Soliciting international perspectives on an American national research agenda for inherited bleeding disorders

1

KEYWORDS:

• Community
• global health equity
• inherited bleeding disorders
• international perspective
• lived experience expert
• National Hemophilia Foundation
• research priorities
• resource constraints

1. Introduction

The National Hemophilia Foundation’s (NHF) mission is to find cures and address and prevent complications of blood disorders through research, education, and advocacy enabling people and families to thrive. Lived experience experts (LEE), people with inherited bleeding disorders (BD) and their family members, acquire unique expertise and insights into their disorders unavailable to clinicians/researchers [1]. NHF, in partnership with the American Thrombosis and Hemostasis Network (ATHN), therefore, aligned with LEEs in a State of the Science Research Summit (SOSRS) to generate a community-driven National Research Blueprint (NRB) for all Inherited Bleeding Disorders [2,3]. Research questions distilled from community-identified priorities by multidisciplinary teams of health care professionals (HCP), researchers, and LEEs, and the resources and infrastructure required to pursue them [4–9], underpin ongoing multi-stakeholder efforts to establish a people-centric research enterprise with an expanded national infrastructure and reinvigorated sustainable workforce [10].

This exciting initiative aims to accelerate the research with the greatest potential to transform the lives of all people with inherited BDs and their families in the US. We seek to understand the global applicability of this community-driven approach to research agenda setting. Might other countries identify with the research prioritized in this supplement [4–9]? How would they evaluate this approach to setting their own research agendas? High-income countries where BD diagnosis rates and access to treatment products are comparable to those in the US [11], and LEE roles in policy/decision making (e.g. on product procurement tender boards) [12] are increasingly established might expect similar results and find a similar approach amenable. This may not be the case in lower-middle income countries and where the role of LEEs has not similarly expanded [13].

Colleagues from Asia, Africa, and Latin America suggested a survey approach (Supplementary Tables S1 and S2) to these questions. Responses were received from hematologists leading care for people with inherited BDs in Argentina, Egypt, Nepal, Senegal, Thailand, and Venezuela and from LEEs active in local advocacy and education initiatives in Argentina, Brazil, Nigeria, Thailand, and South Africa. From these responses, we offer some preliminary insights into the wider applicability of these initiatives, cognizant that more extensive consultation is required.

2. Inherited bleeding disorders research priorities

2.1. Shared priorities

Asia, Africa, and Latin America are large regions encompassing many countries, each with its own diversity of contexts. Inherited BD research priorities and the resources required to pursue them also vary greatly. Survey responses, however, highlighted several priorities (Table 1) which aligned with some of those identified by the SOSRS [4–9].

Table 1. Examples of inherited BD research and infrastructure priorities shared across many countries and contexts.

Research topics

Elucidating risk factors for the development of inhibitors (neutralizing antibodies) to replacement factor

Optimal management of inhibitors

Optimal management of musculoskeletal sequelae of joint bleeds

Engaging HCPs and community members beyond the traditional inherited BD team to identify women/girls/people with the potential to menstruate who have inherited BDs

Effective approaches to implementing successful and cost-effective initiatives throughout the health care system

Research infrastructure, workforce, and resources

Need for administrative, infrastructure, workforce development, and funding to support research

Protected time to conduct research and mentor junior research team members

Acquisition of data collection and analysis expertise

Increased awareness of inherited BDs amongst medical professionals

More classical (benign) hematology specialty education and research opportunities in professional training streams

Sustained funding for research

BD: bleeding disorder, HCP: health care professional

2.2. Impact of resource constraints

Disparities in access to inherited BD diagnosis and treatment between countries and regions are enormous. Though not the most prevalent, hemophilia is the most commonly diagnosed inherited BD worldwide [11]. Approximately 83% of the expected number of people with hemophilia had been diagnosed in Europe in 2021 [14]; in South East Asia and Africa the rates were 17% and 8%, respectively [11]. This trend is even more pronounced for rates of diagnosis of other disorders, including the more prevalent von Willebrand disease (VWD) [11]. Priorities reported by survey respondents reflect these disparities. Whereas the NHF SOSRS prioritized advancing genotypic/phenotypic inherited BD characterization with the latest technology, the international respondents highlighted the need to increase a more basic diagnostic capacity and awareness, prioritizing:

• expanded outreach programs (e.g. mobile caravans combining diagnosis and comprehensive care delivery),

• rapid, robust diagnostic techniques requiring less specialized equipment/reagents/sample transport conditions (e.g. whole blood chromogenic factor assays, simpler/more robust VWD diagnostic assays),

• improved transport/storage methods (e.g. solar powered cold chain),

• increased diagnostic resources and facilities, and

• establishment of national registries.

