Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for ultra-rare inherited bleeding disorders

Figures & data

Table 1. Estimated prevalence, correlation of factor level with clinical presentation, and availability of a single clotting factor concentrate of selected ultra-rare inherited bleeding disorders.

Disorder (deficient factor)	Prevalence	Correlation between factor level and bleeding severity	Availability of single protein replacement concentrate	References
Fibrinogen	1:1,000,000	Strong	Plasma-derived fibrinogen concentrate	[17–22]
Prothrombin (Factor II)	1:2,000,000	Undetermined	None	[14–16, 18, 20]
α2-Antiplasmin	<1:1,000,000	Undetermined	None	[15, 20]
Plasminogen activator inhibitor (PAI-1)	Undetermined	Undetermined	None	[15, 20]
Factor V	1:1,000,000	Weak	None	[15, 16, 18–20]
Factor V/Factor VIII	1:1,000,000	Good	Numerous factor VIII recombinant and plasma-derived concentrates None for factor V	[15, 16, 18–20]
Factor VII	1:500,000	Weak	Recombinant activated factor VII	[14–16, 18–20]
Factor X	1:1,000,000	Strong	Plasma-derived factor X and plasma-derived factor IX / factor X concentrates (i.e. prothrombin concentrates)	[14–16, 18–20]
Factor XI	1:1,000,000	No correlation	Plasma-derived factor XI concentrate	[15, 16, 18–20][1–5]
Factor XIII	1:2,000,000	Strong	Plasma-derived and recombinant factor XIII concentrates	[15, 16, 18–20]
Glanzmann thrombasthenia	1:1,000,000	Not applicable	Not applicable	[20]
Bernard-Soulier syndrome	1:1,000,000	Not applicable	Not applicable	[20]

Table 2. Members of Working Group 3, by subgroup.

Member	Stakeholder Group	Affiliation
Diagnostics, Systems Biology, Mechanistic Science
Diane Nugent, MD(WG cochair, subgroup lead)	Pediatric hematologist; Researcher	Center for Inherited Blood Disorders, and CHOC Children's Hematology Advanced Diagnostic Lab, Orange, California
David Ginsburg, MD	Hematologist; Human genetics and hemostasis and thrombosis researcher	Howard Hughes Medical Institute; Human Genetics, University of Michigan, Ann Arbor, Michigan
Catherine P.M. Hayward, MD, PhD, FRCP(C)	Hematologist; Laboratory (Clinical pathologist); Researcher	Hamilton Regional Laboratory Medicine, Hamilton Health Sciences, Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
Kate Nammacher	NHF staff	NHF
Roberta Palla*, MSc, PhD	Coagulation disorders, including ultra-rare, researcher	Department of Pathophysiology and Transplantation, University of Milan, Italy; Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
Rajiv K. Pruthi, MD	Hematologist	Comprehensive Hemophilia Center, Mayo Clinic, Rochester, Minnesota
Alisa S. Wolberg, PhD	Coagulation, including ultra-rare clotting factors, and biology researcher	Department of Pathology and Laboratory Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, North Carolina
Clinical, Data Collection, Research Infrastructure
Suchitra S. Acharya, MD(WG cochair, subgroup lead)	Pediatric hematologist, Inherited bleeding disorders, including ultra-rare, researcher	Hemostasis and Thrombosis Center, Northwell Health, New Hyde Park, New York
Kimberly J. Baumann, PT, MPT	Physical therapist	Center for Bleeding and Clotting Disorders, M Health Fairview, Minneapolis, Minnesota
Camille Bedrosian, MD, MS	Industry	Ultragenyx, Novato, California
Marzia Menegatti, MSc, PhD	Biology researcher	Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and Fondazione Luigi Villa, Milan, Italy
Margaret E. Miller, MS	Genetic counselor	Providence Alaska Medical Center, Anchorage, Alaska
Michael Recht^**,†, MD, PhD	American Thrombosis and Hemostasis Network national administrator; Pediatric hematologist	ATHN; The Hemophilia Center, Oregon Health & Science University, Portland, Oregon
Michael Tarantino, MD	Pediatric hematologist	Bleeding and Clotting Disorders Institute, Peoria, Illinois
Regulatory Process for Novel Therapeutics and Required Data Collection
Amy D. Shapiro, MD(WG cochair, subgroup lead)	Pediatric hematologist; Inherited bleeding disorders, including ultra-rare, researcher	Indiana Hemophilia & Thrombosis Center, Indianapolis, Indiana
Rebecca Bialas, MD	LEE; Physician; Patient organization leader	Plasminogen Deficiency Foundation, Durham, North Carolina
Kai Brown, MS, MBA	NHF Board member	NHF
Deya Corzo, MD	Industry	Sigilon Therapeutics, Cambridge, Massachusetts
Amar Haidar	LEE
Peter Marks^‡, MD, PhD	Federal agency partner; Hematologist	U.S Food and Drug Administration, Center for Biologics Evaluation and Research
Skye Peltier, PA-C	LEE; Advanced practice provider	Children’s Minnesota – Center for Bleeding and Clotting Disorders, Minneapolis, Minnesota
Benny Sørensen, MD, PhD	Industry	Hemab Therapeutics, Copenhagen, Denmark

*Also a member of the Clinical, Data Collection, Research Infrastructure subgroup**Also a member of the Regulatory Process for Novel Therapeutics and Required Data Collection subgroup^†NHF SOSRS Steering Committee^‡NHF SOSRS Advisory Committee LEE: lived experience expert, NHF: National Hemophilia Foundation, SOSRS: State of the Science Research Summit

Figure 1. Working Group 3 research priorities for ultra-rare inherited bleeding disorders schematic of community-identified areas for priority research framework POC: point of care.

