcts assessed with magnetic resonance imaging. Consecutively, twenty-one acute stroke patients were included prospectively into our study. In blood samples drawn within 24 h after onset, MMP-9 RNA-expression and proteolytic-activity were analyzed by quantitative polymerase chain reaction and gelatin zymography, respectively. The ischemic lesion volumes in time to peak perfusion maps and diffusion weighted imaging were measured morphometrically. RNA-expression levels of MMP-9 in peripheral blood mononuclear cells (PBMCs) correlated with the brain infarct lesion (TTP-delay 4 s, r = -0.61, p = 0.007; TTP-delay 6 s: r = -0.58, p = 0.012; DWI r = -0.47; p = 0.047). Our preliminary results demonstrate that MMP-9 RNA is upregulated in PBMCs in proportion to ischemia. These findings suggest that MMP-9 might contribute to the manifestation of ischemic brain damage. Since MMP-9 is upregulated in acute ischemia inhibition of MMP-9 may represent a complementary treatment target in acute stroke therapy.

[Report on notifications pursuant to §21 German Transfusion Act for 2010 and 2011]. / Bericht zur Meldung nach § 21 TFG für die Jahre 2010 und 2011.

This report covers the blood supply situation in Germany over the past 12 years and provides detailed data on the years 2010 and 2011. Nearly 7.6 million donations, thereof 4.9 million whole blood donations, were reported in 2011 - the highest number since 1998. At the same time, 4.8 million red blood cell concentrates (RBC) were produced, the highest amount per year to date. While the RBC loss rate increased for both the manufacturers and the users, the RBC transfusion rate decreased for the first time since 2003. The number of platelet concentrates increased again to 0.57 million. About 60 % of this originated from apheresis donations. An amount of 3.4 million liters of plasma for fractionation was provided. Around 60 % was processed in Germany. The number of hematopoietic stem cell transplantations increased from 5,922 in 2009 to 7,093 in 2011. More than 99 % of the 16,364 transplants derived from peripheral blood and marrow; 43 % of the preparations were transplanted in Germany and 27 % were exported. Overall, the supply of blood products is considered to be good. However, because data are collected on an annual basis, seasonal shortages cannot be detected.

Identification of kallikrein and FXIa as impurities in therapeutic immunoglobulins: implications for the safety and control of intravenous blood products.

BACKGROUND AND OBJECTIVES: The occurrence of thromboembolic events (TEEs) with intravenous immunoglobulin lots (IVIGs) raised the question of the causative agent for these adverse events. We investigated the predominant plasma proteases in 19 IVIG lots from five manufacturers including three lots associated with adverse events. MATERIAL AND METHODS: The inhibitor profile of the amidolytic activity in IVIG lots was investigated with substrates S-2302 and S-2288. In immunocapture assays, prekallikrein and FXI antigen and respective active proteases were quantified. Non-activated partial thromboplastin time (NAPTT) and a modified FXIa PTT served as global and FXIa-specific clotting assays, respectively. RESULTS: Kallikrein was identified as one major contaminant activity in IVIGs. A second activity was seen in some IVIGs with substrate S-2288, but not with S-2302. Inhibition studies excluded FXIIa, thrombin or plasmin as contaminant activity. FXI antigen was seen in all 19 IVIG lots, and FXIa activity was found as second major impurity in some IVIGs, including all lots involved in TEEs. FXIa highly correlated with a short clotting time in NAPTT. CONCLUSIONS: Kallikrein and FXIa are the major contaminants in IVIGs. FXIa was highly procoagulant, with highest level in TEE-associated IVIGs. Since the NAPTT unambiguously identified FXIa procoagulant activity in IVIGs, its implementation as a release test would improve the safety of IVIGs.

Taking immunogenicity assessment of therapeutic proteins to the next level.

Therapeutic proteins provide innovative and effective therapies for numerous diseases. However, some of these products are associated with unwanted immunogenicity that may lead to clinical consequences such as reduced or loss of efficacy, altered pharmacokinetics (PK), general immune and hypersensitivity reactions, and neutralisation of the natural counterpart (e.g. the physiological hormone). Regulatory guidance on immunogenicity assessment needs to take into consideration a great diversity of products, indications and patient populations as well as constantly advancing manufacturing technologies. Such guidance needs to be sufficiently specific while, at the same time, allowing interactive discussion and adjusted benefit-risk weighing of each product on a case-by-case basis, e.g. for a unique treatment of a life threatening disease acceptable treatment risks may differ considerably from the ones in case of less serious disease. This theme was the focus of the international conference "Taking immunogenicity assessment of therapeutic proteins to the next level", held at the Paul-Ehrlich-Institut in Langen, Germany, on the 10-11. June 2010. The objectives of the conference were to highlight how the field could move from that of a mere description of risk factors to a system of risk assessment and mitigation, as well as an understanding of the impact of unwanted immunogenicity on the overall benefit/risk consideration for a medicinal product. More than 150 experts from industry, academia and regulatory authorities worldwide discussed the phenomenon of undesired immunogenicity from different perspectives. The conference focussed on issues relevant to three areas: (1) new European guidelines that are currently the subject of discussion; (2) testing strategies for immunogenicity assessment; and (3) scientific progress on the product-related factors that may contribute to the development of pathogenesis of immunogenicity, in particular in the field of protein aggregation and post-translational modifications. This report provides an overview of issues, insights, and conclusions that were discussed and achieved during the meeting.

