Monitoring Blood Supply in Germany: A Regulatory Perspective.

Background and Objectives: A sufficient supply of safe, high-quality blood components for transfusion is essential to the healthcare system in Germany. The requirements for the current reporting system are laid down in the German Transfusion Act. The present work elaborates on the advantages and limitations of the current reporting system and investigates the feasibility of a pilot project that collects specific data on blood supply based on weekly reports. Materials and Methods: Selected data on blood collection and supply from 2009 to 2021 derived from the §21 German Transfusion Act database were examined. In addition, a pilot study over a period of 12 months was conducted on a voluntary basis. The number of red blood cell (RBC) concentrates was documented and stock availability was calculated weekly. Results: From 2009 to 2021, the annual number of RBC concentrates decreased from 4.68 to 3.43 million, the per capita distribution decreased from 58 to 41 RBC concentrates per 1,000 inhabitants. These figures did not change significantly during the COVID-19 pandemic. The data of the 1-year pilot project represented 77% of the released RBC concentrates in Germany. Percentage share of O RhD positive RBC concentrates fluctuated between 35% and 22% and for O RhD negative concentrates between 17% and 5%. The availability of O RhD positive RBC concentrate stocks varied between 2.1 and 7.6 days. Conclusion: The data presented shows a decrease in annual RBC concentrate sales over an 11-year period and no further change over the past 2 years. A weekly monitoring of blood components detects acute problems in RBC provision and supply. Close monitoring seems helpful but should be combined with a nationwide supply strategy.

Strengthening Blood Regulatory Systems to Tackle Africa's Unmet Needs for Blood and Blood Products.

Background: Assuring the quality and safety of blood and blood components is an essential element of health care in all countries and requires government commitment and legal frameworks. Ineffective regulation of blood and blood components has far-reaching consequences that are not limited to the affected countries but also have extensive global implications. Summary: In this review, we summarize the work of the project BloodTrain funded by the German Ministry of Health within the framework of the Global Health Protection Programme to strengthen regulatory structures in Africa that are imperative to guarantee the improved availability, safety, and quality of blood and blood products. Key Messages: Intense interaction with the stakeholders in African partner countries lead to first measurable successes in the strengthening of blood regulation, as shown here for hemovigilance.

The critical need for postmarketing surveillance in gene therapy for haemophilia.

INTRODUCTION: The goal of gene therapy for haemophilia is to alter the clinical phenotype to a milder form or even cure, by increasing endogenous coagulation factor levels through transfer of a functional gene encoding the respective deficient coagulation factor and subsequent transgene expression. Over the past decade, there has been tremendous progress in gene therapy, particularly in use of liver-directed adeno-associated viral vectors, such that several programmes for both haemophilia A and B are in phase 3 trials. With regulatory approval of the first gene therapy product expected as early as mid-2020, there is an urgent need for a mechanism to collect long-term data on safety and variability and durability of efficacy. There will be elements required by regulators for postmarketing surveillance and additional data needed to enhance our understanding of gene therapy outcomes and their impact on the lives of people with haemophilia. AIM: The aim of this manuscript was to describe efforts underway by the American Thrombosis and Hemostasis Network and the World Federation of Hemophilia to collect long-term harmonized data and considerations of the European and US regulatory agencies, which will inform ongoing data collection. METHODS: The status of data collection around gene therapy in haemophilia and important outcome measures were obtained by literature review. Each author described elements relevant to the activities of their organization. CONCLUSION: Support of all stakeholders in gene therapy, providers, patients, industry and regulators, augers successful capture of uniform long-term safety and efficacy data to ensure optimal treatment of people with haemophilia.

The German Hemophilia Registry: Growing with Its Tasks.

Hemophilia is a rare heredity bleeding disorder that requires treatment for life. While few therapeutic options were available in the past, multiple recent breakthroughs have fundamentally altered and diversified hemophilia therapy, with even more new therapeutic options forthcoming. These changes are mirrored by significant regulatory and legal changes, which have redefined the role of hemophilia registries in the European Union (EU). This dual paradigm shift poses new regulatory, scientific but also structural requirements for hemophilia registries. The aim of this manuscript is to enumerate these significant challenges and to demonstrate their incorporation into the redesign of the German Hemophilia Registry (Deutsches Hämophilieregister, dhr). To identify the spectrum of hemophilia therapies and the degree of regulatory changes, a horizon screening was performed. Consequently, a core dataset for the dhr was defined by harmonization with regulatory guidelines as well as other hemophilia registries and by heeding the needs of different stakeholders (patients, clinicians, regulators, and scientists). Based on this information, a new registry structure was established, which is optimized for capturing data on new and established hemophilia therapies in a changing therapeutic and regulatory landscape.

