Race and ethnicity reporting and representation in hemophilia clinical trials.

ABSTRACT: Racial and ethnic representativeness in clinical trials is crucial to mitigate disparities in outcomes; however, diversity among hemophilia trials is unknown. The aim of this study is to examine the reporting and representation of race and ethnicity in trials of people with hemophilia (PwH). In this cross-sectional study, the ClinicalTrials.gov database was queried in April 2023 for interventional clinical trials involving PwH between 2007 and 2022. The distribution of participants (observed) was compared with expected proportions based on US Hemophilia Treatment Center (HTC) and country-specific census data with observed-to-expected ratios (OERs). Of 129 trials included, 94.6% were industry sponsored, with a mean of 62 participants and mean age of 26.8 years. Overall, 52.0% (n = 66) of trials reported data on race and ethnicity, increasing from 13.9% in 2007-2012 to 22.5% in 2013-2016 to 100% in 2017-2022 (P = .001). Among these 66 trials, 65.8%, 22.8%, 5.1%, 3.9% of participants were White, Asian, Hispanic, and Black, respectively. OERs were 10% to 20% lower for White participants vs US HTC, and US, UK, and Canadian census populations and ∼75% lower for Black or Hispanic participants when compared with US HTC and US census population. OERs for Asian participants were 1.6 to 3 times higher than Canada, US, and UK census populations. The reporting of race and ethnicity in hemophilia trials has drastically improved; however, Black and Hispanic PwH remain especially underrepresented. To address these disparities, stakeholders across the clinical trial enterprise need to implement strategies to ensure equitable participation.

Neuroinflammatory markers in patients with haemophilia and healthy controls: Where are the differences?

INTRODUCTION: People with haemophilia (PwH) suffer from haemophilic arthropathy which is accompanied by acute and chronic inflammation. The aim of this study was to examine the neuroinflammatory network operative in PwH and to compare it to healthy controls. MATERIAL AND METHODS: Blood samples were collected from 41 PwH (age 54.7 ± 11.7 years) and 33 healthy controls (age 50.9 ± 10.5 years) and the levels of 13 neuroinflammatory markers were analyzed by applying an antibody-based detection kit in a flow cytometer. RESULTS: From 13 analyzed markers, three-ß-nerve growth factor (ß-NGF), soluble receptor for advanced glycation endproducts (sRAGE) and Interleukin-18 (IL-18) differed significantly between the groups (ß-NGF p = .045; sRAGE p = .003; IL-18 p = .007). While ß-NGF was downregulated in PwH, sRAGE and IL-18 were upregulated. None of the analyzed markers corelated to the joint status of PwH while CCL2 (C-C motif ligand 2 chemokine) correlated to HIV infections in PwH (r = .313, p = .007). Correlation analyses of the markers studied also revealed many differences between PwH and controls suggesting a number of deregulations in PwH. CONCLUSION: The altered levels of sRAGE and ß-NGF in PwH, which have not been analyzed in PwH before, may help to understand the neuroinflammatory network operative in PwH. The general inflammatory processes in PwH and the involved biomarkers in PwH remain poorly understood. PwH could benefit from new therapies against neuroinflammation which may help to reduce inflammation or also chronic pain.

Hemophilia gene therapy: first, do no harm.

The introduction of adeno-associated virus-mediated, liver-directed gene therapy into the hemophilia treatment landscape brings not only great promise but also considerable uncertainty to a community that has a history punctuated by the devastating effects of HIV and hepatitis C virus. These infections were introduced into people with hemophilia through the innovation of factor concentrates in the 1970s and 1980s. Concentrates, heralded as a major advance in treatment at the time, brought devastation and death to the community already challenged by the complications of bleeding into joints, vital organs, and the brain. Over the past 5 decades, considerable advances in hemophilia treatment have improved the survival, quality of life, and participation of people with hemophilia, although challenges remain and health equity with their unaffected peers has not yet been achieved. The decision to take a gene therapy product is one in which an informed, holistic, and shared decision-making approach must be employed. Bias on the part of health care professionals and people with hemophilia must be addressed and minimized. Here, we review data leading to the regulatory authorization of valoctocogene roxaparvovec, an adeno-associated virus 5 gene therapy, in Europe to treat hemophilia A and etranacogene dezaparvovec-drlb in the United States and Europe to treat hemophilia B. We also provide an overview of the decision-making process and recommend steps that should be taken by the hemophilia community to ensure the safety of and optimal outcomes for people with hemophilia who choose to receive a gene therapy product.