[Documentation of haemophilia treatment supported by the German Hemophilia Registry]. / Dokumentation in der Hämophilietherapie mit Unterstützung des Deutschen Hämophilieregisters.

The DHR (Deutsches Hämophilieregister, German Haemophilia Register) records patient data on haemophilia A, haemophilia B, von Willebrand disease, and other coagulation factor deficiency disorders. The DHR has been online since 2009. The participation in the DHR leads to additional administrative workload for the hospitals and physicians, but provides many advantages as well: A standard of documentation will be developed to give evidence for the hospitals. They may use their own data as well as with new possibilities for data processing at any time. Reports in accordance with Section21 TFG (Transfusionsgesetz, German Transfusion Act) are compiled automatically and transmitted to the Paul-Ehrlich-Institut. The DHR may support the searching for patients fulfilling the requirements for participation in a study.

[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.

A neural basis for general intelligence.

Universal positive correlations between different cognitive tests motivate the concept of "general intelligence" or Spearman's g. Here the neural basis for g is investigated by means of positron emission tomography. Spatial, verbal, and perceptuo-motor tasks with high-g involvement are compared with matched low-g control tasks. In contrast to the common view that g reflects a broad sample of major cognitive functions, high-g tasks do not show diffuse recruitment of multiple brain regions. Instead they are associated with selective recruitment of lateral frontal cortex in one or both hemispheres. Despite very different task content in the three high-g-low-g contrasts, lateral frontal recruitment is markedly similar in each case. Many previous experiments have shown these same frontal regions to be recruited by a broad range of different cognitive demands. The results suggest that "general intelligence" derives from a specific frontal system important in the control of diverse forms of behavior.

Evidence for frequent focal and diffuse acute axonal injury in human bacterial meningitis.

AIMS: We aimed at quantifying acute axonal injury in victims of bacterial meningitis. METHODS: The brains of 26 autopsies with bacterial meningitis and of 10 control cases were studied by histology and quantitative immunohistochemistry for amyloid-beta precursor protein (APP). RESULTS: Mild to severe axonal injury in the white matter was present in 25 of 26 victims of meningitis. The area of axonal damage ranged from 0.0% to 1.38% (median = 0.08%, mean = 0.36%) of the total area studied in each individual case. In 4 of 10 age- and sex-matched control brains small areas also stained for APP (p = 0.0007). Axonal injury in meningitis was most prominent in the basal ganglia and pons, followed by the hippocampal formation, neocortex and the cervical spinal cord. The cerebellum was least affected. CONCLUSION: Axonal injury is a frequent complication of bacterial meningitis probably contributing to long-term sequelae in survivors.

[DHR--ready for take-off]. / Das Deutsche Hämophilieregister am Start.

The collaboration between the Paul-Ehrlich-Institute (PEI) and the GTH as well as the two patient organisations, DHG and IGH has been official since February 2007 with the signing of the collaboration contract. In December 2008, the University of Munich started data enrollment. The DHR is a new software development which includes matters and modules of epidemiological as well as clinical cancer registries. Instead of collaborating with a trustee for personal data the DHR is using a so called "Intermediate". Intermediate is an independent software module installed on a separate server without hard disk and with solely random access memory. It receives personal data from the treaters over the internet, calculates the pseudonyms, which are then forwarded to the database. The Intermediate needs to be protected from data access by the PEI and its operating system and software has to be started afresh with each start. These facts require the involvement of a trustworthy third party. It shuts Intermediate off from the PEI without itself coming into the possession of personal data.

[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.

Valuating other people's emotional face expression: a combined functional magnetic resonance imaging and electroencephalography study.

Reading the facial expression of other people is a fundamental skill for social interaction. Human facial expressions of emotions are readily recognized but may also evoke the same experiential emotional state in the observer. We used event-related functional magnetic resonance imaging and multi-channel electroencephalography to determine in 14 right-handed healthy volunteers (29+/-6 years) which brain structures mediate the perception of such a shared experiential emotional state. Statistical parametric mapping showed that an area in the dorsal medial frontal cortex was specifically activated during the perception of emotions that reflected the seen happy and sad emotional face expressions. This area mapped to the pre-supplementary motor area which plays a central role in control of behavior. Low resolution brain electromagnetic tomography-based analysis of the encephalographic data revealed that the activation was detected 100 ms after face presentation onset lasting until 740 ms. Our observation substantiates recently emerging evidence suggesting that the subjective perception of an experiential emotional state-empathy-is mediated by the involvement of the dorsal medial frontal cortex.