The National Hemophilia Foundation’s State of the Science Research Summit: the foundation of a national research blueprint for inherited bleeding disorders

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KEYWORDS:

• Bleeding disorder
• blueprint
• community
• health equity
• National Hemophilia Foundation
• patient-centric
• research

1. Introduction

People with hemophilia and, to a somewhat lesser extent, people living with other inherited bleeding disorders (BD) have experienced increases in life expectancy and improvements in quality-of-life over the last seven decades as a result of integrated comprehensive care [1] and development of treatments approaching a functional cure for hemophilia A and B [2,3]. Despite these remarkable achievements, the normalization of hemostasis leading to optimized health and well-being and the attainment of health equity [4] remains out of reach for most people with an inherited bleeding disorder (PWIBD). The National Hemophilia Foundation (NHF) set out to understand the current state of health equity of the inherited BD community, that is with respect to their attainment of the highest level of health, where everyone has a fair and just opportunity to attain their optimal health regardless of race, ethnicity, (dis)ability, sexual orientation, gender identity, socioeconomic status, geography, preferred language, or other factors that affect access to care and health outcomes [5].

The State of the Science Research Summit (SOSRS) initiative began, in 2020, when NHF asked the US inherited BD community to share their brightest vision for the future, setting aside potential restrictions on resources, time, and effort. The key themes revealed by this ‘Blue Sky’ brainstorming shaped the SOSRS initiative [6]:

• Sustaining and expanding the comprehensive care model to strive toward health equity and promote access to care

• Harnessing/leveraging technology to expand access to care

• Envisioning the NHF in 2030 and beyond

A coordinated inherited BD research plan will be an essential cornerstone in the realization of the community’s vision for their future. PWIBD and their families develop unique, intimate, real-world knowledge of the physical and psychosocial realities of BDs, making them lived experience experts (LEE) [7]. To inform this research plan, the NHF, therefore, asked the community what they needed from research to achieve their life goals. Community research priorities were further developed with perspectives from all stakeholders, including LEEs, clinicians, and other members of the multidisciplinary comprehensive care team, researchers, local community leaders, and industry (Table 1) [6].

Table 1. Common themes of community-identified research priorities [6].

Continuation of the hemophilia treatment center (HTC) model of care

Training future health care professionals (HCP)

Ensuring financial sustainability of comprehensive care

Health care disparities between various communities (based on race, ethnicity, gender, education, income, etc.)

Access to research and mechanisms to conduct research

Access to specialized care, for all people with inherited BDs

Mental health (depression, anxiety, emotional impact, substance use disorders, etc.)

Pain management

Therapeutic advances for all inherited BDs (gene therapy, non-factor replacements, etc.)

Treatment specifically for rare and ultra-rare inherited BDs, beyond hemophilia and VWD

Women’s health and access to care

Treatment of other chronic disorders and issues affecting PWIBD (e.g. heart disease, diabetes, etc.)

Treatment of the aging population with inherited BDs

Mechanisms of joint disease and optimization of diagnosis and management

BD: bleeding disorder, HCP: health care professional, HTC: hemophilia treatment center, VWD: von Willebrand disease

Community consultations detailed research needs shared across and specific to individual BDs, as well as infrastructure, workforce, and resource issues. Articulating these needs as concrete, actionable research questions was the next step in developing and implementing a coordinated research plan. NHF partnered with the American Thrombosis and Hemostasis Network (ATHN) to analyze community insights into six focus areas and recruit multidisciplinary working groups (WG) to take on this challenge (Table 2) [6].

Table 2. Six working groups convened to distill research questions from community priorities in specific focus areas [6].

WG1	Hemophilia A and B
WG2	Von Willebrand disease (VWD), platelet dysfunction, and other mucocutaneous inherited BDs
WG3	Ultra-rare inherited BDs
WG4	Women, girls, and people with the potential to menstruate
WG5	Diversity, equity, and inclusion; health services research; and implementation science
WG6	Facilitating priority research in the inherited BD community (infrastructure, workforce, resources and funding)

BD: bleeding disorder, WG: working group

2. State of the Science Research Summit working groups

The SOSRS WGs were charged with addressing the community priorities in their respective focus area while considering the use of new technologies for therapeutic advancements (e.g. precision medicine, genetic testing, and point-of-care diagnostics), the pursuit of novel therapies for underserved populations, improvements in comprehensive care (e.g. mental health, diagnosis, and supportive care), and health disparities [8]. They were asked to assess whether adequate data exist to identify the most important hypothesis-based research questions, and if not, how a better dataset could be established [6]. Members were recruited from the wealth of inherited BD experts across the US and included an international perspective, drawing upon diverse professionals from multidisciplinary comprehensive care teams, community advocacy leaders, regulators, industry, foundations, government and non-government agencies, and LEEs. WGs were enriched with members from other specializations, such as women’s health; small clinical trial design; diversity, equity, inclusion, and antiracism; big data management and analysis; and other patient and disorder organizations/foundations, to address the full breadth of needs prioritized by the community.