A review of the rationale for gene therapy for hemophilia A with inhibitors: one-shot tolerance and treatment?

The therapeutic landscape for people living with hemophilia A (PwHA) has changed dramatically in recent years, but many clinical challenges remain, including the development of inhibitory antibodies directed against factor VIII (FVIII) that occur in approximately 30% of people with severe hemophilia A. Emicizumab, an FVIII mimetic bispecific monoclonal antibody, provides safe and effective bleeding prophylaxis for many PwHA, but clinicians still explore therapeutic strategies that result in immunologic tolerance to FVIII to enable effective treatment with FVIII for problematic bleeding events. This immune tolerance induction (ITI) to FVIII is typically accomplished through repeated long-term exposure to FVIII using a variety of protocols. Meanwhile, gene therapy has recently emerged as a novel ITI option that provides an intrinsic, consistent source of FVIII. As gene therapy and other therapies now expand therapeutic options for PwHA, we review the persistent unmet medical needs with respect to FVIII inhibitors and effective ITI in PwHA, the immunology of FVIII tolerization, the latest research on tolerization strategies, and the role of liver-directed gene therapy to mediate FVIII ITI.

The National Hemophilia Foundation State of the Science Research Summit initiative: executive summary.

INTRODUCTION: The National Hemophilia Foundation State of the Science Research Summit initiative sought to unify research efforts in the US inherited bleeding disorders (BDs) community around key topics of importance to people living with inherited BDs, the lived experience experts. AREAS COVERED: This community-led and -informed project focused on six broad areas - hemophilia A or B; von Willebrand Disease (VWD), platelet dysfunctions and other mucocutaneous inherited BDs; ultra-rare inherited BDs; the unique challenges of people with the potential to menstruate with inherited BDs; diversity, equity and inclusion, health services research, and implementation science; and facilitating research in the inherited BD community through designing an optimizied research infrastructure, enabling resources and funding, and furthering workforce capabilities required to execute the research priorities. EXPERT OPINION: The work summarized here, and in the accompanying supplement manuscripts , has implications not only for the US population but for people globally who have inherited BDs. The information is equally relevant to people living with hemophilia, VWD, the spectrum of inherited platelet disorders, ultra-rare factor deficiencies, and all other inherited BDs as it is to the health care providers and researchers focused on the care and treatment of inherited BDs in the US and globally.

Patient-centered pharmacovigilance: priority actions from the inherited bleeding disorders community.

Pharmacovigilance, the science and practice of monitoring the effects of medicinals and their safety, is the responsibility of all stakeholders involved in the development, manufacture, regulation, distribution, prescription, and use of drugs and devices. The patient is the stakeholder most impacted by and the greatest source of information on safety issues. It is rare, however, for the patient to take a central role and exert leadership in the design and execution of pharmacovigilance. Patient organizations in the inherited bleeding disorders community are among the most established and empowered, particularly in the rare disorders. In this review, two of the largest bleeding disorders patient organizations, Hemophilia Federation of America (HFA) and National Hemophilia Foundation (NHF), offer insights into the priority actions required of all stakeholders to improve pharmacovigilance. The recent and ongoing increase in incidents raising safety concerns and a therapeutic landscape on the cusp of unprecedented expansion heighten the urgency of a recommitment to the primacy of patient safety and well-being in drug development and distribution. Plain Language Summary: Patients at the center of product safety Every medical device and therapeutic product has potential benefits and harms. The pharmaceutical and biomedical companies that develop them must demonstrate that they are effective, and the safety risks are limited or manageable, for regulators to approve them for use and sale. After the product has been approved and people are using it in their daily lives, it is important to continue to collect information about any negative side effects or adverse events; this is called pharmacovigilance. Regulators, like the United States (US) Food and Drug Administration, the companies that sell and distribute the products, and healthcare professionals who prescribe them are all required to participate in collecting, reporting, analyzing, and communicating this information. The people with the most firsthand knowledge of the benefits and harms of the drug or device are the patients who use them. They have an important responsibility to learn how to recognize adverse events, how to report them, and to stay informed of any news about the product from the other partners in the pharmacovigilance network. Those partners have a crucial responsibility to provide clear, easy-to-understand information to patients about any new safety concerns that come to light. The community of people with inherited bleeding disorders has recently encountered problems with poor communication of product safety issues, prompting two large US patient organizations, National Hemophilia Foundation and Hemophilia Federation of America, to hold a Safety Summit with all the pharmacovigilance network partners. Together they developed recommendations to improve the collection and communication of information about product safety so that patients can make well-informed, timely decisions about their use of drugs and devices. This article presents these recommendations in the context of how pharmacovigilance is supposed to work and some of the challenges encountered by the community.

