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.

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.

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.

End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings.

To address the global burden of sickle cell disease and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to patient-reported outcome, pain (non-patient-reported outcomes), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the end-organ considerations, measurement of cure, and low-resource settings panels as well as relevant findings and recommendations from the biomarkers panel.

Origins and organization of the NHLBI State of the Science Workshop: Generating a national blueprint for future research on factor VIII inhibitors.

INTRODUCTION: The major complication of protein replacement therapy for haemophilia A is the development of anti-FVIII antibodies or inhibitors that occur in 25%-30% of persons with severe haemophilia A. Alternative therapeutics such as bypassing agents or immune tolerance induction protocols have additional challenges and are not always effective. AIM: Assemble a National Heart, Lung and Blood Institute (NHLBI) State of the Science (SOS) Workshop to generate a national blueprint for research on inhibitors to solve the problem of FVIII immunogenicity. METHODS: An Executive Steering Committee was formed in October 2017 to establish the scientific focus and Scientific Working Groups for the SOS Workshop in May 2018. Four working groups were assembled to address scientific priorities in basic, translational and clinical research on inhibitors. RESULTS: Working Group 1 was charged with determining the scientific priorities for clinical trials to include the integration of non-intravenous, non-factor therapeutics including gene therapy into the standard of care for people with haemophilia A with inhibitors. Working Group 2 established the scientific priorities for 21st-century data science and biospecimen collection for observational inhibitor cohort studies. The scientific priorities for acquiring an actionable understanding of FVIII immunogenicity and the immunology of the host response and FVIII tolerance were developed by Working Group 3. Working Group 4 designed prospective pregnancy/birth cohorts to study FVIII immunogenicity, inhibitor development and eradication. CONCLUSION: The NHLBI SOS Workshop generated a focused summary of scientific priorities and implementation strategies to overcome the challenges of eradicating and preventing inhibitors in haemophilia A.

Navigating Speed Bumps on the Innovation Highway in Hemophilia Therapeutics.

The unprecedented emergence of novel therapeutics for both hemophilia A and B during the last half decade has been accompanied by the promise of even more extraordinary progress in ameliorative and curative strategies for both disorders. Paradoxically, the speed of innovation has created new dilemmas for persons with hemophilia and their physicians with respect to optimizing individual choices from the expanding menu of standard and novel therapies and approaches to symptom or risk reduction, and ultimately, to normalizing the hemophilia phenotype. Among the most disruptive new approaches, challenges remain in the form of the adverse reactions that have been observed with nonfactor therapies, as well as in the uncertain long-term safety profile of potentially curative gene therapy. Together, these challenges have generated uncertainty as to how to adopt novel therapies and treatment strategies across a diverse patient population, creating speed bumps on the hemophilia innovation highway. It is from this perspective that this article discusses the current state of gene therapy and bleeding prophylaxis for hemophilia A and B, as well as prevention and treatment of the factor VIII inhibitor phenotype in hemophilia A. It further posits that these speed bumps may provide important clues to the mechanistic understanding of both symptom manifestation and resilience within the hemophilia phenotype, as well as opportunities to reconsider and reconfigure the current paradigms for symptom prediction and individualized therapeutic decision making.

Planning for the future workforce in hematology research.

The medical research and training enterprise in the United States is complex in both its scope and implementation. Accordingly, adaptations to the associated workforce needs present particular challenges. This is particularly true for maintaining or expanding national needs for physician-scientists where training resource requirements and competitive transitional milestones are substantial. For the individual, these phenomena can produce financial burden, prolong the career trajectory, and significantly influence career pathways. Hence, when national data suggest that future medical research needs in a scientific area may be met in a less than optimal manner, strategies to expand research and training capacity must follow. This article defines such an exigency for research and training in nonneoplastic hematology and presents potential strategies for addressing these critical workforce needs. The considerations presented herein reflect a summary of the discussions presented at 2 workshops cosponsored by the National Heart, Lung, and Blood Institute and the American Society of Hematology.

Citation impact of NHLBI R01 grants funded through the American Recovery and Reinvestment Act as compared to R01 grants funded through a standard payline.