Evaluation of the in vitro Function of Platelet Concentrates from Pooled Buffy Coats or Apheresis.

BACKGROUND: Platelet concentrates play an important role in transfusion medicine. Their short lifespan and lack of robustness require efforts to ensure adequate product quality. In this study, we compared the in vitro quality of the main concentrate types, pooled platelet concentrate (PPC) from whole blood donations, and platelet concentrate from single-donor apheresis (APC). METHODS: Twenty PPCs and 20 APCs prepared in plasma were analyzed on days 2, 4, and 7 of storage. Variables related to metabolism, degranulation, platelet aggregation, P-selectin expression, and annexin V binding were analyzed. Morphology was assessed by transmission electron microscopy of ultrathin sections. A microfluidic device was applied to test the effects of shear stress on platelet function. RESULTS: The metabolic parameters indicated stable storage conditions throughout the 7-day period. The resting discoid form was the prevailing morphology on days 2 and 4 in the PPCs and APCs. Chemokine release and receptor shedding of soluble P-selectin and soluble CD40L equally increased in PPCs and APCs. Aggregation responses to ADP and collagen were heterogeneous, with marked losses in collagen responsiveness on day 4 in individual concentrates. Baseline expression of P-selectin in PPCs and APCs was low, and inducibility of P-selectin was well preserved until day 4. Under shear stress, equal adhesiveness and stability were found with platelets from PPCs and APCs. CONCLUSIONS: Platelets from PPCs and APCs showed similar in vitro function and stability parameters. However, platelet concentrates presented a high variability and individual concentrates an impaired functional capability. Identifying the factors contributing to this would help increase product reliability.

Summary of the WHO hearing on the development of product-specific reference materials for coagulation factor VIII and factor IX products.

In recent years, several modified recombinant factor (F) VIII and FIX therapeutics with extended half-life have been licensed internationally for the treatment of haemophilia. Safe and effective use of these products requires monitoring of factor activity in patient plasma. The potency of all FVIII and FIX products is currently assigned in International Units (IU) which anchors the relationship between potency labelling, dosing and clinical monitoring. However, varying degrees of discrepancies in factor activity assays are observed between and within the factor activity analytical methods (one-stage clotting and chromogenic), when measuring these modified products against plasma and plasma-derived (concentrate) International Standards (IS) or in-house reference standard traceable to the IS. Availability of product-specific reference reagents would mitigate assay discrepancies, facilitate independent testing of assay methods and reagents, and ensure long-term continuity of the IU related to each product. A hearing meeting was organised by the WHO to discuss the requirements for product-specific reference materials for these products and whether these reference materials should be produced by the WHO. Advantages and disadvantages of product-specific reference materials were identified and discussed.

Annual Bleeding Rates: Pitfalls of Clinical Trial Outcomes in Hemophilia Patients.

Emerging treatment options for hemophilia, including gene therapy, modified factor products, antibody-based products, and other nonreplacement therapies, are in development or on their way to marketing authorization. For proof of efficacy, annual bleeding rates (ABRs) have become an increasingly important endpoint in hemophilia trials. We hypothesized that ABR analyses differ substantially between and within medicinal product classes and that the ABR observation period constitutes a major bias. For ABR characterization, an internal factor VIII (FVIII) treatment database has been built based on confidential clinical trial data submitted to the Paul-Ehrlich-Institut (PEI). Furthermore, anonymized data from 46 trial protocols submitted for review to the PEI were analyzed (FVIII replacement, n = 27; antibody-based, n = 12; and gene therapy, n = 7) for methodology. Definitions of bleeding episodes and ABR observational periods differed substantially in clinical trials. In the initial observation phase, individual ABRs of patients, treated prophylactically for 1 year, vary by about 40% (P < 0.001), which finally led to a significant reduction of the ABR group mean by 20% (P < 0.05). Furthermore, the high variance in ABRs constitutes a major challenge in statistical analyses. In conclusion, considerable heterogeneity and bias in the ABR estimation in clinical trials was identified, which makes it substantially more difficult to compare the efficacy of different treatment regimens and products. Thus, awareness of the important pitfalls when using ABR as a clinical outcome is needed in the evaluation of hemophilia therapies for patients, physicians, regulators, and health technology assessment agencies.