Return to Sport Activities and Risk of Reinjury Following Primary Anterior Cruciate Ligament Reconstruction.

This article examines the elements that affect the return to sport (RTS) and the risk and percentages of reinjury following a prior primary anterior cruciate ligament reconstruction (ACLR). The prevalence of RTS following ACLR ranges from 71% to 83%. Concerning elements affecting RTS, a limb symmetry index score of 90 or more duplicates the likelihood of RTS and triplicates it when the International Knee Documentation Committee (IKDC) score is 95 or more, irrespective of age. Other elements recognized to be preindicative of RTS at 1 year include complete rehabilitation, age ≤25, and higher IKDC scores. The prevalence of reinjury following ACLR ranges from 1.5% to 37.5% (between 9% and 29% in the majority of reports). It has been published that 1 in 5 individuals suffers reinjury to either knee, and that male individuals are more prone to reinjure following ACLR. The highest percentage of ACLR reinjury happens in younger male (<18 years), being substantially higher than in female of the same age. Passing a combination of functional tests with predetermined cut-off points utilized as RTS criteria are related diminished ACLR reinjury percentages.

Achieving access to haemophilia care in low-income and lower-middle-income countries: expanded Humanitarian Aid Program of the World Federation of Hemophilia after 5 years.

Highly effective treatment of haemophilia A and B is primarily available to 15% of the world's population, in high-income countries. In low-income countries (LICs) and lower-middle-income countries (LMICs), morbidity and mortality are high because of greatly reduced access to diagnosis, care, and treatment. We report the challenges and impact after the first 5 years (mid-2015-2020) of the expanded World Federation of Hemophilia (WFH) Humanitarian Aid Program (HAP). WFH HAP donated coagulation products were used to treat more than 250 000 acute bleeding episodes, manage approximately 4000 surgeries, and establish bleeding preventive prophylaxis in about 2000 patients in 73 countries. Health-care providers worldwide learned optimal management of patients with complex needs through virtual and in-person training. In response to the programme, some governments increased investment in haemophilia care, including independent purchases of small amounts of treatment products. With unparalleled scope and complexity, and substantial benefits to people with haemophilia and society in general, the WFH HAP is an exemplar of partnership between for-profit and not-for-profit organisations advancing health-care equity in LICs and LMICs, which could be replicated by other organisations supporting people with different monogenic diseases.

Defining the Impact of Social Drivers on Health Outcomes for People with Inherited Bleeding Disorders.

The ways in which the social drivers of health, also known as the social determinants of health (SDOH), affect health outcomes for people with inherited bleeding disorders (PwIBDs) is unclear. This systematic review of the published literature examines the impact of SDOH on health outcomes in PwIBDs. Articles that included the following parameters in PubMed informed this study: published in English between 2011-2021; available in free full text; study population diagnosed with an inherited bleeding disorder; and study measured at least one of the clinical/non-clinical outcome measures: bleeding frequency, chronic pain, mortality, quality of life (QOL), and/or cost. The main findings from the 13 included articles emphasized the unmet need for reducing the economic burden with sustainable population health strategies and treatment options for PwIBDs. Rural location was also a significant contributor to both delayed diagnosis and decreased access to care. Furthermore, the need for a multidisciplinary comprehensive care team to address physical, psychosocial, and emotional needs of PwIBDs was raised as a priority target in the desire for equitable and optimal health. This systematic literature review suggests that the SDOH are associated with inferior health outcomes and may influence the clinical progression of inherited bleeding disorders.