RATIONALE: The American Recovery and Reinvestment Act (ARRA) allowed National Heart, Lung, and Blood Institute to fund R01 grants that fared less well on peer review than those funded by meeting a payline threshold. It is not clear whether the sudden availability of additional funding enabled research of similar or lesser citation impact than already funded work. OBJECTIVE: To compare the citation impact of ARRA-funded de novo National Heart, Lung, and Blood Institute R01 grants with concurrent de novo National Heart, Lung, and Blood Institute R01 grants funded by standard payline mechanisms. METHODS AND RESULTS: We identified de novo (type 1) R01 grants funded by National Heart, Lung, and Blood Institute in fiscal year 2009: these included 458 funded by meeting Institute's published payline and 165 funded only because of ARRA funding. Compared with payline grants, ARRA grants received fewer total funds (median values, $1.03 versus $1.87 million; P<0.001) for a shorter duration (median values including no-cost extensions, 3.0 versus 4.9 years; P<0.001). Through May 2014, the payline R01 grants generated 3895 publications, whereas the ARRA R01 grants generated 996. Using the InCites database from Thomson-Reuters, we calculated a normalized citation impact for each grant by weighting each article for the number of citations it received normalizing for subject, article type, and year of publication. The ARRA R01 grants had a similar normalized citation impact per $1 million spent as the payline grants (median values [interquartile range], 2.15 [0.73-4.68] versus 2.03 [0.75-4.10]; P=0.61). The similar impact of the ARRA grants persisted even after accounting for potential confounders. CONCLUSIONS: Despite shorter durations and lower budgets, ARRA R01 grants had comparable citation outcomes per $million spent to that of contemporaneously funded payline R01 grants.

Prior publication productivity, grant percentile ranking, and topic-normalized citation impact of NHLBI cardiovascular R01 grants.

RATIONALE: We previously demonstrated absence of association between peer-review-derived percentile ranking and raw citation impact in a large cohort of National Heart, Lung, and Blood Institute cardiovascular R01 grants, but we did not consider pregrant investigator publication productivity. We also did not normalize citation counts for scientific field, type of article, and year of publication. OBJECTIVE: To determine whether measures of investigator prior productivity predict a grant's subsequent scientific impact as measured by normalized citation metrics. METHODS AND RESULTS: We identified 1492 investigator-initiated de novo National Heart, Lung, and Blood Institute R01 grant applications funded between 2001 and 2008 and linked the publications from these grants to their InCites (Thompson Reuters) citation record. InCites provides a normalized citation count for each publication stratifying by year of publication, type of publication, and field of science. The coprimary end points for this analysis were the normalized citation impact per million dollars allocated and the number of publications per grant that has normalized citation rate in the top decile per million dollars allocated (top 10% articles). Prior productivity measures included the number of National Heart, Lung, and Blood Institute-supported publications each principal investigator published in the 5 years before grant review and the corresponding prior normalized citation impact score. After accounting for potential confounders, there was no association between peer-review percentile ranking and bibliometric end points (all adjusted P>0.5). However, prior productivity was predictive (P<0.0001). CONCLUSIONS: Even after normalizing citation counts, we confirmed a lack of association between peer-review grant percentile ranking and grant citation impact. However, prior investigator publication productivity was predictive of grant-specific citation impact.

National surveillance for hemophilia inhibitors in the United States: Summary report of an expert meeting.

On March 12, 2012, the Centers for Disease Control and Prevention (CDC) held a meeting of its partners in hemophilia treatment, community-based organizations, industry, and government to review data and discuss implementation issues relevant to planned United States (U.S.) national inhibitor surveillance. Issues discussed included the current status of inhibitor surveillance in the United Kingdom (UK) and the US, the results of a US inhibitor surveillance feasibility study, proposed national surveillance schemes, laboratory testing and reporting issues and potential opportunities for future inhibitor-related research. It was concluded that implementation of a national program of inhibitor surveillance using standardized testing through an established public health registry along with patient and care provider education and targeted research provide the best opportunity to inform efforts to develop and evaluate effective prevention strategies.

The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.

Studies of determinants of development of inhibitory Abs to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort was formed to extend our understanding of the genetic background of risk. The study group contains 833 subjects from 3 independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using an Illumina iSelect platform, 13 331 single-nucleotide polymorphisms from 1081 genes, primarily immune response and immune modifier genes, were typed. Each cohort was analyzed separately with results combined using a meta-analytic technique. After adjustment for potential confounders, 53 single-nucleotide polymorphisms were found to be significant predictors of inhibitor status using the criteria of odds ratios in the same direction in all cohorts or allowing for a 20% interval around an odds ratio = 1 in 1 of the 3 and significant in at least 2. Of the 53 markers, 13 had meta P < .001. Eight of the 53 were significant predictors among the discordant pairs. Results support the complexity of the immune response and encourage further research with the goal of understanding the pathways involved.