Research validating such assays, reagents (and in-house preparation of specialized reagents), and innovations and programs such as the World Federation of Hemophilia (WFH) World Bleeding Disorders Registry (the first to collect global data on VWD) [15,16], stand to benefit countries facing the greatest diagnostic challenges.

In 2021, 91% of the 9.8 billion IU factor VIII consumed by the 102 countries in the WFH Report on the Annual Global Survey was used by high- and upper-middle income countries, 9% in lower-middle income, and only 0.4% in low-income countries; these groupings represent 34%, 57%, and 9% of the population of reporting countries, respectively [11]. Most of the small amount of replacement factor products in many of these lower-middle/low-income countries is donated through the WFH Humanitarian Aid Program [11,17]. Disparities in access to treatment products for other inherited BDs (e.g. VWD) are even more pronounced [11]. The potential of novel therapies to improve the lives of all people with inherited BDs, including those with BDs other than hemophilia and facing barriers to accessing diagnosis and care, was an important SOSRS theme [4–9]. Survey respondents, however, prioritized improved access to well-established safe and effective treatments readily available in high-income countries. Advocacy demonstrating the cost-effectiveness of replacement factor or other hemostatic rebalancing prophylaxis and comprehensive care, supporting infrastructure, workforce, and resources expansion to provide complete multidisciplinary care, will be important. Establishing low-dose prophylaxis [18,19], immune tolerance induction [20], and hemostatic control in surgical settings [21,22] with diverse established therapeutics would facilitate impact maximization with available products. Demonstrating the effectiveness of low-cost alternatives (e.g. fibrin glue for some dental extractions, desmopressin to treat mild hemophilia A or some types of VWD) [23,24] and their safe preparation in-house were also highlighted. The World Health Organization (WHO) Model List of Essential Medicines [25] includes plasma-derived medicinal products (e.g. cryoprecipitate, fresh frozen plasma) which play a major role in the treatment of multiple BDs (e.g. hemophilia A, VWD, Glanzmann thrombasthenia, fibrinogen deficiency, factor XIII deficiency) in low- and middle-income countries. Their global availability is limited by the inadequate supply of plasma meeting internationally recognized fractionation standards [26]. Survey respondents emphasized the need to establish safe and efficient local production capitalizing on advances in mini-pool fractionation, solvent detergent treatment, heat-treated lyophilization, and serology and nucleic acid testing to eliminate pathogen (e.g. human immunodeficiency virus [HIV], hepatitis C virus [HCV]) transmission. Importantly, they also advocated for innovative, collaborative research to ensure not only high-income countries, who already enjoy the greatest access to conventional therapies, benefit from novel therapies.

2.3. Individual contexts define individual priorities

Some respondents’ research priorities were specific to individual contexts (e.g. participation of regional centers in clinical trials of the latest novel therapies) [27,28]. These priorities constitute exciting opportunities for people with inherited BDs to access experimental treatments that may not be immediately available upon regulatory approval, to generate more globally representative data (e.g. the distribution of geographically disparate factor VII polymorphisms [29]), and to highlight community public health programs particularly successful in specific contexts (e.g. culturally appropriate outreach to women and girls experiencing excessive bleeding) [30]. These examples highlight the importance of local determination of research agendas, and of diverse countries leading research to ensure these needs are met.