Kreuth V initiative: European consensus proposals for treatment of hemophilia using standard products, extended half-life coagulation factor concentrates and non-replacement therapies.

This report contains the updated consensus recommendations for optimal hemophilia care produced in 2019 by three Working Groups (WG) on behalf of the European Directorate for Quality of Medicines and Healthcare in the frame of the Kreuth V Initiative. WG1 recommended access to prophylaxis for all patients, the achievement of plasma factor trough levels of at least 3-5% when extended half-life factor VIII (FVIII) and FIX products are used, a personalized treatment regimen, and a choice of chromogenic assays for treatment monitoring. It was also emphasized that innovative therapies should be supervised by hemophilia comprehensive care centers. WG2 recommended mandatory collection of postmarketing data to assure the long-term safety and efficacy of new hemophilia therapies, the establishment of national patient registries including the core data recommended by the European Medicines Agency and the International Society on Thrombosis and Haemostasis, with adequate support under public control, and greater collaboration to facilitate a comprehensive data evaluation throughout Europe. WG3 discussed methodological aspects of hemophilia care in the context of access decisions, particularly for innovative therapies, and recommended that clinical studies should be designed to provide the quality of evidence needed by regulatory authorities, HTA bodies and healthcare providers. The dialogue between all stakeholders in hemophilia care and patient organizations should be fostered to implement these recommendations.

Epidemiological Challenges in Rare Bleeding Disorders: FVIII Inhibitor Incidence in Haemophilia A Patients-A Known Issue of Unknown Origin.

There is a broad range of factor products approved in Germany for haemophilia A treatment. Since the introduction of recombinant coagulation factor VIII (FVIII) products in the 1990s, there has been substantial debate whether there is a difference in inhibitor incidence between single FVIII products or product classes. Neither haemophilia registries nor clinical studies, including a randomised controlled clinical trial, provided a consistent and definite answer. The reasons were mainly related to methodological challenges in conducting controlled studies in a rare disease. In this analysis, the most relevant epidemiological challenges and main problems were examined, including study bias, potential overlap of individual studies and advanced development of therapy and methods in the course of time. Meta-analyses on two levels showed that therapies using recombinant products resulted in different event rates when compared to plasma-derived products. These results are accompanied by substantial study heterogeneity evidenced by Cochran's Q tests. Only three studies have been identified that meet the standards of current clinical guidance. To finally resolve this ongoing and disputable safety issue of replacement therapy, collaboration among registry owners, academia and regulators must be fostered.

[Authorization of tissue and blood stem cell preparations for hematopoietic reconstitution: Documentation of clinical and nonclinical data in a central expert report]. / Genehmigungsverfahren für Gewebezubereitungen und Blutstammzellzubereitungen zur hämatopoetischen Rekonstitution: Dokumentation klinischer und nicht klinischer Daten mittels eines Zentralgutachtens.

In order to address the European Directive 2004/23 on human tissues and cells, the authorization obligation for tissue and blood stem cell preparations was introduced (§ 21a AMG) in the year 2007 in the German medicinal products act. Stem cell transplantation for hematopoietic reconstitution has been in use for decades and is well established for the treatment of many malignancies. The manufacture of stem cell preparations varies, but in terms of hematopoietic reconstitution, different products are intended for the same indication. Taking these aspects into account, it was considered inappropriate that every single applicant should provide their own documentation, including an expert report on clinical and nonclinical data. Consequently, the idea came up to create a central expert report, to which all applicants could refer and would include relevant clinical and nonclinical data according to current knowledge. A central expert report was therefore generated, called the "Gemeinsame Stellungnahme der Fachgesellschaften Deutsche Gesellschaft für Transfusionsmedizin und Immunhämatologie (DGTI), Deutsche Gesellschaft für Hämatologie und Onkologie (DGH) und Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH)". Applicants are allowed to refer to this central expert report provided their stem cell product is comparable with the cell preparations included in the report. In order to represent current knowledge, the content of the central expert report was already reworked once, but should be updated regularly.