Figure 2. Questions and elements/modalities considered by the WG3 subgroup to address community priorities in diagnostics, systems biology, and mechanistic science of ultra-rare inherited bleeding disorders.

DNA: deoxyribonucleic acid, WG: working group

Figure 3. Questions and elements/modalities considered by WG3 to address clinical, data collection, and research infrastructure community priorities for ultra-rare inherited bleeding disorders.

DNA: deoxyribonucleic acid, IRB: institutional review board, QoL: quality-of-life

Figure 4. Questions and elements/modalities considered by WG3 to address community priorities in regulatory processes for novel therapeutics and required data collection for ultra-rare inherited bleeding disorders.

FDA: U.S. Food and Drug Administration

Figure 5. Plot of feasibility, impact, and risk scores of the questions evaluated by the three WG3 subgroups.

*Diagnostics, Systems Biology, and Mechanistic Science questions were not scored for risk. Label numbers correspond to those in Table 3, note that some data points have identical coordinates and, therefore, overlap.

Table 3. Actionable initiatives scored for feasibility, impact, and risk in the three domains of ultra-rare inherited bleeding disorders community priorities.

ID	Question/Initiative	Feasibility	Impact	Risk	Total*
Diagnostics, Systems Biology, and Mechanistic Science
1	Can we establish a national pathway to diagnosis for people with ultra-rare inherited BDs?	8	8		16
2	Establish a National Resource Center for approach to diagnosis	9	11		20
3	Establish a few centralized and specialized diagnosis laboratories	7	11		18
4	Establish that these centers can report CAP/CLIA approved results	7	9		16
5	Can we create an innovative process to link people with ultra-rare inherited BDs with researchers?	7	8		15
6	Promote referral to HTC network to capture phenotypic data	9	11		20
7	Specific training for HTC personnel to collect and process samples correctly	9	10		19
8	New funding sources to be established to fund ultra-rare inherited BDs research	9	8		17
9	HTC to facilitate genomic and sample storage in national biobank/repository	6	8		14
10	Can we shorten the time to diagnosis through digital media resources?	8	10		18
11	Website to direct primary care physician to HTC, diagnostic reference labs, assays, as appropriate	8	8		20
12	National Telehealth Center with diagnostic navigator for primary care physician	9	11		17
13	E-consult service supported through healthcare insurers network	7	11		17
Clinical, Data Collection, Research Infrastructure
	Can we develop centralized national data collection through an existing database/agency?
1	A data collection system that supports post-approval data collection (fulfills regulatory requirements), and assures national access to advanced care	9	14	−1	22
2	Disease-specific data collection to support increased knowledge of natural history of ultra-rare inherited BDs	9	13	−1	21
Regulatory Process for Novel Therapeutics and Required Data Collection
	Can we develop a new approach for regulatory pathways to achieve the following?
1	Address ultra-small populations	11	14	−1	24
2	Streamline processes that assesses safety and potential benefit	10	13	0	23
3	Incentivize product development for ultra-rare disorders	8	14	0	22
4	Use of data to support off-label use of currently licensed products when efficacious	6	13	−1	18
5	Harmonization between regulatory agencies of different countries	3	11	−1	13

*Diagnostics, Systems Biology, and Mechanistic Science scores are the sum of feasibility and impact, risk was not scored

BD: bleeding disorder, CAP: College of American Pathologists, CLIA: Clinical Laboratory Improvements Amendments, F-I: feasibility-impact, F-I-R: feasibility-impact-risk, HTC: hemophilia treatment center, ID: subgroup question identifier

Table

340B	340B Drug Pricing Program (US Health Resources & Services Administration)
AAV	Adeno-associated virus
AT	Anti-thrombin III
ATHN	American Thrombosis and Hemostasis Network
BAT	Bleeding Assessment Tool
BD	Bleeding disorder
CAP	College of American Pathologists
CDC	US Centers for Disease Control and Prevention
CFC	Clotting factor concentrate
CLIA	Clinical Laboratory Improvements Amendments
CMS	Centers for Medicare and Medicaid Services
DDAVP	Desmopressin
DNA	Deoxyribonucleic acid
EHC	European Haemophilia Consortium
EMA	European Medicines Agency
EN-RBD	European Network of Rare Bleeding Disorders
FDA	U.S. Food and Drug Administration
FFP	Fresh frozen plasma
HMB	Heavy menstrual bleeding
HTC	Hemophilia treatment center
ID	Subgroup question identifier
IRB	Institutional review board
ISTH	International Society on Thrombosis and Haemostasis
LGBTQ	Lesbian, gay, bisexual, transgender and queer
LEE	Lived experience expert
NCBI	National Center for Biotechnology Information
NHF	National Hemophilia Foundation
NIH	National Institutes of Health
PAI-1	Plasminogen activator inhibitor-1
PBAC	Pictorial bleeding assessment chart
PCC	Prothrombin complex concentrate
POC	Point of care
QoL	Quality-of-life
SC	Steering Committee
SOSRS	State of the Science Research Summit
SSC	Scientific and Standardization Committee
TFPI	Tissue factor pathway inhibitor
US	United States
VUS	Variants of unknown significance
WFH	World Federation of Hemophilia
WG	Working Group