3. Lived experience experts as research leaders

As explored by Vázquez et al. in the accompanying editorial [1], relationships between people with inherited BDs and clinicians/researchers vary greatly as does recognition and valuation of their expertise. Aligning with LEEs to determine research priorities and empowering their leadership within the conceptualization, elaboration, and operationalization of the NHF NRB is a very intentional process requiring ongoing investment in education and stakeholder relationship building. While the international survey responses suggested that LEE contributions to education, advocacy, and outreach initiatives are widely valued, their involvement in research may face restrictions. In most societies, recognition of expertise is heavily weighted toward formal education and qualifications, discouraging LEEs from challenging the opinions or authority of HCPs. At its extreme, this deference may exclude all but the most established from research leadership and decision-making. In many countries, LEEs partner in the management of their disorders [31] through shared decision-making in various degrees of collaboration with their comprehensive care team [32,33]. In some countries, the relationship between physician and LEE may be more paternalistic, with LEEs ceding self-determination to a benevolent expert who acts in their best interests without having the benefit of understanding their personal circumstances. Practical considerations of time, language skills, and resources may also constitute barriers to LEE leadership in research. Empowering local organizations with capacity building resources (e.g. translated educational resources, advocacy workshops, diagnostic/treatment product donations), guided by local knowledge of needs and opportunities, may enable more BD research to benefit from LEE involvement beyond trial participation.

4. Conclusions

The NHF NRB for Inherited Bleeding Disorders is an evolving commitment to facilitating the research that will allow all people with inherited BDs and their families to thrive, rooted in their expressed needs and integrating LEEs in research prioritization, design, governance, and conduct. A preliminary consultation of international hematologists and LEEs demonstrated the importance of assessing needs and establishing research priorities in different contexts throughout the world, and of enabling the thus prioritized research. Resource constraints on access to BD diagnosis and care, local and regional factors (e.g. demographics, geography, systems of government, public health priorities), and societal and cultural norms, will likely impact the suitability of the approach reported in this supplement, and any results it might generate.

Observations from a small-scale consultation, reported herein, offer a lens onto a diversity of perspectives. To elaborate the picture, we invite the international community to contribute their input on the top priorities for inherited BD research (Figure 1A) and the role of LEEs in research (Figure 1B) through two ongoing surveys (Suppl Tables S3 and S4). Anonymized responses collected through a Health Insurance Portability and Accountability Act compliant, password protected site will be stored on its secure server. We aim to share aggregate data and any expanded understanding gleaned from these surveys with the BD community in the future through scientific posters, articles, and similar communications.

Figure 1. QR codes linking to ongoing surveys of international perspectives on (A) inherited bleeding disorders research priorities and (B) the role of LEEs in research. LEE: lived experience expert, QR: quick response

Abbreviations

Table

ATHN	American Thrombosis and Hemostasis Network
BD	Bleeding disorder
HCP	Health care professional
HCV	Hepatitis C virus
HIV	Human immunodeficiency virus
LEE	Lived experience expert
NHF	National Hemophilia Foundation
NRB	National Research Blueprint
PCORI	Patient-Centered Outcomes Research Institute
SOSRS	State of the Science Research Summit
US	United States
VWD	Von Willebrand disease
WFH	World Federation of Hemophilia
WHO	World Health Organization

Declaration of interest

ML Witkop discloses: employed at NHF at time of research, now a paid consultant to NHF.

F Robinson discloses: all support for the present manuscript: National Hemophilia Foundation; consulting Fees: American Thrombosis and Hemostasis Network, European Haemophilia Consortium, World Federation of Hemophilia, National Hemophilia Foundation; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche; other financial or non-financial interests: World Federation of Hemophilia.

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: travel to meetings relevant to the SOS and NRB projects paid by 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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 wish to thank the international colleagues who contributed to our preliminary survey of inherited BD research priorities and LEE roles in research: Megan Adediran, Apsara Boadas de Sanchez, MD, Ampaiwain Chuansumrit, MD, Saliou Diop, MD, Magdy El Ekiaby, MD, Daniela Neme, MD, Francisco de Paula Careta, PhD, Bradley Rayner, Carlos Safadi Marquez, Bishesh Sharma Poudyal, MD, Arlette Ruiz-Sáez, MD, and Ekawat Suwantaroj.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17474086.2023.2178411

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). Fiona Robinson, PhD provided professional medical writing support during manuscript development, paid by NHF.