Building the blueprint: Formulating a community-generated national plan for future research in inherited bleeding disorders.

INTRODUCTION: Decades of inherited bleeding disorders (BD) research transformed severe haemophilia from a childhood killer to a disorder managed across a full lifespan for many in economically developed countries. Health equity, a life unimpaired by disease complications, however, remains unimaginable for most people with an inherited BD (PWIBD). AIM: The National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network (ATHN) undertook the development of a community-driven United States (US) National Blueprint for Inherited Bleeding Disorders Research to transform the experience of all PWIBD and those who care for them. METHODS: Extensive community consultations were conducted to identify the issues most important to PWIBD and those who love and care for them. Expert multidisciplinary teams distilled these key areas of need into prioritised research questions, and identified the resources and infrastructure required to pursue them. A summit was held to gather feedback and inform the detailed blueprint. RESULTS: Community-prioritised research areas fell into three broad categories: issues common across inherited BDs, those specific to individual disorders, and issues of infrastructure and capacity. NHF State of the Science Research Summit discussions of the research questions derived from the community priorities by six working groups provided important input for the drafting of the research blueprint for the coming decades. CONCLUSION: The inherited BD community came together to develop the US National Blueprint for Inherited Bleeding Disorders Research dedicated to transforming the lives of all PWIBD including innovating solutions for the rarest disorders and under-represented populations.

Results of genetic analysis of 11 341 participants enrolled in the My Life, Our Future hemophilia genotyping initiative in the United States.

BACKGROUND: Hemophilia A (HA) and hemophilia B (HB) are rare inherited bleeding disorders. Although causative genetic variants are clinically relevant, in 2012 only 20% of US patients had been genotyped. OBJECTIVES: My Life, Our Future (MLOF) was a multisector cross-sectional US initiative to improve our understanding of hemophilia through widespread genotyping. METHODS: Subjects and potential genetic carriers were enrolled at US hemophilia treatment centers (HTCs). Bloodworks performed genotyping and returned results to providers. Clinical data were abstracted from the American Thrombosis and Hemostasis Network dataset. Community education was provided by the National Hemophilia Foundation. RESULTS: From 2013 to 2017, 107 HTCs enrolled 11 341 subjects (68.8% male, 31.2% female) for testing for HA (n = 8976), HB (n = 2358), HA/HB (n = 3), and hemophilia not otherwise specified (n = 4). Variants were detected in most male patients (98.2%% HA, 98.1% HB). 1914 unique variants were found (1482 F8, 431 F9); 744 were novel (610 F8, 134 F9). Inhibitor data were available for 6986 subjects (5583 HA; 1403 HB). In severe HA, genotypes with the highest inhibitor rates were large deletions (77/80), complex intron 22 inversions (9/17), and no variant found (7/14). In severe HB, the highest rates were large deletions (24/42). Inhibitors were reported in 27.3% of Black versus 16.2% of White patients. CONCLUSIONS: The findings of MLOF are reported, the largest hemophilia genotyping project performed to date. The results support the need for comprehensive genetic approaches in hemophilia. This effort has contributed significantly towards better understanding variation in the F8 and F9 genes in hemophilia and risks of inhibitor formation.

Big picture initiatives in bleeding disorders.