WGs met virtually (to accommodate diverse time zones, schedules, and pandemic restrictions) from March to August 2021, distilling research questions from the extensive consultation results. Each WG tailored its approach, integrating digital tools into their processes, breaking into subgroups, tackling all sub-foci as a whole group, inviting external expert speakers, engaging in cross-discipline peer education, studying background literature, exchanging summaries and synopses, brainstorming overarching themes and key elements in addressing them, identifying fundamental knowledge gaps, defining specific research questions, delineating common and specific needs, and describing innovative collaborative strategies. They grappled with difficult questions, examining positionality, biases, and disparities that impede access to health equity for all PWIBD. The WGs also consulted and shared ideas relevant to one another’s mandates.

LEEs were full members of WGs and empowered, through NHF accompaniment and the establishment of respectful constructive group structures fostering equity and inclusion, to participate in all aspects of WG deliberations and decision-making. The desire and willingness to be involved in research, remarked on in community consultations, was amplified by WG activities. In addition to study participation, the potential benefits of LEE perspectives in leadership at every stage of research, from priority identification, through study design, participant recruitment, and community integration and communication, to collaborative network building, funding, and governance, became evident.

3. Feasibility-impact-risk scoring

Each WG derived a great many research questions and initiatives from community priorities; generating an actionable National Research Blueprint required a prioritization method. One of the authors (DDM) devised a scoring matrix to assess feasibility, impact, and risk, ranking the potential of each initiative to accelerate progress toward better diagnosis, care, and outcomes [6]. The matrix guided the multilateral assessment of an individual research question/initiative through a series of multiple-choice questions about its feasibility, impact, and risk, automatically generating a score for each answer selected. Scoring against these criteria grounded the prioritization, ensuring that the WGs’ output provided a foundation for a pragmatic blueprint that can be operationalized and executed.

The feasibility evaluation assessed how easy or difficult the research question will be to answer. For clinical research, for example, it considered whether the target sample size can be achieved. For translational research: how translatable a novel strategy might be; and for basic research: whether the necessary tools are available. The nature of expertise and multidisciplinary partnerships required and which community partner(s) should and can undertake the research was also examined. Associated infrastructure and resource needs were weighed against what already exists, as were required funding sources [8].

Impact scoring estimated the productive change that may be fostered by the question/initiative. It considered how a specific research endeavor might impact the standard of care, equity of access to care, and/or the affordability of care. It looked at how the answer might impact the larger therapeutic paradigm and the potential for that to extend beyond the particular BD at its center. The training opportunities that accompanied the initiative were also examined [8]. High impact is an essential element for inclusion of priority questions/initiatives in the National Research Blueprint.

Increasing risk yielded an increasingly negative score in the matrix. Questions in this dimension evaluated how acceptable the proposed study will be to various stakeholders (e.g. PWIBD, investigators, and funders). They considered the risk/benefit ratio of a proposed basic/translational pathway for a novel strategy, and how acceptable that might be. They also addressed whether there are any associated ethical considerations [8]. Minimizing risk, especially for all participants in (particularly clinical) research, is another overarching goal of the National Research Blueprint.

WGs 1–5 were provided a common scoring matrix (Supplementary Table S1). Due to the distinct nature of their foci, specific adaptations of the matrix were provided to the WG6 subgroups examining the infrastructure and resources and funding (Suppl Table S2) and workforce (Suppl Table S3) required to facilitate priority research in the inherited BD community.

Totaling the answers from each question in a dimension provided overall feasibility, impact, and risk scores for a research initiative, which were plotted for comparison (Figure 1). Questions in the ideal, front top right quadrant have a highly feasible methodology, promise to be very impactful, and incur little to no risk. Questions falling into other quadrants were not, however, excluded from prioritization. Scores from the three dimensions were totaled into a final sum score to rank the priorities in order, ensuring that not only ‘easy’ questions were prioritized. A research question requiring challenging methodology, but with great potential impact could still achieve a high sum score. This approach allows comparison of very different questions and initiatives, with diverse strengths and potentials, paving the way for a more complete National Research Blueprint. Observing how questions cluster in three dimensions, for example, those concerning specific research foci or challenges, may also help inform judicious allocation of resources to create real and lasting improvements for PWIBD.

Figure 1. Plotting feasibility, impact, and risk in the evaluation of individual research questions and initiatives Reproduced with permission from Valentino et al. (2022) [6].

Some WGs encountered challenges applying these matrices to the output of their deliberations. In some cases, the most pressing needs identified were broad foundational knowledge gaps or strategic knowledge networking. Others struggled to apply the standard population/patient problem, intervention, control/comparison, outcome, timing, setting structure to describe questions of access, equity, bias, and social determinants of health. Their reports, in this supplement, detail not only the results of their deliberations and these challenges but also how they surmounted them to contribute clear and constructive priorities to the National Research Blueprint initiative [9–14].