Inhibitors in childhood hemophilia A: genetic and treatment-related risk factors for development and eradication.

The development of neutralizing antibodies remains a serious complication of hemophilia replacement therapy. Factor VIII inhibiting antibodies (inhibitors) occur commonly following replacement therapy in hemophilia A, creating a significant burden of clinical disease. This article will review our current understanding of risk factors and their known impact on inhibitor development in previously untreated or minimally treated children with severe and mild hemophilia A. It will also explore how the most recently elucidated immunology of inhibitor development might hold important clues to more effective inhibitor eradication and prevention in this heavily impacted patient population.

Are central institutional review boards the solution? The National Heart, Lung, and Blood Institute Working Group's report on optimizing the IRB process.

The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened a working group in June 2011 to examine alternative institutional review board (IRB) models. The working group was held in response to proposed changes in the regulations for government-supported research and the proliferation of multicenter clinical trials where multiple individual reviews may be inefficient. Group members included experts in heart, lung, and blood research, research oversight, bioethics, health economics, regulations, and information technology (IT). The group discussed alternative IRB models, ethical concerns, metrics for evaluating IRBs, IT needs, and economic considerations. Participants noted research gaps in IRB best practices and in metrics. The group arrived at recommendations for process changes, such as defining specific IRB performance requirements in funding announcements, requiring funded researchers to use more efficient alternative IRB models, and developing IT systems to facilitate information sharing and collaboration among IRBs. Despite the success of the National Cancer Institute's central IRB (CIRB), the working group, concerned about the creation costs and unknown cost-efficiency of a new CIRB, and about the risk of shifting the burden of dealing with multiple IRBs from sponsors to research institutions, did not recommend the creation of an NHLBI-funded CIRB.

Immune tolerance in haemophilia: the long journey to the fork in the road.

Antibody eradication is the ultimate goal of inhibitor management. The only clinically proven strategy for achieving antigen-specific tolerance to factor VIII is immune tolerance induction (ITI). Our knowledge about ITI in haemophilia A and B was, historically, derived from small cohort studies and retrospective national and international ITI registries. Practice is now further influenced by prospective cohort data, and the results of a single prospective randomized international ITI trial. However, due to the low incidence of inhibitors in haemophilia B, there are few comparable data from which to develop a useful evidence-based approach to the prevention and eradication of factor IX inhibitors. The lack of an effective strategy is particularly problematic given the morbidity associated with the unique occurrence of allergic and anaphylactic reactions that often herald factor IX antibody development and preclude effective eradication. This paper will discuss our current understanding of immune tolerance outcome and outcome predictors for haemophilia A and B; review the current consensus practice recommendations for ITI; and summarize the emerging body of immunological science relating to antibody formation and tolerance. It will conclude by suggesting how our knowledge might inform the future investigative priorities impacting the therapeutic and preventative tolerance strategies of tomorrow.

The principal results of the International Immune Tolerance Study: a randomized dose comparison.

The International Immune Tolerance Study was a multicenter, prospective, randomized comparison of high-dose (HD; 200 IU/kg/d) and low-dose (LD; 50 IU/kg 3 times/week) factor VIII regimens in 115 "good-risk," severe high-titer inhibitor hemophilia A subjects. Sixty-six of 115 subjects reached the defined study end points: success, n = 46 (69.7%); partial response, n = 3 (4.5%); and failure, n = 17 (25.8%). Successes did not differ between treatment arms (24 of 58 LD vs 22/57 HD, P = .909). The times taken to achieve a negative titer (P = .027), a normal recovery (P = .002), and tolerance (P = .116, nonsignificant) were shorter with the HD immune tolerance induction (ITI). Peak historical (P = .026) and on-ITI (P = .002) titers were correlated inversely with success, but only peak titer on ITI predicted outcome in a multivariate analysis (P = .002). LD subjects bled more often (odds ratio, 2.2; P = .0019). The early bleed rate/month was 0.62 (LD) and 0.28 (HD; P = .000 24), decreasing by 90% once negative titers were achieved. Bleeding was absent in 8 of 58 LD versus 21 of 57 HD subjects (P = .0085). One hundred twenty-four central catheter infections were reported in 41 subjects (19 LD); infection frequency did not differ between the treatment arms. Neither bleeding nor infection influenced outcome. Although it was stopped early for futility and safety considerations, this trial contributed valuable data toward evidence-based ITI practice.