INTRODUCTION: The inherited bleeding disorders (IBD) community has witnessed significant therapeutic advances recently, yet important gaps persist, particularly for those with rare disorders and historically underserved populations. AIMS: -To create a national research blueprint agenda, led by the National Hemophilia Foundation (NHF), enhancing patient-centric principles, accelerate research progress and address important gaps in care. -To review critical gaps that remain to be addressed in women with IBDs, who face specific bleeding challenges. METHODS: The NHF research blueprint research agenda was defined by input from across the community, including caregivers and patients who are considered subject matter experts of their IBD, research leaders, allied health professionals and specialists, and representatives of the biopharmaceutical industry. In addition, two medical experts in the field of IBDs performed a comprehensive review to address the knowledge gaps in women with IBDs. RESULTS: Two foundational principles of the NHF blueprint are: (1) it must deliver on key issues that significantly impact the lives of those affected by IBDs, and (2) the priorities defined are relevant and actionable aimed to achieve health equity among all those affected by IBDs. A multidisciplinary approach is necessary for an optimal management of puberty, transition to adulthood and pregnancy. Even if strict guidelines are followed, recent studies show that women with IBDs are still facing a high burden. CONCLUSION: NHF blueprint will be issued in 2022. A specific research agenda is needed in women with IBDs to further improve their management and quality of life.

Integrated Hemophilia Patient Care via a National Network of Care Centers in the United States: A Model for Rare Coagulation Disorders.

Rare, chronic diseases such as hemophilia and other congenital coagulation disorders require coordinated delivery of services for optimal outcomes. Hemophilia Treatment Centers (HTCs) are specialized, multidisciplinary health-care centers providing team-based care to meet the physical, psychosocial, and emotional needs of people with hemophilia (PWH) and may serve as a model for other rare coagulation disorders. Health-care purchasers, as well as the general medical community, may not appreciate the breadth and quality of services provided by HTCs. They exemplify the acculturalization and actualization of integrated care by providing comprehensive diagnostic and treatment services that reduce morbidity, mortality, avoidable emergency room visits, hospitalizations, and overall costs, while promoting a longer lifespan and improved patient functioning and outcomes. This is accomplished by a team-based approach relying upon a shared decision-making model to effectively prevent complications and manage symptoms in PWH, who are dependent on high-cost treatments. This article provides a concise yet comprehensive description of the core components of an HTC and the regional and national networks in the United States, which together achieve their incomparable value for all stakeholders.

The intersection of vector biology, gene therapy, and hemophilia.

Gene therapy is at the forefront of the drive to bring the potential of cure to patients with genetic diseases. Multiple mechanisms of effective and efficient gene therapy delivery (eg, lentiviral, adeno-associated) for transgene expression as well as gene editing have been explored to improve vector and construct attributes and achieve therapeutic success. Recent clinical research has focused on recombinant adeno-associated viral (rAAV) vectors as a preferred method owing to their naturally occurring vector biology characteristics, such as serotypes with specific tissue tropisms, facilitated in vivo delivery, and stable physicochemical properties. For those living with hereditary diseases like hemophilia, this potential curative approach is balanced against the need to provide safe, predictable, effective, and durable factor expression. While in vivo studies of rAAV gene therapy have demonstrated amelioration of the bleeding phenotype in adults, long-term safety and effectiveness remain to be established. This review discusses vector biology in the context of rAAV-based liver-directed gene therapy for hemophilia and provides an overview of the types of viral vectors and vector components that are under investigation, as well as an assessment of the challenges associated with gene therapy delivery and durability of expression.

Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia.

Adeno-associated viral (AAV) vector gene therapy has shown promise as a possible cure for hemophilia. However, immune responses directed against AAV vectors remain a hurdle to the broader use of this gene transfer platform. Both innate and adaptive immune responses can affect the safety and efficacy of AAV vector-mediated gene transfer in humans. These immune responses may be triggered by the viral capsid, the vector's nucleic acid payload, or other vector contaminants or excipients, or by the transgene product encoded by the vector itself. Various preclinical and clinical strategies have been explored to overcome the issues of AAV vector immunogenicity and transgene-related immune responses. Although results of these strategies are encouraging, more efficient approaches are needed to deliver safe, predictable, and durable outcomes for people with hemophilia. In addition to durability, long-term follow-up of gene therapy trial participants will allow us to address potential safety concerns related to vector integration. Herein, we describe the challenges with current methodologies to deliver optimal outcomes for people with hemophilia who choose to undergo AAV vector gene therapy and the potential opportunities to improve on the results.