4. The National Hemophilia Foundation State of the Science Research Summit

WG co-chairs sought community input on their deliberations and resulting scored research priorities in a well-attended (>880 virtual attendees) free summit in September 2021 [6,8]. Multiple live panel discussions in which co-chairs responded to delegate comments and questions, and Remote Participation Groups (supported by the NHLBI R13 grant: R13HL158209) which lowered the burden of participation for underrepresented populations [6,8] contributed to the refinement of the output of each WG and informed reports in this supplement [9–14]. A number of themes common to the discussions of the six WGs emerged (Table 3) [8].

Table 3. Common State of the Science Research Summit discussion themes [8].

The importance of people-centricity in research, involving LEEs at all levels of research, and evolving new inclusive research models

The essential nature of people-centric outcomes

The need to strive for diversity, inclusion, and equity in research and health care

The importance of future research across the spectrum of inherited BDs to advancing and optimizing an equitable and accessible standard of care

The need for innovative clinical trial designs including decentralization, adaptive strategies, and incorporation of real-world experience

The importance of data science and infrastructure in research and clinical practice

The need for a clinical trial network with integrated infrastructure with funding and oversight capabilities

The need for HTCs to evolve and realign to transform access to more holistic care

The need for a comprehensive and long-term approach to workforce expansion, recruitment, career growth, and retention

The importance of multidisciplinary collaboration within and beyond the inherited BD community

BD: bleeding disorder, HTC: hemophilia treatment center, LEE: lived experience expert

5. Conclusions

The NHF State of the Science Research Summit initiative was an attempt to assess the current state of affairs for the US inherited BD community by evaluating the dreams, desires, and vision of the community for their future. A thorough evaluation process has been implemented to address these community priorities while continuously incorporating input and ‘course correcting’ based on ongoing consultation with those with lived experience of an inherited BD. This led to the identification of research questions and strategies, which were then interrogated using an objective, rigorous scoring scheme assessing risk-reward in three dimensions: feasibility, impact, and risk. The resulting research questions determined by the SOSRS WGs to have the greatest potential to advance the needs prioritized by the community form the basis of the US National Research Blueprint for Inherited Bleeding Disorders [9–14]. Currently, under development through continuous collaboration between those living with inherited BDs, clinicians, scientists, researchers, and other health professionals, the blueprint initiative seeks to create an action plan that will significantly improve the experience of the inherited BD community, not only in the US but also globally [15,16]. They are working to make the current research paradigm more efficient, effective, and collaborative following patient-centered and health equity, diversity, and inclusion (HEDI) principles, to empower successful realization of the prioritized research. Throughout this process, recognition of the importance of LEE involvement has blossomed, and LEEs have stepped ever more confidently into leadership roles [7]. The vision for this substantial multi-year effort is to create lasting impact on the path to optimal health and health equity for all people living with an inherited BD regardless of race, ethnicity, (dis)ability, sexual orientation, gender identity, socioeconomic status, geography, preferred language, or other factors that affect access to care and health outcomes.

Abbreviations

Table

ATHN	American Thrombosis and Hemostasis Network
BD	Bleeding disorder
HCP	Health care professional
HEDI	Health equity, diversity, and inclusion
HTC	Hemophilia treatment center
LEE	Lived experience expert
NHF	National Hemophilia Foundation
PWIBD	Person with an inherited bleeding disorder
SOSRS	State of the Science Research Summit
U.S.	United States
VWD	Von Willebrand Disease
WG	Working group

Declaration of interest

D DiMichele discloses consulting fees: paid consultant to the NHF on their State of the Science (SOS) and National Research Blueprint (NRB) projects; support for attending meetings and/or travel; and travel to meetings relevant to the SOS and NRB projects paid by NHF.

M Recht discloses grants or contracts from any entity: Bayer, BioMarin, CSL Behring, Genentech, Grifols, Hema Biologics, LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi, Spark, Takeda, uniQure; consulting fees: Catalyst Biosciences, CSL Behring, Genentech, Hema Biologics, Kedrion, NovoNordisk, Pfizer, Sanofi, Takeda, uniQure; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Foundation for Women and Girls with Blood Disorders; Partners in Bleeding Disorders, Thrombosis, and Hemostasis Societies of North America.

LA Valentino and ME Santaella are employees of NHF. M Witkop was an employee of NHF at the time of the study and is now a paid consultant to NHF.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgments

The Executive Committee of the National Hemophilia Foundation, National Research Blueprint initiative, were actively engaged in the conception, design, preparation, and oversight of each of the State of the Science manuscripts in this supplement. Maria E. Santaella actively engaged with the lived experience expert (LEE) WG members throughout the process, empowering their inclusion and participation. The Executive Committee consisted of Kevin Mills, Michael Recht, Michelle L. Witkop, Maria E. Santaella, Donna DiMichele, Keri L. Norris, Esmeralda Vázquez, and Brett Spitale.

The authors acknowledge Fiona Robinson, PhD, for providing professional medical writing support during manuscript development, paid for by NHF, and Matt Evans for the creation of professional illustrations, paid for by NHF.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17474086.2023.2178412

Additional information

Funding

The entire State of the Science Research Summit and National Research Blueprint (to date) initiatives and this manuscript were funded by the National Hemophilia Foundation (NHF). Research reported in this publication was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R13HL158209. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.